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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Colitis'. | Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection.
The safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).
This was a single-institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.
We identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non-small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1-2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).
Adverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.
The safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors' institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.
Introduction
Immune checkpoint inhibitors (ICIs), namely programmed death receptor‐1 (PD‐1) and programmed death receptor‐1 ligand (PD‐1L) inhibitors and cytotoxic T‐lymphocytic antigen 4 (CTLA‐4), have changed the cancer therapy paradigm and are approved for various malignancies: melanoma, lung cancer, hepatocellular carcinoma, and many others (Table 1). CTLA‐4 and PD‐1L are intrinsic downregulators of immunity that dampen the immune regulatory response. Cancer cells hijack this system to evade the immune system. ICIs, by blocking these cell surface proteins, enhance the antitumor immune response. In hepatitis C virus (HCV) infection, the expression of PD‐1/PD‐1L contributes to the persistence of infection [1]. Therefore, to avoid unforeseen adverse events (AEs; e.g., viral reactivation), patients with HCV infections were excluded from most clinical trials evaluating ICI even though HCV is a major health care problem, with a prevalence of 0.5%–2.3% worldwide [2]. Absence of ICI safety data in patients with cancer with HCV makes it challenging to adequately assess the risk‐benefit of ICI and to advise the patient on the likelihood of AEs to assist them in making an informed decision. This may result in ICIs being denied or delayed pending treatment of the underlying HCV. In this article, we conducted a retrospective study of all patients with cancer with HCV untreated and resolved who received ICI at our institution.
Table 1 Immune checkpoint inhibitor indications
Melanoma; adjuvant, unresectable, or metastatic
Non‐small cell lung cancer; metastatic
Small cell lung cancer; metastatic
Hepatocellular carcinoma
Renal cell carcinoma; advanced, or metastatic
Hodgkin lymphoma
Head and neck squamous cell carcinoma; recurrent or metastatic
Urothelial carcinoma; locally advanced or metastatic
Breast cancer; triple‐negative locally advanced or metastatic
Colon cancer, metastatic (MSI‐H or dMMR)
Glioblastoma
Cutaneous squamous cell carcinoma; locally advanced or metastatic
Gastric cancer; recurrent locally advanced or metastatic
Anal cancer; metastatic
Merkel cell carcinoma
Primary mediastinal large B‐cell lymphoma
Mesothelioma
Abbreviations: dMMR mismatch repair deficient; MSI‐H, microsatellite instability‐high.
Materials and Methods
This was a single‐institution retrospective electronic chart review of all patients with active or resolved hepatitis C viral infection who were treated with an immune checkpoint inhibitor (ICI) for cancer of any type and stage from January 2012 to December 2019. Data collected included age, gender, ethnicity, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at the time of cancer diagnosis, cancer type and stage, hepatitis C status (specified as untreated chronic infection if the viral load was detected at the time of cancer diagnosis, treated if a history of treatment with undetectable viral load was documented, and spontaneously resolved if only hepatitis C virus antibody was present with undetectable viral load and absence of treatment history), viral genotype, presence of cirrhosis, liver function test before and throughout treatment, type of ICI, length of therapy in weeks, the reason for discontinuation of therapy, and toxicities. Patients with coinfection with hepatitis B virus or human immunodeficiency virus were excluded. The severity of immune‐mediated toxicities was graded using National Cancer Institute CTCAE, Version 5.0 [3]. The study was approved by the institutional review board.
Results
We identified 40 cases, 30 (75%) men and 10 (25%) women, with median age of 64 years (range, 51–80). The largest ethnicity was Black (22; 55%), followed by White (17; 42.5%) and others (1; 2.5%). ECOG was 0–1 in 36 patients (90%) and 2 in four patients (10%). Median BMI was 24.3 kg/m2 (range, 16.7–42.8). Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (1; 2.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 patients (35%), and spontaneously resolved in 9 (22.5%) patients. Hepatitis C genotype was 1a in 25 patients (62.5%), 1b in 1 patient (2.5%), 3 in 1 (2.5%) patients, and unavailable for the rest. Viral load in untreated patients ranged from 45 to 7,620 × 103 copies per mL. Cirrhosis was documented in 22 patients (55%). None of the untreated patients received treatment for HCV at the time of cancer diagnosis before the commencement of ICI. ICIs used were nivolumab alone in 23 patients (57.5%), pembrolizumab in 10 (25%), atezolizumab in 4 (10%), durvalumab in 2 (5%), and combination of ipilimumab and nivolumab in 1 (2.5%). The median length of therapy with ICI was 16 weeks (range, 2–199). AEs noted (see Table 2) were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab, grade 3 colitis in one patient (2.5%) on nivolumab, hepatotoxicity in two patients (5%) on nivolumab (one patient with grade 1 and the other had grade 2), grade 1–2 fatigue in three patients (7.5%), and hypothyroidism in one patient (2.5%).
Table 2 Characteristics of patients with HCV with adverse events while on immune checkpoint inhibitors
Case Age, years Sex Ethnicity ECOG PS Cancer HCV status Genotype Viral Load Cirrhosis Therapy Length of therapy, weeks Reason for discontinuation Toxicities
1 65 M Black 0 NSCLC Untreated 1a 385 × 103 No Nivolumab 78 Toxicities Pneumonitis, grade 3
2 61 F Black 1 NSCLC Untreated 1a 744 × 103 No Nivolumab 5 PD Fatigue grade, 1
3 64 F Black 0 NSCLC Treated 1a 0 No Nivolumab and ipilimumab 24 Ongoing Hypothyroidism, grade 1 and fatigue, grade 2
4 55 F White 1 SCLC Untreated 1a 152 × 103 No 1 9 Toxicities Colitis, grade 3
5 74 F Other 1 HCC Treated 1a 0 Yes Nivolumab 25 PD Fatigue, grade 1
6 66 M White 0 HCC Untreated 1a 557 × 103 Yes Nivolumab 12 PD Hepatotoxicity, grade 1
7 59 M Black 1 HCC Untreated 1b 3,190 × 103 Yes Nivolumab 16 PD Hepatotoxicity, grade 2
Abbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; NSCLC, non‐small cell lung cancer; PD, progressive disease; SCLC, small cell lung cancer.
The patient with grade 2 hepatotoxicity was a 55‐year‐old African American man with HCC. He had liver cirrhosis with MELD score of 7, ascites, and HCV with genotype 1b. The hepatotoxicity occurred after the first dose of nivolumab. Hepatotoxicity was marked by transaminitis, whereas alkalyine phosphatase, bilirubin, albumin, and clotting factors remained within the normal range. He was treated with prednisone 1 mg/kg with a taper over 2 weeks with a return of liver function test to baseline. He was continued on nivolumab with no further recurrence of hepatotoxicity, for timeline, and degree of transaminitis (see Fig. 1).
Figure 1 Timeline of the patient with grade 2 hepatotoxicity due to nivolumab.
Abbreviations: ALT alanine transaminase; AST aspartate transaminase.
Discussion
Chronic hepatitis C infection is a major health problem, with a prevalence of approximately 1% in the U.S., with higher rates in states with a worse opioid crisis, likely owing to increased injection drug use [4]. Although effective therapy for HCV is now present, challenges in prevention, case detection, treatment affordability, and access propose that HCV burden will continue to be a significant health care issue in the foreseeable future [4]. Population‐based studies concerning cancer risk in HCV‐infected patients showed an increased risk for hepatocellular carcinoma, non‐Hodgkin lymphoma, and lung cancer [5, 6]. Along with the expanding indications for ICI, the coexistence of HCV and potentially ICI‐responsive cancer will be encountered more frequently. Two landmark trials that studied PD‐1 inhibitors in hepatocellular carcinoma included treated and untreated HCV patients: a phase I–II study of nivolumab in hepatocellular carcinoma included 50 patients with HCV, CheckMate‐40 (NCT01658878), and a phase II study of pembrolizumab in hepatocellular carcinoma that included 26 patients with HCV, Keynote‐224 (NCT02702414) [7, 8]. However, trials investigating ICIs in cancers other than hepatocellular carcinoma have excluded patients with HCV infection, as it is unknown how the ICIs will interplay with the underlying chronic infection (e.g., the potential for a flare of chronic HCV infection or higher rate of AEs).
In this article, we report our case series of 40 patients covering the past 8 years addressing the safety of ICIs in patients with HCV. The predominance of men in our study may be explained by predominant tumor subtypes in our cohort, namely, non‐small cell lung cancer and hepatocellular carcinoma, both of which are more common in men, which is likely attributed to an increased likelihood of adapting high‐risk behaviors in men that increase their risk for these cancers (e.g., smoking and injectable drug use) [6, 9]. Ethnicities reported were reflective of the background population [10].
In our study, PD‐1/PD‐L1 inhibitor AE rates were comparable to those reported in clinical trials that excluded 1%–3% of patients with HCV [11, 12]. No deaths related to ICI were identified. Only two patients suffered grade 3 AEs: one with colitis on nivolumab and another with pneumonitis on pembrolizumab, with resultant discontinuation of treatment in both. There were only two cases of hepatotoxicity, with the worst being grade 2 in a patient with genotype 1b; however, the patient was able to continue ICI following glucocorticoid course. Both patients with hepatotoxicity had hepatocellular carcinoma, untreated HCV, and liver cirrhosis and were treated with nivolumab. Viral load was not checked at the time of liver enzyme derangement; therefore, it is not possible to comment if an HCV flare was contributing. In the aforementioned trials of PD‐1 inhibitors in hepatocellular carcinoma, CheckMate‐40 and Keynote‐224, no HCV flares were reported [7, 8].
Study limitations include single‐center study and all the limitations of a retrospective design; selection bias and lack of rigorousness in documenting all possible treatment toxicities compared with a prospective study. The majority of patients were male, and the prevailing genotype was 1a. HCV genotype varies racially and geographically; therefore, our findings may not be generalizable [13]. Interestingly, the patient with grade 2 hepatotoxicity had HCV genotype 1b, which was under‐represented in our cohort. Further studies, including all HCV genotypes, are needed to evaluate if certain genotypes carry a higher risk of ICI‐related AEs. Other areas of study include characterization of PD‐L1 expression in the liver and its effect on AE rates, the safety of ICIs in patients with HCV coinfected with hepatitis B virus and/or human immunodeficiency virus, and cancer registry studies to explore possible health disparities should patients with HCV and cancer be less likely to receive ICI.
Conclusion
In the lack of randomized controlled trials to address the safety of ICI in HCV and other major chronic viral infections across different cancers, observational studies may help to illustrate if such populations tend to have higher rates of ICI AEs. This observational study showed no deaths related to ICIs, and AE profiles in untreated and resolved patients with HCV were comparable to rates of non‐HCV patients. ICI was not delayed in our cohort pending treatment for active HCV. These findings may aid the oncologist in discussing ICI toxicities in patients with cancer with untreated and resolved HCV.
Author Contributions
Conception/design: Akram Alkrekshi, Ila Tamaskar
Provision of study material or patients: Akram Alkrekshi, Ila Tamaskar
Collection and/or assembly of data: Akram Alkrekshi, Ila Tamaskar
Data analysis and interpretation: Akram Alkrekshi, Ila Tamaskar
Manuscript writing: Akram Alkrekshi, Ila Tamaskar
Final approval of manuscript: Akram Alkrekshi, Ila Tamaskar
Disclosures
The authors indicated no financial relationships | NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33655663 | 19,066,357 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatotoxicity'. | Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection.
The safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).
This was a single-institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.
We identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non-small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1-2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).
Adverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.
The safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors' institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.
Introduction
Immune checkpoint inhibitors (ICIs), namely programmed death receptor‐1 (PD‐1) and programmed death receptor‐1 ligand (PD‐1L) inhibitors and cytotoxic T‐lymphocytic antigen 4 (CTLA‐4), have changed the cancer therapy paradigm and are approved for various malignancies: melanoma, lung cancer, hepatocellular carcinoma, and many others (Table 1). CTLA‐4 and PD‐1L are intrinsic downregulators of immunity that dampen the immune regulatory response. Cancer cells hijack this system to evade the immune system. ICIs, by blocking these cell surface proteins, enhance the antitumor immune response. In hepatitis C virus (HCV) infection, the expression of PD‐1/PD‐1L contributes to the persistence of infection [1]. Therefore, to avoid unforeseen adverse events (AEs; e.g., viral reactivation), patients with HCV infections were excluded from most clinical trials evaluating ICI even though HCV is a major health care problem, with a prevalence of 0.5%–2.3% worldwide [2]. Absence of ICI safety data in patients with cancer with HCV makes it challenging to adequately assess the risk‐benefit of ICI and to advise the patient on the likelihood of AEs to assist them in making an informed decision. This may result in ICIs being denied or delayed pending treatment of the underlying HCV. In this article, we conducted a retrospective study of all patients with cancer with HCV untreated and resolved who received ICI at our institution.
Table 1 Immune checkpoint inhibitor indications
Melanoma; adjuvant, unresectable, or metastatic
Non‐small cell lung cancer; metastatic
Small cell lung cancer; metastatic
Hepatocellular carcinoma
Renal cell carcinoma; advanced, or metastatic
Hodgkin lymphoma
Head and neck squamous cell carcinoma; recurrent or metastatic
Urothelial carcinoma; locally advanced or metastatic
Breast cancer; triple‐negative locally advanced or metastatic
Colon cancer, metastatic (MSI‐H or dMMR)
Glioblastoma
Cutaneous squamous cell carcinoma; locally advanced or metastatic
Gastric cancer; recurrent locally advanced or metastatic
Anal cancer; metastatic
Merkel cell carcinoma
Primary mediastinal large B‐cell lymphoma
Mesothelioma
Abbreviations: dMMR mismatch repair deficient; MSI‐H, microsatellite instability‐high.
Materials and Methods
This was a single‐institution retrospective electronic chart review of all patients with active or resolved hepatitis C viral infection who were treated with an immune checkpoint inhibitor (ICI) for cancer of any type and stage from January 2012 to December 2019. Data collected included age, gender, ethnicity, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at the time of cancer diagnosis, cancer type and stage, hepatitis C status (specified as untreated chronic infection if the viral load was detected at the time of cancer diagnosis, treated if a history of treatment with undetectable viral load was documented, and spontaneously resolved if only hepatitis C virus antibody was present with undetectable viral load and absence of treatment history), viral genotype, presence of cirrhosis, liver function test before and throughout treatment, type of ICI, length of therapy in weeks, the reason for discontinuation of therapy, and toxicities. Patients with coinfection with hepatitis B virus or human immunodeficiency virus were excluded. The severity of immune‐mediated toxicities was graded using National Cancer Institute CTCAE, Version 5.0 [3]. The study was approved by the institutional review board.
Results
We identified 40 cases, 30 (75%) men and 10 (25%) women, with median age of 64 years (range, 51–80). The largest ethnicity was Black (22; 55%), followed by White (17; 42.5%) and others (1; 2.5%). ECOG was 0–1 in 36 patients (90%) and 2 in four patients (10%). Median BMI was 24.3 kg/m2 (range, 16.7–42.8). Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (1; 2.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 patients (35%), and spontaneously resolved in 9 (22.5%) patients. Hepatitis C genotype was 1a in 25 patients (62.5%), 1b in 1 patient (2.5%), 3 in 1 (2.5%) patients, and unavailable for the rest. Viral load in untreated patients ranged from 45 to 7,620 × 103 copies per mL. Cirrhosis was documented in 22 patients (55%). None of the untreated patients received treatment for HCV at the time of cancer diagnosis before the commencement of ICI. ICIs used were nivolumab alone in 23 patients (57.5%), pembrolizumab in 10 (25%), atezolizumab in 4 (10%), durvalumab in 2 (5%), and combination of ipilimumab and nivolumab in 1 (2.5%). The median length of therapy with ICI was 16 weeks (range, 2–199). AEs noted (see Table 2) were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab, grade 3 colitis in one patient (2.5%) on nivolumab, hepatotoxicity in two patients (5%) on nivolumab (one patient with grade 1 and the other had grade 2), grade 1–2 fatigue in three patients (7.5%), and hypothyroidism in one patient (2.5%).
Table 2 Characteristics of patients with HCV with adverse events while on immune checkpoint inhibitors
Case Age, years Sex Ethnicity ECOG PS Cancer HCV status Genotype Viral Load Cirrhosis Therapy Length of therapy, weeks Reason for discontinuation Toxicities
1 65 M Black 0 NSCLC Untreated 1a 385 × 103 No Nivolumab 78 Toxicities Pneumonitis, grade 3
2 61 F Black 1 NSCLC Untreated 1a 744 × 103 No Nivolumab 5 PD Fatigue grade, 1
3 64 F Black 0 NSCLC Treated 1a 0 No Nivolumab and ipilimumab 24 Ongoing Hypothyroidism, grade 1 and fatigue, grade 2
4 55 F White 1 SCLC Untreated 1a 152 × 103 No 1 9 Toxicities Colitis, grade 3
5 74 F Other 1 HCC Treated 1a 0 Yes Nivolumab 25 PD Fatigue, grade 1
6 66 M White 0 HCC Untreated 1a 557 × 103 Yes Nivolumab 12 PD Hepatotoxicity, grade 1
7 59 M Black 1 HCC Untreated 1b 3,190 × 103 Yes Nivolumab 16 PD Hepatotoxicity, grade 2
Abbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; NSCLC, non‐small cell lung cancer; PD, progressive disease; SCLC, small cell lung cancer.
The patient with grade 2 hepatotoxicity was a 55‐year‐old African American man with HCC. He had liver cirrhosis with MELD score of 7, ascites, and HCV with genotype 1b. The hepatotoxicity occurred after the first dose of nivolumab. Hepatotoxicity was marked by transaminitis, whereas alkalyine phosphatase, bilirubin, albumin, and clotting factors remained within the normal range. He was treated with prednisone 1 mg/kg with a taper over 2 weeks with a return of liver function test to baseline. He was continued on nivolumab with no further recurrence of hepatotoxicity, for timeline, and degree of transaminitis (see Fig. 1).
Figure 1 Timeline of the patient with grade 2 hepatotoxicity due to nivolumab.
Abbreviations: ALT alanine transaminase; AST aspartate transaminase.
Discussion
Chronic hepatitis C infection is a major health problem, with a prevalence of approximately 1% in the U.S., with higher rates in states with a worse opioid crisis, likely owing to increased injection drug use [4]. Although effective therapy for HCV is now present, challenges in prevention, case detection, treatment affordability, and access propose that HCV burden will continue to be a significant health care issue in the foreseeable future [4]. Population‐based studies concerning cancer risk in HCV‐infected patients showed an increased risk for hepatocellular carcinoma, non‐Hodgkin lymphoma, and lung cancer [5, 6]. Along with the expanding indications for ICI, the coexistence of HCV and potentially ICI‐responsive cancer will be encountered more frequently. Two landmark trials that studied PD‐1 inhibitors in hepatocellular carcinoma included treated and untreated HCV patients: a phase I–II study of nivolumab in hepatocellular carcinoma included 50 patients with HCV, CheckMate‐40 (NCT01658878), and a phase II study of pembrolizumab in hepatocellular carcinoma that included 26 patients with HCV, Keynote‐224 (NCT02702414) [7, 8]. However, trials investigating ICIs in cancers other than hepatocellular carcinoma have excluded patients with HCV infection, as it is unknown how the ICIs will interplay with the underlying chronic infection (e.g., the potential for a flare of chronic HCV infection or higher rate of AEs).
In this article, we report our case series of 40 patients covering the past 8 years addressing the safety of ICIs in patients with HCV. The predominance of men in our study may be explained by predominant tumor subtypes in our cohort, namely, non‐small cell lung cancer and hepatocellular carcinoma, both of which are more common in men, which is likely attributed to an increased likelihood of adapting high‐risk behaviors in men that increase their risk for these cancers (e.g., smoking and injectable drug use) [6, 9]. Ethnicities reported were reflective of the background population [10].
In our study, PD‐1/PD‐L1 inhibitor AE rates were comparable to those reported in clinical trials that excluded 1%–3% of patients with HCV [11, 12]. No deaths related to ICI were identified. Only two patients suffered grade 3 AEs: one with colitis on nivolumab and another with pneumonitis on pembrolizumab, with resultant discontinuation of treatment in both. There were only two cases of hepatotoxicity, with the worst being grade 2 in a patient with genotype 1b; however, the patient was able to continue ICI following glucocorticoid course. Both patients with hepatotoxicity had hepatocellular carcinoma, untreated HCV, and liver cirrhosis and were treated with nivolumab. Viral load was not checked at the time of liver enzyme derangement; therefore, it is not possible to comment if an HCV flare was contributing. In the aforementioned trials of PD‐1 inhibitors in hepatocellular carcinoma, CheckMate‐40 and Keynote‐224, no HCV flares were reported [7, 8].
Study limitations include single‐center study and all the limitations of a retrospective design; selection bias and lack of rigorousness in documenting all possible treatment toxicities compared with a prospective study. The majority of patients were male, and the prevailing genotype was 1a. HCV genotype varies racially and geographically; therefore, our findings may not be generalizable [13]. Interestingly, the patient with grade 2 hepatotoxicity had HCV genotype 1b, which was under‐represented in our cohort. Further studies, including all HCV genotypes, are needed to evaluate if certain genotypes carry a higher risk of ICI‐related AEs. Other areas of study include characterization of PD‐L1 expression in the liver and its effect on AE rates, the safety of ICIs in patients with HCV coinfected with hepatitis B virus and/or human immunodeficiency virus, and cancer registry studies to explore possible health disparities should patients with HCV and cancer be less likely to receive ICI.
Conclusion
In the lack of randomized controlled trials to address the safety of ICI in HCV and other major chronic viral infections across different cancers, observational studies may help to illustrate if such populations tend to have higher rates of ICI AEs. This observational study showed no deaths related to ICIs, and AE profiles in untreated and resolved patients with HCV were comparable to rates of non‐HCV patients. ICI was not delayed in our cohort pending treatment for active HCV. These findings may aid the oncologist in discussing ICI toxicities in patients with cancer with untreated and resolved HCV.
Author Contributions
Conception/design: Akram Alkrekshi, Ila Tamaskar
Provision of study material or patients: Akram Alkrekshi, Ila Tamaskar
Collection and/or assembly of data: Akram Alkrekshi, Ila Tamaskar
Data analysis and interpretation: Akram Alkrekshi, Ila Tamaskar
Manuscript writing: Akram Alkrekshi, Ila Tamaskar
Final approval of manuscript: Akram Alkrekshi, Ila Tamaskar
Disclosures
The authors indicated no financial relationships | NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33655663 | 19,069,936 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypothyroidism'. | Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection.
The safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).
This was a single-institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.
We identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non-small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1-2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).
Adverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.
The safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors' institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.
Introduction
Immune checkpoint inhibitors (ICIs), namely programmed death receptor‐1 (PD‐1) and programmed death receptor‐1 ligand (PD‐1L) inhibitors and cytotoxic T‐lymphocytic antigen 4 (CTLA‐4), have changed the cancer therapy paradigm and are approved for various malignancies: melanoma, lung cancer, hepatocellular carcinoma, and many others (Table 1). CTLA‐4 and PD‐1L are intrinsic downregulators of immunity that dampen the immune regulatory response. Cancer cells hijack this system to evade the immune system. ICIs, by blocking these cell surface proteins, enhance the antitumor immune response. In hepatitis C virus (HCV) infection, the expression of PD‐1/PD‐1L contributes to the persistence of infection [1]. Therefore, to avoid unforeseen adverse events (AEs; e.g., viral reactivation), patients with HCV infections were excluded from most clinical trials evaluating ICI even though HCV is a major health care problem, with a prevalence of 0.5%–2.3% worldwide [2]. Absence of ICI safety data in patients with cancer with HCV makes it challenging to adequately assess the risk‐benefit of ICI and to advise the patient on the likelihood of AEs to assist them in making an informed decision. This may result in ICIs being denied or delayed pending treatment of the underlying HCV. In this article, we conducted a retrospective study of all patients with cancer with HCV untreated and resolved who received ICI at our institution.
Table 1 Immune checkpoint inhibitor indications
Melanoma; adjuvant, unresectable, or metastatic
Non‐small cell lung cancer; metastatic
Small cell lung cancer; metastatic
Hepatocellular carcinoma
Renal cell carcinoma; advanced, or metastatic
Hodgkin lymphoma
Head and neck squamous cell carcinoma; recurrent or metastatic
Urothelial carcinoma; locally advanced or metastatic
Breast cancer; triple‐negative locally advanced or metastatic
Colon cancer, metastatic (MSI‐H or dMMR)
Glioblastoma
Cutaneous squamous cell carcinoma; locally advanced or metastatic
Gastric cancer; recurrent locally advanced or metastatic
Anal cancer; metastatic
Merkel cell carcinoma
Primary mediastinal large B‐cell lymphoma
Mesothelioma
Abbreviations: dMMR mismatch repair deficient; MSI‐H, microsatellite instability‐high.
Materials and Methods
This was a single‐institution retrospective electronic chart review of all patients with active or resolved hepatitis C viral infection who were treated with an immune checkpoint inhibitor (ICI) for cancer of any type and stage from January 2012 to December 2019. Data collected included age, gender, ethnicity, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at the time of cancer diagnosis, cancer type and stage, hepatitis C status (specified as untreated chronic infection if the viral load was detected at the time of cancer diagnosis, treated if a history of treatment with undetectable viral load was documented, and spontaneously resolved if only hepatitis C virus antibody was present with undetectable viral load and absence of treatment history), viral genotype, presence of cirrhosis, liver function test before and throughout treatment, type of ICI, length of therapy in weeks, the reason for discontinuation of therapy, and toxicities. Patients with coinfection with hepatitis B virus or human immunodeficiency virus were excluded. The severity of immune‐mediated toxicities was graded using National Cancer Institute CTCAE, Version 5.0 [3]. The study was approved by the institutional review board.
Results
We identified 40 cases, 30 (75%) men and 10 (25%) women, with median age of 64 years (range, 51–80). The largest ethnicity was Black (22; 55%), followed by White (17; 42.5%) and others (1; 2.5%). ECOG was 0–1 in 36 patients (90%) and 2 in four patients (10%). Median BMI was 24.3 kg/m2 (range, 16.7–42.8). Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (1; 2.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 patients (35%), and spontaneously resolved in 9 (22.5%) patients. Hepatitis C genotype was 1a in 25 patients (62.5%), 1b in 1 patient (2.5%), 3 in 1 (2.5%) patients, and unavailable for the rest. Viral load in untreated patients ranged from 45 to 7,620 × 103 copies per mL. Cirrhosis was documented in 22 patients (55%). None of the untreated patients received treatment for HCV at the time of cancer diagnosis before the commencement of ICI. ICIs used were nivolumab alone in 23 patients (57.5%), pembrolizumab in 10 (25%), atezolizumab in 4 (10%), durvalumab in 2 (5%), and combination of ipilimumab and nivolumab in 1 (2.5%). The median length of therapy with ICI was 16 weeks (range, 2–199). AEs noted (see Table 2) were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab, grade 3 colitis in one patient (2.5%) on nivolumab, hepatotoxicity in two patients (5%) on nivolumab (one patient with grade 1 and the other had grade 2), grade 1–2 fatigue in three patients (7.5%), and hypothyroidism in one patient (2.5%).
Table 2 Characteristics of patients with HCV with adverse events while on immune checkpoint inhibitors
Case Age, years Sex Ethnicity ECOG PS Cancer HCV status Genotype Viral Load Cirrhosis Therapy Length of therapy, weeks Reason for discontinuation Toxicities
1 65 M Black 0 NSCLC Untreated 1a 385 × 103 No Nivolumab 78 Toxicities Pneumonitis, grade 3
2 61 F Black 1 NSCLC Untreated 1a 744 × 103 No Nivolumab 5 PD Fatigue grade, 1
3 64 F Black 0 NSCLC Treated 1a 0 No Nivolumab and ipilimumab 24 Ongoing Hypothyroidism, grade 1 and fatigue, grade 2
4 55 F White 1 SCLC Untreated 1a 152 × 103 No 1 9 Toxicities Colitis, grade 3
5 74 F Other 1 HCC Treated 1a 0 Yes Nivolumab 25 PD Fatigue, grade 1
6 66 M White 0 HCC Untreated 1a 557 × 103 Yes Nivolumab 12 PD Hepatotoxicity, grade 1
7 59 M Black 1 HCC Untreated 1b 3,190 × 103 Yes Nivolumab 16 PD Hepatotoxicity, grade 2
Abbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; NSCLC, non‐small cell lung cancer; PD, progressive disease; SCLC, small cell lung cancer.
The patient with grade 2 hepatotoxicity was a 55‐year‐old African American man with HCC. He had liver cirrhosis with MELD score of 7, ascites, and HCV with genotype 1b. The hepatotoxicity occurred after the first dose of nivolumab. Hepatotoxicity was marked by transaminitis, whereas alkalyine phosphatase, bilirubin, albumin, and clotting factors remained within the normal range. He was treated with prednisone 1 mg/kg with a taper over 2 weeks with a return of liver function test to baseline. He was continued on nivolumab with no further recurrence of hepatotoxicity, for timeline, and degree of transaminitis (see Fig. 1).
Figure 1 Timeline of the patient with grade 2 hepatotoxicity due to nivolumab.
Abbreviations: ALT alanine transaminase; AST aspartate transaminase.
Discussion
Chronic hepatitis C infection is a major health problem, with a prevalence of approximately 1% in the U.S., with higher rates in states with a worse opioid crisis, likely owing to increased injection drug use [4]. Although effective therapy for HCV is now present, challenges in prevention, case detection, treatment affordability, and access propose that HCV burden will continue to be a significant health care issue in the foreseeable future [4]. Population‐based studies concerning cancer risk in HCV‐infected patients showed an increased risk for hepatocellular carcinoma, non‐Hodgkin lymphoma, and lung cancer [5, 6]. Along with the expanding indications for ICI, the coexistence of HCV and potentially ICI‐responsive cancer will be encountered more frequently. Two landmark trials that studied PD‐1 inhibitors in hepatocellular carcinoma included treated and untreated HCV patients: a phase I–II study of nivolumab in hepatocellular carcinoma included 50 patients with HCV, CheckMate‐40 (NCT01658878), and a phase II study of pembrolizumab in hepatocellular carcinoma that included 26 patients with HCV, Keynote‐224 (NCT02702414) [7, 8]. However, trials investigating ICIs in cancers other than hepatocellular carcinoma have excluded patients with HCV infection, as it is unknown how the ICIs will interplay with the underlying chronic infection (e.g., the potential for a flare of chronic HCV infection or higher rate of AEs).
In this article, we report our case series of 40 patients covering the past 8 years addressing the safety of ICIs in patients with HCV. The predominance of men in our study may be explained by predominant tumor subtypes in our cohort, namely, non‐small cell lung cancer and hepatocellular carcinoma, both of which are more common in men, which is likely attributed to an increased likelihood of adapting high‐risk behaviors in men that increase their risk for these cancers (e.g., smoking and injectable drug use) [6, 9]. Ethnicities reported were reflective of the background population [10].
In our study, PD‐1/PD‐L1 inhibitor AE rates were comparable to those reported in clinical trials that excluded 1%–3% of patients with HCV [11, 12]. No deaths related to ICI were identified. Only two patients suffered grade 3 AEs: one with colitis on nivolumab and another with pneumonitis on pembrolizumab, with resultant discontinuation of treatment in both. There were only two cases of hepatotoxicity, with the worst being grade 2 in a patient with genotype 1b; however, the patient was able to continue ICI following glucocorticoid course. Both patients with hepatotoxicity had hepatocellular carcinoma, untreated HCV, and liver cirrhosis and were treated with nivolumab. Viral load was not checked at the time of liver enzyme derangement; therefore, it is not possible to comment if an HCV flare was contributing. In the aforementioned trials of PD‐1 inhibitors in hepatocellular carcinoma, CheckMate‐40 and Keynote‐224, no HCV flares were reported [7, 8].
Study limitations include single‐center study and all the limitations of a retrospective design; selection bias and lack of rigorousness in documenting all possible treatment toxicities compared with a prospective study. The majority of patients were male, and the prevailing genotype was 1a. HCV genotype varies racially and geographically; therefore, our findings may not be generalizable [13]. Interestingly, the patient with grade 2 hepatotoxicity had HCV genotype 1b, which was under‐represented in our cohort. Further studies, including all HCV genotypes, are needed to evaluate if certain genotypes carry a higher risk of ICI‐related AEs. Other areas of study include characterization of PD‐L1 expression in the liver and its effect on AE rates, the safety of ICIs in patients with HCV coinfected with hepatitis B virus and/or human immunodeficiency virus, and cancer registry studies to explore possible health disparities should patients with HCV and cancer be less likely to receive ICI.
Conclusion
In the lack of randomized controlled trials to address the safety of ICI in HCV and other major chronic viral infections across different cancers, observational studies may help to illustrate if such populations tend to have higher rates of ICI AEs. This observational study showed no deaths related to ICIs, and AE profiles in untreated and resolved patients with HCV were comparable to rates of non‐HCV patients. ICI was not delayed in our cohort pending treatment for active HCV. These findings may aid the oncologist in discussing ICI toxicities in patients with cancer with untreated and resolved HCV.
Author Contributions
Conception/design: Akram Alkrekshi, Ila Tamaskar
Provision of study material or patients: Akram Alkrekshi, Ila Tamaskar
Collection and/or assembly of data: Akram Alkrekshi, Ila Tamaskar
Data analysis and interpretation: Akram Alkrekshi, Ila Tamaskar
Manuscript writing: Akram Alkrekshi, Ila Tamaskar
Final approval of manuscript: Akram Alkrekshi, Ila Tamaskar
Disclosures
The authors indicated no financial relationships | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33655663 | 19,071,152 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product use issue'. | Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection.
The safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).
This was a single-institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.
We identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non-small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1-2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).
Adverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.
The safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors' institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.
Introduction
Immune checkpoint inhibitors (ICIs), namely programmed death receptor‐1 (PD‐1) and programmed death receptor‐1 ligand (PD‐1L) inhibitors and cytotoxic T‐lymphocytic antigen 4 (CTLA‐4), have changed the cancer therapy paradigm and are approved for various malignancies: melanoma, lung cancer, hepatocellular carcinoma, and many others (Table 1). CTLA‐4 and PD‐1L are intrinsic downregulators of immunity that dampen the immune regulatory response. Cancer cells hijack this system to evade the immune system. ICIs, by blocking these cell surface proteins, enhance the antitumor immune response. In hepatitis C virus (HCV) infection, the expression of PD‐1/PD‐1L contributes to the persistence of infection [1]. Therefore, to avoid unforeseen adverse events (AEs; e.g., viral reactivation), patients with HCV infections were excluded from most clinical trials evaluating ICI even though HCV is a major health care problem, with a prevalence of 0.5%–2.3% worldwide [2]. Absence of ICI safety data in patients with cancer with HCV makes it challenging to adequately assess the risk‐benefit of ICI and to advise the patient on the likelihood of AEs to assist them in making an informed decision. This may result in ICIs being denied or delayed pending treatment of the underlying HCV. In this article, we conducted a retrospective study of all patients with cancer with HCV untreated and resolved who received ICI at our institution.
Table 1 Immune checkpoint inhibitor indications
Melanoma; adjuvant, unresectable, or metastatic
Non‐small cell lung cancer; metastatic
Small cell lung cancer; metastatic
Hepatocellular carcinoma
Renal cell carcinoma; advanced, or metastatic
Hodgkin lymphoma
Head and neck squamous cell carcinoma; recurrent or metastatic
Urothelial carcinoma; locally advanced or metastatic
Breast cancer; triple‐negative locally advanced or metastatic
Colon cancer, metastatic (MSI‐H or dMMR)
Glioblastoma
Cutaneous squamous cell carcinoma; locally advanced or metastatic
Gastric cancer; recurrent locally advanced or metastatic
Anal cancer; metastatic
Merkel cell carcinoma
Primary mediastinal large B‐cell lymphoma
Mesothelioma
Abbreviations: dMMR mismatch repair deficient; MSI‐H, microsatellite instability‐high.
Materials and Methods
This was a single‐institution retrospective electronic chart review of all patients with active or resolved hepatitis C viral infection who were treated with an immune checkpoint inhibitor (ICI) for cancer of any type and stage from January 2012 to December 2019. Data collected included age, gender, ethnicity, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at the time of cancer diagnosis, cancer type and stage, hepatitis C status (specified as untreated chronic infection if the viral load was detected at the time of cancer diagnosis, treated if a history of treatment with undetectable viral load was documented, and spontaneously resolved if only hepatitis C virus antibody was present with undetectable viral load and absence of treatment history), viral genotype, presence of cirrhosis, liver function test before and throughout treatment, type of ICI, length of therapy in weeks, the reason for discontinuation of therapy, and toxicities. Patients with coinfection with hepatitis B virus or human immunodeficiency virus were excluded. The severity of immune‐mediated toxicities was graded using National Cancer Institute CTCAE, Version 5.0 [3]. The study was approved by the institutional review board.
Results
We identified 40 cases, 30 (75%) men and 10 (25%) women, with median age of 64 years (range, 51–80). The largest ethnicity was Black (22; 55%), followed by White (17; 42.5%) and others (1; 2.5%). ECOG was 0–1 in 36 patients (90%) and 2 in four patients (10%). Median BMI was 24.3 kg/m2 (range, 16.7–42.8). Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (1; 2.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 patients (35%), and spontaneously resolved in 9 (22.5%) patients. Hepatitis C genotype was 1a in 25 patients (62.5%), 1b in 1 patient (2.5%), 3 in 1 (2.5%) patients, and unavailable for the rest. Viral load in untreated patients ranged from 45 to 7,620 × 103 copies per mL. Cirrhosis was documented in 22 patients (55%). None of the untreated patients received treatment for HCV at the time of cancer diagnosis before the commencement of ICI. ICIs used were nivolumab alone in 23 patients (57.5%), pembrolizumab in 10 (25%), atezolizumab in 4 (10%), durvalumab in 2 (5%), and combination of ipilimumab and nivolumab in 1 (2.5%). The median length of therapy with ICI was 16 weeks (range, 2–199). AEs noted (see Table 2) were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab, grade 3 colitis in one patient (2.5%) on nivolumab, hepatotoxicity in two patients (5%) on nivolumab (one patient with grade 1 and the other had grade 2), grade 1–2 fatigue in three patients (7.5%), and hypothyroidism in one patient (2.5%).
Table 2 Characteristics of patients with HCV with adverse events while on immune checkpoint inhibitors
Case Age, years Sex Ethnicity ECOG PS Cancer HCV status Genotype Viral Load Cirrhosis Therapy Length of therapy, weeks Reason for discontinuation Toxicities
1 65 M Black 0 NSCLC Untreated 1a 385 × 103 No Nivolumab 78 Toxicities Pneumonitis, grade 3
2 61 F Black 1 NSCLC Untreated 1a 744 × 103 No Nivolumab 5 PD Fatigue grade, 1
3 64 F Black 0 NSCLC Treated 1a 0 No Nivolumab and ipilimumab 24 Ongoing Hypothyroidism, grade 1 and fatigue, grade 2
4 55 F White 1 SCLC Untreated 1a 152 × 103 No 1 9 Toxicities Colitis, grade 3
5 74 F Other 1 HCC Treated 1a 0 Yes Nivolumab 25 PD Fatigue, grade 1
6 66 M White 0 HCC Untreated 1a 557 × 103 Yes Nivolumab 12 PD Hepatotoxicity, grade 1
7 59 M Black 1 HCC Untreated 1b 3,190 × 103 Yes Nivolumab 16 PD Hepatotoxicity, grade 2
Abbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; NSCLC, non‐small cell lung cancer; PD, progressive disease; SCLC, small cell lung cancer.
The patient with grade 2 hepatotoxicity was a 55‐year‐old African American man with HCC. He had liver cirrhosis with MELD score of 7, ascites, and HCV with genotype 1b. The hepatotoxicity occurred after the first dose of nivolumab. Hepatotoxicity was marked by transaminitis, whereas alkalyine phosphatase, bilirubin, albumin, and clotting factors remained within the normal range. He was treated with prednisone 1 mg/kg with a taper over 2 weeks with a return of liver function test to baseline. He was continued on nivolumab with no further recurrence of hepatotoxicity, for timeline, and degree of transaminitis (see Fig. 1).
Figure 1 Timeline of the patient with grade 2 hepatotoxicity due to nivolumab.
Abbreviations: ALT alanine transaminase; AST aspartate transaminase.
Discussion
Chronic hepatitis C infection is a major health problem, with a prevalence of approximately 1% in the U.S., with higher rates in states with a worse opioid crisis, likely owing to increased injection drug use [4]. Although effective therapy for HCV is now present, challenges in prevention, case detection, treatment affordability, and access propose that HCV burden will continue to be a significant health care issue in the foreseeable future [4]. Population‐based studies concerning cancer risk in HCV‐infected patients showed an increased risk for hepatocellular carcinoma, non‐Hodgkin lymphoma, and lung cancer [5, 6]. Along with the expanding indications for ICI, the coexistence of HCV and potentially ICI‐responsive cancer will be encountered more frequently. Two landmark trials that studied PD‐1 inhibitors in hepatocellular carcinoma included treated and untreated HCV patients: a phase I–II study of nivolumab in hepatocellular carcinoma included 50 patients with HCV, CheckMate‐40 (NCT01658878), and a phase II study of pembrolizumab in hepatocellular carcinoma that included 26 patients with HCV, Keynote‐224 (NCT02702414) [7, 8]. However, trials investigating ICIs in cancers other than hepatocellular carcinoma have excluded patients with HCV infection, as it is unknown how the ICIs will interplay with the underlying chronic infection (e.g., the potential for a flare of chronic HCV infection or higher rate of AEs).
In this article, we report our case series of 40 patients covering the past 8 years addressing the safety of ICIs in patients with HCV. The predominance of men in our study may be explained by predominant tumor subtypes in our cohort, namely, non‐small cell lung cancer and hepatocellular carcinoma, both of which are more common in men, which is likely attributed to an increased likelihood of adapting high‐risk behaviors in men that increase their risk for these cancers (e.g., smoking and injectable drug use) [6, 9]. Ethnicities reported were reflective of the background population [10].
In our study, PD‐1/PD‐L1 inhibitor AE rates were comparable to those reported in clinical trials that excluded 1%–3% of patients with HCV [11, 12]. No deaths related to ICI were identified. Only two patients suffered grade 3 AEs: one with colitis on nivolumab and another with pneumonitis on pembrolizumab, with resultant discontinuation of treatment in both. There were only two cases of hepatotoxicity, with the worst being grade 2 in a patient with genotype 1b; however, the patient was able to continue ICI following glucocorticoid course. Both patients with hepatotoxicity had hepatocellular carcinoma, untreated HCV, and liver cirrhosis and were treated with nivolumab. Viral load was not checked at the time of liver enzyme derangement; therefore, it is not possible to comment if an HCV flare was contributing. In the aforementioned trials of PD‐1 inhibitors in hepatocellular carcinoma, CheckMate‐40 and Keynote‐224, no HCV flares were reported [7, 8].
Study limitations include single‐center study and all the limitations of a retrospective design; selection bias and lack of rigorousness in documenting all possible treatment toxicities compared with a prospective study. The majority of patients were male, and the prevailing genotype was 1a. HCV genotype varies racially and geographically; therefore, our findings may not be generalizable [13]. Interestingly, the patient with grade 2 hepatotoxicity had HCV genotype 1b, which was under‐represented in our cohort. Further studies, including all HCV genotypes, are needed to evaluate if certain genotypes carry a higher risk of ICI‐related AEs. Other areas of study include characterization of PD‐L1 expression in the liver and its effect on AE rates, the safety of ICIs in patients with HCV coinfected with hepatitis B virus and/or human immunodeficiency virus, and cancer registry studies to explore possible health disparities should patients with HCV and cancer be less likely to receive ICI.
Conclusion
In the lack of randomized controlled trials to address the safety of ICI in HCV and other major chronic viral infections across different cancers, observational studies may help to illustrate if such populations tend to have higher rates of ICI AEs. This observational study showed no deaths related to ICIs, and AE profiles in untreated and resolved patients with HCV were comparable to rates of non‐HCV patients. ICI was not delayed in our cohort pending treatment for active HCV. These findings may aid the oncologist in discussing ICI toxicities in patients with cancer with untreated and resolved HCV.
Author Contributions
Conception/design: Akram Alkrekshi, Ila Tamaskar
Provision of study material or patients: Akram Alkrekshi, Ila Tamaskar
Collection and/or assembly of data: Akram Alkrekshi, Ila Tamaskar
Data analysis and interpretation: Akram Alkrekshi, Ila Tamaskar
Manuscript writing: Akram Alkrekshi, Ila Tamaskar
Final approval of manuscript: Akram Alkrekshi, Ila Tamaskar
Disclosures
The authors indicated no financial relationships | NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33655663 | 19,066,357 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'. | Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection.
The safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).
This was a single-institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.
We identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non-small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1-2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).
Adverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.
The safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors' institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.
Introduction
Immune checkpoint inhibitors (ICIs), namely programmed death receptor‐1 (PD‐1) and programmed death receptor‐1 ligand (PD‐1L) inhibitors and cytotoxic T‐lymphocytic antigen 4 (CTLA‐4), have changed the cancer therapy paradigm and are approved for various malignancies: melanoma, lung cancer, hepatocellular carcinoma, and many others (Table 1). CTLA‐4 and PD‐1L are intrinsic downregulators of immunity that dampen the immune regulatory response. Cancer cells hijack this system to evade the immune system. ICIs, by blocking these cell surface proteins, enhance the antitumor immune response. In hepatitis C virus (HCV) infection, the expression of PD‐1/PD‐1L contributes to the persistence of infection [1]. Therefore, to avoid unforeseen adverse events (AEs; e.g., viral reactivation), patients with HCV infections were excluded from most clinical trials evaluating ICI even though HCV is a major health care problem, with a prevalence of 0.5%–2.3% worldwide [2]. Absence of ICI safety data in patients with cancer with HCV makes it challenging to adequately assess the risk‐benefit of ICI and to advise the patient on the likelihood of AEs to assist them in making an informed decision. This may result in ICIs being denied or delayed pending treatment of the underlying HCV. In this article, we conducted a retrospective study of all patients with cancer with HCV untreated and resolved who received ICI at our institution.
Table 1 Immune checkpoint inhibitor indications
Melanoma; adjuvant, unresectable, or metastatic
Non‐small cell lung cancer; metastatic
Small cell lung cancer; metastatic
Hepatocellular carcinoma
Renal cell carcinoma; advanced, or metastatic
Hodgkin lymphoma
Head and neck squamous cell carcinoma; recurrent or metastatic
Urothelial carcinoma; locally advanced or metastatic
Breast cancer; triple‐negative locally advanced or metastatic
Colon cancer, metastatic (MSI‐H or dMMR)
Glioblastoma
Cutaneous squamous cell carcinoma; locally advanced or metastatic
Gastric cancer; recurrent locally advanced or metastatic
Anal cancer; metastatic
Merkel cell carcinoma
Primary mediastinal large B‐cell lymphoma
Mesothelioma
Abbreviations: dMMR mismatch repair deficient; MSI‐H, microsatellite instability‐high.
Materials and Methods
This was a single‐institution retrospective electronic chart review of all patients with active or resolved hepatitis C viral infection who were treated with an immune checkpoint inhibitor (ICI) for cancer of any type and stage from January 2012 to December 2019. Data collected included age, gender, ethnicity, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at the time of cancer diagnosis, cancer type and stage, hepatitis C status (specified as untreated chronic infection if the viral load was detected at the time of cancer diagnosis, treated if a history of treatment with undetectable viral load was documented, and spontaneously resolved if only hepatitis C virus antibody was present with undetectable viral load and absence of treatment history), viral genotype, presence of cirrhosis, liver function test before and throughout treatment, type of ICI, length of therapy in weeks, the reason for discontinuation of therapy, and toxicities. Patients with coinfection with hepatitis B virus or human immunodeficiency virus were excluded. The severity of immune‐mediated toxicities was graded using National Cancer Institute CTCAE, Version 5.0 [3]. The study was approved by the institutional review board.
Results
We identified 40 cases, 30 (75%) men and 10 (25%) women, with median age of 64 years (range, 51–80). The largest ethnicity was Black (22; 55%), followed by White (17; 42.5%) and others (1; 2.5%). ECOG was 0–1 in 36 patients (90%) and 2 in four patients (10%). Median BMI was 24.3 kg/m2 (range, 16.7–42.8). Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (1; 2.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 patients (35%), and spontaneously resolved in 9 (22.5%) patients. Hepatitis C genotype was 1a in 25 patients (62.5%), 1b in 1 patient (2.5%), 3 in 1 (2.5%) patients, and unavailable for the rest. Viral load in untreated patients ranged from 45 to 7,620 × 103 copies per mL. Cirrhosis was documented in 22 patients (55%). None of the untreated patients received treatment for HCV at the time of cancer diagnosis before the commencement of ICI. ICIs used were nivolumab alone in 23 patients (57.5%), pembrolizumab in 10 (25%), atezolizumab in 4 (10%), durvalumab in 2 (5%), and combination of ipilimumab and nivolumab in 1 (2.5%). The median length of therapy with ICI was 16 weeks (range, 2–199). AEs noted (see Table 2) were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab, grade 3 colitis in one patient (2.5%) on nivolumab, hepatotoxicity in two patients (5%) on nivolumab (one patient with grade 1 and the other had grade 2), grade 1–2 fatigue in three patients (7.5%), and hypothyroidism in one patient (2.5%).
Table 2 Characteristics of patients with HCV with adverse events while on immune checkpoint inhibitors
Case Age, years Sex Ethnicity ECOG PS Cancer HCV status Genotype Viral Load Cirrhosis Therapy Length of therapy, weeks Reason for discontinuation Toxicities
1 65 M Black 0 NSCLC Untreated 1a 385 × 103 No Nivolumab 78 Toxicities Pneumonitis, grade 3
2 61 F Black 1 NSCLC Untreated 1a 744 × 103 No Nivolumab 5 PD Fatigue grade, 1
3 64 F Black 0 NSCLC Treated 1a 0 No Nivolumab and ipilimumab 24 Ongoing Hypothyroidism, grade 1 and fatigue, grade 2
4 55 F White 1 SCLC Untreated 1a 152 × 103 No 1 9 Toxicities Colitis, grade 3
5 74 F Other 1 HCC Treated 1a 0 Yes Nivolumab 25 PD Fatigue, grade 1
6 66 M White 0 HCC Untreated 1a 557 × 103 Yes Nivolumab 12 PD Hepatotoxicity, grade 1
7 59 M Black 1 HCC Untreated 1b 3,190 × 103 Yes Nivolumab 16 PD Hepatotoxicity, grade 2
Abbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; NSCLC, non‐small cell lung cancer; PD, progressive disease; SCLC, small cell lung cancer.
The patient with grade 2 hepatotoxicity was a 55‐year‐old African American man with HCC. He had liver cirrhosis with MELD score of 7, ascites, and HCV with genotype 1b. The hepatotoxicity occurred after the first dose of nivolumab. Hepatotoxicity was marked by transaminitis, whereas alkalyine phosphatase, bilirubin, albumin, and clotting factors remained within the normal range. He was treated with prednisone 1 mg/kg with a taper over 2 weeks with a return of liver function test to baseline. He was continued on nivolumab with no further recurrence of hepatotoxicity, for timeline, and degree of transaminitis (see Fig. 1).
Figure 1 Timeline of the patient with grade 2 hepatotoxicity due to nivolumab.
Abbreviations: ALT alanine transaminase; AST aspartate transaminase.
Discussion
Chronic hepatitis C infection is a major health problem, with a prevalence of approximately 1% in the U.S., with higher rates in states with a worse opioid crisis, likely owing to increased injection drug use [4]. Although effective therapy for HCV is now present, challenges in prevention, case detection, treatment affordability, and access propose that HCV burden will continue to be a significant health care issue in the foreseeable future [4]. Population‐based studies concerning cancer risk in HCV‐infected patients showed an increased risk for hepatocellular carcinoma, non‐Hodgkin lymphoma, and lung cancer [5, 6]. Along with the expanding indications for ICI, the coexistence of HCV and potentially ICI‐responsive cancer will be encountered more frequently. Two landmark trials that studied PD‐1 inhibitors in hepatocellular carcinoma included treated and untreated HCV patients: a phase I–II study of nivolumab in hepatocellular carcinoma included 50 patients with HCV, CheckMate‐40 (NCT01658878), and a phase II study of pembrolizumab in hepatocellular carcinoma that included 26 patients with HCV, Keynote‐224 (NCT02702414) [7, 8]. However, trials investigating ICIs in cancers other than hepatocellular carcinoma have excluded patients with HCV infection, as it is unknown how the ICIs will interplay with the underlying chronic infection (e.g., the potential for a flare of chronic HCV infection or higher rate of AEs).
In this article, we report our case series of 40 patients covering the past 8 years addressing the safety of ICIs in patients with HCV. The predominance of men in our study may be explained by predominant tumor subtypes in our cohort, namely, non‐small cell lung cancer and hepatocellular carcinoma, both of which are more common in men, which is likely attributed to an increased likelihood of adapting high‐risk behaviors in men that increase their risk for these cancers (e.g., smoking and injectable drug use) [6, 9]. Ethnicities reported were reflective of the background population [10].
In our study, PD‐1/PD‐L1 inhibitor AE rates were comparable to those reported in clinical trials that excluded 1%–3% of patients with HCV [11, 12]. No deaths related to ICI were identified. Only two patients suffered grade 3 AEs: one with colitis on nivolumab and another with pneumonitis on pembrolizumab, with resultant discontinuation of treatment in both. There were only two cases of hepatotoxicity, with the worst being grade 2 in a patient with genotype 1b; however, the patient was able to continue ICI following glucocorticoid course. Both patients with hepatotoxicity had hepatocellular carcinoma, untreated HCV, and liver cirrhosis and were treated with nivolumab. Viral load was not checked at the time of liver enzyme derangement; therefore, it is not possible to comment if an HCV flare was contributing. In the aforementioned trials of PD‐1 inhibitors in hepatocellular carcinoma, CheckMate‐40 and Keynote‐224, no HCV flares were reported [7, 8].
Study limitations include single‐center study and all the limitations of a retrospective design; selection bias and lack of rigorousness in documenting all possible treatment toxicities compared with a prospective study. The majority of patients were male, and the prevailing genotype was 1a. HCV genotype varies racially and geographically; therefore, our findings may not be generalizable [13]. Interestingly, the patient with grade 2 hepatotoxicity had HCV genotype 1b, which was under‐represented in our cohort. Further studies, including all HCV genotypes, are needed to evaluate if certain genotypes carry a higher risk of ICI‐related AEs. Other areas of study include characterization of PD‐L1 expression in the liver and its effect on AE rates, the safety of ICIs in patients with HCV coinfected with hepatitis B virus and/or human immunodeficiency virus, and cancer registry studies to explore possible health disparities should patients with HCV and cancer be less likely to receive ICI.
Conclusion
In the lack of randomized controlled trials to address the safety of ICI in HCV and other major chronic viral infections across different cancers, observational studies may help to illustrate if such populations tend to have higher rates of ICI AEs. This observational study showed no deaths related to ICIs, and AE profiles in untreated and resolved patients with HCV were comparable to rates of non‐HCV patients. ICI was not delayed in our cohort pending treatment for active HCV. These findings may aid the oncologist in discussing ICI toxicities in patients with cancer with untreated and resolved HCV.
Author Contributions
Conception/design: Akram Alkrekshi, Ila Tamaskar
Provision of study material or patients: Akram Alkrekshi, Ila Tamaskar
Collection and/or assembly of data: Akram Alkrekshi, Ila Tamaskar
Data analysis and interpretation: Akram Alkrekshi, Ila Tamaskar
Manuscript writing: Akram Alkrekshi, Ila Tamaskar
Final approval of manuscript: Akram Alkrekshi, Ila Tamaskar
Disclosures
The authors indicated no financial relationships | NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33655663 | 19,066,196 | 2021-05 |
What was the dosage of drug 'IPILIMUMAB'? | Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection.
The safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).
This was a single-institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.
We identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non-small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1-2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).
Adverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.
The safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors' institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.
Introduction
Immune checkpoint inhibitors (ICIs), namely programmed death receptor‐1 (PD‐1) and programmed death receptor‐1 ligand (PD‐1L) inhibitors and cytotoxic T‐lymphocytic antigen 4 (CTLA‐4), have changed the cancer therapy paradigm and are approved for various malignancies: melanoma, lung cancer, hepatocellular carcinoma, and many others (Table 1). CTLA‐4 and PD‐1L are intrinsic downregulators of immunity that dampen the immune regulatory response. Cancer cells hijack this system to evade the immune system. ICIs, by blocking these cell surface proteins, enhance the antitumor immune response. In hepatitis C virus (HCV) infection, the expression of PD‐1/PD‐1L contributes to the persistence of infection [1]. Therefore, to avoid unforeseen adverse events (AEs; e.g., viral reactivation), patients with HCV infections were excluded from most clinical trials evaluating ICI even though HCV is a major health care problem, with a prevalence of 0.5%–2.3% worldwide [2]. Absence of ICI safety data in patients with cancer with HCV makes it challenging to adequately assess the risk‐benefit of ICI and to advise the patient on the likelihood of AEs to assist them in making an informed decision. This may result in ICIs being denied or delayed pending treatment of the underlying HCV. In this article, we conducted a retrospective study of all patients with cancer with HCV untreated and resolved who received ICI at our institution.
Table 1 Immune checkpoint inhibitor indications
Melanoma; adjuvant, unresectable, or metastatic
Non‐small cell lung cancer; metastatic
Small cell lung cancer; metastatic
Hepatocellular carcinoma
Renal cell carcinoma; advanced, or metastatic
Hodgkin lymphoma
Head and neck squamous cell carcinoma; recurrent or metastatic
Urothelial carcinoma; locally advanced or metastatic
Breast cancer; triple‐negative locally advanced or metastatic
Colon cancer, metastatic (MSI‐H or dMMR)
Glioblastoma
Cutaneous squamous cell carcinoma; locally advanced or metastatic
Gastric cancer; recurrent locally advanced or metastatic
Anal cancer; metastatic
Merkel cell carcinoma
Primary mediastinal large B‐cell lymphoma
Mesothelioma
Abbreviations: dMMR mismatch repair deficient; MSI‐H, microsatellite instability‐high.
Materials and Methods
This was a single‐institution retrospective electronic chart review of all patients with active or resolved hepatitis C viral infection who were treated with an immune checkpoint inhibitor (ICI) for cancer of any type and stage from January 2012 to December 2019. Data collected included age, gender, ethnicity, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at the time of cancer diagnosis, cancer type and stage, hepatitis C status (specified as untreated chronic infection if the viral load was detected at the time of cancer diagnosis, treated if a history of treatment with undetectable viral load was documented, and spontaneously resolved if only hepatitis C virus antibody was present with undetectable viral load and absence of treatment history), viral genotype, presence of cirrhosis, liver function test before and throughout treatment, type of ICI, length of therapy in weeks, the reason for discontinuation of therapy, and toxicities. Patients with coinfection with hepatitis B virus or human immunodeficiency virus were excluded. The severity of immune‐mediated toxicities was graded using National Cancer Institute CTCAE, Version 5.0 [3]. The study was approved by the institutional review board.
Results
We identified 40 cases, 30 (75%) men and 10 (25%) women, with median age of 64 years (range, 51–80). The largest ethnicity was Black (22; 55%), followed by White (17; 42.5%) and others (1; 2.5%). ECOG was 0–1 in 36 patients (90%) and 2 in four patients (10%). Median BMI was 24.3 kg/m2 (range, 16.7–42.8). Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (1; 2.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 patients (35%), and spontaneously resolved in 9 (22.5%) patients. Hepatitis C genotype was 1a in 25 patients (62.5%), 1b in 1 patient (2.5%), 3 in 1 (2.5%) patients, and unavailable for the rest. Viral load in untreated patients ranged from 45 to 7,620 × 103 copies per mL. Cirrhosis was documented in 22 patients (55%). None of the untreated patients received treatment for HCV at the time of cancer diagnosis before the commencement of ICI. ICIs used were nivolumab alone in 23 patients (57.5%), pembrolizumab in 10 (25%), atezolizumab in 4 (10%), durvalumab in 2 (5%), and combination of ipilimumab and nivolumab in 1 (2.5%). The median length of therapy with ICI was 16 weeks (range, 2–199). AEs noted (see Table 2) were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab, grade 3 colitis in one patient (2.5%) on nivolumab, hepatotoxicity in two patients (5%) on nivolumab (one patient with grade 1 and the other had grade 2), grade 1–2 fatigue in three patients (7.5%), and hypothyroidism in one patient (2.5%).
Table 2 Characteristics of patients with HCV with adverse events while on immune checkpoint inhibitors
Case Age, years Sex Ethnicity ECOG PS Cancer HCV status Genotype Viral Load Cirrhosis Therapy Length of therapy, weeks Reason for discontinuation Toxicities
1 65 M Black 0 NSCLC Untreated 1a 385 × 103 No Nivolumab 78 Toxicities Pneumonitis, grade 3
2 61 F Black 1 NSCLC Untreated 1a 744 × 103 No Nivolumab 5 PD Fatigue grade, 1
3 64 F Black 0 NSCLC Treated 1a 0 No Nivolumab and ipilimumab 24 Ongoing Hypothyroidism, grade 1 and fatigue, grade 2
4 55 F White 1 SCLC Untreated 1a 152 × 103 No 1 9 Toxicities Colitis, grade 3
5 74 F Other 1 HCC Treated 1a 0 Yes Nivolumab 25 PD Fatigue, grade 1
6 66 M White 0 HCC Untreated 1a 557 × 103 Yes Nivolumab 12 PD Hepatotoxicity, grade 1
7 59 M Black 1 HCC Untreated 1b 3,190 × 103 Yes Nivolumab 16 PD Hepatotoxicity, grade 2
Abbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; NSCLC, non‐small cell lung cancer; PD, progressive disease; SCLC, small cell lung cancer.
The patient with grade 2 hepatotoxicity was a 55‐year‐old African American man with HCC. He had liver cirrhosis with MELD score of 7, ascites, and HCV with genotype 1b. The hepatotoxicity occurred after the first dose of nivolumab. Hepatotoxicity was marked by transaminitis, whereas alkalyine phosphatase, bilirubin, albumin, and clotting factors remained within the normal range. He was treated with prednisone 1 mg/kg with a taper over 2 weeks with a return of liver function test to baseline. He was continued on nivolumab with no further recurrence of hepatotoxicity, for timeline, and degree of transaminitis (see Fig. 1).
Figure 1 Timeline of the patient with grade 2 hepatotoxicity due to nivolumab.
Abbreviations: ALT alanine transaminase; AST aspartate transaminase.
Discussion
Chronic hepatitis C infection is a major health problem, with a prevalence of approximately 1% in the U.S., with higher rates in states with a worse opioid crisis, likely owing to increased injection drug use [4]. Although effective therapy for HCV is now present, challenges in prevention, case detection, treatment affordability, and access propose that HCV burden will continue to be a significant health care issue in the foreseeable future [4]. Population‐based studies concerning cancer risk in HCV‐infected patients showed an increased risk for hepatocellular carcinoma, non‐Hodgkin lymphoma, and lung cancer [5, 6]. Along with the expanding indications for ICI, the coexistence of HCV and potentially ICI‐responsive cancer will be encountered more frequently. Two landmark trials that studied PD‐1 inhibitors in hepatocellular carcinoma included treated and untreated HCV patients: a phase I–II study of nivolumab in hepatocellular carcinoma included 50 patients with HCV, CheckMate‐40 (NCT01658878), and a phase II study of pembrolizumab in hepatocellular carcinoma that included 26 patients with HCV, Keynote‐224 (NCT02702414) [7, 8]. However, trials investigating ICIs in cancers other than hepatocellular carcinoma have excluded patients with HCV infection, as it is unknown how the ICIs will interplay with the underlying chronic infection (e.g., the potential for a flare of chronic HCV infection or higher rate of AEs).
In this article, we report our case series of 40 patients covering the past 8 years addressing the safety of ICIs in patients with HCV. The predominance of men in our study may be explained by predominant tumor subtypes in our cohort, namely, non‐small cell lung cancer and hepatocellular carcinoma, both of which are more common in men, which is likely attributed to an increased likelihood of adapting high‐risk behaviors in men that increase their risk for these cancers (e.g., smoking and injectable drug use) [6, 9]. Ethnicities reported were reflective of the background population [10].
In our study, PD‐1/PD‐L1 inhibitor AE rates were comparable to those reported in clinical trials that excluded 1%–3% of patients with HCV [11, 12]. No deaths related to ICI were identified. Only two patients suffered grade 3 AEs: one with colitis on nivolumab and another with pneumonitis on pembrolizumab, with resultant discontinuation of treatment in both. There were only two cases of hepatotoxicity, with the worst being grade 2 in a patient with genotype 1b; however, the patient was able to continue ICI following glucocorticoid course. Both patients with hepatotoxicity had hepatocellular carcinoma, untreated HCV, and liver cirrhosis and were treated with nivolumab. Viral load was not checked at the time of liver enzyme derangement; therefore, it is not possible to comment if an HCV flare was contributing. In the aforementioned trials of PD‐1 inhibitors in hepatocellular carcinoma, CheckMate‐40 and Keynote‐224, no HCV flares were reported [7, 8].
Study limitations include single‐center study and all the limitations of a retrospective design; selection bias and lack of rigorousness in documenting all possible treatment toxicities compared with a prospective study. The majority of patients were male, and the prevailing genotype was 1a. HCV genotype varies racially and geographically; therefore, our findings may not be generalizable [13]. Interestingly, the patient with grade 2 hepatotoxicity had HCV genotype 1b, which was under‐represented in our cohort. Further studies, including all HCV genotypes, are needed to evaluate if certain genotypes carry a higher risk of ICI‐related AEs. Other areas of study include characterization of PD‐L1 expression in the liver and its effect on AE rates, the safety of ICIs in patients with HCV coinfected with hepatitis B virus and/or human immunodeficiency virus, and cancer registry studies to explore possible health disparities should patients with HCV and cancer be less likely to receive ICI.
Conclusion
In the lack of randomized controlled trials to address the safety of ICI in HCV and other major chronic viral infections across different cancers, observational studies may help to illustrate if such populations tend to have higher rates of ICI AEs. This observational study showed no deaths related to ICIs, and AE profiles in untreated and resolved patients with HCV were comparable to rates of non‐HCV patients. ICI was not delayed in our cohort pending treatment for active HCV. These findings may aid the oncologist in discussing ICI toxicities in patients with cancer with untreated and resolved HCV.
Author Contributions
Conception/design: Akram Alkrekshi, Ila Tamaskar
Provision of study material or patients: Akram Alkrekshi, Ila Tamaskar
Collection and/or assembly of data: Akram Alkrekshi, Ila Tamaskar
Data analysis and interpretation: Akram Alkrekshi, Ila Tamaskar
Manuscript writing: Akram Alkrekshi, Ila Tamaskar
Final approval of manuscript: Akram Alkrekshi, Ila Tamaskar
Disclosures
The authors indicated no financial relationships | LENGTH OF THERAPY WEEKS WAS 24 | DrugDosageText | CC BY-NC-ND | 33655663 | 19,071,152 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Candida infection'. | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | BEGELOMAB, HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dehiscence'. | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | BEGELOMAB, HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33655912 | 19,495,214 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | BEGELOMAB, HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33655912 | 19,495,214 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | IMMUNE GLOBULIN NOS, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33655912 | 19,029,671 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ileal perforation'. | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | BEGELOMAB, HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33655912 | 19,495,214 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Jejunal perforation'. | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | BEGELOMAB, HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | IMMUNE GLOBULIN NOS, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33655912 | 19,029,671 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | BEGELOMAB, HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33655912 | 19,495,214 | 2021-03-05 |
What was the administration route of drug 'IMMUNE GLOBULIN NOS'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33655912 | 19,029,671 | 2021-03-05 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Oral | DrugAdministrationRoute | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
What was the administration route of drug 'PREDNISONE'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Oral | DrugAdministrationRoute | CC BY | 33655912 | 19,495,214 | 2021-03-05 |
What was the dosage of drug 'TACROLIMUS'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | 1 GR | DrugDosageText | CC BY | 33655912 | 19,495,214 | 2021-03-05 |
What was the outcome of reaction 'Acute hepatitis C'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Fatal | ReactionOutcome | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
What was the outcome of reaction 'Condition aggravated'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33655912 | 19,029,671 | 2021-03-05 |
What was the outcome of reaction 'Enterococcal sepsis'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
What was the outcome of reaction 'Ileal perforation'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
What was the outcome of reaction 'Jejunal perforation'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
What was the outcome of reaction 'Off label use'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Fatal | ReactionOutcome | CC BY | 33655912 | 19,082,542 | 2021-03-05 |
What was the outcome of reaction 'Pneumonia aspiration'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Fatal | ReactionOutcome | CC BY | 33655912 | 19,495,214 | 2021-03-05 |
What was the outcome of reaction 'Respiratory failure'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Fatal | ReactionOutcome | CC BY | 33655912 | 19,495,214 | 2021-03-05 |
What was the outcome of reaction 'Vasculitis gastrointestinal'? | Begelomab for severe refractory dermatomyositis: A case report.
BACKGROUND
Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.
A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.
METHODS
Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.
METHODS
The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.
RESULTS
Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.
CONCLUSIONS
Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.
1 Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by skin lesions and skeletal muscle weakness.[1] A breakdown of immune-tolerance towards specific antigens, driven by a combination of environmental factors and genetic predisposition, leads to the perpetuation of tissue inflammation and damage. This may translate into clinically evident organ dysfunction. Depending on the tissue tropism of the inflammatory response, organs other than skin and muscles are affected. Vasculitis of the gastrointestinal tract has been described in juvenile DM patients,[2–4] while in adults is anecdotal.[5,6] Management of severe multi-organ forms of disease is arduous, and complete disease remission with currently available treatments is often unattainable.
T lymphocytes are key players in DM pathogenesis,[7,8] and vascular damage and insufficiency downstream their activation cause architectural and functional alterations in DM muscle tissue.[9] The signals involved in disrupting hometostasis of T cells in tissues of patients with DM are poorly characterized.[8,10–12] Dipeptidyl peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), is a candidate for such a role. It is a membrane glycoprotein endowed with enzymatic activity,[13,14] expressed by cells that play a direct or indirect role in the pathogenesis of DM including hematopoietc cells, endothelial cells and activated fibroblasts involved in wound healing.[15–20] It promotes effector T cell activation by sustaining selected signal transduction pathways[21] specifically promoting the clonal expansion of Th17 and Th1 cells,[22] known to have a role in IIM pathogenesis.[23–26] DPP-4/CD26high CD4+ T cells respond maximally to recall antigens, migrate to inflammatory tissues and efficiently activate B cells for antibody production.[16,27] In contrast, it is not or very poorly expressed by T regulatory cells.[28] Moreover, DPP-4/CD26 expression in different tissues influences glucose control and systemic inflammation.[20] Since DPP-4/CD26 is highly expressed on T cells that infiltrate the gut and skin, and its integrity is required for migration through the endothelial barrier, CD26 has represented a target for the treatment of graft versus host disease (GvHD) with monoclonal antibodies.[29] Here we verified that DPP-4/CD26 was indeed expressed in the skin and skeletal muscle of a patient with a severe life-threating DM characterized by multiple organ involvement and refractory to multiple conventional immunosuppressive therapies. The patient has benefitted from treatment with Begelomab, a murine immunoglobulin G (IgG) 2b monoclonal antibody against DPP-4/CD26.
2 Case presentation
We describe the case of a 55-year old man with a history of acute myocardial infarction causing secondary dilative cardiomyopathy, under statin treatment since the age of 41, with no family history for autoimmune diseases. He developed persisting low-grade fever, proximal symmetrical muscle weakness and a diffuse erythematous rash of chest, neck and upper back, as wells as violaceous papules at metacarpophalangeal and interphalangeal joints and other bony prominences. Few weeks later, swallowing difficulty, dysphonia and dyspnea due to oral cavity edema appeared, cutaneous lesions developed into ulcers, while muscle weakness became severe and disabling. Blood tests revealed increased creatine kinase levels (1085 U/L) and slightly elevated C-reactive protein concentration (7.7 mg/dl). Myositis-specific and -associated autoantibodies were negative. Muscle biopsy revealed myofiber necrosis, degeneration and regeneration of myofibers with variation in myofiber size, and perifascicular atrophy. Histopathological findings of skin biopsy comprised interface dermatitis with focal, granular deposits of IgG and complement component 3 at the dermo-epidermal junction. In light of the clinical presentation and the above mentioned diagnostic outcomes, the patient was diagnosed with DM. An oncological screening excluded the presence of malignancy. Statins were immediately discontinued. The patient started methylprednisolone 0.7 mg/Kg daily to be slowly tapered, and received intravenous immunoglobulins (IVIG, 2 g/Kg over 5 consecutive days) with clinical benefit. One month later, however, he experienced the abrupt onset of high-grade fever and incoercible abdominal pain. A computed tomography scan with oral contrast revealed jejunal perforation and an emergency laparotomy followed by segmental jejunal resection with latero-lateral anastomosis was performed. Multiple macroscopic ischemic lesions and ulcers were found intraoperatively within the intestinal mucosa, and the histopathological analysis indicated intestinal vasculitis. One week later the patient underwent a revision surgery because of anastomosis dehiscence and subsequent enteric fistula. After clinical stabilization, the patient was treated with pulses of glucocorticoids (over 3 consecutive days) and a cycle of IVIG 400 mg/kg. The therapy was continued with prednisone 10 mg and mycophenolate mofetil (MMF) 1 gr daily, which was increased progressively up to 3 gr daily over 3 weeks. Three months after MMF introduction, the clinical response was not satisfactory. Due to significant dysphagia, a percutaneous endoscopic gastrostomy had to be placed and muscle weakness was so debilitating that the patient needed a wheelchair. After 2 more months, while under MMF therapy, the patient experienced a further worsening of cutaneous lesions and the sudden onset of bloody diarrhea, requiring repeated blood transfusions. In-hospital diagnostics excluded an infectious etiology of intestinal symptoms and Rituximab (RTX) was administered. Unfortunately, enterococcal sepsis developed. Immunosuppressive treatment was thus interrupted and antibiotics initiated. At the end of antimicrobial therapy, due to the poor clinical response to RTX, MMF was reintroduced together with low-dose prednisone. Despite some improvement in intestinal symptoms, control of skin manifestations was not achieved and MMF was substituted with Tacrolimus (Fig. 1). In the following 2 months, the patient also received IVIG and RTX while continuing glucocorticoids, with no clinical benefit. Ulcerated skin lesions expanded in size and number, especially on the face, genitals and arms, and significant sarcopenia became evident. Tacrolimus was suspended and MMF reintroduced again. Two other cycles of IVIG were administered in the following 2 months. One month after the last IVIG administration, high-grade fever, extensive gastrointestinal bleeding and skin and mucosal ulcerations reappeared. In consideration of the inadequate response to multiple immunosuppressive regimens, we reasoned that an alternative strategy should be found. Given the clinical features of the patient, resembling cutaneous and intestinal involvement of GvHD, the skin and muscle biopsies were analyzed by immunocytochemistry and immunofluorescence for DPP-4/CD26 expression. The antigen was expressed in both tissues (Figs. 2 and 3).
Figure 1 Disease and treatments over time. Infectious events and temporary treatment suspensions due to surgery or infections are not depicted. ∗ At the dosage of 4 mg/m2 daily for 5 consecutive days. ∗∗ Two cycles were performed at a distance of 3 weeks one from the other: the first one between the onset of skin symptoms and ileal perforation, and the other soon after ileal resection. The second one included a maintenance regimen of 11 infusions (one infusion of 4 mg/m2 daily) every other day. DM = dermatomyositis, CRP = C reactive protein, GC = glucocorticoids, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, GI = gastrointestinal tract, TAC = tacrolimus.
Figure 2 CD26 expression in the skin. Skin was analyzed through immunohistochemistry for DPP-4/CD26 expression (brown). Infiltrating leucocytes and cells of the basal epidermal layer express the antigen (arrows).
Figure 3 CD26 expression in the skeletal muscle. Muscles from the patient (A) and a healthy control (B) were analyzed through Hematoxylin and eosin (H&E, left) and immunofluorescence (green color, right) for DPP-4/CD26 expression. DAPI (blue) was used to counterstain nuclei and laminin expression (red) to identify fiber boundaries. DPP-4/CD26 is preferentially expressed in the interstitial and perivascular spaces.
After extensive discussion of the pros and cons with the patient, Ethical Committee approval and patient's written informed consent, MMF was discontinued and the anti-DPP-4 monoclonal antibody Begelomab was intravenously administered at the dosage of 4 mg/m2 daily for 5 consecutive days. At the end of the 5-day cycle of Begelomab, erythematous rash and skin ulcers almost completely healed (Fig. 4), the bloody diarrhea ceased, and C-reactive protein levels normalized. After 2 months, the patient experienced a further flare with the reappearance of high-grade fever, bloody diarrhea, and skin ulcers. A new 5-day cycle of Begelomab at the dosage of 4 mg/m2 daily was eventually administered (3 months and a half from the previous one). One week later, ileal perforation was recognized and the patient underwent emergency laparotomy with ileal resection. The postoperative course was complicated by anastomosis dehiscence and Candida peritonitis. A revision surgery was performed and, after resolution of the septic event, due to the persistence of significant diarrhea, the patient was treated with IVIG and a new 5-day cycle of Begelomab 4 mg/m2 daily followed by maintenance therapy with Begelomab at the dosage of 4 mg/m2 every other day for additional eleven infusions (Fig. 1). The treatment accomplished a considerable clinical response few days after Begelomab initiation. Gastrointestinal symptoms resolved completely and skin ulcers healed. Although severe muscle weakness persisted, improvement in dysphagia allowed the patient to gradually start semi-solid oral feeding. In the follow-up period, no DM exacerbation occurred and the patient's quality of life improved dramatically (Fig. 1).
Figure 4 Cutaneous manifestations. Pictures of skin lesions before the first cycle of Begelomab (A) and skin soon after the end of the 5-day cycle of Begelomab (B).
Unfortunately, 2 months later, liver transaminase levels were found to be elevated at routine blood tests and an acute hepatitis C viral infection was diagnosed. Anti-viral therapy was soon initiated but the patient's general conditions progressively worsened until he died of respiratory failure following an episode of aspiration pneumonia.
3 Discussion
DM is a chronic relapsing-remitting disorder with great variability in disease phenotype. Clinical presentations range from amyopathic forms with exclusive cutaneous involvement to severe multi-organ dysfunction causing life-threatening complications.[30] Gastrointestinal vasculitis is a fearsome manifestation and should be always suspected in case of DM patients complaining of persistent diarrhea or abdominal pain.[31] Prompt recognition is crucial and treatment with immunosuppressive agents should be initiated as soon as infectious etiologies have been excluded, in order to avoid intestinal perforation. Cutaneous manifestations may also be disabling when ulcers and intense itching predominate. Despite physiotherapy, the immune-mediated damage of skeletal muscle often results in muscle atrophy and sarcopenia, with the co-existence of dysphagia when pharyngeal muscles are affected. Besides dramatically impacting on quality of life, DM clinical manifestations may represent a serious risk to life. An effective control of disease activity is critical.
Refractoriness to therapy is relatively common among patients with DM. Because of the lack of consensus guidelines for treatment in refractory cases, strategies for non-responders are based on largely empirical evidence, mostly from small case series and ongoing clinical trials.[32] Adequate management of severe cases represents a major medical challenge and may require surgical procedures which expose immunocompromised patients to a considerable infectious risk.[31] Also, the perioperative vacancy of immunosuppressive therapies may result in disease exacerbations.
The skin and muscle biopsies of the presented patient were studied for DPP-4/CD26 expression. Results guided the therapeutic choice to administer Begelomab to the patient through compassionate use in agreement with the patient and his family. Begelomab is a murine IgG2b monoclonal antibody against DPP-4/CD26, which upon binding to the molecule on activated T cells induces internalization of the DPP-4/CD26-Begelomab complex and inhibition of DPP-4/CD26-mediated immune mechanisms, ultimately leading to impaired expansion of auto-reactive T cells, key players in tissue damage occurring in DM.[13–16,21] Published data on the clinical use of Begelomab are limited to patients with acute GvHD and demonstrated encouraging efficacy with an acceptable safety profile.[29] In our patient, the clinical response was striking and above expectations. Begelomab induced clinical remission in our DM patient with the disappearance of cutaneous lesions, resolution of intestinal vasculitis, and improvement of dysphagia. Disease flares in the presented patient were sudden and rapidly progressive. Due to the lack of previous experience of Begelomab use in IIM, the interval between drug administrations was arbitrarily established based on the clinical picture. The ileal perforation observed soon after the second cycle of Begelomab presumably reflects a delay in drug administration when high disease activity had already caused irreversible intestinal damage. The subsequent cycle, performed after ileal resection, effectively reversed the DM flare with the resolution of both skin and gastrointestinal manifestations, suggesting that the immune response is efficiently switched off by Begelomab, whatever its degree of activation.
4 Conclusion
The patient had a very severe and refractory form of DM with relapsing intestinal vasculitis which underwent complete remission upon Begelomab therapy. This is the first described case of a patient with IIM treated with the anti-DPP-4 monoclonal antibody. This therapy was effective, suggesting that Begelomab might represent a novel promising agent for the treatment of refractory DM.
Acknowledgments
The authors wish to thank ADIENNE Pharma & Biotech for the kind provision of Begelomab.
Author contributions
Conceptualization: Rebecca De Lorenzo, Stefano Previtali, Patrizia Rovere-Querini.
Data curation: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali.
Investigation: Rebecca De Lorenzo, Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Patrizia Rovere-Querini.
Methodology: Stefano Tronci.
Resources: Rebecca De Lorenzo.
Supervision: Patrizia Rovere-Querini.
Writing – original draft: Rebecca De Lorenzo.
Writing – review & editing: Clara Sciorati, Antonella Monno, Silvia Cavalli, Francesco Bonomi, Stefano Tronci, Stefano Previtali, Patrizia Rovere-Querini.
Abbreviations: CD26 = cluster of differentiation 26, DM = dermatomyositis, DPP4 = dipeptidyl peptidase-4, GvHD = graft versus host disease, IgG = immunoglobulin G, IIM = idiopathic inflammatory myopathies, IVIG = intravenous immunoglobulins, MMF = mycophenolate mofetil, RTX = Rituximab.
How to cite this article: De Lorenzo R, Sciorati C, Monno A, Cavalli S, Bonomi F, Tronci S, Previtali S, Rovere-Querini P. Begelomab for severe refractory dermatomyositis: a case report. Medicine. 2021;100:9(e24372).
Written informed consent was obtained from the patient for publication of the case details and accompanying images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33655912 | 19,055,049 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood lactate dehydrogenase abnormal'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood lactic acid increased'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardio-respiratory arrest'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coma'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QRS complex prolonged'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Generalised tonic-clonic seizure'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemodynamic instability'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mental disorder'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mental status changes'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Status epilepticus'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular tachycardia'. | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | AMITRIPTYLINE | DrugsGivenReaction | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
What was the administration route of drug 'AMITRIPTYLINE'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Oral | DrugAdministrationRoute | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
What was the outcome of reaction 'Blood lactate dehydrogenase abnormal'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovering | ReactionOutcome | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
What was the outcome of reaction 'Blood lactic acid increased'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovering | ReactionOutcome | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
What was the outcome of reaction 'Cardio-respiratory arrest'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovered | ReactionOutcome | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
What was the outcome of reaction 'Electrocardiogram QRS complex prolonged'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovering | ReactionOutcome | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
What was the outcome of reaction 'Electrocardiogram QT prolonged'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovering | ReactionOutcome | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
What was the outcome of reaction 'Generalised tonic-clonic seizure'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovered | ReactionOutcome | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
What was the outcome of reaction 'Haemodynamic instability'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovered | ReactionOutcome | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
What was the outcome of reaction 'Mental disorder'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovered | ReactionOutcome | CC BY | 33655968 | 19,026,284 | 2021-03-05 |
What was the outcome of reaction 'Mental status changes'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovering | ReactionOutcome | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
What was the outcome of reaction 'Overdose'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovering | ReactionOutcome | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
What was the outcome of reaction 'Status epilepticus'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovering | ReactionOutcome | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
What was the outcome of reaction 'Ventricular tachycardia'? | Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: A case report and literature review.
BACKGROUND
Cardiotoxicity is a common cause of death in tricyclic antidepressant (TCA) intoxication. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is effective in critically ill poisoned patients who do not respond to conventional therapies, and targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors. However, few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM.
A 19-year-old Japanese man with a history of depression was brought to our hospital because he was in a comatose state with a generalized seizure. Before admission, he had taken an unknown amount of amitriptyline.
METHODS
After intubation, the electrocardiogram (ECG) displayed a wide QRS complex tachycardia, and the patient suffered from cardiovascular instability despite intravenous bolus of sodium bicarbonate. At 200 minutes after ingestion, he experienced a TCA-induced cardiac arrest.
METHODS
We initiated VA-ECMO 240 minutes after ingestion. The hemodynamic status stabilized, and the ECG abnormality improved gradually. In addition, we initiated targeted temperature management (TTM) with a target temperature of 34°C.
RESULTS
Twenty seven hours after starting the pump, the patient was weaned off the VA-ECMO. After completing the TTM, his mental status improved, and he was extubated on day 5. He was discharged on day 15 without neurological impairment, and the post-discharge course was uneventful.
CONCLUSIONS
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. Second, routine ECG screening during VA-ECMO support is useful for assessing the timing to wean off the VA-ECMO, as well as the degree of cardiotoxicity. Third, TTM is safe in comatose survivors of cardiac arrest caused by severe TCA intoxication.
1 Introduction
Tricyclic antidepressants (TCAs), including amitriptyline, are commonly used in the management of depression. However, overprescription or inappropriate use of TCAs can lead to coma and seizure. Large TCA overdoses are cardiotoxic, resulting in fatal arrhythmia and refractory hypotension, which is one of the most common causes of death in TCA intoxication.[1]
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-supporting procedure that can be considered for critically ill patients with refractory cardiogenic shock, pulmonary embolism, hypothermia, and cardiac arrest.[2] Specifically, VA-ECMO is effective in critically ill poisoned patients who do not respond to conventional therapies.[3] Targeted temperature management (TTM) is associated with improved neurological outcomes and mortality in comatose out-of-hospital cardiac arrest survivors.[4] However, only a few reports have documented cases of TCA intoxication that require intensive care, including VA-ECMO or TTM. Here, we report a case of amitriptyline intoxication. The patient, who had suffered cardiac arrest caused by the drug's cardiotoxicity, was successfully resuscitated using both VA-ECMO and TTM.
2 Case presentation
A 19-year-old Japanese man with a history of depression was brought to our hospital in a comatose state with a generalized seizure. His family had received a phone call from him, informing them that he had taken an unknown amount of amitriptyline. His family found the patient in an altered mental status with a seizure and called for an emergency medical service. On admission (150 minutes after ingestion), his initial body temperature, pulse rate, blood pressure, and SpO2 were 36.1°C, 86 bpm, 92/39 mm Hg, and 98%, respectively. He also presented a comatose status (Glasgow Coma Scale score 3; E1V1M1), along with generalized tonic-clonic seizure. Laboratory analysis detected a substantially elevated serum lactate level (>20 mmol/L). His urine test result was positive for TCA. The admission serum concentrations of amitriptyline and its active metabolite nortriptyline, 2902 ng/ml and 712 ng/ml, respectively, were measured at a later date.
His seizure stopped after intravenous administration of diazepam, and he was intubated because of his comatose status and generalized status epilepticus. After the intubation, he received an electrocardiogram (ECG), which displayed a wide QRS complex tachycardia and a prolonged QT interval (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms), and he suffered from cardiovascular instability. Despite synchronized cardioversion and an intravenous bolus of sodium bicarbonate (210 mEq), hemodynamically unstable refractory tachycardia persisted. Two hundred minutes after ingestion, his carotid artery was not palpated, and the ECG indicated polymorphic ventricular tachycardia (VT) and pulseless electric activity (Fig. 2B). Although he regained spontaneous circulation after 2 minutes of cardiopulmonary resuscitation, he had another cardiopulmonary arrest shortly afterward. The VA-ECMO procedure was initiated 240 minutes after ingestion based on the prediction that refractory arrhythmia and cardiac arrest could easily recur until the TCA-associated cardiotoxicity had disappeared. The VA-ECMO conditions were as follows: a 22 Fr drainage catheter passed from the right vein to the right atrium, and a 20 Fr arterial catheter was used for the left femoral artery. The pump was started at 2400 rpm, and the resulting blood flow was approximately 3.0 L/minute.
Figure 1 A 12-lead electrocardiogram of the case after intubation. It shows a wide QRS complex tachycardia and a prolonged QT interval (QRS complex duration, 234 ms; QTc (corrected QT) interval, 512 ms).
Figure 2 The electrocardiogram (lead II) time course of the case. (A) Recorded after intubation (the same as in Fig. 1). (B) Recorded at cardiac arrest: Indicates pulseless polymorphic ventricular tachycardia and pulseless electric activity. (C) Recorded shortly after starting the pump for VA-ECMO: Shows a ventricular tachycardia but no arterial pulse pressure. (D) Recorded 3 hours after starting the pump for VA-ECMO: Shows a normal QRS complex duration and a prolongation of the PQ and QT interval (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). (E) Recorded on day 2: Shows a normal PQ interval and a prolongation of the QT interval (PQ interval, 184 ms; QTc interval, 487 ms). (F) Recorded on day 4: Shows a normal QT interval (QTc interval, 429 ms).
After starting VA-ECMO, the patient's mean arterial pressure increased to 70 mm Hg without catecholamine use, but his arterial pulse pressure was not observed, and the ECG indicated a pulseless VT (Fig. 2C). His hemodynamic status stabilized on VA-ECMO. Three hours after initiating the pump for the VA-ECMO procedure, the patient regained his arterial pulse pressure (91/69 mm Hg without catecholamine), and the ECG returned to sinus rhythm with normalized QRS complex duration, although the prolongation of the PQ and QT interval remained (Figs. 2D and Fig. 3: QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms). The TTM was initiated with the VA-ECMO procedure using a target temperature of 34°C. Activated charcoal was administered via a nasogastric tube because it was predicted that he had ingested a large amitriptyline overdose that caused cardiotoxicity and even cardiac arrest.
Figure 3 A 12-lead electrocardiogram of the case 3 hours after starting the pump for VA-ECMO. QRS complex duration was normal; the abnormal ratio of the R and S waves in the lead aVR had disappeared; the PQ and QT intervals were still prolonged (QRS complex duration, 96 ms; PQ interval, 218 ms; QTc interval, 461 ms).
On day 2, the ECG did not show a recurrence of the ventricular arrhythmia and a prolongation of the PQ interval (Fig. 2E: PQ interval 184 ms, QTc interval 487 ms). Therefore, 27 hours after initiating the pump, the patient was weaned off the VA-ECMO. After the patient was weaned off the VA-ECMO, the temperature control method was changed to a surface cooling device. The targeted temperature was maintained at 34°C for 24 hours (including the temperature control period with VA-ECMO), followed by a gradual rewarming at 0.05°C/hour (Fig. 4). His hemodynamic status was stable after VA-ECMO weaning off, and the ECG displayed a normal sinus rhythm without a prolonged QT interval on day 4 (Figs. 2F and Fig. 5: QTc interval 429 ms). The TTM was completed after confirming that his body temperature was rewarmed to 36°C.
Figure 4 The clinical course of the case. The hemodynamic status stabilized after initiating the VA-ECMO pump, and ECMO was weaned off 27 hours after starting the pump. A target temperature of 34°C was maintained for 24 hours, followed by rewarming at a rate of 0.05°C/hour.
Figure 5 A 12-lead electrocardiogram of the case on day 4. QT interval was normalized (QTc interval 429 ms).
His mental status improved, and he was extubated on day 5. His general condition was good, and he moved to the psychiatric ward on day 8. He was discharged on day 15 without neurological impairment, and the postdischarge course was uneventful.
3 Discussion and conclusion
In this study, we report a case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO in combination with TTM. Although VA-ECMO and TTM are widely used in critical settings, only a few reports have documented cases of TCA intoxication that required intensive care, including VA-ECMO or TTM. We searched PubMed (up to November 2020) using the following terms: (“extracorporeal circulation” OR “extracorporeal membrane oxygenation” OR “percutaneous cardiopulmonary support”) AND (“tricyclic antidepressant”). We found 6 published cases of TCA intoxication (except for cases of polyintoxication) that required VA-ECMO support for cardiotoxicity, including the present case.[5–8] The mean age of these 6 cases was 22.7 years (range, 1–37 years). To our knowledge, this is the first reported case of TCA-induced cardiac arrest that was successfully resuscitated using VA-ECMO combined with TTM. Our case provides 3 important clinical insights as follows.
First, VA-ECMO is effective in patients with TCA-induced cardiac arrest. A previous report showed that intoxication accounts for an extremely small percentage of the causes of introducing VA-ECMO (50/5, 263 cases, 0.95%).[9] However, several reports have shown that VA-ECMO is a relatively safe therapeutic option and may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.[3,10] The most likely reason for this result is that the pathology of intoxication is generally reversible, and an improvement of the crisis situations is expected to occur by removing the causative substance. The first-line treatments for patients with hemodynamic instability or wide QRS complex due to TCA-induced cardiotoxicity include fluid resuscitation, sodium bicarbonate administration, vasopressor administration, and antiarrhythmic-agent administration.[11,12] VA-ECMO is considered in patients refractory to those interventions.[11–13] In all cases presented in Table 1, including this case, the serum concentration of ingested drugs exceeded the therapeutic range, suggesting that TCA-induced cardiotoxicity can easily occur. Moreover, all cases went into refractory shock and cardiac arrest despite adequate fluid resuscitation and sodium bicarbonate administration, and all cases were successfully weaned from VA-ECMO. If VA-ECMO is available, clinicians should consider its early initiation in patients refractory to conventional therapies.
Table 1 Case reports of TCA-induced cardiac arrest requiring VA-ECMO support[5–8].
Age/Sex Ingested drug Serum concentration of drug on arrival (ng/mL) Time from arrival to ECMO start (hours) Duration of ECMO support (hours) TTM CPC/OPC Reference
1 1, F Desipramine > 3,000 10.5 60 Not Stated 1, 1 [5]
2 37, F Imipramine Not measured 3.5 7 Not Stated 5, 5 [6]
3 26, F Nortriptyline 1,100 1.8 14 Not Stated 1, 1 [7]
4 32, F Imipramine Not measured 14 23 Not Stated 1, 1 [7]
5 21, M Amitriptyline 306.2 1.6 Not Stated 33°C, but discontinued 4, 4 [8]
6 19, M Amitriptyline 2,902 1.5 27 34°C for 24 hours 1, 1 This case
Second, routine ECG screening during VA-ECMO is useful to assess the timing for weaning off the VA-ECMO support, as well as the degree of cardiotoxicity. The following ECG findings suggest an increased risk of seizure and ventricular arrhythmia:
1. prolongation of the QRS complex (QRS complex duration >100 ms),
2. prolongation of QT interval (QTc interval > 430 ms), and
3. abnormal ratio of the R and S waves in lead aVR (R-to-S ratio >0.7).[11]
In our case, the ECG on admission met these 3 criteria (Figs. 1 and 2A: QRS complex duration, 234 ms; QTc interval, 512 ms; R-to-S ratio, 3.0), suggesting that the occurrence of cardiotoxicity led to ventricular arrhythmia and cardiac arrest despite intravenous bolus of sodium bicarbonate. However, the ECG obtained 3 hours after initiating the pump for VA-ECMO displayed only a prolongation of the QT interval, suggesting that the risk of seizure and ventricular arrhythmia had decreased. A prolongation of PQ was observed at that time, but it was normalized on day 2 before weaning off the VA-ECMO. Previous reports described that improving the prolongation of the QRS complex duration or the PQ/QT interval, as along with the stabilization of the hemodynamic status, are necessary for weaning off the VA-ECMO, although a clear criterion for weaning off has not been established.[5–7] Our case is consistent with previous reports, and routine ECG screening during VA-ECMO support will be a useful tool for determining the timing to wean off the VA-ECMO.
Third, TTM is safe in comatose survivors of cardiac arrest due to severe TCA intoxication. Potentially, TTM itself can aggravate the effect of amitriptyline by two mechanisms:
1. It affects the cardiac conducting system, resulting in a prolongation of the QT interval and the QRS complex duration,[14] and
2. it decreases the activity of CYP2D6 (cytochrome P450 2D6), which metabolizes amitriptyline and nortriptyline.[15,16]
However, 1 report found that TTM was safe in a patient with drug-induced cardiac arrest.[17] In this case, the target temperature was set at 33°C for 24 hours after resuscitation from cardiac arrest induced by amitriptyline and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and serious cardiac arrhythmia was not observed during therapeutic hypothermia. In the context of safety and efficacy, our case suggests that TTM represents a reasonable strategy for survivors of cardiac arrest caused by acute intoxication.
Acknowledgments
We thank all colleagues in the Emergency and Critical Care Center, Mie University Hospital (Drs. F. Okuno, R. Esumi, Y. Senga, T. Yamaguchi, T. Shinkai, A. Ito, D. Niimi, G. Miyamura, T. Kaneko, Y. Omori, M. Fujioka, and T. Takeda) for their assistance. We would like to thank Editage (www.editage.jp) for English language editing.
Author contributions
Conceptualization: Kaoru Ikejiri.
Supervision: Hiroshi Imai.
Writing – original draft: Kaoru Ikejiri.
Writing – review & editing: Yuichi Akama, Yohei Ieki, Eiji Kawamoto, Kei Suzuki, Kazuto Yokoyama, Ken Ishikura.
Abbreviations: ECG = electrocardiogram, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation.
How to cite this article: Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K, Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest: a case report and literature review. Medicine. 2021;100:9(e24980).
Approval of the study by our hospital's ethics committee was not required because it was a case report. Written informed consent was obtained from the patient and his parents for publication of this case report.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
CPC = cerebral performance categories, OPC = overall performance categories, TCA = tricyclic antidepressant, TTM = targeted temperature management, VA-ECMO = veno-arterial extracorporeal membrane oxygenation. | Recovering | ReactionOutcome | CC BY | 33655968 | 19,094,331 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | CARBAMAZEPINE, IRBESARTAN, TACROLIMUS, VALPROATE SODIUM | DrugsGivenReaction | CC BY | 33655969 | 19,078,405 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | CARBAMAZEPINE, TACROLIMUS, VALPROIC ACID | DrugsGivenReaction | CC BY | 33655969 | 19,069,043 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug level fluctuating'. | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | CARBAMAZEPINE, IRBESARTAN, TACROLIMUS, VALPROATE SODIUM | DrugsGivenReaction | CC BY | 33655969 | 19,078,405 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Generalised tonic-clonic seizure'. | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | TACROLIMUS | DrugsGivenReaction | CC BY | 33655969 | 19,388,842 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immunosuppressant drug level decreased'. | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | CARBAMAZEPINE, TACROLIMUS | DrugsGivenReaction | CC BY | 33655969 | 19,007,616 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | CARBAMAZEPINE, IRBESARTAN, TACROLIMUS, VALPROATE SODIUM | DrugsGivenReaction | CC BY | 33655969 | 19,078,405 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | CARBAMAZEPINE, TACROLIMUS | DrugsGivenReaction | CC BY | 33655969 | 19,007,616 | 2021-03-05 |
What was the dosage of drug 'VALPROIC ACID'? | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | .25 g (grams). | DrugDosage | CC BY | 33655969 | 19,010,883 | 2021-03-05 |
What was the outcome of reaction 'Condition aggravated'? | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | Recovered | ReactionOutcome | CC BY | 33655969 | 19,078,405 | 2021-03-05 |
What was the outcome of reaction 'Drug ineffective'? | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | Recovered | ReactionOutcome | CC BY | 33655969 | 19,069,043 | 2021-03-05 |
What was the outcome of reaction 'Drug interaction'? | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | Recovered | ReactionOutcome | CC BY | 33655969 | 19,069,043 | 2021-03-05 |
What was the outcome of reaction 'Epilepsy'? | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | Recovered | ReactionOutcome | CC BY | 33655969 | 19,007,616 | 2021-03-05 |
What was the outcome of reaction 'Immunosuppressant drug level decreased'? | Tacrolimus-induced epilepsy with primary membranous nephropathy: A case report.
BACKGROUND
Tacrolimus-associated neurologic disorders can be found in some cases, mainly in organ transplantation patients. However, epilepsy induced by tacrolimus in primary membranous nephropathy (PMN) patient is scare.
A 63-year-old man experienced 1-year history of foamy urine, and edema of lower extremity.
METHODS
The patient had proteinuria, hypoalbuminemia, which indicated nephrotic syndrome. Further, we performed renal biopsy for this patient. Combined with the renal biopsy result, the diagnosis of primary membranous nephropathy was established.
METHODS
At first, irbesartan was administrated for 6 months. However, the proteinuria had no obvious improvement. Tacrolimus was administrated afterwards.
RESULTS
Twenty-two days after tacrolimus treatment, epilepsy occurred. Sodium valproate and carbamazepine were successively given to control epilepsy. However, the epileptic symptoms were not effectively controlled. During the treatment, the concentration of tacrolimus fluctuated greatly. At last, levetiracetam was given to maintain the curative effect. Fortunately, the patient did not suffer from epilepsy again. The concentration of temporary tacrolimus was stable, whereas proteinuria gradually decreased.
CONCLUSIONS
Tacrolimus-induced epilepsy should be considered in patients exhibiting acute neurological symptoms. Early diagnosis and effective treatment play a vital role for favorable prognosis.
1 Introduction
Primary membranous nephropathy (PMN) is an immune-mediated cause of nephrotic syndrome. In 2009, Beck et al[1] found M-type phospholipase A2 receptor (PLA2R) was colocalization with IgG in glomeruli of PMN. PLA2R-antibodies (Abs) can be detected in serum of 70% of PMN patients. In 2014, Tomas et al[2] discovered 8% to 14% PMN patients with thrombospondin Type I domain-containing 7A (THSD7A) antibody positive, whereas with negative PLA2R-Ab in serum. Because spontaneous remission is relatively common in PMN and immunosuppressive treatment has adverse effects, it is important to assess the risk of progressive loss of kidney function prior to determine whether and when to implement immunosuppressive treatment. When patients present with deteriorating renal function, rituximab, cyclophosphamide or calcineurin inhibitors such as cyclosporine and tacrolimus may be considered for immediate immunosuppressive therapy.[3]
KDIGO guideline in 2020 and other literatures have indicated that tacrolimus is safe and effective for patients with PMN. However, in clinical practice, common adverse events following tacrolimus such as gastrointestinal disorders, endocrine abnormalities, infection, and hematological abnormalities can occur. Occasionally, tacrolimus-associated neurologic disorders, including common confusion, somnolence, cortical blindness, epilepsy, uncommon coma, could be found in some organ transplantation cases.[4–6] Herein, we report a rare case of epilepsy induced by concentration fluctuations of tacrolimus in a PMN patient, who was recovered after therapy with levetiracetam. To the best of our knowledge, this is the first case report that tacrolimus-induced epilepsy occurred in a patient with PMN.
2 Case report
A 63-year-old man presented to our hospital with 1-year history of foamy urine, and edema of lower extremity in May 2019. He had a history of hypertension for 2 years, chronic atrial fibrillation for 1 year, and cerebral infarction for 3 months. On examination, his blood pressure was 120/80 mm Hg, accompanying with atrial fibrillation rhythm, limb disorders after cerebral infarction, left side deviation, and edema of both lower limbs.
Urinalysis test showed proteinuria levels of 1.56 to 2.7 g/24 h. Biochemistry analysis revealed the level of serum albumin of 29.1 g/L, and serum creatinine level of 89 μmol/L. The abdominal ultrasound, anti-neutrophil cytoplasmic antibodies, anti-GBM antibody, antinuclear antibody, viral hepatitis, and tumor markers were all normal. Interestingly, anti-PLA2R antibody was at high level (110.41 RU/mL). We performed renal biopsy for further diagnosis. Prominent granular deposition of IgG was found along the glomerular capillary by immunofluorescence patterns. The light microscopy demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. The electron microscopy displayed abundant subepithelial deposits with intervening GBM “spikes” (Fig. 1). Eventually, PMN was diagnosed.
Figure 1 The pathological results of kidney biopsy. (A) Immunofluorescence showed immunoglobin G (IgG) deposited along the glomerular capillary. (B) Periodic Acid-Schiff (PAS) and (C) Periodic Acid-Silver Metheramine (PASM) staining demonstrated discrete subepithelial “spike” formation along all of the glomerular capillaries in this patient. (D) The electron microscopy displayed abundant subepithelial deposits with intervening glomerular basement membrane (GBM) “spikes” (red arrow).
At first, irbesartan was administrated for 6 months. However, proteinuria and serum albumin had no obvious improvement. On December 24, 2019, tacrolimus (1 mg bid) was administrated. Twenty-two days after tacrolimus treatment, he was admitted to the emergency room. His symptoms were a sudden numbness in his left upper limb, disturbance of consciousness, convulsions in his limbs, and rolling up of his eyes, which lasted for about 10 minutes and then recovered. The magnetic resonance imaging (MRI) disclosed multiple lacunar cerebral infarction with the right temporal and occipital lobe softened lesion formation, leukoaraiosis, and brain atrophy. Electroencephalogram showed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance (Fig. 2). He was diagnosed as symptomatic epilepsy, then sodium valproate was administrated (0.25 g bid), combined with tacrolimus. In the next 2 days, the patient had complete reversal of neurological symptoms. However, on April 3, 2020, the patient developed epilepsy again. Although the concentration of sodium valproate was normal, which was 128.1 μg/mL (50–100). Carbamazepine (0.2 g bid) was chosen instead of sodium valproate. Unfortunately, on April 21, 2020, epilepsy occurred again. We tested the concentration of carbamazepine, which was also in a normal range (6.2 μg/mL).
Figure 2 Electroencephalogram revealed diffuse β fast wave activity, with some Q wave activity and some eye movement disturbance.
Why did this patient suffer from epilepsy again and again under the antiepileptic drug treatment? According to the epilepsy manifestations of patient, neurologist concluded that location diagnosis of epilepsy originated from brainstem reticular structure, thalamus or cerebral cortex, and qualitative diagnosis attributed to vascular injury. Considering the common inducers of epilepsy without new cerebral infarction, abnormal electrolyte, the administration of tacrolimus was suspected. According to previous studies,[7,8] 2 factors might contribute to tacrolimus induced epilepsy higher plasma levels of tacrolimus; the fluctuations of tacrolimus concentration. Firstly, we tested CYP3A5 gene for tacrolimus. Tacrolimus is metabolized by CYP3A5, and its gene polymorphism is an important factor affecting the plasma concentration. The result showed the gene type of CYP3A5 for this patient was AG, which indicated that tacrolimus was intermediate metabolic type. Consequently, we found that tacrolimus concentrations fluctuated greatly from January 7 to April 24. However, it was unclear what caused the fluctuation. We further analyzed the drug interactions to identify possible reasons.
Carbamazepine is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus (the concentrations of tacrolimus were showed in Fig. 3). Levetiracetam (0.5 g, q12 h) was administered in April 2020, instead of carbamazepine. The drug has a weak interference on cytochrome P450 enzyme, and hardly affects the plasma concentration of tacrolimus. Up to June 2020, the plasma concentration of tacrolimus was 7.8 to 8.6 ng/mL, and fortunately, the patient had not suffered from epilepsy again. The proteinuria gradually decreased (Fig. 3).
Figure 3 The concentration of tacrolimus and the change of 24 hours urine protein levels for this patient.
3 Discussion
Herein, we reported a 63-year-old man who received tacrolimus with PMN. Tacrolimus-induced epilepsy was diagnosed by electroencephalography and clinical symptoms. After the patient was treated with levetiracetam, the plasma concentration of tacrolimus was maintained normally, epilepsy never occurred to this patient.
Immunosuppressants such as cyclosporine A, cyclophosphamide, and tacrolimus have been widely used in PMN.[3] Tacrolimus gradually becomes the first-line therapy among them. However, in recent years, some cases have reported tacrolimus could induce seizures after organ transplant.[4] The prevalence of neurotoxicity induced by calcineurin inhibitor ranges from 10% to 33% among organ transplant recipients.[5,6] Among these neurologic complications, seizures have been reported abort 5% to 10% in transplant patient.[9] In 2019, Li et al[10] reported 2 cases occurred acute symptomatic seizure triggered by tacrolimus after liver transplantation. However, studies about tacrolimus induced epilepsy with nephropathy are scare. In 2004, Loeffler et al[11] reported 16 children received tacrolimus with resistant nephrotic syndrome. They only found 1 patient had a 2-minute generalized tonic-clonic seizure accident after taking tacrolimus for 1 month, who did not need anticonvulsant therapy. In this case, we reported a patient occurred tacrolimus induced epilepsy with PMN with long-term anticonvulsant. This might be due to the patient's older age and cerebrovascular disease.
The exact mechanism on neurotoxicity of calcineurin inhibitors (CNIs) remained unclear. One possible hypothesis is that CNIs may be mediated by upregulating endothelin receptors, damaging blood-brain barrier, and interacting with neuromodulatory systems. An alternative hypothesis is that long term application of CNIs might impair cerebral mitochondrial energy metabolism, leading to neurodegeneration and cognitive impairment. What's more, Zhang et al[12] has found that the complex of CNIs and immunophilins might be related with neurotoxicity. In addition, vasculopathy may also be included in CNI-induced neurotoxicity.[12]
One study in rats found that the threshold tacrolimus concentration in the brain triggering neurotoxic events was approximately 700 ng/g, whereas for the whole blood as 20 ng/mL in rats.[7] What is more, Lyson et al[13] demonstrated that tacrolimus-binding protein, calmodulin, and cyclophilic protein were distributed in most brain tissue, and they further confirmed that sympathetic activation which induced by FK-506 associated with calcineurin-mediated inhibition of T-cell signaling in brain. All the evidence suggests that the concentration of tacrolimus in the brain may determine the occurrence of encephalopathy. Further studies have found that encephalopathy symptoms in patients are related with high blood levels of tacrolimus,[7–8] but can also be happened in those with concentration in therapeutic range.[14] The patient in our case had the history of cerebral infarction, hypertension, and volatility of tacrolimus concentration, which maybe cause him to be more susceptible to encephalopathy.
Apart from the case like ours, many studies have found that immunosuppressants can induce reversible posterior leucoencephalopathy syndrome (RPES), which was first reported in 1996.[15] The major clinical manifestations of RPES are headaches, an altered mental status, and seizures with typical imaging changes.[16] One case reported a female patient who received tacrolimus as an immunosuppressive regimen after kidney transplantation. Five weeks after transplantation, she was admitted to the emergency due to RPES, manifested by sudden onset of confusion, disorientation, visual disturbances, and major headache.[17] Another case-control study, including 51 patients receiving tacrolimus, cyclosporine or prednisolone owing to nephrotic syndrome, of these 21 with RPES and 30 without, found that hypertension, proteinuria, hypercholesterolemia, and lower serum albumin levels were more common in RPES patients.[18] Our patient also had these risk factors, but not clear whether is caused by RPES. RPES has classic imaging findings of presence of edema of the gray and white matter in posterior brain, and it can be complete recovery. However, after 4 months follow-up, compared with his cerebral MRI in January 2020, the MRI did not recover.
In our case, the epilepsy was discontinued with levetiracetam instead of other antiepileptic drugs, such as sodium valproate and carbamazepine. Pharmacologically, the effect of sodium valproate is related to its concentration in brain. The possible mechanism is to enhance the inhibitory effect of γ-aminobutyric acid (GABA) by affecting the synthesis or metabolism of GABA.[19] Initially, the patient was treated with sodium valproate, but symptoms were not controlled. This might be due to poor blood brain barrier penetration of sodium valproate, therefore limited its efficacy in epilepsy. Carbamazepine may limit the release of presynaptic and postsynaptic neuronal action potentials by increasing the efficacy of sodium channel inactivation, limiting postsynaptic neurons and blocking presynaptic sodium channels, blocking the release of excitatory neurotransmitters and reducing neuronal excitability.[20] However, it is a CYP3A4 liver enzyme inducer, which can reduce the concentration of tacrolimus. Levetiracetam has a weak interference on cytochrome P450 enzyme, and hardly affects the blood concentration of tacrolimus. At last, this drug was used to control epilepsy, and follow-up for 4 months, the epilepsy never occurred.
4 Conclusion
In summary, we report a case of tacrolimus-induced epilepsy with PMN, which emphasizes that history of cerebral vascular injury, hypertension, hypoproteinemia, and interacting drugs might contribute to the development of epilepsy with tacrolimus administration in these patients.
Acknowledgment
The authors thank Jie Zhang for English language editing. Jie Zhang is a PhD student at Aarhus University. She received her master of medicine (equivalent to MD degree) at Fudan University and master of public health degree at Brown University.
Author contributions
Data curation: Rong Ren.
Methodology: Ying Mo.
Project administration: Fengmei Wang.
Writing – original draft: Yan Yang.
Writing – review & editing: Lei Zhang, Fengmei Wang.
Abbreviations: CNI = calcineurin inhibitors, GABA = γ-aminobutyric acid, MRI = magnetic resonance imaging, PLA2R = phospholipase A2 receptor, PMN = primary membranous nephropathy, RPES = reversible posterior leucoencephalopathy syndrome, THSD7A = thrombospondin Type I domain-containing 7A antibody.
How to cite this article: Yang Y, Zhang L, Mo Y, Ren R, Wang F. Tacrolimus-induced epilepsy with primary membranous nephropathy: a case report. Medicine. 2021;100:9(e24989).
YY and LZ have contributed equally to this work.
Statement of Ethics: There was no research involving animal participants. Patient had provided informed consent for publication of the case.
This work was supported by grants from National Natural Science Foundation of China (No. 81400704, 82060132), Science and Technology Assistance Project of Science and Technology Department of Xinjiang Autonomous Region (No. 2020E0276).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available. | Recovered | ReactionOutcome | CC BY | 33655969 | 19,007,616 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebrovascular accident'. | Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: A nationwide retrospective cohort study.
Type 2 diabetes mellitus (T2DM) is a progressive disease. After metformin failure, the addition of insulin or sulfonylureas might increase the risk of hypoglycemia and cardiovascular (CV) morbidity. Here, the risk of all-cause mortality was compared between early insulin treatment and glimepiride use in T2DM patients with background metformin therapy.We conducted a 9-year retrospective cohort study from the population-based National Health Insurance Research Database in Taiwan. A total of 2054 patients with T2DM under insulin or glimepiride treatment were enrolled during 2004 to 2012. Overall event rates of all-cause mortality were compared between 1027 insulin users and 1027 matched glimepiride users.After the propensity score matching, the mortality rates were 72.5 and 4.42 per 1000 person-years for insulin users and glimepiride users. The adjusted hazard ratio of mortality was 14.47 (95% CI: 8.64-24.24; P value <.001) as insulin compared with glimepiride users. The insulin users had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65-38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4-26.3, P < .001).The nationwide study demonstrated that metformin plus insulin therapy was associated with higher risk of all-cause mortality.
1 Introduction
Type 2 diabetes mellitus had the property of progressive β-cell failure. Upon diagnosis of diabetes, most patients were found to have a 50% decrease in their insulin secretion with a relentless 4% decline per year.[1] At last, most patients would require insulin treatment, alone or in combination with oral hypoglycemic agents.[2] United Kingdom Prospective Diabetes Study (UKPDS) suggested that earlier initiation of treatment was associated with better outcome.[3] There were also some reports which demonstrated that early intensive insulin treatment of hyperglycemia had favorable outcomes on recovery and maintenance of β-cell function with lengthened glycemic remission as compared with treatments of oral hypoglycemic agents.[4–6] The epidemiological studies disclosed that Asian diabetic patients had the characteristics of declining β-cell function more sharply than insulin sensitivity with age and rapid oral drug failure[7]; therefore the promotion of early insulin treatment in Asian patients was reasonable.
The UKPDS study[8] disclosed that intensive therapy with insulin or sulfonylureas (SU) had similar effect. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes and cancer occurrence.[9] But Holden et al[10] reported 6484 T2DM patients who progressed to treatment with insulin monotherapy, the adjusted hazard ratio (aHR) in relation to 1-unit increases in insulin dose was 1.54 for all-cause mortality and 1.35 for cancer. A retrospective cohort study of 63,579 diabetic patients treated in general practice disclosed that the aHR of association with serious atherosclerotic vascular disease of the heart was 1.3 for insulin.[11] One report from the Euro Heart Survey on Diabetes and the Heart disclosed that insulin therapy might relate to a more serious prognosis in patients with coronary artery disease (CAD) and diabetes.[12]
Sulfonylureas were prescribed in very large quantities due to their low cost and rapid lowering of glucose level. In recent years, there were always debates on the detrimental effect of SU in diabetic patients, including its possible CV morbidity and mortality;[13,14] some studies suggested avoiding the use of SU in diabetes treatment, especially after insulin initiation.[15] Both insulin and SU had the propensities of hypoglycemia, body weight increase and possibly CV injury. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications (including SU) vs no diabetes medications, and found that the insulin plus oral medications group had higher risk of getting CV events (odds ratio = 2.56). Currie et al[17] compared insulin based regimens with metformin plus SU, and found that the hazard ratio for all-cause mortality in people given insulin-based regimens vs those given combined oral agents was 1.49. Though, there were some reports implying the benefits of early insulin therapy, but these were all short-term clinical studies without long-term outcomes.[18] Many observational studies have also indicated that insulin therapy is more risky than oral hypoglycemic agents.[10–12,16,17] And there are currently few risk comparisons of using insulin vs sulfonylurea after metformin use. Therefore, we conducted this cohort study to see the risks of all-cause mortality between insulin and glimepiride use in T2DM patients with background metformin therapy.
2 Materials and methods
2.1 Data source
NHIRD contained the medical data of National Health Insurance (NHI), which had been implemented since March 1995, and over 99% of Taiwan residents had joined the NHI.[19] We used the data from Longitudinal Health Insurance database 2000 (LHID2000), a sub-dataset of NHIRD. The LHID2000 recorded the medical care data of 1 million people. The demographics of the LHID2000 were similar to the whole Taiwan population. In the LHID2000, the medical information included encrypted identification, demographics, the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes, surgery records and drug records.
2.2 Study design
Using the National Health Insurance Research Database (NHIRD), we investigated the difference of diabetes treatments in this population-based cohort study. We compared the adults of aged 18 to 100 years with metformin plus insulin vs metformin plus glimepiride therapy. Our study was approved by the Research Ethics Committee of China Medical University and Hospital, Taichung, Taiwan (CMUH104-REC2–115 (CR-2)). Our research was granted a waiver of informed consent. The information and records of patients were de-identified prior to analysis and encrypted the identification of each participant.
2.3 Study population
The study population consisted of diabetic patients (ICD-9-CM: 250.x) with metformin treatment excluding type 1 diabetic patients (250.1x). We categorized diabetic patients as insulin cohort or glimepiride cohort with underlying metformin treatment in 2004 to 2012 years. The insulin cohort contained type 2 diabetic patients with metfomin plus insulin treatment and exlcuded all concurrent sulfonylureas users. The glimepiride cohort contained type 2 diabetic patients with metfomin plus glimepiride treatmen. The index date was the time of receiving insulin or glimepiride.
2.4 Identification of confounders
The demographics of gender and age were confounders of this study. Baseline comorbidity was defined as having following diseases before the index date: coronary artery disease (ICD-9-CM: 410–414), stroke (ICD-9-CM: 430–438), hypertension (ICD-9-CM: 401–405), and dyslipidemia (ICD-9-CM: 272). We used the Charlson Comorbidity Index (CCI) to quantify patients’ comorbidity profiles.[20] We defined the severity of diabetes according to Diabetes Complications Severity Index (DCSI) score.[21] The CCI and DCSI scores were calculated using participant status 1 year before the index date. We also considered other drugs for diabetes such as thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) as possible confounders.
2.5 The primary outcome and causes of death
The primary outcome of this study was all- cause mortality. The observation period started from the index date to the withdrawal from the NHI or 31st December, 2013 or the date of death, whichever came first. We assessed the last primary diagnosis of discharge 3 months before death, to search for the causes of death.[22] The causes of CV death were according to the Standardized Definitions for End Point Events in Cardiovascular Trials.[23] Death due to other causes was defined as noncardiovascular death. The cases that we could not get last primary diagnosis 3 months before death were defined as undetermined.
2.6 Statistical methods
To match the insulin cohort and glimepiride cohort, we performed 1:1 propensity score matching[24] with the criteria of age, gender, comorbidities, CCI scores, DCSI scores and other antidiabetic drugs use. We summarized the variables in insulin and glimepiride cohorts, and compared those between 2 groups using Chi-Squared test for dichotomous variables and two-sample Student t test for continuous variables. In this study, we used simple and multivariable Cox proportional hazards regression models to estimate the excess risk of all-cause mortality for the insulin cohort compared to the glimepiride cohort. We calculated the crude and adjusted HR with corresponding 95% confidence intervals (95% CIs). The multivariable Cox proportional hazards regression models were done under the control of age, gender, comorbidities, other antidiabetic drugs, CCI and DCSI scores. The stratified analysis of each variable using Cox proportional hazards regression model was conducted in the outcome of mortality. The cumulative incidences of survival rate of each cohort were estimated using Kaplan–Meier method and examined by log-rank test.
All statistical analyses were conducted by the statistical software package, SAS, version 9.4 (SAS Institute, Inc., Cary, NC). P value less than .05 was the threshold of statistical significance in our study.
3 Results
From the data file of 2000 to 2012 years of LHID2000 (Fig. 1), there were 1798 patients injected insulin without using sulfonyureas and 6138 were treated with glimepiride with background metformin therapy. After excluding and matching, we enrolled 1027 diabetic patients in insulin and glimepiride cohorts, respectively. The mean (median) follow-up duration was 4.47 (3.16) and 4.72 (3.06) years for metformin plus insulin group and metformin plus glimepiride group. Men comprised 54.2% in the insulin group, and 55% in the glimepiride group (Table 1). Patients over 65 years old had the highest proportion in insulin cohort (49.4%), but a greater proportion was found in patients between 41 and 65 years old in the glimepiride cohort (48.7%). Between the 2 groups, only the distribution of age classification was notably different (P value = .011), there was no significant difference in mean age between the 2 populations (P value = .29).
Figure 1 The flow chart that identified the number of patients and study design.
Table 1 Demographic characteristics and co-morbidity of insulin group and glimepiride group in diabetic patients with background metformin therapy.
Glimepiride (N = 1027) Insulin (N = 1027)
n (%) n (%) P value
Gender .72∗
Women 462 (45) 470 (45.8)
Men 565 (55) 557 (54.2)
Age, years .011∗
≤40 37 (3.6) 63 (6.1)
41–65 500 (48.7) 457 (44.5)
>65 490 (47.7) 507 (49.4)
Mean (SD) 63.5 (12.5) 64.2 (14.6) .29†
Baseline comorbidity
Coronary artery disease 431 (42) 423 (41.2) .72∗
Stroke 337 (32.8) 311 (30.3) .22∗
Hypertension 746 (72.6) 752 (73.2) .77∗
Dyslipidemia 654 (63.7) 649 (63.2) .82∗
CCI scores .24∗
0, 1 346 (33.7) 381 (37.1)
2, 3 407 (39.6) 378 (36.8)
>3 274 (26.7) 268 (26.1)
DSCI scores .59∗
0 703 (68.5) 683 (66.5)
1 229 (22.3) 238 (23.2)
≥2 95 (9.3) 106 (10.3)
DM drugs
TZDs 117 (11.4) 107 (10.4) .48∗
Alpha glucosidase inhibitors 260 (25.3) 239 (23.3) .28∗
DPP-4i 208 (20.3) 197 (19.2) .54∗
Mean DM duration, days (medium) 1724 (1106) 1630 (1152)
The mortality risk was higher by 14.19-fold in the insulin cohort, as compared with the glimepiride cohort (95% CI = 8.48–23.75, P value < .001; Table 2). The gender of male also had higher risk of mortality (men aHR = 1.47, 95% CI = 1.09–1.99, P value = .01). Diabetic patients using alpha-glucosidase inhibitors or DPP-4i had lower risk of mortality (alpha-glucosidase inhibitors aHR = 0.54, 95% CI = 0.34–0.84, P value = .01; DPP-4i aHR = 0.26, 95% CI = 0.13–0.52, P value <.001).
Table 2 Cox model measured hazard ratio and 95% confidence intervals of death associated treatment groups and covariates in diabetic patients with background metformin therapy.
Event no. Crude Adjusted
Characteristics (n = 182) HR (95% CI) P value HR (95% CI) P value
Treatment
Glimepiride 16 1 reference 1 reference
Insulin 166 13.33 (7.97–22.28) <.001 14.19 (8.48–23.75) <.001
Gender
Women 73 1 reference 1 reference
Men 109 1.27 (0.95–1.71) .11 1.47 (1.09–1.99) .01
Age, years
≤40 7 1 reference 1 reference
41–65 50 0.74 (0.34–1.64) .47 0.78 (0.35–1.78) .56
>65 125 1.97 (0.92–4.22) .08 1.73 (0.76–3.95) .19
Baseline comorbidity
Coronary artery disease
No 92 1 reference 1 reference
Yes 90 1.43 (1.07–1.91) .02 1.1 (0.79–1.54) .56
Stroke
No 114 1 reference 1 reference
Yes 68 1.34 (0.99–1.81) .06 1.08 (0.79–1.48) .64
Hypertension
No 32 1 reference 1 reference
Yes 150 1.8 (1.23–2.63) .003 1.33 (0.87–2.03) .19
Dyslipidemia
No 76 1 reference 1 reference
Yes 106 0.79 (0.59–1.06) .11 0.73 (0.53–0.99) .05
CCI scores
0, 1 50 1 reference 1 reference
2, 3 73 1.38 (0.96–1.98) .08 1.29 (0.88–1.87) .19
>3 59 1.66 (1.14–2.42) .01 1.37 (0.91–2.07) .14
DSCI scores
0 116 1 reference 1 reference
1 46 1.21 (0.86–1.7) .28 0.92 (0.63–1.34) .67
≥2 20 1.17 (0.73–1.88) .52 0.66 (0.39–1.11) .11
DM drugs
TZDs
No 172 1 reference 1 reference
Yes 10 0.43 (0.23–0.81) .01 0.75 (0.39–1.43) .38
AGIs
No 159 1 reference 1 reference
Yes 23 0.43 (0.28–0.66) <.001 0.54 (0.34–0.84) .01
DPP-4i
No 173 1 reference 1 reference
Yes 9 0.19 (0.1–0.37) <.001 0.26 (0.13–0.52) <.001
The overall mortality rates in insulin and glimepiride cohort were 72.5 and 4.42 per 1000 person-years (Table 3). During the study period, the cumulative survival rate among insulin cohort was significantly lower than the cumulative survival rate among glimepiride cohort (P value <.001; Fig. 2). Table 3 showed the subgroup analysis of mortality of metformin plus insulin vs metform plus glimepiride. Notably, metfomin plus insulin had higher risk of mortlity among all the subgroups of genders, age, comorbidites, CCI scores DCSI scores, and other DM drugs use.
Table 3 Cox model of measured hazard ratio and 95% confidence intervals of mortality between insulin group and glimepiride group with background metformin therapy and covariates.
Metformin Insulin vs glimepiride
Glimepiride (n = 1027) Insulin (n = 1027)
Variables Event Person years IR† Event Person years IR† Crude HR (95% CI) Adjusted HR (95% CI)
Overall 16 3623 4.42 166 2290 72.5 13.33 (7.97–22.28)∗∗∗ 14.47 (8.64–24.24)∗∗∗
Gender
Women 3 1664 1.8 70 1097 63.8 29.03 (9.13–92.24)∗∗∗ 31.36 (9.83–100.05)∗∗∗
Men 13 1959 6.64 96 1193 80.4 9.7 (5.43–17.33)∗∗∗ 10.91 (6.08–19.57)∗∗∗
Age, years
≤40 0 148 0 7 163 43.0 20291126.21 (0-.) 128397943.32 (0-.)
41–65 2 1818 1.1 48 1179 40.7 30.03 (7.3–123.57)∗∗∗ 30.4 (7.37–125.34)∗∗∗
>65 14 1658 8.44 111 949 117 11.18 (6.4–19.52)∗∗∗ 11.88 (6.78–20.82)∗∗∗
Comorbidity
Coronary artery disease
No 6 2202 2.72 86 1398 61.5 17.78 (7.77–40.72)∗∗∗ 18.62 (8.11–42.75)∗∗∗
Yes 10 1421 7.04 80 892 89.7 10.68 (5.53–20.63)∗∗∗ 12.96 (6.65–25.24)∗∗∗
Stroke
No 7 2468 2.84 107 1663 64.4 18.18 (8.46–39.09)∗∗∗ 19.25 (8.94–41.44)∗∗∗
Yes 9 1155 7.79 59 627 94.0 10.16 (5.02–20.55)∗∗∗ 11.11 (5.43–22.74)∗∗∗
Hypertension
No 1 1011 0.99 31 660 46.9 38.09 (5.2–279.31)∗∗∗ 37.16 (5.05–273.56)∗∗∗
Yes 15 2612 5.74 135 1630 82.8 11.74 (6.88–20.03)∗∗∗ 12.79 (7.48–21.87)∗∗∗
Dyslipidemia
No 7 1396 5.01 69 794 86.9 13.38 (6.14–29.17)∗∗∗ 14.54 (6.6–32.02)∗∗∗
Yes 9 2227 4.04 97 1497 64.8 13.4 (6.77–26.55)∗∗∗ 14.77 (7.44–29.35)∗∗∗
CCI scores
0, 1 2 1302 1.54 48 938 51.2 26.68 (6.48–109.87)∗∗∗ 24.55 (5.93–101.6)∗∗∗
2, 3 5 1433 3.49 68 820 82.9 19.17 (7.72–47.6)∗∗∗ 21.04 (8.45–52.39)∗∗∗
>3 9 887 10.1 50 532 93.9 7.66 (3.76–15.6)∗∗∗ 8.72 (4.22–17.99)∗∗∗
DSCI scores
0 11 2464 4.46 105 1493 70.3 12.7 (6.82–23.67)∗∗∗ 13.98 (7.47–26.14)∗∗∗
1 2 789 2.53 44 510 86.3 26.89 (6.51–111.02)∗∗∗ 33.66 (8.07–140.48)∗∗∗
≥2 3 369 8.12 17 287 59.3 6.28 (1.84–21.45)∗∗ 6.42 (1.85–22.31)∗∗
DM drugs
TZDs
No 15 3112 4.82 157 2002 78.4 13.3 (7.82–22.6)∗∗∗ 14.35 (8.43–24.43)∗∗∗
Yes 1 511 1.96 9 288 31.2 13.92 (1.75–110.92)∗ 44.28 (3.43–572.18)∗∗
AGIs
No 14 2699 5.19 145 1705 85.1 13.23 (7.64–22.92)∗∗∗ 14.46 (8.33–25.09)∗∗∗
Yes 2 924 2.16 21 585 35.9 13.9 (3.25–59.44)∗∗∗ 14.57 (3.37–63.07)∗∗∗
DPP-4i
No 16 2801 5.71 157 1779 88.3 12.76 (7.63–21.36)∗∗∗ 13.61 (8.12–22.83)∗∗∗
Yes 0 822 0 9 512 17.6
Figure 2 The estimated survival rates between the insulin group and glimepiride group in diabetic patients with background metformin therapy by Kaplan–-Meier method.
The major identifiable causes of death of the insulin cohort included: 10 (0.97%) CV death (1 ischemic heart disease, 3 sudden cardiac deaths, 1 heart failure, 2 stroke, 3 CV hemorrhage); 142 (13.832%) noncardiovascular death (52 cancers, 90 others); and 14 (1.36%) undetermined cases. The major identifiable causes of death of the glimepiride cohort included: 2 (0.20%) CV death (1 heart failure, 1 strokes); 13 (1.27%) noncardiovascular death (3 cancers, 10 others); and 1 (0.10%) undetermined cases (Table 4). The insulin users, as compared with the glimepiride users, had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65–38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4–26.3, P < .001, Table 4).
Table 4 The causes of death of insulin vs glimepiride groups in patients with background metformin therapy.
Metformin Insulin vs glimepiride
Glimepiride n (%) Insulin n (%) Adjusted HR (95% CI) P value
Causes of CV death 2 (0.20) 10 (0.97) 7.95 (1.65–38.3) .01
Ischemic heart disease 0 1
Sudden cardiac death 0 3
Heart failure 1 1
Stroke 1 2
Cardiovascular procedure
Cardiovascular hemorrhage 0 3
Other cardiovascular causes
Non-cardiovascular causes of death 13 (1.27) 142 (13.83) 14.9 (8.4–26.3) <.001
Cancers 3 52
others 10 90
Undetermined 1 (0.10) 14 (1.36) 23.9 (3.1–184) .002
4 Discussion
We used a one to one propensity score matching to compare the risk of all-cause mortality between insulin and glimepiride users with background metformin therapy. Our results disclosed that insulin users had significantly higher risk of all-cause mortality, significantly higher risk of CV and noncardiovascular death. This overwhelming high risk of mortality was apparent across genders, age groups, baseline comorbidities, concurrent antidiabetic drugs use and DCSI scores.
The UKPDS study[8] disclosed that intensive therapy with insulin or SU had similar effect, but this study was not designed to compare these 2 regimens. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes, but the dose of insulin was very low (0.4 μ/kg/day) in quite early diabetic stage. Eleven percent of the placebo group also used exogenous insulin, which made the comparison not so adequate.[9] Margolis et al[11] conducted a retrospective cohort study and disclosed that insulin (aHR = 1.2) based treatment (including SU) was associated with an increased risk of myocardial infarction, and the risk increased with longer use. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications with no diabetic medications, the insulin based group had higher risk (odds ratio = 2.56) of getting CV events. The post-hoc analysis from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial on extended long-term outcome disclosed that insulin based treatment might be associated with increased risk of nonfatal cardiac events.[25] Hall et al[26] reported that adding insulin after 1 oral glucose-lowering drug (OGLD), when compared with adding another OGLD, had poor macrovascular outcomes. Currie et al[17] compared insulin based therapy with metformin plus SU regimens and found that insulin-based treatment had higher risk of all-cause mortality (HR = 1.49). Gamble et al[27] used the administrative databases of Saskatchewan Health to survey the cumulative insulin exposure based on total insulin dispensations per year. They observed a significant and graded association between mortality risk and insulin exposure. These were all insulin combined with oral medications including SU compared with oral medications or no medication, and showed that insulin based managements had higher risk of CV events and all-cause mortality.
As for the early use of insulin after metformin failure without adding SU compared with metformin plus SU. Roumie et al[28] reported the intensification of metformin with insulin vs sulfonylureas was associated with an increased risk of a composite of nonfatal CV outcomes and all-cause mortality in white male veterans. Mogensen et al[29] conducted a retrospective nationwide study in Danish individuals and disclosed that metformin combined with insulin had higher risk (rate ratios = 1.95) of all-cause mortality as compared with metformin plus SU. Our results were consistent with these 2 studies that early initiation of insulin after metformin failure, as compared with glimepiride, had high risk of all-cause mortality, CV and noncardiovascular death, after adjusting for all comorbidities and diabetes severity in a Chinese population.
The reasons why insulin might increase CV events and mortality in type 2 diabetes were many, including: insulin use might increase in body weight, raise the risk of hypoglycemia, and arrhythmias;[30] exogenous insulin using would increase insulin resistance and hyperinsulinemia,[31] which could exacerbate vascular inflammation,[32] alter vascular hemodynamic,[33] coagulopathy,[34] and cellular mitogenicity.[35]
Our cohort also disclosed that male (aHR = 1.43) and old-aged diabetic persons (>65 year old, aHR = 2.31) had higher risk of all-cause mortality, which were consistent with Taiwan's nationwide survey.[36] This cohort also showed that AGIs had lower risk of all-cause mortality (aHR = 0.48). Hanefeld conducted a meta-analysis of 7 long term studies and reported that acarbose could prevent myocardial infarction and CV disease in type 2 diabetic patients though most of them were already on intensive concomitant CV medication.[37] Our study also revealed that DPP-4 inhibitors using had lower risk of mortality, which was consistent with Monami meta-analysis.[38] But these 2 extra findings might need more rigorous matching study of insulin and other possible confounding factors to clarify them in the real word practice.
Our study had some strength. First, this was a population-based design and a real world finding, a 9-year follow-up data collected from the national insurance database. Second, the database contained a highly representative specimen of Taiwan's general population. Ninety nine percent of the entire 23 million people were enrolled in the national health insurance program. Third, we well matched the control group by using a propensity score calculated from age, gender, comorbidities, other oral antidiabetic drugs, DCSI scores, and diabetes duration to reduce probable confounding.
Nevertheless, our study was subjected to a few limitations. First, the NHIRD did not give patients’ information about lifestyle, physical activity, smoking habits, and family history; all were possible confounding factors in this study. To avoid this bias, we matched the DCSI scores, duration of diabetes, comorbidities, and other oral antidiabetic drugs to abate the influence of disease severity. Second, the database was dearth of biochemical blood test results that could tell us the treated condition of patients. Finally, this study was an observational cohort study instead of a randomized controlled trial. The results required further prospective clinical trials to verify.
5 Conclusions
In summary, our study disclosed that insulin vs glimepiride in patients with background metformin therapy had higher risk of all-cause mortality. For the most of patients with type 2 diabetes, there was no unambiguous evidence of benefit from insulin. Early insulin treatment in type 2 diabetic patient might associate with unacceptable risks.[39] However, insulin is the only option available to control blood glucose levels in the advanced stage of diabetes.
Acknowledgments
This manuscript was edited by Wallace Academic Editing.
Author contributions
Conceptualization: Fu-Shun Yen.
Data curation: Yuan-Chih Su, James Cheng-Chung Wei, Chii-Min Hwu.
Writing – original draft: Fu-Shun Yen, Chii-Min Hwu.
Writing – review & editing: Chih-Cheng Hsu, Yuan-Chih Su, James Cheng-Chung Wei.
Abbreviations: AGIs = alpha-glucosidase inhibitors, CAD = coronary artery disease, CCI = Charlson Comorbidity Index, CV = cardiovascular, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SU = sulfonylureas, T2DM = Type 2 diabetes mellitus, TZDs = thiazolidinediones.
How to cite this article: Yen FS, Hsu CC, Su YC, Wei JC, Hwu CM. Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: a nationwide retrospective cohort study. Medicine. 2021;100:9(e25085).
This work was supported by grants from the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005)., Tseng-Lien Lin Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in the study design, data collection and analysis and interpretation, and writing of the report. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication.
Data are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National Health Insurance (NHI) Bureau. The data utilized in this study cannot be made available in the paper, the supplemental files, or in a public repository due to the “Personal Information Protection Act” executed by Taiwan's government, starting from 2012. Requests for data can be sent as a formal proposal to the NHIRD (http://nhird.nhri.org.tw) or by email to nhird@nhri.org.tw.
The authors have no conflicts of interest to disclose.
The data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the third party.
∗ Chi-Squared test.
† Two sample t test.
CCI = Charlson Comorbidity Index, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SD = standard deviation, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase -4 inhibitors, HR = hazard ratio, TZDs = thiazolidinediones.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, HR = hazard ratio, IR = incidence rates, per 1,000 person-years, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
∗ p < .05.
∗∗ p < .01.
∗∗∗ p < .001.
Adjusted HR: adjusted for sex, age, comorbidities, medications, CCI score and DCSI score in Cox proportional hazards regression.
The codes of ICD-9-CM of diseases or procedures: Ischemic heart disease (myocardial infarction: 410, 411.0, 412, 429.79; coronary artery disease: 410–414, 429.2). Sudden cardiac death (sudden cardiac arrest: V12.53, cardiac arrhythmia: 427). Heart failure (398.91, 402.01, 402.11, 402.91, and 428). Stroke (430–438). Cardiovascular procedures (668.1 and 997.1). Cardiovascular hemorrhage (aortic aneurysm and dissection: 441; cardiac tamponade: 423.3). Other cardiovascular causes (arterial embolism and thrombosis: 444). Cancers (140–208). | GLIMEPIRIDE, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33655987 | 19,030,039 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocardial ischaemia'. | Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: A nationwide retrospective cohort study.
Type 2 diabetes mellitus (T2DM) is a progressive disease. After metformin failure, the addition of insulin or sulfonylureas might increase the risk of hypoglycemia and cardiovascular (CV) morbidity. Here, the risk of all-cause mortality was compared between early insulin treatment and glimepiride use in T2DM patients with background metformin therapy.We conducted a 9-year retrospective cohort study from the population-based National Health Insurance Research Database in Taiwan. A total of 2054 patients with T2DM under insulin or glimepiride treatment were enrolled during 2004 to 2012. Overall event rates of all-cause mortality were compared between 1027 insulin users and 1027 matched glimepiride users.After the propensity score matching, the mortality rates were 72.5 and 4.42 per 1000 person-years for insulin users and glimepiride users. The adjusted hazard ratio of mortality was 14.47 (95% CI: 8.64-24.24; P value <.001) as insulin compared with glimepiride users. The insulin users had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65-38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4-26.3, P < .001).The nationwide study demonstrated that metformin plus insulin therapy was associated with higher risk of all-cause mortality.
1 Introduction
Type 2 diabetes mellitus had the property of progressive β-cell failure. Upon diagnosis of diabetes, most patients were found to have a 50% decrease in their insulin secretion with a relentless 4% decline per year.[1] At last, most patients would require insulin treatment, alone or in combination with oral hypoglycemic agents.[2] United Kingdom Prospective Diabetes Study (UKPDS) suggested that earlier initiation of treatment was associated with better outcome.[3] There were also some reports which demonstrated that early intensive insulin treatment of hyperglycemia had favorable outcomes on recovery and maintenance of β-cell function with lengthened glycemic remission as compared with treatments of oral hypoglycemic agents.[4–6] The epidemiological studies disclosed that Asian diabetic patients had the characteristics of declining β-cell function more sharply than insulin sensitivity with age and rapid oral drug failure[7]; therefore the promotion of early insulin treatment in Asian patients was reasonable.
The UKPDS study[8] disclosed that intensive therapy with insulin or sulfonylureas (SU) had similar effect. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes and cancer occurrence.[9] But Holden et al[10] reported 6484 T2DM patients who progressed to treatment with insulin monotherapy, the adjusted hazard ratio (aHR) in relation to 1-unit increases in insulin dose was 1.54 for all-cause mortality and 1.35 for cancer. A retrospective cohort study of 63,579 diabetic patients treated in general practice disclosed that the aHR of association with serious atherosclerotic vascular disease of the heart was 1.3 for insulin.[11] One report from the Euro Heart Survey on Diabetes and the Heart disclosed that insulin therapy might relate to a more serious prognosis in patients with coronary artery disease (CAD) and diabetes.[12]
Sulfonylureas were prescribed in very large quantities due to their low cost and rapid lowering of glucose level. In recent years, there were always debates on the detrimental effect of SU in diabetic patients, including its possible CV morbidity and mortality;[13,14] some studies suggested avoiding the use of SU in diabetes treatment, especially after insulin initiation.[15] Both insulin and SU had the propensities of hypoglycemia, body weight increase and possibly CV injury. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications (including SU) vs no diabetes medications, and found that the insulin plus oral medications group had higher risk of getting CV events (odds ratio = 2.56). Currie et al[17] compared insulin based regimens with metformin plus SU, and found that the hazard ratio for all-cause mortality in people given insulin-based regimens vs those given combined oral agents was 1.49. Though, there were some reports implying the benefits of early insulin therapy, but these were all short-term clinical studies without long-term outcomes.[18] Many observational studies have also indicated that insulin therapy is more risky than oral hypoglycemic agents.[10–12,16,17] And there are currently few risk comparisons of using insulin vs sulfonylurea after metformin use. Therefore, we conducted this cohort study to see the risks of all-cause mortality between insulin and glimepiride use in T2DM patients with background metformin therapy.
2 Materials and methods
2.1 Data source
NHIRD contained the medical data of National Health Insurance (NHI), which had been implemented since March 1995, and over 99% of Taiwan residents had joined the NHI.[19] We used the data from Longitudinal Health Insurance database 2000 (LHID2000), a sub-dataset of NHIRD. The LHID2000 recorded the medical care data of 1 million people. The demographics of the LHID2000 were similar to the whole Taiwan population. In the LHID2000, the medical information included encrypted identification, demographics, the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes, surgery records and drug records.
2.2 Study design
Using the National Health Insurance Research Database (NHIRD), we investigated the difference of diabetes treatments in this population-based cohort study. We compared the adults of aged 18 to 100 years with metformin plus insulin vs metformin plus glimepiride therapy. Our study was approved by the Research Ethics Committee of China Medical University and Hospital, Taichung, Taiwan (CMUH104-REC2–115 (CR-2)). Our research was granted a waiver of informed consent. The information and records of patients were de-identified prior to analysis and encrypted the identification of each participant.
2.3 Study population
The study population consisted of diabetic patients (ICD-9-CM: 250.x) with metformin treatment excluding type 1 diabetic patients (250.1x). We categorized diabetic patients as insulin cohort or glimepiride cohort with underlying metformin treatment in 2004 to 2012 years. The insulin cohort contained type 2 diabetic patients with metfomin plus insulin treatment and exlcuded all concurrent sulfonylureas users. The glimepiride cohort contained type 2 diabetic patients with metfomin plus glimepiride treatmen. The index date was the time of receiving insulin or glimepiride.
2.4 Identification of confounders
The demographics of gender and age were confounders of this study. Baseline comorbidity was defined as having following diseases before the index date: coronary artery disease (ICD-9-CM: 410–414), stroke (ICD-9-CM: 430–438), hypertension (ICD-9-CM: 401–405), and dyslipidemia (ICD-9-CM: 272). We used the Charlson Comorbidity Index (CCI) to quantify patients’ comorbidity profiles.[20] We defined the severity of diabetes according to Diabetes Complications Severity Index (DCSI) score.[21] The CCI and DCSI scores were calculated using participant status 1 year before the index date. We also considered other drugs for diabetes such as thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) as possible confounders.
2.5 The primary outcome and causes of death
The primary outcome of this study was all- cause mortality. The observation period started from the index date to the withdrawal from the NHI or 31st December, 2013 or the date of death, whichever came first. We assessed the last primary diagnosis of discharge 3 months before death, to search for the causes of death.[22] The causes of CV death were according to the Standardized Definitions for End Point Events in Cardiovascular Trials.[23] Death due to other causes was defined as noncardiovascular death. The cases that we could not get last primary diagnosis 3 months before death were defined as undetermined.
2.6 Statistical methods
To match the insulin cohort and glimepiride cohort, we performed 1:1 propensity score matching[24] with the criteria of age, gender, comorbidities, CCI scores, DCSI scores and other antidiabetic drugs use. We summarized the variables in insulin and glimepiride cohorts, and compared those between 2 groups using Chi-Squared test for dichotomous variables and two-sample Student t test for continuous variables. In this study, we used simple and multivariable Cox proportional hazards regression models to estimate the excess risk of all-cause mortality for the insulin cohort compared to the glimepiride cohort. We calculated the crude and adjusted HR with corresponding 95% confidence intervals (95% CIs). The multivariable Cox proportional hazards regression models were done under the control of age, gender, comorbidities, other antidiabetic drugs, CCI and DCSI scores. The stratified analysis of each variable using Cox proportional hazards regression model was conducted in the outcome of mortality. The cumulative incidences of survival rate of each cohort were estimated using Kaplan–Meier method and examined by log-rank test.
All statistical analyses were conducted by the statistical software package, SAS, version 9.4 (SAS Institute, Inc., Cary, NC). P value less than .05 was the threshold of statistical significance in our study.
3 Results
From the data file of 2000 to 2012 years of LHID2000 (Fig. 1), there were 1798 patients injected insulin without using sulfonyureas and 6138 were treated with glimepiride with background metformin therapy. After excluding and matching, we enrolled 1027 diabetic patients in insulin and glimepiride cohorts, respectively. The mean (median) follow-up duration was 4.47 (3.16) and 4.72 (3.06) years for metformin plus insulin group and metformin plus glimepiride group. Men comprised 54.2% in the insulin group, and 55% in the glimepiride group (Table 1). Patients over 65 years old had the highest proportion in insulin cohort (49.4%), but a greater proportion was found in patients between 41 and 65 years old in the glimepiride cohort (48.7%). Between the 2 groups, only the distribution of age classification was notably different (P value = .011), there was no significant difference in mean age between the 2 populations (P value = .29).
Figure 1 The flow chart that identified the number of patients and study design.
Table 1 Demographic characteristics and co-morbidity of insulin group and glimepiride group in diabetic patients with background metformin therapy.
Glimepiride (N = 1027) Insulin (N = 1027)
n (%) n (%) P value
Gender .72∗
Women 462 (45) 470 (45.8)
Men 565 (55) 557 (54.2)
Age, years .011∗
≤40 37 (3.6) 63 (6.1)
41–65 500 (48.7) 457 (44.5)
>65 490 (47.7) 507 (49.4)
Mean (SD) 63.5 (12.5) 64.2 (14.6) .29†
Baseline comorbidity
Coronary artery disease 431 (42) 423 (41.2) .72∗
Stroke 337 (32.8) 311 (30.3) .22∗
Hypertension 746 (72.6) 752 (73.2) .77∗
Dyslipidemia 654 (63.7) 649 (63.2) .82∗
CCI scores .24∗
0, 1 346 (33.7) 381 (37.1)
2, 3 407 (39.6) 378 (36.8)
>3 274 (26.7) 268 (26.1)
DSCI scores .59∗
0 703 (68.5) 683 (66.5)
1 229 (22.3) 238 (23.2)
≥2 95 (9.3) 106 (10.3)
DM drugs
TZDs 117 (11.4) 107 (10.4) .48∗
Alpha glucosidase inhibitors 260 (25.3) 239 (23.3) .28∗
DPP-4i 208 (20.3) 197 (19.2) .54∗
Mean DM duration, days (medium) 1724 (1106) 1630 (1152)
The mortality risk was higher by 14.19-fold in the insulin cohort, as compared with the glimepiride cohort (95% CI = 8.48–23.75, P value < .001; Table 2). The gender of male also had higher risk of mortality (men aHR = 1.47, 95% CI = 1.09–1.99, P value = .01). Diabetic patients using alpha-glucosidase inhibitors or DPP-4i had lower risk of mortality (alpha-glucosidase inhibitors aHR = 0.54, 95% CI = 0.34–0.84, P value = .01; DPP-4i aHR = 0.26, 95% CI = 0.13–0.52, P value <.001).
Table 2 Cox model measured hazard ratio and 95% confidence intervals of death associated treatment groups and covariates in diabetic patients with background metformin therapy.
Event no. Crude Adjusted
Characteristics (n = 182) HR (95% CI) P value HR (95% CI) P value
Treatment
Glimepiride 16 1 reference 1 reference
Insulin 166 13.33 (7.97–22.28) <.001 14.19 (8.48–23.75) <.001
Gender
Women 73 1 reference 1 reference
Men 109 1.27 (0.95–1.71) .11 1.47 (1.09–1.99) .01
Age, years
≤40 7 1 reference 1 reference
41–65 50 0.74 (0.34–1.64) .47 0.78 (0.35–1.78) .56
>65 125 1.97 (0.92–4.22) .08 1.73 (0.76–3.95) .19
Baseline comorbidity
Coronary artery disease
No 92 1 reference 1 reference
Yes 90 1.43 (1.07–1.91) .02 1.1 (0.79–1.54) .56
Stroke
No 114 1 reference 1 reference
Yes 68 1.34 (0.99–1.81) .06 1.08 (0.79–1.48) .64
Hypertension
No 32 1 reference 1 reference
Yes 150 1.8 (1.23–2.63) .003 1.33 (0.87–2.03) .19
Dyslipidemia
No 76 1 reference 1 reference
Yes 106 0.79 (0.59–1.06) .11 0.73 (0.53–0.99) .05
CCI scores
0, 1 50 1 reference 1 reference
2, 3 73 1.38 (0.96–1.98) .08 1.29 (0.88–1.87) .19
>3 59 1.66 (1.14–2.42) .01 1.37 (0.91–2.07) .14
DSCI scores
0 116 1 reference 1 reference
1 46 1.21 (0.86–1.7) .28 0.92 (0.63–1.34) .67
≥2 20 1.17 (0.73–1.88) .52 0.66 (0.39–1.11) .11
DM drugs
TZDs
No 172 1 reference 1 reference
Yes 10 0.43 (0.23–0.81) .01 0.75 (0.39–1.43) .38
AGIs
No 159 1 reference 1 reference
Yes 23 0.43 (0.28–0.66) <.001 0.54 (0.34–0.84) .01
DPP-4i
No 173 1 reference 1 reference
Yes 9 0.19 (0.1–0.37) <.001 0.26 (0.13–0.52) <.001
The overall mortality rates in insulin and glimepiride cohort were 72.5 and 4.42 per 1000 person-years (Table 3). During the study period, the cumulative survival rate among insulin cohort was significantly lower than the cumulative survival rate among glimepiride cohort (P value <.001; Fig. 2). Table 3 showed the subgroup analysis of mortality of metformin plus insulin vs metform plus glimepiride. Notably, metfomin plus insulin had higher risk of mortlity among all the subgroups of genders, age, comorbidites, CCI scores DCSI scores, and other DM drugs use.
Table 3 Cox model of measured hazard ratio and 95% confidence intervals of mortality between insulin group and glimepiride group with background metformin therapy and covariates.
Metformin Insulin vs glimepiride
Glimepiride (n = 1027) Insulin (n = 1027)
Variables Event Person years IR† Event Person years IR† Crude HR (95% CI) Adjusted HR (95% CI)
Overall 16 3623 4.42 166 2290 72.5 13.33 (7.97–22.28)∗∗∗ 14.47 (8.64–24.24)∗∗∗
Gender
Women 3 1664 1.8 70 1097 63.8 29.03 (9.13–92.24)∗∗∗ 31.36 (9.83–100.05)∗∗∗
Men 13 1959 6.64 96 1193 80.4 9.7 (5.43–17.33)∗∗∗ 10.91 (6.08–19.57)∗∗∗
Age, years
≤40 0 148 0 7 163 43.0 20291126.21 (0-.) 128397943.32 (0-.)
41–65 2 1818 1.1 48 1179 40.7 30.03 (7.3–123.57)∗∗∗ 30.4 (7.37–125.34)∗∗∗
>65 14 1658 8.44 111 949 117 11.18 (6.4–19.52)∗∗∗ 11.88 (6.78–20.82)∗∗∗
Comorbidity
Coronary artery disease
No 6 2202 2.72 86 1398 61.5 17.78 (7.77–40.72)∗∗∗ 18.62 (8.11–42.75)∗∗∗
Yes 10 1421 7.04 80 892 89.7 10.68 (5.53–20.63)∗∗∗ 12.96 (6.65–25.24)∗∗∗
Stroke
No 7 2468 2.84 107 1663 64.4 18.18 (8.46–39.09)∗∗∗ 19.25 (8.94–41.44)∗∗∗
Yes 9 1155 7.79 59 627 94.0 10.16 (5.02–20.55)∗∗∗ 11.11 (5.43–22.74)∗∗∗
Hypertension
No 1 1011 0.99 31 660 46.9 38.09 (5.2–279.31)∗∗∗ 37.16 (5.05–273.56)∗∗∗
Yes 15 2612 5.74 135 1630 82.8 11.74 (6.88–20.03)∗∗∗ 12.79 (7.48–21.87)∗∗∗
Dyslipidemia
No 7 1396 5.01 69 794 86.9 13.38 (6.14–29.17)∗∗∗ 14.54 (6.6–32.02)∗∗∗
Yes 9 2227 4.04 97 1497 64.8 13.4 (6.77–26.55)∗∗∗ 14.77 (7.44–29.35)∗∗∗
CCI scores
0, 1 2 1302 1.54 48 938 51.2 26.68 (6.48–109.87)∗∗∗ 24.55 (5.93–101.6)∗∗∗
2, 3 5 1433 3.49 68 820 82.9 19.17 (7.72–47.6)∗∗∗ 21.04 (8.45–52.39)∗∗∗
>3 9 887 10.1 50 532 93.9 7.66 (3.76–15.6)∗∗∗ 8.72 (4.22–17.99)∗∗∗
DSCI scores
0 11 2464 4.46 105 1493 70.3 12.7 (6.82–23.67)∗∗∗ 13.98 (7.47–26.14)∗∗∗
1 2 789 2.53 44 510 86.3 26.89 (6.51–111.02)∗∗∗ 33.66 (8.07–140.48)∗∗∗
≥2 3 369 8.12 17 287 59.3 6.28 (1.84–21.45)∗∗ 6.42 (1.85–22.31)∗∗
DM drugs
TZDs
No 15 3112 4.82 157 2002 78.4 13.3 (7.82–22.6)∗∗∗ 14.35 (8.43–24.43)∗∗∗
Yes 1 511 1.96 9 288 31.2 13.92 (1.75–110.92)∗ 44.28 (3.43–572.18)∗∗
AGIs
No 14 2699 5.19 145 1705 85.1 13.23 (7.64–22.92)∗∗∗ 14.46 (8.33–25.09)∗∗∗
Yes 2 924 2.16 21 585 35.9 13.9 (3.25–59.44)∗∗∗ 14.57 (3.37–63.07)∗∗∗
DPP-4i
No 16 2801 5.71 157 1779 88.3 12.76 (7.63–21.36)∗∗∗ 13.61 (8.12–22.83)∗∗∗
Yes 0 822 0 9 512 17.6
Figure 2 The estimated survival rates between the insulin group and glimepiride group in diabetic patients with background metformin therapy by Kaplan–-Meier method.
The major identifiable causes of death of the insulin cohort included: 10 (0.97%) CV death (1 ischemic heart disease, 3 sudden cardiac deaths, 1 heart failure, 2 stroke, 3 CV hemorrhage); 142 (13.832%) noncardiovascular death (52 cancers, 90 others); and 14 (1.36%) undetermined cases. The major identifiable causes of death of the glimepiride cohort included: 2 (0.20%) CV death (1 heart failure, 1 strokes); 13 (1.27%) noncardiovascular death (3 cancers, 10 others); and 1 (0.10%) undetermined cases (Table 4). The insulin users, as compared with the glimepiride users, had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65–38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4–26.3, P < .001, Table 4).
Table 4 The causes of death of insulin vs glimepiride groups in patients with background metformin therapy.
Metformin Insulin vs glimepiride
Glimepiride n (%) Insulin n (%) Adjusted HR (95% CI) P value
Causes of CV death 2 (0.20) 10 (0.97) 7.95 (1.65–38.3) .01
Ischemic heart disease 0 1
Sudden cardiac death 0 3
Heart failure 1 1
Stroke 1 2
Cardiovascular procedure
Cardiovascular hemorrhage 0 3
Other cardiovascular causes
Non-cardiovascular causes of death 13 (1.27) 142 (13.83) 14.9 (8.4–26.3) <.001
Cancers 3 52
others 10 90
Undetermined 1 (0.10) 14 (1.36) 23.9 (3.1–184) .002
4 Discussion
We used a one to one propensity score matching to compare the risk of all-cause mortality between insulin and glimepiride users with background metformin therapy. Our results disclosed that insulin users had significantly higher risk of all-cause mortality, significantly higher risk of CV and noncardiovascular death. This overwhelming high risk of mortality was apparent across genders, age groups, baseline comorbidities, concurrent antidiabetic drugs use and DCSI scores.
The UKPDS study[8] disclosed that intensive therapy with insulin or SU had similar effect, but this study was not designed to compare these 2 regimens. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes, but the dose of insulin was very low (0.4 μ/kg/day) in quite early diabetic stage. Eleven percent of the placebo group also used exogenous insulin, which made the comparison not so adequate.[9] Margolis et al[11] conducted a retrospective cohort study and disclosed that insulin (aHR = 1.2) based treatment (including SU) was associated with an increased risk of myocardial infarction, and the risk increased with longer use. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications with no diabetic medications, the insulin based group had higher risk (odds ratio = 2.56) of getting CV events. The post-hoc analysis from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial on extended long-term outcome disclosed that insulin based treatment might be associated with increased risk of nonfatal cardiac events.[25] Hall et al[26] reported that adding insulin after 1 oral glucose-lowering drug (OGLD), when compared with adding another OGLD, had poor macrovascular outcomes. Currie et al[17] compared insulin based therapy with metformin plus SU regimens and found that insulin-based treatment had higher risk of all-cause mortality (HR = 1.49). Gamble et al[27] used the administrative databases of Saskatchewan Health to survey the cumulative insulin exposure based on total insulin dispensations per year. They observed a significant and graded association between mortality risk and insulin exposure. These were all insulin combined with oral medications including SU compared with oral medications or no medication, and showed that insulin based managements had higher risk of CV events and all-cause mortality.
As for the early use of insulin after metformin failure without adding SU compared with metformin plus SU. Roumie et al[28] reported the intensification of metformin with insulin vs sulfonylureas was associated with an increased risk of a composite of nonfatal CV outcomes and all-cause mortality in white male veterans. Mogensen et al[29] conducted a retrospective nationwide study in Danish individuals and disclosed that metformin combined with insulin had higher risk (rate ratios = 1.95) of all-cause mortality as compared with metformin plus SU. Our results were consistent with these 2 studies that early initiation of insulin after metformin failure, as compared with glimepiride, had high risk of all-cause mortality, CV and noncardiovascular death, after adjusting for all comorbidities and diabetes severity in a Chinese population.
The reasons why insulin might increase CV events and mortality in type 2 diabetes were many, including: insulin use might increase in body weight, raise the risk of hypoglycemia, and arrhythmias;[30] exogenous insulin using would increase insulin resistance and hyperinsulinemia,[31] which could exacerbate vascular inflammation,[32] alter vascular hemodynamic,[33] coagulopathy,[34] and cellular mitogenicity.[35]
Our cohort also disclosed that male (aHR = 1.43) and old-aged diabetic persons (>65 year old, aHR = 2.31) had higher risk of all-cause mortality, which were consistent with Taiwan's nationwide survey.[36] This cohort also showed that AGIs had lower risk of all-cause mortality (aHR = 0.48). Hanefeld conducted a meta-analysis of 7 long term studies and reported that acarbose could prevent myocardial infarction and CV disease in type 2 diabetic patients though most of them were already on intensive concomitant CV medication.[37] Our study also revealed that DPP-4 inhibitors using had lower risk of mortality, which was consistent with Monami meta-analysis.[38] But these 2 extra findings might need more rigorous matching study of insulin and other possible confounding factors to clarify them in the real word practice.
Our study had some strength. First, this was a population-based design and a real world finding, a 9-year follow-up data collected from the national insurance database. Second, the database contained a highly representative specimen of Taiwan's general population. Ninety nine percent of the entire 23 million people were enrolled in the national health insurance program. Third, we well matched the control group by using a propensity score calculated from age, gender, comorbidities, other oral antidiabetic drugs, DCSI scores, and diabetes duration to reduce probable confounding.
Nevertheless, our study was subjected to a few limitations. First, the NHIRD did not give patients’ information about lifestyle, physical activity, smoking habits, and family history; all were possible confounding factors in this study. To avoid this bias, we matched the DCSI scores, duration of diabetes, comorbidities, and other oral antidiabetic drugs to abate the influence of disease severity. Second, the database was dearth of biochemical blood test results that could tell us the treated condition of patients. Finally, this study was an observational cohort study instead of a randomized controlled trial. The results required further prospective clinical trials to verify.
5 Conclusions
In summary, our study disclosed that insulin vs glimepiride in patients with background metformin therapy had higher risk of all-cause mortality. For the most of patients with type 2 diabetes, there was no unambiguous evidence of benefit from insulin. Early insulin treatment in type 2 diabetic patient might associate with unacceptable risks.[39] However, insulin is the only option available to control blood glucose levels in the advanced stage of diabetes.
Acknowledgments
This manuscript was edited by Wallace Academic Editing.
Author contributions
Conceptualization: Fu-Shun Yen.
Data curation: Yuan-Chih Su, James Cheng-Chung Wei, Chii-Min Hwu.
Writing – original draft: Fu-Shun Yen, Chii-Min Hwu.
Writing – review & editing: Chih-Cheng Hsu, Yuan-Chih Su, James Cheng-Chung Wei.
Abbreviations: AGIs = alpha-glucosidase inhibitors, CAD = coronary artery disease, CCI = Charlson Comorbidity Index, CV = cardiovascular, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SU = sulfonylureas, T2DM = Type 2 diabetes mellitus, TZDs = thiazolidinediones.
How to cite this article: Yen FS, Hsu CC, Su YC, Wei JC, Hwu CM. Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: a nationwide retrospective cohort study. Medicine. 2021;100:9(e25085).
This work was supported by grants from the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005)., Tseng-Lien Lin Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in the study design, data collection and analysis and interpretation, and writing of the report. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication.
Data are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National Health Insurance (NHI) Bureau. The data utilized in this study cannot be made available in the paper, the supplemental files, or in a public repository due to the “Personal Information Protection Act” executed by Taiwan's government, starting from 2012. Requests for data can be sent as a formal proposal to the NHIRD (http://nhird.nhri.org.tw) or by email to nhird@nhri.org.tw.
The authors have no conflicts of interest to disclose.
The data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the third party.
∗ Chi-Squared test.
† Two sample t test.
CCI = Charlson Comorbidity Index, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SD = standard deviation, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase -4 inhibitors, HR = hazard ratio, TZDs = thiazolidinediones.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, HR = hazard ratio, IR = incidence rates, per 1,000 person-years, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
∗ p < .05.
∗∗ p < .01.
∗∗∗ p < .001.
Adjusted HR: adjusted for sex, age, comorbidities, medications, CCI score and DCSI score in Cox proportional hazards regression.
The codes of ICD-9-CM of diseases or procedures: Ischemic heart disease (myocardial infarction: 410, 411.0, 412, 429.79; coronary artery disease: 410–414, 429.2). Sudden cardiac death (sudden cardiac arrest: V12.53, cardiac arrhythmia: 427). Heart failure (398.91, 402.01, 402.11, 402.91, and 428). Stroke (430–438). Cardiovascular procedures (668.1 and 997.1). Cardiovascular hemorrhage (aortic aneurysm and dissection: 441; cardiac tamponade: 423.3). Other cardiovascular causes (arterial embolism and thrombosis: 444). Cancers (140–208). | INSULIN NOS, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33655987 | 19,029,014 | 2021-03-05 |
What was the outcome of reaction 'Cardiac failure'? | Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: A nationwide retrospective cohort study.
Type 2 diabetes mellitus (T2DM) is a progressive disease. After metformin failure, the addition of insulin or sulfonylureas might increase the risk of hypoglycemia and cardiovascular (CV) morbidity. Here, the risk of all-cause mortality was compared between early insulin treatment and glimepiride use in T2DM patients with background metformin therapy.We conducted a 9-year retrospective cohort study from the population-based National Health Insurance Research Database in Taiwan. A total of 2054 patients with T2DM under insulin or glimepiride treatment were enrolled during 2004 to 2012. Overall event rates of all-cause mortality were compared between 1027 insulin users and 1027 matched glimepiride users.After the propensity score matching, the mortality rates were 72.5 and 4.42 per 1000 person-years for insulin users and glimepiride users. The adjusted hazard ratio of mortality was 14.47 (95% CI: 8.64-24.24; P value <.001) as insulin compared with glimepiride users. The insulin users had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65-38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4-26.3, P < .001).The nationwide study demonstrated that metformin plus insulin therapy was associated with higher risk of all-cause mortality.
1 Introduction
Type 2 diabetes mellitus had the property of progressive β-cell failure. Upon diagnosis of diabetes, most patients were found to have a 50% decrease in their insulin secretion with a relentless 4% decline per year.[1] At last, most patients would require insulin treatment, alone or in combination with oral hypoglycemic agents.[2] United Kingdom Prospective Diabetes Study (UKPDS) suggested that earlier initiation of treatment was associated with better outcome.[3] There were also some reports which demonstrated that early intensive insulin treatment of hyperglycemia had favorable outcomes on recovery and maintenance of β-cell function with lengthened glycemic remission as compared with treatments of oral hypoglycemic agents.[4–6] The epidemiological studies disclosed that Asian diabetic patients had the characteristics of declining β-cell function more sharply than insulin sensitivity with age and rapid oral drug failure[7]; therefore the promotion of early insulin treatment in Asian patients was reasonable.
The UKPDS study[8] disclosed that intensive therapy with insulin or sulfonylureas (SU) had similar effect. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes and cancer occurrence.[9] But Holden et al[10] reported 6484 T2DM patients who progressed to treatment with insulin monotherapy, the adjusted hazard ratio (aHR) in relation to 1-unit increases in insulin dose was 1.54 for all-cause mortality and 1.35 for cancer. A retrospective cohort study of 63,579 diabetic patients treated in general practice disclosed that the aHR of association with serious atherosclerotic vascular disease of the heart was 1.3 for insulin.[11] One report from the Euro Heart Survey on Diabetes and the Heart disclosed that insulin therapy might relate to a more serious prognosis in patients with coronary artery disease (CAD) and diabetes.[12]
Sulfonylureas were prescribed in very large quantities due to their low cost and rapid lowering of glucose level. In recent years, there were always debates on the detrimental effect of SU in diabetic patients, including its possible CV morbidity and mortality;[13,14] some studies suggested avoiding the use of SU in diabetes treatment, especially after insulin initiation.[15] Both insulin and SU had the propensities of hypoglycemia, body weight increase and possibly CV injury. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications (including SU) vs no diabetes medications, and found that the insulin plus oral medications group had higher risk of getting CV events (odds ratio = 2.56). Currie et al[17] compared insulin based regimens with metformin plus SU, and found that the hazard ratio for all-cause mortality in people given insulin-based regimens vs those given combined oral agents was 1.49. Though, there were some reports implying the benefits of early insulin therapy, but these were all short-term clinical studies without long-term outcomes.[18] Many observational studies have also indicated that insulin therapy is more risky than oral hypoglycemic agents.[10–12,16,17] And there are currently few risk comparisons of using insulin vs sulfonylurea after metformin use. Therefore, we conducted this cohort study to see the risks of all-cause mortality between insulin and glimepiride use in T2DM patients with background metformin therapy.
2 Materials and methods
2.1 Data source
NHIRD contained the medical data of National Health Insurance (NHI), which had been implemented since March 1995, and over 99% of Taiwan residents had joined the NHI.[19] We used the data from Longitudinal Health Insurance database 2000 (LHID2000), a sub-dataset of NHIRD. The LHID2000 recorded the medical care data of 1 million people. The demographics of the LHID2000 were similar to the whole Taiwan population. In the LHID2000, the medical information included encrypted identification, demographics, the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes, surgery records and drug records.
2.2 Study design
Using the National Health Insurance Research Database (NHIRD), we investigated the difference of diabetes treatments in this population-based cohort study. We compared the adults of aged 18 to 100 years with metformin plus insulin vs metformin plus glimepiride therapy. Our study was approved by the Research Ethics Committee of China Medical University and Hospital, Taichung, Taiwan (CMUH104-REC2–115 (CR-2)). Our research was granted a waiver of informed consent. The information and records of patients were de-identified prior to analysis and encrypted the identification of each participant.
2.3 Study population
The study population consisted of diabetic patients (ICD-9-CM: 250.x) with metformin treatment excluding type 1 diabetic patients (250.1x). We categorized diabetic patients as insulin cohort or glimepiride cohort with underlying metformin treatment in 2004 to 2012 years. The insulin cohort contained type 2 diabetic patients with metfomin plus insulin treatment and exlcuded all concurrent sulfonylureas users. The glimepiride cohort contained type 2 diabetic patients with metfomin plus glimepiride treatmen. The index date was the time of receiving insulin or glimepiride.
2.4 Identification of confounders
The demographics of gender and age were confounders of this study. Baseline comorbidity was defined as having following diseases before the index date: coronary artery disease (ICD-9-CM: 410–414), stroke (ICD-9-CM: 430–438), hypertension (ICD-9-CM: 401–405), and dyslipidemia (ICD-9-CM: 272). We used the Charlson Comorbidity Index (CCI) to quantify patients’ comorbidity profiles.[20] We defined the severity of diabetes according to Diabetes Complications Severity Index (DCSI) score.[21] The CCI and DCSI scores were calculated using participant status 1 year before the index date. We also considered other drugs for diabetes such as thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) as possible confounders.
2.5 The primary outcome and causes of death
The primary outcome of this study was all- cause mortality. The observation period started from the index date to the withdrawal from the NHI or 31st December, 2013 or the date of death, whichever came first. We assessed the last primary diagnosis of discharge 3 months before death, to search for the causes of death.[22] The causes of CV death were according to the Standardized Definitions for End Point Events in Cardiovascular Trials.[23] Death due to other causes was defined as noncardiovascular death. The cases that we could not get last primary diagnosis 3 months before death were defined as undetermined.
2.6 Statistical methods
To match the insulin cohort and glimepiride cohort, we performed 1:1 propensity score matching[24] with the criteria of age, gender, comorbidities, CCI scores, DCSI scores and other antidiabetic drugs use. We summarized the variables in insulin and glimepiride cohorts, and compared those between 2 groups using Chi-Squared test for dichotomous variables and two-sample Student t test for continuous variables. In this study, we used simple and multivariable Cox proportional hazards regression models to estimate the excess risk of all-cause mortality for the insulin cohort compared to the glimepiride cohort. We calculated the crude and adjusted HR with corresponding 95% confidence intervals (95% CIs). The multivariable Cox proportional hazards regression models were done under the control of age, gender, comorbidities, other antidiabetic drugs, CCI and DCSI scores. The stratified analysis of each variable using Cox proportional hazards regression model was conducted in the outcome of mortality. The cumulative incidences of survival rate of each cohort were estimated using Kaplan–Meier method and examined by log-rank test.
All statistical analyses were conducted by the statistical software package, SAS, version 9.4 (SAS Institute, Inc., Cary, NC). P value less than .05 was the threshold of statistical significance in our study.
3 Results
From the data file of 2000 to 2012 years of LHID2000 (Fig. 1), there were 1798 patients injected insulin without using sulfonyureas and 6138 were treated with glimepiride with background metformin therapy. After excluding and matching, we enrolled 1027 diabetic patients in insulin and glimepiride cohorts, respectively. The mean (median) follow-up duration was 4.47 (3.16) and 4.72 (3.06) years for metformin plus insulin group and metformin plus glimepiride group. Men comprised 54.2% in the insulin group, and 55% in the glimepiride group (Table 1). Patients over 65 years old had the highest proportion in insulin cohort (49.4%), but a greater proportion was found in patients between 41 and 65 years old in the glimepiride cohort (48.7%). Between the 2 groups, only the distribution of age classification was notably different (P value = .011), there was no significant difference in mean age between the 2 populations (P value = .29).
Figure 1 The flow chart that identified the number of patients and study design.
Table 1 Demographic characteristics and co-morbidity of insulin group and glimepiride group in diabetic patients with background metformin therapy.
Glimepiride (N = 1027) Insulin (N = 1027)
n (%) n (%) P value
Gender .72∗
Women 462 (45) 470 (45.8)
Men 565 (55) 557 (54.2)
Age, years .011∗
≤40 37 (3.6) 63 (6.1)
41–65 500 (48.7) 457 (44.5)
>65 490 (47.7) 507 (49.4)
Mean (SD) 63.5 (12.5) 64.2 (14.6) .29†
Baseline comorbidity
Coronary artery disease 431 (42) 423 (41.2) .72∗
Stroke 337 (32.8) 311 (30.3) .22∗
Hypertension 746 (72.6) 752 (73.2) .77∗
Dyslipidemia 654 (63.7) 649 (63.2) .82∗
CCI scores .24∗
0, 1 346 (33.7) 381 (37.1)
2, 3 407 (39.6) 378 (36.8)
>3 274 (26.7) 268 (26.1)
DSCI scores .59∗
0 703 (68.5) 683 (66.5)
1 229 (22.3) 238 (23.2)
≥2 95 (9.3) 106 (10.3)
DM drugs
TZDs 117 (11.4) 107 (10.4) .48∗
Alpha glucosidase inhibitors 260 (25.3) 239 (23.3) .28∗
DPP-4i 208 (20.3) 197 (19.2) .54∗
Mean DM duration, days (medium) 1724 (1106) 1630 (1152)
The mortality risk was higher by 14.19-fold in the insulin cohort, as compared with the glimepiride cohort (95% CI = 8.48–23.75, P value < .001; Table 2). The gender of male also had higher risk of mortality (men aHR = 1.47, 95% CI = 1.09–1.99, P value = .01). Diabetic patients using alpha-glucosidase inhibitors or DPP-4i had lower risk of mortality (alpha-glucosidase inhibitors aHR = 0.54, 95% CI = 0.34–0.84, P value = .01; DPP-4i aHR = 0.26, 95% CI = 0.13–0.52, P value <.001).
Table 2 Cox model measured hazard ratio and 95% confidence intervals of death associated treatment groups and covariates in diabetic patients with background metformin therapy.
Event no. Crude Adjusted
Characteristics (n = 182) HR (95% CI) P value HR (95% CI) P value
Treatment
Glimepiride 16 1 reference 1 reference
Insulin 166 13.33 (7.97–22.28) <.001 14.19 (8.48–23.75) <.001
Gender
Women 73 1 reference 1 reference
Men 109 1.27 (0.95–1.71) .11 1.47 (1.09–1.99) .01
Age, years
≤40 7 1 reference 1 reference
41–65 50 0.74 (0.34–1.64) .47 0.78 (0.35–1.78) .56
>65 125 1.97 (0.92–4.22) .08 1.73 (0.76–3.95) .19
Baseline comorbidity
Coronary artery disease
No 92 1 reference 1 reference
Yes 90 1.43 (1.07–1.91) .02 1.1 (0.79–1.54) .56
Stroke
No 114 1 reference 1 reference
Yes 68 1.34 (0.99–1.81) .06 1.08 (0.79–1.48) .64
Hypertension
No 32 1 reference 1 reference
Yes 150 1.8 (1.23–2.63) .003 1.33 (0.87–2.03) .19
Dyslipidemia
No 76 1 reference 1 reference
Yes 106 0.79 (0.59–1.06) .11 0.73 (0.53–0.99) .05
CCI scores
0, 1 50 1 reference 1 reference
2, 3 73 1.38 (0.96–1.98) .08 1.29 (0.88–1.87) .19
>3 59 1.66 (1.14–2.42) .01 1.37 (0.91–2.07) .14
DSCI scores
0 116 1 reference 1 reference
1 46 1.21 (0.86–1.7) .28 0.92 (0.63–1.34) .67
≥2 20 1.17 (0.73–1.88) .52 0.66 (0.39–1.11) .11
DM drugs
TZDs
No 172 1 reference 1 reference
Yes 10 0.43 (0.23–0.81) .01 0.75 (0.39–1.43) .38
AGIs
No 159 1 reference 1 reference
Yes 23 0.43 (0.28–0.66) <.001 0.54 (0.34–0.84) .01
DPP-4i
No 173 1 reference 1 reference
Yes 9 0.19 (0.1–0.37) <.001 0.26 (0.13–0.52) <.001
The overall mortality rates in insulin and glimepiride cohort were 72.5 and 4.42 per 1000 person-years (Table 3). During the study period, the cumulative survival rate among insulin cohort was significantly lower than the cumulative survival rate among glimepiride cohort (P value <.001; Fig. 2). Table 3 showed the subgroup analysis of mortality of metformin plus insulin vs metform plus glimepiride. Notably, metfomin plus insulin had higher risk of mortlity among all the subgroups of genders, age, comorbidites, CCI scores DCSI scores, and other DM drugs use.
Table 3 Cox model of measured hazard ratio and 95% confidence intervals of mortality between insulin group and glimepiride group with background metformin therapy and covariates.
Metformin Insulin vs glimepiride
Glimepiride (n = 1027) Insulin (n = 1027)
Variables Event Person years IR† Event Person years IR† Crude HR (95% CI) Adjusted HR (95% CI)
Overall 16 3623 4.42 166 2290 72.5 13.33 (7.97–22.28)∗∗∗ 14.47 (8.64–24.24)∗∗∗
Gender
Women 3 1664 1.8 70 1097 63.8 29.03 (9.13–92.24)∗∗∗ 31.36 (9.83–100.05)∗∗∗
Men 13 1959 6.64 96 1193 80.4 9.7 (5.43–17.33)∗∗∗ 10.91 (6.08–19.57)∗∗∗
Age, years
≤40 0 148 0 7 163 43.0 20291126.21 (0-.) 128397943.32 (0-.)
41–65 2 1818 1.1 48 1179 40.7 30.03 (7.3–123.57)∗∗∗ 30.4 (7.37–125.34)∗∗∗
>65 14 1658 8.44 111 949 117 11.18 (6.4–19.52)∗∗∗ 11.88 (6.78–20.82)∗∗∗
Comorbidity
Coronary artery disease
No 6 2202 2.72 86 1398 61.5 17.78 (7.77–40.72)∗∗∗ 18.62 (8.11–42.75)∗∗∗
Yes 10 1421 7.04 80 892 89.7 10.68 (5.53–20.63)∗∗∗ 12.96 (6.65–25.24)∗∗∗
Stroke
No 7 2468 2.84 107 1663 64.4 18.18 (8.46–39.09)∗∗∗ 19.25 (8.94–41.44)∗∗∗
Yes 9 1155 7.79 59 627 94.0 10.16 (5.02–20.55)∗∗∗ 11.11 (5.43–22.74)∗∗∗
Hypertension
No 1 1011 0.99 31 660 46.9 38.09 (5.2–279.31)∗∗∗ 37.16 (5.05–273.56)∗∗∗
Yes 15 2612 5.74 135 1630 82.8 11.74 (6.88–20.03)∗∗∗ 12.79 (7.48–21.87)∗∗∗
Dyslipidemia
No 7 1396 5.01 69 794 86.9 13.38 (6.14–29.17)∗∗∗ 14.54 (6.6–32.02)∗∗∗
Yes 9 2227 4.04 97 1497 64.8 13.4 (6.77–26.55)∗∗∗ 14.77 (7.44–29.35)∗∗∗
CCI scores
0, 1 2 1302 1.54 48 938 51.2 26.68 (6.48–109.87)∗∗∗ 24.55 (5.93–101.6)∗∗∗
2, 3 5 1433 3.49 68 820 82.9 19.17 (7.72–47.6)∗∗∗ 21.04 (8.45–52.39)∗∗∗
>3 9 887 10.1 50 532 93.9 7.66 (3.76–15.6)∗∗∗ 8.72 (4.22–17.99)∗∗∗
DSCI scores
0 11 2464 4.46 105 1493 70.3 12.7 (6.82–23.67)∗∗∗ 13.98 (7.47–26.14)∗∗∗
1 2 789 2.53 44 510 86.3 26.89 (6.51–111.02)∗∗∗ 33.66 (8.07–140.48)∗∗∗
≥2 3 369 8.12 17 287 59.3 6.28 (1.84–21.45)∗∗ 6.42 (1.85–22.31)∗∗
DM drugs
TZDs
No 15 3112 4.82 157 2002 78.4 13.3 (7.82–22.6)∗∗∗ 14.35 (8.43–24.43)∗∗∗
Yes 1 511 1.96 9 288 31.2 13.92 (1.75–110.92)∗ 44.28 (3.43–572.18)∗∗
AGIs
No 14 2699 5.19 145 1705 85.1 13.23 (7.64–22.92)∗∗∗ 14.46 (8.33–25.09)∗∗∗
Yes 2 924 2.16 21 585 35.9 13.9 (3.25–59.44)∗∗∗ 14.57 (3.37–63.07)∗∗∗
DPP-4i
No 16 2801 5.71 157 1779 88.3 12.76 (7.63–21.36)∗∗∗ 13.61 (8.12–22.83)∗∗∗
Yes 0 822 0 9 512 17.6
Figure 2 The estimated survival rates between the insulin group and glimepiride group in diabetic patients with background metformin therapy by Kaplan–-Meier method.
The major identifiable causes of death of the insulin cohort included: 10 (0.97%) CV death (1 ischemic heart disease, 3 sudden cardiac deaths, 1 heart failure, 2 stroke, 3 CV hemorrhage); 142 (13.832%) noncardiovascular death (52 cancers, 90 others); and 14 (1.36%) undetermined cases. The major identifiable causes of death of the glimepiride cohort included: 2 (0.20%) CV death (1 heart failure, 1 strokes); 13 (1.27%) noncardiovascular death (3 cancers, 10 others); and 1 (0.10%) undetermined cases (Table 4). The insulin users, as compared with the glimepiride users, had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65–38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4–26.3, P < .001, Table 4).
Table 4 The causes of death of insulin vs glimepiride groups in patients with background metformin therapy.
Metformin Insulin vs glimepiride
Glimepiride n (%) Insulin n (%) Adjusted HR (95% CI) P value
Causes of CV death 2 (0.20) 10 (0.97) 7.95 (1.65–38.3) .01
Ischemic heart disease 0 1
Sudden cardiac death 0 3
Heart failure 1 1
Stroke 1 2
Cardiovascular procedure
Cardiovascular hemorrhage 0 3
Other cardiovascular causes
Non-cardiovascular causes of death 13 (1.27) 142 (13.83) 14.9 (8.4–26.3) <.001
Cancers 3 52
others 10 90
Undetermined 1 (0.10) 14 (1.36) 23.9 (3.1–184) .002
4 Discussion
We used a one to one propensity score matching to compare the risk of all-cause mortality between insulin and glimepiride users with background metformin therapy. Our results disclosed that insulin users had significantly higher risk of all-cause mortality, significantly higher risk of CV and noncardiovascular death. This overwhelming high risk of mortality was apparent across genders, age groups, baseline comorbidities, concurrent antidiabetic drugs use and DCSI scores.
The UKPDS study[8] disclosed that intensive therapy with insulin or SU had similar effect, but this study was not designed to compare these 2 regimens. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes, but the dose of insulin was very low (0.4 μ/kg/day) in quite early diabetic stage. Eleven percent of the placebo group also used exogenous insulin, which made the comparison not so adequate.[9] Margolis et al[11] conducted a retrospective cohort study and disclosed that insulin (aHR = 1.2) based treatment (including SU) was associated with an increased risk of myocardial infarction, and the risk increased with longer use. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications with no diabetic medications, the insulin based group had higher risk (odds ratio = 2.56) of getting CV events. The post-hoc analysis from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial on extended long-term outcome disclosed that insulin based treatment might be associated with increased risk of nonfatal cardiac events.[25] Hall et al[26] reported that adding insulin after 1 oral glucose-lowering drug (OGLD), when compared with adding another OGLD, had poor macrovascular outcomes. Currie et al[17] compared insulin based therapy with metformin plus SU regimens and found that insulin-based treatment had higher risk of all-cause mortality (HR = 1.49). Gamble et al[27] used the administrative databases of Saskatchewan Health to survey the cumulative insulin exposure based on total insulin dispensations per year. They observed a significant and graded association between mortality risk and insulin exposure. These were all insulin combined with oral medications including SU compared with oral medications or no medication, and showed that insulin based managements had higher risk of CV events and all-cause mortality.
As for the early use of insulin after metformin failure without adding SU compared with metformin plus SU. Roumie et al[28] reported the intensification of metformin with insulin vs sulfonylureas was associated with an increased risk of a composite of nonfatal CV outcomes and all-cause mortality in white male veterans. Mogensen et al[29] conducted a retrospective nationwide study in Danish individuals and disclosed that metformin combined with insulin had higher risk (rate ratios = 1.95) of all-cause mortality as compared with metformin plus SU. Our results were consistent with these 2 studies that early initiation of insulin after metformin failure, as compared with glimepiride, had high risk of all-cause mortality, CV and noncardiovascular death, after adjusting for all comorbidities and diabetes severity in a Chinese population.
The reasons why insulin might increase CV events and mortality in type 2 diabetes were many, including: insulin use might increase in body weight, raise the risk of hypoglycemia, and arrhythmias;[30] exogenous insulin using would increase insulin resistance and hyperinsulinemia,[31] which could exacerbate vascular inflammation,[32] alter vascular hemodynamic,[33] coagulopathy,[34] and cellular mitogenicity.[35]
Our cohort also disclosed that male (aHR = 1.43) and old-aged diabetic persons (>65 year old, aHR = 2.31) had higher risk of all-cause mortality, which were consistent with Taiwan's nationwide survey.[36] This cohort also showed that AGIs had lower risk of all-cause mortality (aHR = 0.48). Hanefeld conducted a meta-analysis of 7 long term studies and reported that acarbose could prevent myocardial infarction and CV disease in type 2 diabetic patients though most of them were already on intensive concomitant CV medication.[37] Our study also revealed that DPP-4 inhibitors using had lower risk of mortality, which was consistent with Monami meta-analysis.[38] But these 2 extra findings might need more rigorous matching study of insulin and other possible confounding factors to clarify them in the real word practice.
Our study had some strength. First, this was a population-based design and a real world finding, a 9-year follow-up data collected from the national insurance database. Second, the database contained a highly representative specimen of Taiwan's general population. Ninety nine percent of the entire 23 million people were enrolled in the national health insurance program. Third, we well matched the control group by using a propensity score calculated from age, gender, comorbidities, other oral antidiabetic drugs, DCSI scores, and diabetes duration to reduce probable confounding.
Nevertheless, our study was subjected to a few limitations. First, the NHIRD did not give patients’ information about lifestyle, physical activity, smoking habits, and family history; all were possible confounding factors in this study. To avoid this bias, we matched the DCSI scores, duration of diabetes, comorbidities, and other oral antidiabetic drugs to abate the influence of disease severity. Second, the database was dearth of biochemical blood test results that could tell us the treated condition of patients. Finally, this study was an observational cohort study instead of a randomized controlled trial. The results required further prospective clinical trials to verify.
5 Conclusions
In summary, our study disclosed that insulin vs glimepiride in patients with background metformin therapy had higher risk of all-cause mortality. For the most of patients with type 2 diabetes, there was no unambiguous evidence of benefit from insulin. Early insulin treatment in type 2 diabetic patient might associate with unacceptable risks.[39] However, insulin is the only option available to control blood glucose levels in the advanced stage of diabetes.
Acknowledgments
This manuscript was edited by Wallace Academic Editing.
Author contributions
Conceptualization: Fu-Shun Yen.
Data curation: Yuan-Chih Su, James Cheng-Chung Wei, Chii-Min Hwu.
Writing – original draft: Fu-Shun Yen, Chii-Min Hwu.
Writing – review & editing: Chih-Cheng Hsu, Yuan-Chih Su, James Cheng-Chung Wei.
Abbreviations: AGIs = alpha-glucosidase inhibitors, CAD = coronary artery disease, CCI = Charlson Comorbidity Index, CV = cardiovascular, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SU = sulfonylureas, T2DM = Type 2 diabetes mellitus, TZDs = thiazolidinediones.
How to cite this article: Yen FS, Hsu CC, Su YC, Wei JC, Hwu CM. Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: a nationwide retrospective cohort study. Medicine. 2021;100:9(e25085).
This work was supported by grants from the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005)., Tseng-Lien Lin Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in the study design, data collection and analysis and interpretation, and writing of the report. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication.
Data are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National Health Insurance (NHI) Bureau. The data utilized in this study cannot be made available in the paper, the supplemental files, or in a public repository due to the “Personal Information Protection Act” executed by Taiwan's government, starting from 2012. Requests for data can be sent as a formal proposal to the NHIRD (http://nhird.nhri.org.tw) or by email to nhird@nhri.org.tw.
The authors have no conflicts of interest to disclose.
The data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the third party.
∗ Chi-Squared test.
† Two sample t test.
CCI = Charlson Comorbidity Index, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SD = standard deviation, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase -4 inhibitors, HR = hazard ratio, TZDs = thiazolidinediones.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, HR = hazard ratio, IR = incidence rates, per 1,000 person-years, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
∗ p < .05.
∗∗ p < .01.
∗∗∗ p < .001.
Adjusted HR: adjusted for sex, age, comorbidities, medications, CCI score and DCSI score in Cox proportional hazards regression.
The codes of ICD-9-CM of diseases or procedures: Ischemic heart disease (myocardial infarction: 410, 411.0, 412, 429.79; coronary artery disease: 410–414, 429.2). Sudden cardiac death (sudden cardiac arrest: V12.53, cardiac arrhythmia: 427). Heart failure (398.91, 402.01, 402.11, 402.91, and 428). Stroke (430–438). Cardiovascular procedures (668.1 and 997.1). Cardiovascular hemorrhage (aortic aneurysm and dissection: 441; cardiac tamponade: 423.3). Other cardiovascular causes (arterial embolism and thrombosis: 444). Cancers (140–208). | Fatal | ReactionOutcome | CC BY | 33655987 | 19,030,040 | 2021-03-05 |
What was the outcome of reaction 'Cerebrovascular accident'? | Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: A nationwide retrospective cohort study.
Type 2 diabetes mellitus (T2DM) is a progressive disease. After metformin failure, the addition of insulin or sulfonylureas might increase the risk of hypoglycemia and cardiovascular (CV) morbidity. Here, the risk of all-cause mortality was compared between early insulin treatment and glimepiride use in T2DM patients with background metformin therapy.We conducted a 9-year retrospective cohort study from the population-based National Health Insurance Research Database in Taiwan. A total of 2054 patients with T2DM under insulin or glimepiride treatment were enrolled during 2004 to 2012. Overall event rates of all-cause mortality were compared between 1027 insulin users and 1027 matched glimepiride users.After the propensity score matching, the mortality rates were 72.5 and 4.42 per 1000 person-years for insulin users and glimepiride users. The adjusted hazard ratio of mortality was 14.47 (95% CI: 8.64-24.24; P value <.001) as insulin compared with glimepiride users. The insulin users had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65-38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4-26.3, P < .001).The nationwide study demonstrated that metformin plus insulin therapy was associated with higher risk of all-cause mortality.
1 Introduction
Type 2 diabetes mellitus had the property of progressive β-cell failure. Upon diagnosis of diabetes, most patients were found to have a 50% decrease in their insulin secretion with a relentless 4% decline per year.[1] At last, most patients would require insulin treatment, alone or in combination with oral hypoglycemic agents.[2] United Kingdom Prospective Diabetes Study (UKPDS) suggested that earlier initiation of treatment was associated with better outcome.[3] There were also some reports which demonstrated that early intensive insulin treatment of hyperglycemia had favorable outcomes on recovery and maintenance of β-cell function with lengthened glycemic remission as compared with treatments of oral hypoglycemic agents.[4–6] The epidemiological studies disclosed that Asian diabetic patients had the characteristics of declining β-cell function more sharply than insulin sensitivity with age and rapid oral drug failure[7]; therefore the promotion of early insulin treatment in Asian patients was reasonable.
The UKPDS study[8] disclosed that intensive therapy with insulin or sulfonylureas (SU) had similar effect. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes and cancer occurrence.[9] But Holden et al[10] reported 6484 T2DM patients who progressed to treatment with insulin monotherapy, the adjusted hazard ratio (aHR) in relation to 1-unit increases in insulin dose was 1.54 for all-cause mortality and 1.35 for cancer. A retrospective cohort study of 63,579 diabetic patients treated in general practice disclosed that the aHR of association with serious atherosclerotic vascular disease of the heart was 1.3 for insulin.[11] One report from the Euro Heart Survey on Diabetes and the Heart disclosed that insulin therapy might relate to a more serious prognosis in patients with coronary artery disease (CAD) and diabetes.[12]
Sulfonylureas were prescribed in very large quantities due to their low cost and rapid lowering of glucose level. In recent years, there were always debates on the detrimental effect of SU in diabetic patients, including its possible CV morbidity and mortality;[13,14] some studies suggested avoiding the use of SU in diabetes treatment, especially after insulin initiation.[15] Both insulin and SU had the propensities of hypoglycemia, body weight increase and possibly CV injury. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications (including SU) vs no diabetes medications, and found that the insulin plus oral medications group had higher risk of getting CV events (odds ratio = 2.56). Currie et al[17] compared insulin based regimens with metformin plus SU, and found that the hazard ratio for all-cause mortality in people given insulin-based regimens vs those given combined oral agents was 1.49. Though, there were some reports implying the benefits of early insulin therapy, but these were all short-term clinical studies without long-term outcomes.[18] Many observational studies have also indicated that insulin therapy is more risky than oral hypoglycemic agents.[10–12,16,17] And there are currently few risk comparisons of using insulin vs sulfonylurea after metformin use. Therefore, we conducted this cohort study to see the risks of all-cause mortality between insulin and glimepiride use in T2DM patients with background metformin therapy.
2 Materials and methods
2.1 Data source
NHIRD contained the medical data of National Health Insurance (NHI), which had been implemented since March 1995, and over 99% of Taiwan residents had joined the NHI.[19] We used the data from Longitudinal Health Insurance database 2000 (LHID2000), a sub-dataset of NHIRD. The LHID2000 recorded the medical care data of 1 million people. The demographics of the LHID2000 were similar to the whole Taiwan population. In the LHID2000, the medical information included encrypted identification, demographics, the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes, surgery records and drug records.
2.2 Study design
Using the National Health Insurance Research Database (NHIRD), we investigated the difference of diabetes treatments in this population-based cohort study. We compared the adults of aged 18 to 100 years with metformin plus insulin vs metformin plus glimepiride therapy. Our study was approved by the Research Ethics Committee of China Medical University and Hospital, Taichung, Taiwan (CMUH104-REC2–115 (CR-2)). Our research was granted a waiver of informed consent. The information and records of patients were de-identified prior to analysis and encrypted the identification of each participant.
2.3 Study population
The study population consisted of diabetic patients (ICD-9-CM: 250.x) with metformin treatment excluding type 1 diabetic patients (250.1x). We categorized diabetic patients as insulin cohort or glimepiride cohort with underlying metformin treatment in 2004 to 2012 years. The insulin cohort contained type 2 diabetic patients with metfomin plus insulin treatment and exlcuded all concurrent sulfonylureas users. The glimepiride cohort contained type 2 diabetic patients with metfomin plus glimepiride treatmen. The index date was the time of receiving insulin or glimepiride.
2.4 Identification of confounders
The demographics of gender and age were confounders of this study. Baseline comorbidity was defined as having following diseases before the index date: coronary artery disease (ICD-9-CM: 410–414), stroke (ICD-9-CM: 430–438), hypertension (ICD-9-CM: 401–405), and dyslipidemia (ICD-9-CM: 272). We used the Charlson Comorbidity Index (CCI) to quantify patients’ comorbidity profiles.[20] We defined the severity of diabetes according to Diabetes Complications Severity Index (DCSI) score.[21] The CCI and DCSI scores were calculated using participant status 1 year before the index date. We also considered other drugs for diabetes such as thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) as possible confounders.
2.5 The primary outcome and causes of death
The primary outcome of this study was all- cause mortality. The observation period started from the index date to the withdrawal from the NHI or 31st December, 2013 or the date of death, whichever came first. We assessed the last primary diagnosis of discharge 3 months before death, to search for the causes of death.[22] The causes of CV death were according to the Standardized Definitions for End Point Events in Cardiovascular Trials.[23] Death due to other causes was defined as noncardiovascular death. The cases that we could not get last primary diagnosis 3 months before death were defined as undetermined.
2.6 Statistical methods
To match the insulin cohort and glimepiride cohort, we performed 1:1 propensity score matching[24] with the criteria of age, gender, comorbidities, CCI scores, DCSI scores and other antidiabetic drugs use. We summarized the variables in insulin and glimepiride cohorts, and compared those between 2 groups using Chi-Squared test for dichotomous variables and two-sample Student t test for continuous variables. In this study, we used simple and multivariable Cox proportional hazards regression models to estimate the excess risk of all-cause mortality for the insulin cohort compared to the glimepiride cohort. We calculated the crude and adjusted HR with corresponding 95% confidence intervals (95% CIs). The multivariable Cox proportional hazards regression models were done under the control of age, gender, comorbidities, other antidiabetic drugs, CCI and DCSI scores. The stratified analysis of each variable using Cox proportional hazards regression model was conducted in the outcome of mortality. The cumulative incidences of survival rate of each cohort were estimated using Kaplan–Meier method and examined by log-rank test.
All statistical analyses were conducted by the statistical software package, SAS, version 9.4 (SAS Institute, Inc., Cary, NC). P value less than .05 was the threshold of statistical significance in our study.
3 Results
From the data file of 2000 to 2012 years of LHID2000 (Fig. 1), there were 1798 patients injected insulin without using sulfonyureas and 6138 were treated with glimepiride with background metformin therapy. After excluding and matching, we enrolled 1027 diabetic patients in insulin and glimepiride cohorts, respectively. The mean (median) follow-up duration was 4.47 (3.16) and 4.72 (3.06) years for metformin plus insulin group and metformin plus glimepiride group. Men comprised 54.2% in the insulin group, and 55% in the glimepiride group (Table 1). Patients over 65 years old had the highest proportion in insulin cohort (49.4%), but a greater proportion was found in patients between 41 and 65 years old in the glimepiride cohort (48.7%). Between the 2 groups, only the distribution of age classification was notably different (P value = .011), there was no significant difference in mean age between the 2 populations (P value = .29).
Figure 1 The flow chart that identified the number of patients and study design.
Table 1 Demographic characteristics and co-morbidity of insulin group and glimepiride group in diabetic patients with background metformin therapy.
Glimepiride (N = 1027) Insulin (N = 1027)
n (%) n (%) P value
Gender .72∗
Women 462 (45) 470 (45.8)
Men 565 (55) 557 (54.2)
Age, years .011∗
≤40 37 (3.6) 63 (6.1)
41–65 500 (48.7) 457 (44.5)
>65 490 (47.7) 507 (49.4)
Mean (SD) 63.5 (12.5) 64.2 (14.6) .29†
Baseline comorbidity
Coronary artery disease 431 (42) 423 (41.2) .72∗
Stroke 337 (32.8) 311 (30.3) .22∗
Hypertension 746 (72.6) 752 (73.2) .77∗
Dyslipidemia 654 (63.7) 649 (63.2) .82∗
CCI scores .24∗
0, 1 346 (33.7) 381 (37.1)
2, 3 407 (39.6) 378 (36.8)
>3 274 (26.7) 268 (26.1)
DSCI scores .59∗
0 703 (68.5) 683 (66.5)
1 229 (22.3) 238 (23.2)
≥2 95 (9.3) 106 (10.3)
DM drugs
TZDs 117 (11.4) 107 (10.4) .48∗
Alpha glucosidase inhibitors 260 (25.3) 239 (23.3) .28∗
DPP-4i 208 (20.3) 197 (19.2) .54∗
Mean DM duration, days (medium) 1724 (1106) 1630 (1152)
The mortality risk was higher by 14.19-fold in the insulin cohort, as compared with the glimepiride cohort (95% CI = 8.48–23.75, P value < .001; Table 2). The gender of male also had higher risk of mortality (men aHR = 1.47, 95% CI = 1.09–1.99, P value = .01). Diabetic patients using alpha-glucosidase inhibitors or DPP-4i had lower risk of mortality (alpha-glucosidase inhibitors aHR = 0.54, 95% CI = 0.34–0.84, P value = .01; DPP-4i aHR = 0.26, 95% CI = 0.13–0.52, P value <.001).
Table 2 Cox model measured hazard ratio and 95% confidence intervals of death associated treatment groups and covariates in diabetic patients with background metformin therapy.
Event no. Crude Adjusted
Characteristics (n = 182) HR (95% CI) P value HR (95% CI) P value
Treatment
Glimepiride 16 1 reference 1 reference
Insulin 166 13.33 (7.97–22.28) <.001 14.19 (8.48–23.75) <.001
Gender
Women 73 1 reference 1 reference
Men 109 1.27 (0.95–1.71) .11 1.47 (1.09–1.99) .01
Age, years
≤40 7 1 reference 1 reference
41–65 50 0.74 (0.34–1.64) .47 0.78 (0.35–1.78) .56
>65 125 1.97 (0.92–4.22) .08 1.73 (0.76–3.95) .19
Baseline comorbidity
Coronary artery disease
No 92 1 reference 1 reference
Yes 90 1.43 (1.07–1.91) .02 1.1 (0.79–1.54) .56
Stroke
No 114 1 reference 1 reference
Yes 68 1.34 (0.99–1.81) .06 1.08 (0.79–1.48) .64
Hypertension
No 32 1 reference 1 reference
Yes 150 1.8 (1.23–2.63) .003 1.33 (0.87–2.03) .19
Dyslipidemia
No 76 1 reference 1 reference
Yes 106 0.79 (0.59–1.06) .11 0.73 (0.53–0.99) .05
CCI scores
0, 1 50 1 reference 1 reference
2, 3 73 1.38 (0.96–1.98) .08 1.29 (0.88–1.87) .19
>3 59 1.66 (1.14–2.42) .01 1.37 (0.91–2.07) .14
DSCI scores
0 116 1 reference 1 reference
1 46 1.21 (0.86–1.7) .28 0.92 (0.63–1.34) .67
≥2 20 1.17 (0.73–1.88) .52 0.66 (0.39–1.11) .11
DM drugs
TZDs
No 172 1 reference 1 reference
Yes 10 0.43 (0.23–0.81) .01 0.75 (0.39–1.43) .38
AGIs
No 159 1 reference 1 reference
Yes 23 0.43 (0.28–0.66) <.001 0.54 (0.34–0.84) .01
DPP-4i
No 173 1 reference 1 reference
Yes 9 0.19 (0.1–0.37) <.001 0.26 (0.13–0.52) <.001
The overall mortality rates in insulin and glimepiride cohort were 72.5 and 4.42 per 1000 person-years (Table 3). During the study period, the cumulative survival rate among insulin cohort was significantly lower than the cumulative survival rate among glimepiride cohort (P value <.001; Fig. 2). Table 3 showed the subgroup analysis of mortality of metformin plus insulin vs metform plus glimepiride. Notably, metfomin plus insulin had higher risk of mortlity among all the subgroups of genders, age, comorbidites, CCI scores DCSI scores, and other DM drugs use.
Table 3 Cox model of measured hazard ratio and 95% confidence intervals of mortality between insulin group and glimepiride group with background metformin therapy and covariates.
Metformin Insulin vs glimepiride
Glimepiride (n = 1027) Insulin (n = 1027)
Variables Event Person years IR† Event Person years IR† Crude HR (95% CI) Adjusted HR (95% CI)
Overall 16 3623 4.42 166 2290 72.5 13.33 (7.97–22.28)∗∗∗ 14.47 (8.64–24.24)∗∗∗
Gender
Women 3 1664 1.8 70 1097 63.8 29.03 (9.13–92.24)∗∗∗ 31.36 (9.83–100.05)∗∗∗
Men 13 1959 6.64 96 1193 80.4 9.7 (5.43–17.33)∗∗∗ 10.91 (6.08–19.57)∗∗∗
Age, years
≤40 0 148 0 7 163 43.0 20291126.21 (0-.) 128397943.32 (0-.)
41–65 2 1818 1.1 48 1179 40.7 30.03 (7.3–123.57)∗∗∗ 30.4 (7.37–125.34)∗∗∗
>65 14 1658 8.44 111 949 117 11.18 (6.4–19.52)∗∗∗ 11.88 (6.78–20.82)∗∗∗
Comorbidity
Coronary artery disease
No 6 2202 2.72 86 1398 61.5 17.78 (7.77–40.72)∗∗∗ 18.62 (8.11–42.75)∗∗∗
Yes 10 1421 7.04 80 892 89.7 10.68 (5.53–20.63)∗∗∗ 12.96 (6.65–25.24)∗∗∗
Stroke
No 7 2468 2.84 107 1663 64.4 18.18 (8.46–39.09)∗∗∗ 19.25 (8.94–41.44)∗∗∗
Yes 9 1155 7.79 59 627 94.0 10.16 (5.02–20.55)∗∗∗ 11.11 (5.43–22.74)∗∗∗
Hypertension
No 1 1011 0.99 31 660 46.9 38.09 (5.2–279.31)∗∗∗ 37.16 (5.05–273.56)∗∗∗
Yes 15 2612 5.74 135 1630 82.8 11.74 (6.88–20.03)∗∗∗ 12.79 (7.48–21.87)∗∗∗
Dyslipidemia
No 7 1396 5.01 69 794 86.9 13.38 (6.14–29.17)∗∗∗ 14.54 (6.6–32.02)∗∗∗
Yes 9 2227 4.04 97 1497 64.8 13.4 (6.77–26.55)∗∗∗ 14.77 (7.44–29.35)∗∗∗
CCI scores
0, 1 2 1302 1.54 48 938 51.2 26.68 (6.48–109.87)∗∗∗ 24.55 (5.93–101.6)∗∗∗
2, 3 5 1433 3.49 68 820 82.9 19.17 (7.72–47.6)∗∗∗ 21.04 (8.45–52.39)∗∗∗
>3 9 887 10.1 50 532 93.9 7.66 (3.76–15.6)∗∗∗ 8.72 (4.22–17.99)∗∗∗
DSCI scores
0 11 2464 4.46 105 1493 70.3 12.7 (6.82–23.67)∗∗∗ 13.98 (7.47–26.14)∗∗∗
1 2 789 2.53 44 510 86.3 26.89 (6.51–111.02)∗∗∗ 33.66 (8.07–140.48)∗∗∗
≥2 3 369 8.12 17 287 59.3 6.28 (1.84–21.45)∗∗ 6.42 (1.85–22.31)∗∗
DM drugs
TZDs
No 15 3112 4.82 157 2002 78.4 13.3 (7.82–22.6)∗∗∗ 14.35 (8.43–24.43)∗∗∗
Yes 1 511 1.96 9 288 31.2 13.92 (1.75–110.92)∗ 44.28 (3.43–572.18)∗∗
AGIs
No 14 2699 5.19 145 1705 85.1 13.23 (7.64–22.92)∗∗∗ 14.46 (8.33–25.09)∗∗∗
Yes 2 924 2.16 21 585 35.9 13.9 (3.25–59.44)∗∗∗ 14.57 (3.37–63.07)∗∗∗
DPP-4i
No 16 2801 5.71 157 1779 88.3 12.76 (7.63–21.36)∗∗∗ 13.61 (8.12–22.83)∗∗∗
Yes 0 822 0 9 512 17.6
Figure 2 The estimated survival rates between the insulin group and glimepiride group in diabetic patients with background metformin therapy by Kaplan–-Meier method.
The major identifiable causes of death of the insulin cohort included: 10 (0.97%) CV death (1 ischemic heart disease, 3 sudden cardiac deaths, 1 heart failure, 2 stroke, 3 CV hemorrhage); 142 (13.832%) noncardiovascular death (52 cancers, 90 others); and 14 (1.36%) undetermined cases. The major identifiable causes of death of the glimepiride cohort included: 2 (0.20%) CV death (1 heart failure, 1 strokes); 13 (1.27%) noncardiovascular death (3 cancers, 10 others); and 1 (0.10%) undetermined cases (Table 4). The insulin users, as compared with the glimepiride users, had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65–38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4–26.3, P < .001, Table 4).
Table 4 The causes of death of insulin vs glimepiride groups in patients with background metformin therapy.
Metformin Insulin vs glimepiride
Glimepiride n (%) Insulin n (%) Adjusted HR (95% CI) P value
Causes of CV death 2 (0.20) 10 (0.97) 7.95 (1.65–38.3) .01
Ischemic heart disease 0 1
Sudden cardiac death 0 3
Heart failure 1 1
Stroke 1 2
Cardiovascular procedure
Cardiovascular hemorrhage 0 3
Other cardiovascular causes
Non-cardiovascular causes of death 13 (1.27) 142 (13.83) 14.9 (8.4–26.3) <.001
Cancers 3 52
others 10 90
Undetermined 1 (0.10) 14 (1.36) 23.9 (3.1–184) .002
4 Discussion
We used a one to one propensity score matching to compare the risk of all-cause mortality between insulin and glimepiride users with background metformin therapy. Our results disclosed that insulin users had significantly higher risk of all-cause mortality, significantly higher risk of CV and noncardiovascular death. This overwhelming high risk of mortality was apparent across genders, age groups, baseline comorbidities, concurrent antidiabetic drugs use and DCSI scores.
The UKPDS study[8] disclosed that intensive therapy with insulin or SU had similar effect, but this study was not designed to compare these 2 regimens. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes, but the dose of insulin was very low (0.4 μ/kg/day) in quite early diabetic stage. Eleven percent of the placebo group also used exogenous insulin, which made the comparison not so adequate.[9] Margolis et al[11] conducted a retrospective cohort study and disclosed that insulin (aHR = 1.2) based treatment (including SU) was associated with an increased risk of myocardial infarction, and the risk increased with longer use. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications with no diabetic medications, the insulin based group had higher risk (odds ratio = 2.56) of getting CV events. The post-hoc analysis from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial on extended long-term outcome disclosed that insulin based treatment might be associated with increased risk of nonfatal cardiac events.[25] Hall et al[26] reported that adding insulin after 1 oral glucose-lowering drug (OGLD), when compared with adding another OGLD, had poor macrovascular outcomes. Currie et al[17] compared insulin based therapy with metformin plus SU regimens and found that insulin-based treatment had higher risk of all-cause mortality (HR = 1.49). Gamble et al[27] used the administrative databases of Saskatchewan Health to survey the cumulative insulin exposure based on total insulin dispensations per year. They observed a significant and graded association between mortality risk and insulin exposure. These were all insulin combined with oral medications including SU compared with oral medications or no medication, and showed that insulin based managements had higher risk of CV events and all-cause mortality.
As for the early use of insulin after metformin failure without adding SU compared with metformin plus SU. Roumie et al[28] reported the intensification of metformin with insulin vs sulfonylureas was associated with an increased risk of a composite of nonfatal CV outcomes and all-cause mortality in white male veterans. Mogensen et al[29] conducted a retrospective nationwide study in Danish individuals and disclosed that metformin combined with insulin had higher risk (rate ratios = 1.95) of all-cause mortality as compared with metformin plus SU. Our results were consistent with these 2 studies that early initiation of insulin after metformin failure, as compared with glimepiride, had high risk of all-cause mortality, CV and noncardiovascular death, after adjusting for all comorbidities and diabetes severity in a Chinese population.
The reasons why insulin might increase CV events and mortality in type 2 diabetes were many, including: insulin use might increase in body weight, raise the risk of hypoglycemia, and arrhythmias;[30] exogenous insulin using would increase insulin resistance and hyperinsulinemia,[31] which could exacerbate vascular inflammation,[32] alter vascular hemodynamic,[33] coagulopathy,[34] and cellular mitogenicity.[35]
Our cohort also disclosed that male (aHR = 1.43) and old-aged diabetic persons (>65 year old, aHR = 2.31) had higher risk of all-cause mortality, which were consistent with Taiwan's nationwide survey.[36] This cohort also showed that AGIs had lower risk of all-cause mortality (aHR = 0.48). Hanefeld conducted a meta-analysis of 7 long term studies and reported that acarbose could prevent myocardial infarction and CV disease in type 2 diabetic patients though most of them were already on intensive concomitant CV medication.[37] Our study also revealed that DPP-4 inhibitors using had lower risk of mortality, which was consistent with Monami meta-analysis.[38] But these 2 extra findings might need more rigorous matching study of insulin and other possible confounding factors to clarify them in the real word practice.
Our study had some strength. First, this was a population-based design and a real world finding, a 9-year follow-up data collected from the national insurance database. Second, the database contained a highly representative specimen of Taiwan's general population. Ninety nine percent of the entire 23 million people were enrolled in the national health insurance program. Third, we well matched the control group by using a propensity score calculated from age, gender, comorbidities, other oral antidiabetic drugs, DCSI scores, and diabetes duration to reduce probable confounding.
Nevertheless, our study was subjected to a few limitations. First, the NHIRD did not give patients’ information about lifestyle, physical activity, smoking habits, and family history; all were possible confounding factors in this study. To avoid this bias, we matched the DCSI scores, duration of diabetes, comorbidities, and other oral antidiabetic drugs to abate the influence of disease severity. Second, the database was dearth of biochemical blood test results that could tell us the treated condition of patients. Finally, this study was an observational cohort study instead of a randomized controlled trial. The results required further prospective clinical trials to verify.
5 Conclusions
In summary, our study disclosed that insulin vs glimepiride in patients with background metformin therapy had higher risk of all-cause mortality. For the most of patients with type 2 diabetes, there was no unambiguous evidence of benefit from insulin. Early insulin treatment in type 2 diabetic patient might associate with unacceptable risks.[39] However, insulin is the only option available to control blood glucose levels in the advanced stage of diabetes.
Acknowledgments
This manuscript was edited by Wallace Academic Editing.
Author contributions
Conceptualization: Fu-Shun Yen.
Data curation: Yuan-Chih Su, James Cheng-Chung Wei, Chii-Min Hwu.
Writing – original draft: Fu-Shun Yen, Chii-Min Hwu.
Writing – review & editing: Chih-Cheng Hsu, Yuan-Chih Su, James Cheng-Chung Wei.
Abbreviations: AGIs = alpha-glucosidase inhibitors, CAD = coronary artery disease, CCI = Charlson Comorbidity Index, CV = cardiovascular, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SU = sulfonylureas, T2DM = Type 2 diabetes mellitus, TZDs = thiazolidinediones.
How to cite this article: Yen FS, Hsu CC, Su YC, Wei JC, Hwu CM. Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: a nationwide retrospective cohort study. Medicine. 2021;100:9(e25085).
This work was supported by grants from the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005)., Tseng-Lien Lin Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in the study design, data collection and analysis and interpretation, and writing of the report. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication.
Data are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National Health Insurance (NHI) Bureau. The data utilized in this study cannot be made available in the paper, the supplemental files, or in a public repository due to the “Personal Information Protection Act” executed by Taiwan's government, starting from 2012. Requests for data can be sent as a formal proposal to the NHIRD (http://nhird.nhri.org.tw) or by email to nhird@nhri.org.tw.
The authors have no conflicts of interest to disclose.
The data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the third party.
∗ Chi-Squared test.
† Two sample t test.
CCI = Charlson Comorbidity Index, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SD = standard deviation, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase -4 inhibitors, HR = hazard ratio, TZDs = thiazolidinediones.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, HR = hazard ratio, IR = incidence rates, per 1,000 person-years, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
∗ p < .05.
∗∗ p < .01.
∗∗∗ p < .001.
Adjusted HR: adjusted for sex, age, comorbidities, medications, CCI score and DCSI score in Cox proportional hazards regression.
The codes of ICD-9-CM of diseases or procedures: Ischemic heart disease (myocardial infarction: 410, 411.0, 412, 429.79; coronary artery disease: 410–414, 429.2). Sudden cardiac death (sudden cardiac arrest: V12.53, cardiac arrhythmia: 427). Heart failure (398.91, 402.01, 402.11, 402.91, and 428). Stroke (430–438). Cardiovascular procedures (668.1 and 997.1). Cardiovascular hemorrhage (aortic aneurysm and dissection: 441; cardiac tamponade: 423.3). Other cardiovascular causes (arterial embolism and thrombosis: 444). Cancers (140–208). | Fatal | ReactionOutcome | CC BY | 33655987 | 19,030,039 | 2021-03-05 |
What was the outcome of reaction 'Myocardial ischaemia'? | Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: A nationwide retrospective cohort study.
Type 2 diabetes mellitus (T2DM) is a progressive disease. After metformin failure, the addition of insulin or sulfonylureas might increase the risk of hypoglycemia and cardiovascular (CV) morbidity. Here, the risk of all-cause mortality was compared between early insulin treatment and glimepiride use in T2DM patients with background metformin therapy.We conducted a 9-year retrospective cohort study from the population-based National Health Insurance Research Database in Taiwan. A total of 2054 patients with T2DM under insulin or glimepiride treatment were enrolled during 2004 to 2012. Overall event rates of all-cause mortality were compared between 1027 insulin users and 1027 matched glimepiride users.After the propensity score matching, the mortality rates were 72.5 and 4.42 per 1000 person-years for insulin users and glimepiride users. The adjusted hazard ratio of mortality was 14.47 (95% CI: 8.64-24.24; P value <.001) as insulin compared with glimepiride users. The insulin users had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65-38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4-26.3, P < .001).The nationwide study demonstrated that metformin plus insulin therapy was associated with higher risk of all-cause mortality.
1 Introduction
Type 2 diabetes mellitus had the property of progressive β-cell failure. Upon diagnosis of diabetes, most patients were found to have a 50% decrease in their insulin secretion with a relentless 4% decline per year.[1] At last, most patients would require insulin treatment, alone or in combination with oral hypoglycemic agents.[2] United Kingdom Prospective Diabetes Study (UKPDS) suggested that earlier initiation of treatment was associated with better outcome.[3] There were also some reports which demonstrated that early intensive insulin treatment of hyperglycemia had favorable outcomes on recovery and maintenance of β-cell function with lengthened glycemic remission as compared with treatments of oral hypoglycemic agents.[4–6] The epidemiological studies disclosed that Asian diabetic patients had the characteristics of declining β-cell function more sharply than insulin sensitivity with age and rapid oral drug failure[7]; therefore the promotion of early insulin treatment in Asian patients was reasonable.
The UKPDS study[8] disclosed that intensive therapy with insulin or sulfonylureas (SU) had similar effect. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes and cancer occurrence.[9] But Holden et al[10] reported 6484 T2DM patients who progressed to treatment with insulin monotherapy, the adjusted hazard ratio (aHR) in relation to 1-unit increases in insulin dose was 1.54 for all-cause mortality and 1.35 for cancer. A retrospective cohort study of 63,579 diabetic patients treated in general practice disclosed that the aHR of association with serious atherosclerotic vascular disease of the heart was 1.3 for insulin.[11] One report from the Euro Heart Survey on Diabetes and the Heart disclosed that insulin therapy might relate to a more serious prognosis in patients with coronary artery disease (CAD) and diabetes.[12]
Sulfonylureas were prescribed in very large quantities due to their low cost and rapid lowering of glucose level. In recent years, there were always debates on the detrimental effect of SU in diabetic patients, including its possible CV morbidity and mortality;[13,14] some studies suggested avoiding the use of SU in diabetes treatment, especially after insulin initiation.[15] Both insulin and SU had the propensities of hypoglycemia, body weight increase and possibly CV injury. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications (including SU) vs no diabetes medications, and found that the insulin plus oral medications group had higher risk of getting CV events (odds ratio = 2.56). Currie et al[17] compared insulin based regimens with metformin plus SU, and found that the hazard ratio for all-cause mortality in people given insulin-based regimens vs those given combined oral agents was 1.49. Though, there were some reports implying the benefits of early insulin therapy, but these were all short-term clinical studies without long-term outcomes.[18] Many observational studies have also indicated that insulin therapy is more risky than oral hypoglycemic agents.[10–12,16,17] And there are currently few risk comparisons of using insulin vs sulfonylurea after metformin use. Therefore, we conducted this cohort study to see the risks of all-cause mortality between insulin and glimepiride use in T2DM patients with background metformin therapy.
2 Materials and methods
2.1 Data source
NHIRD contained the medical data of National Health Insurance (NHI), which had been implemented since March 1995, and over 99% of Taiwan residents had joined the NHI.[19] We used the data from Longitudinal Health Insurance database 2000 (LHID2000), a sub-dataset of NHIRD. The LHID2000 recorded the medical care data of 1 million people. The demographics of the LHID2000 were similar to the whole Taiwan population. In the LHID2000, the medical information included encrypted identification, demographics, the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes, surgery records and drug records.
2.2 Study design
Using the National Health Insurance Research Database (NHIRD), we investigated the difference of diabetes treatments in this population-based cohort study. We compared the adults of aged 18 to 100 years with metformin plus insulin vs metformin plus glimepiride therapy. Our study was approved by the Research Ethics Committee of China Medical University and Hospital, Taichung, Taiwan (CMUH104-REC2–115 (CR-2)). Our research was granted a waiver of informed consent. The information and records of patients were de-identified prior to analysis and encrypted the identification of each participant.
2.3 Study population
The study population consisted of diabetic patients (ICD-9-CM: 250.x) with metformin treatment excluding type 1 diabetic patients (250.1x). We categorized diabetic patients as insulin cohort or glimepiride cohort with underlying metformin treatment in 2004 to 2012 years. The insulin cohort contained type 2 diabetic patients with metfomin plus insulin treatment and exlcuded all concurrent sulfonylureas users. The glimepiride cohort contained type 2 diabetic patients with metfomin plus glimepiride treatmen. The index date was the time of receiving insulin or glimepiride.
2.4 Identification of confounders
The demographics of gender and age were confounders of this study. Baseline comorbidity was defined as having following diseases before the index date: coronary artery disease (ICD-9-CM: 410–414), stroke (ICD-9-CM: 430–438), hypertension (ICD-9-CM: 401–405), and dyslipidemia (ICD-9-CM: 272). We used the Charlson Comorbidity Index (CCI) to quantify patients’ comorbidity profiles.[20] We defined the severity of diabetes according to Diabetes Complications Severity Index (DCSI) score.[21] The CCI and DCSI scores were calculated using participant status 1 year before the index date. We also considered other drugs for diabetes such as thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) as possible confounders.
2.5 The primary outcome and causes of death
The primary outcome of this study was all- cause mortality. The observation period started from the index date to the withdrawal from the NHI or 31st December, 2013 or the date of death, whichever came first. We assessed the last primary diagnosis of discharge 3 months before death, to search for the causes of death.[22] The causes of CV death were according to the Standardized Definitions for End Point Events in Cardiovascular Trials.[23] Death due to other causes was defined as noncardiovascular death. The cases that we could not get last primary diagnosis 3 months before death were defined as undetermined.
2.6 Statistical methods
To match the insulin cohort and glimepiride cohort, we performed 1:1 propensity score matching[24] with the criteria of age, gender, comorbidities, CCI scores, DCSI scores and other antidiabetic drugs use. We summarized the variables in insulin and glimepiride cohorts, and compared those between 2 groups using Chi-Squared test for dichotomous variables and two-sample Student t test for continuous variables. In this study, we used simple and multivariable Cox proportional hazards regression models to estimate the excess risk of all-cause mortality for the insulin cohort compared to the glimepiride cohort. We calculated the crude and adjusted HR with corresponding 95% confidence intervals (95% CIs). The multivariable Cox proportional hazards regression models were done under the control of age, gender, comorbidities, other antidiabetic drugs, CCI and DCSI scores. The stratified analysis of each variable using Cox proportional hazards regression model was conducted in the outcome of mortality. The cumulative incidences of survival rate of each cohort were estimated using Kaplan–Meier method and examined by log-rank test.
All statistical analyses were conducted by the statistical software package, SAS, version 9.4 (SAS Institute, Inc., Cary, NC). P value less than .05 was the threshold of statistical significance in our study.
3 Results
From the data file of 2000 to 2012 years of LHID2000 (Fig. 1), there were 1798 patients injected insulin without using sulfonyureas and 6138 were treated with glimepiride with background metformin therapy. After excluding and matching, we enrolled 1027 diabetic patients in insulin and glimepiride cohorts, respectively. The mean (median) follow-up duration was 4.47 (3.16) and 4.72 (3.06) years for metformin plus insulin group and metformin plus glimepiride group. Men comprised 54.2% in the insulin group, and 55% in the glimepiride group (Table 1). Patients over 65 years old had the highest proportion in insulin cohort (49.4%), but a greater proportion was found in patients between 41 and 65 years old in the glimepiride cohort (48.7%). Between the 2 groups, only the distribution of age classification was notably different (P value = .011), there was no significant difference in mean age between the 2 populations (P value = .29).
Figure 1 The flow chart that identified the number of patients and study design.
Table 1 Demographic characteristics and co-morbidity of insulin group and glimepiride group in diabetic patients with background metformin therapy.
Glimepiride (N = 1027) Insulin (N = 1027)
n (%) n (%) P value
Gender .72∗
Women 462 (45) 470 (45.8)
Men 565 (55) 557 (54.2)
Age, years .011∗
≤40 37 (3.6) 63 (6.1)
41–65 500 (48.7) 457 (44.5)
>65 490 (47.7) 507 (49.4)
Mean (SD) 63.5 (12.5) 64.2 (14.6) .29†
Baseline comorbidity
Coronary artery disease 431 (42) 423 (41.2) .72∗
Stroke 337 (32.8) 311 (30.3) .22∗
Hypertension 746 (72.6) 752 (73.2) .77∗
Dyslipidemia 654 (63.7) 649 (63.2) .82∗
CCI scores .24∗
0, 1 346 (33.7) 381 (37.1)
2, 3 407 (39.6) 378 (36.8)
>3 274 (26.7) 268 (26.1)
DSCI scores .59∗
0 703 (68.5) 683 (66.5)
1 229 (22.3) 238 (23.2)
≥2 95 (9.3) 106 (10.3)
DM drugs
TZDs 117 (11.4) 107 (10.4) .48∗
Alpha glucosidase inhibitors 260 (25.3) 239 (23.3) .28∗
DPP-4i 208 (20.3) 197 (19.2) .54∗
Mean DM duration, days (medium) 1724 (1106) 1630 (1152)
The mortality risk was higher by 14.19-fold in the insulin cohort, as compared with the glimepiride cohort (95% CI = 8.48–23.75, P value < .001; Table 2). The gender of male also had higher risk of mortality (men aHR = 1.47, 95% CI = 1.09–1.99, P value = .01). Diabetic patients using alpha-glucosidase inhibitors or DPP-4i had lower risk of mortality (alpha-glucosidase inhibitors aHR = 0.54, 95% CI = 0.34–0.84, P value = .01; DPP-4i aHR = 0.26, 95% CI = 0.13–0.52, P value <.001).
Table 2 Cox model measured hazard ratio and 95% confidence intervals of death associated treatment groups and covariates in diabetic patients with background metformin therapy.
Event no. Crude Adjusted
Characteristics (n = 182) HR (95% CI) P value HR (95% CI) P value
Treatment
Glimepiride 16 1 reference 1 reference
Insulin 166 13.33 (7.97–22.28) <.001 14.19 (8.48–23.75) <.001
Gender
Women 73 1 reference 1 reference
Men 109 1.27 (0.95–1.71) .11 1.47 (1.09–1.99) .01
Age, years
≤40 7 1 reference 1 reference
41–65 50 0.74 (0.34–1.64) .47 0.78 (0.35–1.78) .56
>65 125 1.97 (0.92–4.22) .08 1.73 (0.76–3.95) .19
Baseline comorbidity
Coronary artery disease
No 92 1 reference 1 reference
Yes 90 1.43 (1.07–1.91) .02 1.1 (0.79–1.54) .56
Stroke
No 114 1 reference 1 reference
Yes 68 1.34 (0.99–1.81) .06 1.08 (0.79–1.48) .64
Hypertension
No 32 1 reference 1 reference
Yes 150 1.8 (1.23–2.63) .003 1.33 (0.87–2.03) .19
Dyslipidemia
No 76 1 reference 1 reference
Yes 106 0.79 (0.59–1.06) .11 0.73 (0.53–0.99) .05
CCI scores
0, 1 50 1 reference 1 reference
2, 3 73 1.38 (0.96–1.98) .08 1.29 (0.88–1.87) .19
>3 59 1.66 (1.14–2.42) .01 1.37 (0.91–2.07) .14
DSCI scores
0 116 1 reference 1 reference
1 46 1.21 (0.86–1.7) .28 0.92 (0.63–1.34) .67
≥2 20 1.17 (0.73–1.88) .52 0.66 (0.39–1.11) .11
DM drugs
TZDs
No 172 1 reference 1 reference
Yes 10 0.43 (0.23–0.81) .01 0.75 (0.39–1.43) .38
AGIs
No 159 1 reference 1 reference
Yes 23 0.43 (0.28–0.66) <.001 0.54 (0.34–0.84) .01
DPP-4i
No 173 1 reference 1 reference
Yes 9 0.19 (0.1–0.37) <.001 0.26 (0.13–0.52) <.001
The overall mortality rates in insulin and glimepiride cohort were 72.5 and 4.42 per 1000 person-years (Table 3). During the study period, the cumulative survival rate among insulin cohort was significantly lower than the cumulative survival rate among glimepiride cohort (P value <.001; Fig. 2). Table 3 showed the subgroup analysis of mortality of metformin plus insulin vs metform plus glimepiride. Notably, metfomin plus insulin had higher risk of mortlity among all the subgroups of genders, age, comorbidites, CCI scores DCSI scores, and other DM drugs use.
Table 3 Cox model of measured hazard ratio and 95% confidence intervals of mortality between insulin group and glimepiride group with background metformin therapy and covariates.
Metformin Insulin vs glimepiride
Glimepiride (n = 1027) Insulin (n = 1027)
Variables Event Person years IR† Event Person years IR† Crude HR (95% CI) Adjusted HR (95% CI)
Overall 16 3623 4.42 166 2290 72.5 13.33 (7.97–22.28)∗∗∗ 14.47 (8.64–24.24)∗∗∗
Gender
Women 3 1664 1.8 70 1097 63.8 29.03 (9.13–92.24)∗∗∗ 31.36 (9.83–100.05)∗∗∗
Men 13 1959 6.64 96 1193 80.4 9.7 (5.43–17.33)∗∗∗ 10.91 (6.08–19.57)∗∗∗
Age, years
≤40 0 148 0 7 163 43.0 20291126.21 (0-.) 128397943.32 (0-.)
41–65 2 1818 1.1 48 1179 40.7 30.03 (7.3–123.57)∗∗∗ 30.4 (7.37–125.34)∗∗∗
>65 14 1658 8.44 111 949 117 11.18 (6.4–19.52)∗∗∗ 11.88 (6.78–20.82)∗∗∗
Comorbidity
Coronary artery disease
No 6 2202 2.72 86 1398 61.5 17.78 (7.77–40.72)∗∗∗ 18.62 (8.11–42.75)∗∗∗
Yes 10 1421 7.04 80 892 89.7 10.68 (5.53–20.63)∗∗∗ 12.96 (6.65–25.24)∗∗∗
Stroke
No 7 2468 2.84 107 1663 64.4 18.18 (8.46–39.09)∗∗∗ 19.25 (8.94–41.44)∗∗∗
Yes 9 1155 7.79 59 627 94.0 10.16 (5.02–20.55)∗∗∗ 11.11 (5.43–22.74)∗∗∗
Hypertension
No 1 1011 0.99 31 660 46.9 38.09 (5.2–279.31)∗∗∗ 37.16 (5.05–273.56)∗∗∗
Yes 15 2612 5.74 135 1630 82.8 11.74 (6.88–20.03)∗∗∗ 12.79 (7.48–21.87)∗∗∗
Dyslipidemia
No 7 1396 5.01 69 794 86.9 13.38 (6.14–29.17)∗∗∗ 14.54 (6.6–32.02)∗∗∗
Yes 9 2227 4.04 97 1497 64.8 13.4 (6.77–26.55)∗∗∗ 14.77 (7.44–29.35)∗∗∗
CCI scores
0, 1 2 1302 1.54 48 938 51.2 26.68 (6.48–109.87)∗∗∗ 24.55 (5.93–101.6)∗∗∗
2, 3 5 1433 3.49 68 820 82.9 19.17 (7.72–47.6)∗∗∗ 21.04 (8.45–52.39)∗∗∗
>3 9 887 10.1 50 532 93.9 7.66 (3.76–15.6)∗∗∗ 8.72 (4.22–17.99)∗∗∗
DSCI scores
0 11 2464 4.46 105 1493 70.3 12.7 (6.82–23.67)∗∗∗ 13.98 (7.47–26.14)∗∗∗
1 2 789 2.53 44 510 86.3 26.89 (6.51–111.02)∗∗∗ 33.66 (8.07–140.48)∗∗∗
≥2 3 369 8.12 17 287 59.3 6.28 (1.84–21.45)∗∗ 6.42 (1.85–22.31)∗∗
DM drugs
TZDs
No 15 3112 4.82 157 2002 78.4 13.3 (7.82–22.6)∗∗∗ 14.35 (8.43–24.43)∗∗∗
Yes 1 511 1.96 9 288 31.2 13.92 (1.75–110.92)∗ 44.28 (3.43–572.18)∗∗
AGIs
No 14 2699 5.19 145 1705 85.1 13.23 (7.64–22.92)∗∗∗ 14.46 (8.33–25.09)∗∗∗
Yes 2 924 2.16 21 585 35.9 13.9 (3.25–59.44)∗∗∗ 14.57 (3.37–63.07)∗∗∗
DPP-4i
No 16 2801 5.71 157 1779 88.3 12.76 (7.63–21.36)∗∗∗ 13.61 (8.12–22.83)∗∗∗
Yes 0 822 0 9 512 17.6
Figure 2 The estimated survival rates between the insulin group and glimepiride group in diabetic patients with background metformin therapy by Kaplan–-Meier method.
The major identifiable causes of death of the insulin cohort included: 10 (0.97%) CV death (1 ischemic heart disease, 3 sudden cardiac deaths, 1 heart failure, 2 stroke, 3 CV hemorrhage); 142 (13.832%) noncardiovascular death (52 cancers, 90 others); and 14 (1.36%) undetermined cases. The major identifiable causes of death of the glimepiride cohort included: 2 (0.20%) CV death (1 heart failure, 1 strokes); 13 (1.27%) noncardiovascular death (3 cancers, 10 others); and 1 (0.10%) undetermined cases (Table 4). The insulin users, as compared with the glimepiride users, had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65–38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4–26.3, P < .001, Table 4).
Table 4 The causes of death of insulin vs glimepiride groups in patients with background metformin therapy.
Metformin Insulin vs glimepiride
Glimepiride n (%) Insulin n (%) Adjusted HR (95% CI) P value
Causes of CV death 2 (0.20) 10 (0.97) 7.95 (1.65–38.3) .01
Ischemic heart disease 0 1
Sudden cardiac death 0 3
Heart failure 1 1
Stroke 1 2
Cardiovascular procedure
Cardiovascular hemorrhage 0 3
Other cardiovascular causes
Non-cardiovascular causes of death 13 (1.27) 142 (13.83) 14.9 (8.4–26.3) <.001
Cancers 3 52
others 10 90
Undetermined 1 (0.10) 14 (1.36) 23.9 (3.1–184) .002
4 Discussion
We used a one to one propensity score matching to compare the risk of all-cause mortality between insulin and glimepiride users with background metformin therapy. Our results disclosed that insulin users had significantly higher risk of all-cause mortality, significantly higher risk of CV and noncardiovascular death. This overwhelming high risk of mortality was apparent across genders, age groups, baseline comorbidities, concurrent antidiabetic drugs use and DCSI scores.
The UKPDS study[8] disclosed that intensive therapy with insulin or SU had similar effect, but this study was not designed to compare these 2 regimens. The ORIGIN trial demonstrated that the use of basal insulin was safe on CV outcomes, but the dose of insulin was very low (0.4 μ/kg/day) in quite early diabetic stage. Eleven percent of the placebo group also used exogenous insulin, which made the comparison not so adequate.[9] Margolis et al[11] conducted a retrospective cohort study and disclosed that insulin (aHR = 1.2) based treatment (including SU) was associated with an increased risk of myocardial infarction, and the risk increased with longer use. Colayco et al[16] conducted a nested case-control study to compare insulin plus oral medications with no diabetic medications, the insulin based group had higher risk (odds ratio = 2.56) of getting CV events. The post-hoc analysis from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial on extended long-term outcome disclosed that insulin based treatment might be associated with increased risk of nonfatal cardiac events.[25] Hall et al[26] reported that adding insulin after 1 oral glucose-lowering drug (OGLD), when compared with adding another OGLD, had poor macrovascular outcomes. Currie et al[17] compared insulin based therapy with metformin plus SU regimens and found that insulin-based treatment had higher risk of all-cause mortality (HR = 1.49). Gamble et al[27] used the administrative databases of Saskatchewan Health to survey the cumulative insulin exposure based on total insulin dispensations per year. They observed a significant and graded association between mortality risk and insulin exposure. These were all insulin combined with oral medications including SU compared with oral medications or no medication, and showed that insulin based managements had higher risk of CV events and all-cause mortality.
As for the early use of insulin after metformin failure without adding SU compared with metformin plus SU. Roumie et al[28] reported the intensification of metformin with insulin vs sulfonylureas was associated with an increased risk of a composite of nonfatal CV outcomes and all-cause mortality in white male veterans. Mogensen et al[29] conducted a retrospective nationwide study in Danish individuals and disclosed that metformin combined with insulin had higher risk (rate ratios = 1.95) of all-cause mortality as compared with metformin plus SU. Our results were consistent with these 2 studies that early initiation of insulin after metformin failure, as compared with glimepiride, had high risk of all-cause mortality, CV and noncardiovascular death, after adjusting for all comorbidities and diabetes severity in a Chinese population.
The reasons why insulin might increase CV events and mortality in type 2 diabetes were many, including: insulin use might increase in body weight, raise the risk of hypoglycemia, and arrhythmias;[30] exogenous insulin using would increase insulin resistance and hyperinsulinemia,[31] which could exacerbate vascular inflammation,[32] alter vascular hemodynamic,[33] coagulopathy,[34] and cellular mitogenicity.[35]
Our cohort also disclosed that male (aHR = 1.43) and old-aged diabetic persons (>65 year old, aHR = 2.31) had higher risk of all-cause mortality, which were consistent with Taiwan's nationwide survey.[36] This cohort also showed that AGIs had lower risk of all-cause mortality (aHR = 0.48). Hanefeld conducted a meta-analysis of 7 long term studies and reported that acarbose could prevent myocardial infarction and CV disease in type 2 diabetic patients though most of them were already on intensive concomitant CV medication.[37] Our study also revealed that DPP-4 inhibitors using had lower risk of mortality, which was consistent with Monami meta-analysis.[38] But these 2 extra findings might need more rigorous matching study of insulin and other possible confounding factors to clarify them in the real word practice.
Our study had some strength. First, this was a population-based design and a real world finding, a 9-year follow-up data collected from the national insurance database. Second, the database contained a highly representative specimen of Taiwan's general population. Ninety nine percent of the entire 23 million people were enrolled in the national health insurance program. Third, we well matched the control group by using a propensity score calculated from age, gender, comorbidities, other oral antidiabetic drugs, DCSI scores, and diabetes duration to reduce probable confounding.
Nevertheless, our study was subjected to a few limitations. First, the NHIRD did not give patients’ information about lifestyle, physical activity, smoking habits, and family history; all were possible confounding factors in this study. To avoid this bias, we matched the DCSI scores, duration of diabetes, comorbidities, and other oral antidiabetic drugs to abate the influence of disease severity. Second, the database was dearth of biochemical blood test results that could tell us the treated condition of patients. Finally, this study was an observational cohort study instead of a randomized controlled trial. The results required further prospective clinical trials to verify.
5 Conclusions
In summary, our study disclosed that insulin vs glimepiride in patients with background metformin therapy had higher risk of all-cause mortality. For the most of patients with type 2 diabetes, there was no unambiguous evidence of benefit from insulin. Early insulin treatment in type 2 diabetic patient might associate with unacceptable risks.[39] However, insulin is the only option available to control blood glucose levels in the advanced stage of diabetes.
Acknowledgments
This manuscript was edited by Wallace Academic Editing.
Author contributions
Conceptualization: Fu-Shun Yen.
Data curation: Yuan-Chih Su, James Cheng-Chung Wei, Chii-Min Hwu.
Writing – original draft: Fu-Shun Yen, Chii-Min Hwu.
Writing – review & editing: Chih-Cheng Hsu, Yuan-Chih Su, James Cheng-Chung Wei.
Abbreviations: AGIs = alpha-glucosidase inhibitors, CAD = coronary artery disease, CCI = Charlson Comorbidity Index, CV = cardiovascular, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SU = sulfonylureas, T2DM = Type 2 diabetes mellitus, TZDs = thiazolidinediones.
How to cite this article: Yen FS, Hsu CC, Su YC, Wei JC, Hwu CM. Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: a nationwide retrospective cohort study. Medicine. 2021;100:9(e25085).
This work was supported by grants from the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005)., Tseng-Lien Lin Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in the study design, data collection and analysis and interpretation, and writing of the report. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication.
Data are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National Health Insurance (NHI) Bureau. The data utilized in this study cannot be made available in the paper, the supplemental files, or in a public repository due to the “Personal Information Protection Act” executed by Taiwan's government, starting from 2012. Requests for data can be sent as a formal proposal to the NHIRD (http://nhird.nhri.org.tw) or by email to nhird@nhri.org.tw.
The authors have no conflicts of interest to disclose.
The data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the third party.
∗ Chi-Squared test.
† Two sample t test.
CCI = Charlson Comorbidity Index, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, SD = standard deviation, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase -4 inhibitors, HR = hazard ratio, TZDs = thiazolidinediones.
AGIs = Alpha glucosidase inhibitors, CCI = Charlson Comorbidity Index, CI = confidence interval, DCSI = Diabetes Complications Severity Index, DPP-4i = dipeptidyl peptidase-4 inhibitors, HR = hazard ratio, IR = incidence rates, per 1,000 person-years, TZDs = thiazolidinediones.
Adjusted HR: adjusted for sex, age, coronary artery disease, stroke, dyslipidemia, hypertension, TZDs, alpha glucosidase inhibitors, DPP-4 inhibitors, CCI score and DCSI score in Cox proportional hazards regression.
∗ p < .05.
∗∗ p < .01.
∗∗∗ p < .001.
Adjusted HR: adjusted for sex, age, comorbidities, medications, CCI score and DCSI score in Cox proportional hazards regression.
The codes of ICD-9-CM of diseases or procedures: Ischemic heart disease (myocardial infarction: 410, 411.0, 412, 429.79; coronary artery disease: 410–414, 429.2). Sudden cardiac death (sudden cardiac arrest: V12.53, cardiac arrhythmia: 427). Heart failure (398.91, 402.01, 402.11, 402.91, and 428). Stroke (430–438). Cardiovascular procedures (668.1 and 997.1). Cardiovascular hemorrhage (aortic aneurysm and dissection: 441; cardiac tamponade: 423.3). Other cardiovascular causes (arterial embolism and thrombosis: 444). Cancers (140–208). | Fatal | ReactionOutcome | CC BY | 33655987 | 19,029,014 | 2021-03-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer.
OBJECTIVE
Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting.
METHODS
This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting.
RESULTS
The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity.
CONCLUSIONS
These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.
INTRODUCTION
Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths both in men and women worldwide, with an estimated 1.7 million deaths in 2018. 1 Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. 2 Clinical outcomes and treatment strategies for NSCLC are directly related to stage at diagnosis. Unfortunately, only 25% of the patients with NSCLC have non-metastatic disease at diagnosis, and recurrence rates are often high even when patients are treated with curative intent. 3
In order to improve patient outcomes, adjuvant cisplatin-based chemotherapy after surgical resection has been extensively studied in the last decades. 4 - 8 The Adjuvant Navelbine International Trialist Association (ANITA) trial 4 demonstrated that cisplatin and vinorelbine significantly improve five-year survival rates (by 8,6%; p = 0,017) in patients with stage IB-IIIA NSCLC. However, a subgroup analysis indicated that the benefit is mainly seen in patients with stage II or IIIA disease. 4 )
The benefit of adjuvant chemotherapy in NSCLC was confirmed in a meta-analysis evaluating more than 4.500 patients in five clinical trials. 5 It showed that platinum-based adjuvant chemotherapy resulted in a 5.4% absolute improvement in overall survival (OS) in patients with stage II or III NSCLC (hazard ratio [HR] = 0.89; 95% CI: 0.82-0.96; p = 0.005). 5 Based on these results, platinum-based adjuvant chemotherapy has become the standard of care for patients with completely resected stage II or IIIA NSCLC, and the most commonly used regimen is a combination of cisplatin and vinorelbine. 4 - 8
Although effectiveness of the cisplatin-vinorelbine regimen has been well established, the combination of cisplatin and vinorelbine is associated with clinically relevant toxicity. High rates of grade 3-4 adverse events can compromise treatment adherence, leading to dose reductions and delays, as well as to treatment discontinuation, which is known to be associated with worse outcomes. 4 - 8 Studies providing real-world data on long-term efficacy and safety of adjuvant chemotherapy in NSCLC are scarce and have heterogeneous methods and outcomes. Therefore, the primary objective of the present study was to evaluate the effectiveness and safety of adjuvant chemotherapy for NSCLC patients in a real-world setting.
METHODS
Study design and participants
In this retrospective cohort study, patients undergoing surgical treatment for localized NSCLC were consecutively evaluated and treated between June of 2009 and January of 2018 at the Instituto do Câncer do Estado de São Paulo (ICESP), located in the city of São Paulo, Brazil. The ICESP has a dedicated multidisciplinary thoracic oncology team responsible for evaluating and discussing the cases of patients considered candidates for surgery with curative intent.
We included patients with histologically confirmed NSCLC and TNM stage I-III NSCLC 3 undergoing surgery with curative intent. In accordance with the institutional guidelines, all patients were submitted to pre-operative staging with CT or PET/CT to exclude metastases and with mediastinoscopy or EBUS for mediastinal staging, when indicated. Exclusion criteria included metastatic disease, primary tumor not amenable to complete resection, and a concurrent diagnosis of other malignancies. Data on clinical and demographic characteristics, as well as on treatment received, toxicity, and oncologic outcomes were obtained from electronic medical records. The study was approved by the local research ethics committee (ID 1011/16).
Treatment
The thoracic surgery team defined the type of surgery required to achieve a tumor-free resection margins (lobectomy or pneumonectomy and lymph node dissection) by using an open surgery or video-assisted thoracic surgery, in accordance with the International Association for the Study of Lung Cancer recommendations. 2 , 3
Adjuvant chemotherapy, radiation therapy, or both were prescribed at the discretion of the physicians involved, in accordance with institutional guidelines or by tumor board consensus. At our institution during the study period, adjuvant chemotherapy was recommended for patients with completely resected stage II-III NSCLC and was considered on a case-by-case basis in patients with stage IB NSCLC. In addition, patients must have an ECOG performance status of 0-1 and adequate hepatic, renal, and hematological function. Standard adjuvant chemotherapy as defined by institutional guidelines is cisplatin (80 mg/m2 on day 1) and vinorelbine (30 mg/m2 on days 1, 8, and 15) every three weeks for four cycles. Alternative platinum-based chemotherapy regimens are allowed in specific settings. Although adjuvant radiation therapy is not part of our routine protocol, it was considered on a case-by-case basis in patients with positive margins or N2 lymph node status.
Statistical analysis
Patient characteristics and treatment-related toxicities were summarized by descriptive statistics. Continuous variables were expressed as median and range, whereas categorical variables were presented as absolute numbers and proportions. Differences in continuous variables between the groups were evaluated by Student’s t-test. Categorical variables were compared between groups with the use of Fisher’s exact test.
The Kaplan-Meier method was used in order to estimate survival function, and curves were compared by the log-rank test. The primary outcome was OS, defined as the time from the date of surgery to the date of death from any cause or the date of the last medical visit. Recurrence-free survival (RFS) was also analyzed and defined as the time from surgery to disease recurrence or death. Patients presenting with no events of interest were censored at the last follow-up date.
Potential prognostic factors were evaluated by univariate and multivariate analysis with Cox proportional hazards regression, which provided the HR and 95% CI. Prognostic factors evaluated in the univariate analysis included age, gender, TNM stage, lymph node status, histology, and use of adjuvant chemotherapy. For the multivariate model, we included the use of adjuvant chemotherapy and factors showing p ≤ 0.10 in the univariate analysis as long as they were not associated with each other. The chi-square test was used in order to evaluate the association between variables.
Statistical analyses were conducted with the Stata statistical software package, version 15.1 (StataCorp LP, College Station, TX, USA). The level of significance was set at 5% (p < 0.05).
RESULTS
Patient characteristics
The study included 231 consecutive patients who met the eligibility criteria. The median follow-up time was 24 months. Of the 231 patients, 80 patients received adjuvant chemotherapy, and 151 were followed after surgical treatment (controls). Of the 80 patients who received adjuvant chemotherapy, 55 patients (68%) received the cisplatin-vinorelbine regimen. Alternative regimens included carboplatin and paclitaxel (n = 17; 21.2%), cisplatin and gemcitabine (n = 5; 6.2%), cisplatin and paclitaxel (n = 1; 1.2%), and carboplatin and vinorelbine (n = 1; 1.2%). Among the patients who received cisplatin and vinorelbine, the median cumulative dose of cisplatin was 286 mg/m2 (range: 72-320 mg/m2), and that of vinorelbine was 292 mg/m2 (range: 60-360 mg/m2).
Patients in the adjuvant chemotherapy group were younger than those in the control group (median age: 63.0 years vs. 67.6 years; p < 0.001) and more frequently underwent pneumonectomy (15.0% vs. 7.9%; p < 0.005). The proportion of early stage disease was higher in the control group, with stage I NSCLC in 56.3% (p < 0.001) and negative lymph nodes (N0) in 67.5% (p < 0.001). Of the patients who received adjuvant chemotherapy, only 2.5% had stage I NSCLC, and 31.2% had negative lymph nodes (N0). Table 1 summarizes the characteristics of the study participants.
Table 1 Characteristics of the patients included in the study (N = 231).a
Characteristic Group P
Adjuvant chemotherapy No adjuvant chemotherapy
(n = 80) (n = 151)
Age, years 63.0 [45.3-79.1] 68.3 [34.0-87.9] < 0.001*
Sex
Male
Female
36 (45.0)
44 (55.0)
73 (48.3)
78 (51.7) 0.388†
Type of surgery
Pneumonectomy
Lobectomy
Other
12 (15.0)
61 (76.2)
7 (8.7)
12 (7.9)
134 (88.7)
5 (3.3) 0.005†
Histology
SCC
Adenocarcinoma
Other
Not available
21 (26.2)
53 (66.2)
6 (7.5)
0 (0)
48 (31.8)
92 (60.9)
10 (6.6)
1 (0.7) 0.747†
Stage
I
II
III
Not available
2 (2.5)
44 (54.9)
34 (42.5)
0 (0)
85 (56.3)
41 (27.1)
24 (15.9)
1 (0.7) < 0.001†
Lymph node status
N0
N1
N2
Not available
25 (31.2)
27 (33.7)
27 (33.7)
1 (1.2)
102 (67.5)
17 (11.3)
14 (9.3)
18 (11.9) < 0.001†
ECOG-PS before chemotherapy
0
1
2
Not available
22 (27.5)
48 (60.0)
1 (1.2)
9 (11.2)
-
-
Radiation therapy
Yes
13 (16.2)
5 (3.3)
SCC: squamous cell carcinoma; and PS: performance status. aValues expressed as median [range] or n (%). *Student’s t-test. †Fisher’s exact test.
Effectiveness
In the univariate analysis, factors associated with shorter OS were TNM stage (stage II vs. stage I: HR = 2.57; 95% CI: 1.40-4.71; p = 0.002; and stage III vs. stage I: HR = 3.81; 95% CI: 2.06-7.07; p < 0.001) and lymph node status (N2 vs. N0: HR = 1.82; 95% CI: 1.07-3.11; p = 0.027). Adjuvant chemotherapy use and TNM stage were included in the multivariate model. Lymph node status was not included, because it is part of the TNM stage (p < 0.001).
The multivariate analysis confirmed that TNM stage was a negative prognostic factor for OS (stage II vs. stage I: HR = 3.93; 95% CI: 2.06-7.49; p < 0.001; and stage III vs. stage I: HR = 6.31; 95% CI: 3.23-12.35; p < 0.001), whereas adjuvant chemotherapy use was associated with longer OS in comparison with the control group (HR = 0.43; 95% CI: 0.25-0.72; p = 0.001). The results of univariate and multivariate Cox regression analyses are presented in Table 2.
Table 2 Factors associated with overall survival after surgery for resection of non-small cell lung cancer (Cox regression).
Factor Univariate analysis Multivariate analysis
HR (95% CI) p HR (95% CI) p
Adjuvant chemotherapy (yes vs. no) 0.97 (0.60-1.55) 0.909 0.43 (0.25-0.72) 0.001
Age (> 60 years vs. ≤ 60 years) 1.26 (0.76-2.08) 0.367
Sex (male vs. female) 1.44 (0.90-2.29) 0.123
TNM stage
I
II
III
Reference
2.57 (1.40-4.71)
3.81 (2.06-7.07)
0.002
0.000
Reference
3.93 (2.06-7.49)
6.31 (3.23-12.35)
< 0.001
< 0.001
Lymph node status
N0
N1
N2
Reference
0.93 (0.48-1.82)
1.82 (1.07-3.11)
0.854
0.027
Histology (SCC vs. adenocarcinoma) 1.38 (0.84-2.27) 0.192
HR: hazard ratio; and SCC: squamous cell carcinoma.
During the study follow-up period, 97 patients (67%) had disease recurrence or died. Given the discrepancy between the study groups regarding tumor stage and the importance of this factor for oncologic outcomes, survival analyses were carried out according to tumor stage. Among stage II NSCLC patients, those who received adjuvant chemotherapy had longer RFS than did those who did not (median RFS: not reached vs. 25.5 months; HR = 0.50; 95% CI: 0.26-0.95; p = 0.036). Adjuvant chemotherapy was also associated with longer OS. The median OS was not reached in the adjuvant chemotherapy group, whereas, in the control group, it was 33.8 months (HR = 0.42; 95% CI: 0.21-0.85; p = 0.017). Five-year OS rates were 62.1% (95% CI: 42.5-76.7%) and 12.3% (95% CI: 0.8-39.4%) in the adjuvant chemotherapy and control groups, respectively. The Kaplan-Meier curves for RFS and OS in stage II NSCLC patients are shown in Figure 1.
Figure 1 Recurrence-free survival (A) and overall survival (B) curves in patients with stage II non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients with stage III NSCLC who received adjuvant chemotherapy had longer RFS than did those in the control group, the absolute difference in the median RFS between the two groups being approximately 30 months (median RFS: 36.5 months vs. 6.9 months; HR = 0.32; 95% CI: 0.16-0.64; p < 0.001). There was a trend toward longer OS in the adjuvant chemotherapy group in comparison with the control group (median OS: 36.5 months vs. 20.5 months; HR = 0.48; 95% CI: 0.22-1.03; p = 0.060). Five-year OS rates were 37.9% (95% CI: 17.0-58.8%) and 31.8% (95% CI: 10.8-55.4%) in the adjuvant chemotherapy and control groups, respectively. Figure 2 presents the RFS and OS curves for patients with stage III NSCLC.
Figure 2 Recurrence-free survival (A) and overall survival (B) curves in patients with stage III non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients who received adjuvant chemotherapy with cisplatin and vinorelbine were compared with controls, and RFS and OS were found to be similar between the two (Figures S1 and S2 in the supplementary material).
Safety
Because the cisplatin and vinorelbine regimen is considered an acceptable chemotherapy regimen and because it was used by most of the patients who received adjuvant chemotherapy in the present study, the safety profile of this regimen was evaluated. Moreover, previous randomized studies and clinical experience have suggested a high toxicity rate. 4 - 8
Of the patients who received adjuvant chemotherapy with cisplatin and vinorelbine, 49 (89%) experienced grade 3-4 toxicities, hospitalization being required in 27 (49%). Sixteen patients (29%) had grade 3-4 febrile neutropenia. In addition, 5 patients (9%) died of treatment toxicity (grade 5 toxicity; Table 3).
Table 3 Characteristics of the patients who died of adjuvant treatment toxicity.
Patient Sex Age, years ECOG-PS Staging Chemotherapy regimen Toxicity
1 Male 71 1 IIIA cisplatin + vinorelbine FN
2 Female 61 0 IIA cisplatin + vinorelbine FN + AKI
3 Male 70 1 IIIA cisplatin + vinorelbine FN + AKI
4 Male 72 1 IIB cisplatin + vinorelbine FN + AKI
5 Male 63 1 IIB cisplatin + vinorelbine FN + AKI
PS: performance status; FN: febrile neutropenia; and AKI: acute kidney injury.
Twenty-five patients discontinued the adjuvant cisplatin and vinorelbine regimen, treatment toxicity being the main reason for treatment discontinuation (in 68%). Table 4 summarizes the safety profile of adjuvant cisplatin and vinorelbine regimen in comparison with the safety results of the pivotal ANITA trial. 4
Table 4 Safety profile of adjuvant chemotherapy with cisplatin and vinorelbine in patients with non-small cell lung cancer after surgery.
Profile Present study ANITA triala
Grade 3-4 toxicity 89% N/A
Grade 5 toxicity 9% 2%
Grade 3-4 febrile neutropenia 29% 9%
Toxicity as reason for chemotherapy discontinuation 68% 34%
Hospitalization due to toxicity 49% N/A
a Results based on Douillard et al. 4 ) ANITA: Adjuvant Navelbine International Trialist Association.
DISCUSSION
Our findings reinforce the survival benefit of adjuvant chemotherapy in patients with NSCLC, both in terms of OS and RFS. A meaningful OS benefit was observed in patients with stage II or III NSCLC. The benefit of adjuvant chemotherapy in NSCLC patients has already been demonstrated in various randomized phase III trials. 4 , 6 - 8 In addition, a meta-analysis evaluating 5,584 patients of five clinical trials showed a 5.4% absolute OS gain with cisplatin-based chemotherapy. Among different chemotherapy regimens, cisplatin plus vinorelbine was marginally better than other drug combinations. Furthermore, the cisplatin-vinorelbine combination was the most commonly used regimen, being the largest (41%) and most homogenous study subgroup. 5 When this regimen was separately analyzed, a significant survival benefit was found (absolute benefit, 8.9% at five years; HR = 0.80; 95% CI: 0.70-0.91; p < 0.001). 9 However, among 6,430 patients of 16 clinical trials included in another meta-analysis, 10 which evaluated the role of adjuvant cisplatin-based chemotherapy in NSCLC patients, an increased risk of non-lung cancer-related deaths was observed in those receiving chemotherapy (relative risk = 1.3, p = 0.002).
More recently, Kenmotsu et al. 11 evaluated adjuvant cisplatin-pemetrexed vs. cisplatin-vinorelbine in the NSCLC setting, and, although the superiority of the pemetrexed-containing regimen over the vinorelbine-containing regimen was not demonstrated, both regimens had similar RFS and OS, pemetrexed showing better tolerability and less toxicity. Therefore, the benefits and risks associated with cisplatin-based adjuvant chemotherapy should be taken into account. Although predictive biomarkers of OS benefits from adjuvant treatments (chemotherapy and, possibly in the future, immunotherapy and targeted therapies) are of utmost importance for patient selection, they have yet to be identified and validated.
Notably, randomized phase III trials generally enroll a carefully selected population; only a small number of elderly patients are included, with few comorbidities and good performance status, and this does not represent a real-world setting. Therefore, studies addressing real-world evidence are required to evaluate the benefits and risks of the interventions used in clinical trials. 12 . Kolek et al. 13 reported better survival with adjuvant treatment in this setting, with the longest survival in the cisplatin-vinorelbine cohort. Morgensztern et al. 14 presented the results of 19,691 patients with NSCLC and showed a 4.2% treatment-related mortality rate in six months, reinforcing the importance of and need for real-world data.
Another important issue to be discussed is that, although effectiveness was similar, the incidence of toxicity and hospital admissions was consistently higher in the patients treated with the cisplatin-vinorelbine combination. The outcomes in real-world studies should be carefully analyzed. In the ANITA trial, 4 9% of the patients presented with grade 3-4 febrile neutropenia, and 2% died of treatment-related toxicity, in contrast to a 29% incidence of febrile neutropenia and a 9% mortality rate in our study, which were excessively high for an adjuvant treatment setting. Given that the aim of adjuvant treatment is to improve OS, the difference in the mortality rate between the two studies is noteworthy and potentially exceeds the OS benefit yielded by this treatment. It is of note that 60% of our patients had an ECOG performance status of 1, whereas, in the ANITA trial, 47% had an ECOG performance status of 1, 4 a difference that could explain the higher toxicity observed in our study.
Given the retrospective nature of the present study, selection bias cannot be ruled out. Chemotherapy was prescribed at the discretion of the physicians involved, and the patients who did not receive adjuvant chemotherapy after surgery could have had a worse prognosis a priori. Nevertheless, an indirect comparison reveals that chemotherapy-treated patients show median OS similar to that seen in historical controls. 4 - 8 Despite the retrospective design and the small sample size, which is prone to treatment bias, our analysis has important strengths. The median cumulative doses of cisplatin and vinorelbine in our study were very similar to those in the ANITA trial. 4 Moreover, our patients were treated at a large cancer center by skilled thoracic oncologists, following standard guidelines and tumor board discussion. These high standards were maintained in patient selection, with 90% of the patients receiving chemotherapy having an ECOG performance status of 0-1. In addition, real-world evidence can validate and extend the results of randomized prospective studies to determine whether they are generalizable. Even regulatory agencies, such as the U.S. Food and Drug Administration, are progressively becoming more interested in data based on real-world evidence. 15
In conclusion, our study shows that adjuvant chemotherapy improves both OS and RFS in patients with NSCLC in a real-world setting. However, the cisplatin-vinorelbine regimen was not only associated with alarming rates of treatment-related grade 3-4 toxicity but also with a remarkably high risk of treatment-related deaths. Our results endorse the relevance of real-world data to current daily practices and public health policies in patients with NSCLC, especially for treatment with curative intent.
Financial support: None.
2 Study carrried out at the Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. | CISPLATIN, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC | 33656100 | 19,030,754 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer.
OBJECTIVE
Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting.
METHODS
This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting.
RESULTS
The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity.
CONCLUSIONS
These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.
INTRODUCTION
Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths both in men and women worldwide, with an estimated 1.7 million deaths in 2018. 1 Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. 2 Clinical outcomes and treatment strategies for NSCLC are directly related to stage at diagnosis. Unfortunately, only 25% of the patients with NSCLC have non-metastatic disease at diagnosis, and recurrence rates are often high even when patients are treated with curative intent. 3
In order to improve patient outcomes, adjuvant cisplatin-based chemotherapy after surgical resection has been extensively studied in the last decades. 4 - 8 The Adjuvant Navelbine International Trialist Association (ANITA) trial 4 demonstrated that cisplatin and vinorelbine significantly improve five-year survival rates (by 8,6%; p = 0,017) in patients with stage IB-IIIA NSCLC. However, a subgroup analysis indicated that the benefit is mainly seen in patients with stage II or IIIA disease. 4 )
The benefit of adjuvant chemotherapy in NSCLC was confirmed in a meta-analysis evaluating more than 4.500 patients in five clinical trials. 5 It showed that platinum-based adjuvant chemotherapy resulted in a 5.4% absolute improvement in overall survival (OS) in patients with stage II or III NSCLC (hazard ratio [HR] = 0.89; 95% CI: 0.82-0.96; p = 0.005). 5 Based on these results, platinum-based adjuvant chemotherapy has become the standard of care for patients with completely resected stage II or IIIA NSCLC, and the most commonly used regimen is a combination of cisplatin and vinorelbine. 4 - 8
Although effectiveness of the cisplatin-vinorelbine regimen has been well established, the combination of cisplatin and vinorelbine is associated with clinically relevant toxicity. High rates of grade 3-4 adverse events can compromise treatment adherence, leading to dose reductions and delays, as well as to treatment discontinuation, which is known to be associated with worse outcomes. 4 - 8 Studies providing real-world data on long-term efficacy and safety of adjuvant chemotherapy in NSCLC are scarce and have heterogeneous methods and outcomes. Therefore, the primary objective of the present study was to evaluate the effectiveness and safety of adjuvant chemotherapy for NSCLC patients in a real-world setting.
METHODS
Study design and participants
In this retrospective cohort study, patients undergoing surgical treatment for localized NSCLC were consecutively evaluated and treated between June of 2009 and January of 2018 at the Instituto do Câncer do Estado de São Paulo (ICESP), located in the city of São Paulo, Brazil. The ICESP has a dedicated multidisciplinary thoracic oncology team responsible for evaluating and discussing the cases of patients considered candidates for surgery with curative intent.
We included patients with histologically confirmed NSCLC and TNM stage I-III NSCLC 3 undergoing surgery with curative intent. In accordance with the institutional guidelines, all patients were submitted to pre-operative staging with CT or PET/CT to exclude metastases and with mediastinoscopy or EBUS for mediastinal staging, when indicated. Exclusion criteria included metastatic disease, primary tumor not amenable to complete resection, and a concurrent diagnosis of other malignancies. Data on clinical and demographic characteristics, as well as on treatment received, toxicity, and oncologic outcomes were obtained from electronic medical records. The study was approved by the local research ethics committee (ID 1011/16).
Treatment
The thoracic surgery team defined the type of surgery required to achieve a tumor-free resection margins (lobectomy or pneumonectomy and lymph node dissection) by using an open surgery or video-assisted thoracic surgery, in accordance with the International Association for the Study of Lung Cancer recommendations. 2 , 3
Adjuvant chemotherapy, radiation therapy, or both were prescribed at the discretion of the physicians involved, in accordance with institutional guidelines or by tumor board consensus. At our institution during the study period, adjuvant chemotherapy was recommended for patients with completely resected stage II-III NSCLC and was considered on a case-by-case basis in patients with stage IB NSCLC. In addition, patients must have an ECOG performance status of 0-1 and adequate hepatic, renal, and hematological function. Standard adjuvant chemotherapy as defined by institutional guidelines is cisplatin (80 mg/m2 on day 1) and vinorelbine (30 mg/m2 on days 1, 8, and 15) every three weeks for four cycles. Alternative platinum-based chemotherapy regimens are allowed in specific settings. Although adjuvant radiation therapy is not part of our routine protocol, it was considered on a case-by-case basis in patients with positive margins or N2 lymph node status.
Statistical analysis
Patient characteristics and treatment-related toxicities were summarized by descriptive statistics. Continuous variables were expressed as median and range, whereas categorical variables were presented as absolute numbers and proportions. Differences in continuous variables between the groups were evaluated by Student’s t-test. Categorical variables were compared between groups with the use of Fisher’s exact test.
The Kaplan-Meier method was used in order to estimate survival function, and curves were compared by the log-rank test. The primary outcome was OS, defined as the time from the date of surgery to the date of death from any cause or the date of the last medical visit. Recurrence-free survival (RFS) was also analyzed and defined as the time from surgery to disease recurrence or death. Patients presenting with no events of interest were censored at the last follow-up date.
Potential prognostic factors were evaluated by univariate and multivariate analysis with Cox proportional hazards regression, which provided the HR and 95% CI. Prognostic factors evaluated in the univariate analysis included age, gender, TNM stage, lymph node status, histology, and use of adjuvant chemotherapy. For the multivariate model, we included the use of adjuvant chemotherapy and factors showing p ≤ 0.10 in the univariate analysis as long as they were not associated with each other. The chi-square test was used in order to evaluate the association between variables.
Statistical analyses were conducted with the Stata statistical software package, version 15.1 (StataCorp LP, College Station, TX, USA). The level of significance was set at 5% (p < 0.05).
RESULTS
Patient characteristics
The study included 231 consecutive patients who met the eligibility criteria. The median follow-up time was 24 months. Of the 231 patients, 80 patients received adjuvant chemotherapy, and 151 were followed after surgical treatment (controls). Of the 80 patients who received adjuvant chemotherapy, 55 patients (68%) received the cisplatin-vinorelbine regimen. Alternative regimens included carboplatin and paclitaxel (n = 17; 21.2%), cisplatin and gemcitabine (n = 5; 6.2%), cisplatin and paclitaxel (n = 1; 1.2%), and carboplatin and vinorelbine (n = 1; 1.2%). Among the patients who received cisplatin and vinorelbine, the median cumulative dose of cisplatin was 286 mg/m2 (range: 72-320 mg/m2), and that of vinorelbine was 292 mg/m2 (range: 60-360 mg/m2).
Patients in the adjuvant chemotherapy group were younger than those in the control group (median age: 63.0 years vs. 67.6 years; p < 0.001) and more frequently underwent pneumonectomy (15.0% vs. 7.9%; p < 0.005). The proportion of early stage disease was higher in the control group, with stage I NSCLC in 56.3% (p < 0.001) and negative lymph nodes (N0) in 67.5% (p < 0.001). Of the patients who received adjuvant chemotherapy, only 2.5% had stage I NSCLC, and 31.2% had negative lymph nodes (N0). Table 1 summarizes the characteristics of the study participants.
Table 1 Characteristics of the patients included in the study (N = 231).a
Characteristic Group P
Adjuvant chemotherapy No adjuvant chemotherapy
(n = 80) (n = 151)
Age, years 63.0 [45.3-79.1] 68.3 [34.0-87.9] < 0.001*
Sex
Male
Female
36 (45.0)
44 (55.0)
73 (48.3)
78 (51.7) 0.388†
Type of surgery
Pneumonectomy
Lobectomy
Other
12 (15.0)
61 (76.2)
7 (8.7)
12 (7.9)
134 (88.7)
5 (3.3) 0.005†
Histology
SCC
Adenocarcinoma
Other
Not available
21 (26.2)
53 (66.2)
6 (7.5)
0 (0)
48 (31.8)
92 (60.9)
10 (6.6)
1 (0.7) 0.747†
Stage
I
II
III
Not available
2 (2.5)
44 (54.9)
34 (42.5)
0 (0)
85 (56.3)
41 (27.1)
24 (15.9)
1 (0.7) < 0.001†
Lymph node status
N0
N1
N2
Not available
25 (31.2)
27 (33.7)
27 (33.7)
1 (1.2)
102 (67.5)
17 (11.3)
14 (9.3)
18 (11.9) < 0.001†
ECOG-PS before chemotherapy
0
1
2
Not available
22 (27.5)
48 (60.0)
1 (1.2)
9 (11.2)
-
-
Radiation therapy
Yes
13 (16.2)
5 (3.3)
SCC: squamous cell carcinoma; and PS: performance status. aValues expressed as median [range] or n (%). *Student’s t-test. †Fisher’s exact test.
Effectiveness
In the univariate analysis, factors associated with shorter OS were TNM stage (stage II vs. stage I: HR = 2.57; 95% CI: 1.40-4.71; p = 0.002; and stage III vs. stage I: HR = 3.81; 95% CI: 2.06-7.07; p < 0.001) and lymph node status (N2 vs. N0: HR = 1.82; 95% CI: 1.07-3.11; p = 0.027). Adjuvant chemotherapy use and TNM stage were included in the multivariate model. Lymph node status was not included, because it is part of the TNM stage (p < 0.001).
The multivariate analysis confirmed that TNM stage was a negative prognostic factor for OS (stage II vs. stage I: HR = 3.93; 95% CI: 2.06-7.49; p < 0.001; and stage III vs. stage I: HR = 6.31; 95% CI: 3.23-12.35; p < 0.001), whereas adjuvant chemotherapy use was associated with longer OS in comparison with the control group (HR = 0.43; 95% CI: 0.25-0.72; p = 0.001). The results of univariate and multivariate Cox regression analyses are presented in Table 2.
Table 2 Factors associated with overall survival after surgery for resection of non-small cell lung cancer (Cox regression).
Factor Univariate analysis Multivariate analysis
HR (95% CI) p HR (95% CI) p
Adjuvant chemotherapy (yes vs. no) 0.97 (0.60-1.55) 0.909 0.43 (0.25-0.72) 0.001
Age (> 60 years vs. ≤ 60 years) 1.26 (0.76-2.08) 0.367
Sex (male vs. female) 1.44 (0.90-2.29) 0.123
TNM stage
I
II
III
Reference
2.57 (1.40-4.71)
3.81 (2.06-7.07)
0.002
0.000
Reference
3.93 (2.06-7.49)
6.31 (3.23-12.35)
< 0.001
< 0.001
Lymph node status
N0
N1
N2
Reference
0.93 (0.48-1.82)
1.82 (1.07-3.11)
0.854
0.027
Histology (SCC vs. adenocarcinoma) 1.38 (0.84-2.27) 0.192
HR: hazard ratio; and SCC: squamous cell carcinoma.
During the study follow-up period, 97 patients (67%) had disease recurrence or died. Given the discrepancy between the study groups regarding tumor stage and the importance of this factor for oncologic outcomes, survival analyses were carried out according to tumor stage. Among stage II NSCLC patients, those who received adjuvant chemotherapy had longer RFS than did those who did not (median RFS: not reached vs. 25.5 months; HR = 0.50; 95% CI: 0.26-0.95; p = 0.036). Adjuvant chemotherapy was also associated with longer OS. The median OS was not reached in the adjuvant chemotherapy group, whereas, in the control group, it was 33.8 months (HR = 0.42; 95% CI: 0.21-0.85; p = 0.017). Five-year OS rates were 62.1% (95% CI: 42.5-76.7%) and 12.3% (95% CI: 0.8-39.4%) in the adjuvant chemotherapy and control groups, respectively. The Kaplan-Meier curves for RFS and OS in stage II NSCLC patients are shown in Figure 1.
Figure 1 Recurrence-free survival (A) and overall survival (B) curves in patients with stage II non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients with stage III NSCLC who received adjuvant chemotherapy had longer RFS than did those in the control group, the absolute difference in the median RFS between the two groups being approximately 30 months (median RFS: 36.5 months vs. 6.9 months; HR = 0.32; 95% CI: 0.16-0.64; p < 0.001). There was a trend toward longer OS in the adjuvant chemotherapy group in comparison with the control group (median OS: 36.5 months vs. 20.5 months; HR = 0.48; 95% CI: 0.22-1.03; p = 0.060). Five-year OS rates were 37.9% (95% CI: 17.0-58.8%) and 31.8% (95% CI: 10.8-55.4%) in the adjuvant chemotherapy and control groups, respectively. Figure 2 presents the RFS and OS curves for patients with stage III NSCLC.
Figure 2 Recurrence-free survival (A) and overall survival (B) curves in patients with stage III non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients who received adjuvant chemotherapy with cisplatin and vinorelbine were compared with controls, and RFS and OS were found to be similar between the two (Figures S1 and S2 in the supplementary material).
Safety
Because the cisplatin and vinorelbine regimen is considered an acceptable chemotherapy regimen and because it was used by most of the patients who received adjuvant chemotherapy in the present study, the safety profile of this regimen was evaluated. Moreover, previous randomized studies and clinical experience have suggested a high toxicity rate. 4 - 8
Of the patients who received adjuvant chemotherapy with cisplatin and vinorelbine, 49 (89%) experienced grade 3-4 toxicities, hospitalization being required in 27 (49%). Sixteen patients (29%) had grade 3-4 febrile neutropenia. In addition, 5 patients (9%) died of treatment toxicity (grade 5 toxicity; Table 3).
Table 3 Characteristics of the patients who died of adjuvant treatment toxicity.
Patient Sex Age, years ECOG-PS Staging Chemotherapy regimen Toxicity
1 Male 71 1 IIIA cisplatin + vinorelbine FN
2 Female 61 0 IIA cisplatin + vinorelbine FN + AKI
3 Male 70 1 IIIA cisplatin + vinorelbine FN + AKI
4 Male 72 1 IIB cisplatin + vinorelbine FN + AKI
5 Male 63 1 IIB cisplatin + vinorelbine FN + AKI
PS: performance status; FN: febrile neutropenia; and AKI: acute kidney injury.
Twenty-five patients discontinued the adjuvant cisplatin and vinorelbine regimen, treatment toxicity being the main reason for treatment discontinuation (in 68%). Table 4 summarizes the safety profile of adjuvant cisplatin and vinorelbine regimen in comparison with the safety results of the pivotal ANITA trial. 4
Table 4 Safety profile of adjuvant chemotherapy with cisplatin and vinorelbine in patients with non-small cell lung cancer after surgery.
Profile Present study ANITA triala
Grade 3-4 toxicity 89% N/A
Grade 5 toxicity 9% 2%
Grade 3-4 febrile neutropenia 29% 9%
Toxicity as reason for chemotherapy discontinuation 68% 34%
Hospitalization due to toxicity 49% N/A
a Results based on Douillard et al. 4 ) ANITA: Adjuvant Navelbine International Trialist Association.
DISCUSSION
Our findings reinforce the survival benefit of adjuvant chemotherapy in patients with NSCLC, both in terms of OS and RFS. A meaningful OS benefit was observed in patients with stage II or III NSCLC. The benefit of adjuvant chemotherapy in NSCLC patients has already been demonstrated in various randomized phase III trials. 4 , 6 - 8 In addition, a meta-analysis evaluating 5,584 patients of five clinical trials showed a 5.4% absolute OS gain with cisplatin-based chemotherapy. Among different chemotherapy regimens, cisplatin plus vinorelbine was marginally better than other drug combinations. Furthermore, the cisplatin-vinorelbine combination was the most commonly used regimen, being the largest (41%) and most homogenous study subgroup. 5 When this regimen was separately analyzed, a significant survival benefit was found (absolute benefit, 8.9% at five years; HR = 0.80; 95% CI: 0.70-0.91; p < 0.001). 9 However, among 6,430 patients of 16 clinical trials included in another meta-analysis, 10 which evaluated the role of adjuvant cisplatin-based chemotherapy in NSCLC patients, an increased risk of non-lung cancer-related deaths was observed in those receiving chemotherapy (relative risk = 1.3, p = 0.002).
More recently, Kenmotsu et al. 11 evaluated adjuvant cisplatin-pemetrexed vs. cisplatin-vinorelbine in the NSCLC setting, and, although the superiority of the pemetrexed-containing regimen over the vinorelbine-containing regimen was not demonstrated, both regimens had similar RFS and OS, pemetrexed showing better tolerability and less toxicity. Therefore, the benefits and risks associated with cisplatin-based adjuvant chemotherapy should be taken into account. Although predictive biomarkers of OS benefits from adjuvant treatments (chemotherapy and, possibly in the future, immunotherapy and targeted therapies) are of utmost importance for patient selection, they have yet to be identified and validated.
Notably, randomized phase III trials generally enroll a carefully selected population; only a small number of elderly patients are included, with few comorbidities and good performance status, and this does not represent a real-world setting. Therefore, studies addressing real-world evidence are required to evaluate the benefits and risks of the interventions used in clinical trials. 12 . Kolek et al. 13 reported better survival with adjuvant treatment in this setting, with the longest survival in the cisplatin-vinorelbine cohort. Morgensztern et al. 14 presented the results of 19,691 patients with NSCLC and showed a 4.2% treatment-related mortality rate in six months, reinforcing the importance of and need for real-world data.
Another important issue to be discussed is that, although effectiveness was similar, the incidence of toxicity and hospital admissions was consistently higher in the patients treated with the cisplatin-vinorelbine combination. The outcomes in real-world studies should be carefully analyzed. In the ANITA trial, 4 9% of the patients presented with grade 3-4 febrile neutropenia, and 2% died of treatment-related toxicity, in contrast to a 29% incidence of febrile neutropenia and a 9% mortality rate in our study, which were excessively high for an adjuvant treatment setting. Given that the aim of adjuvant treatment is to improve OS, the difference in the mortality rate between the two studies is noteworthy and potentially exceeds the OS benefit yielded by this treatment. It is of note that 60% of our patients had an ECOG performance status of 1, whereas, in the ANITA trial, 47% had an ECOG performance status of 1, 4 a difference that could explain the higher toxicity observed in our study.
Given the retrospective nature of the present study, selection bias cannot be ruled out. Chemotherapy was prescribed at the discretion of the physicians involved, and the patients who did not receive adjuvant chemotherapy after surgery could have had a worse prognosis a priori. Nevertheless, an indirect comparison reveals that chemotherapy-treated patients show median OS similar to that seen in historical controls. 4 - 8 Despite the retrospective design and the small sample size, which is prone to treatment bias, our analysis has important strengths. The median cumulative doses of cisplatin and vinorelbine in our study were very similar to those in the ANITA trial. 4 Moreover, our patients were treated at a large cancer center by skilled thoracic oncologists, following standard guidelines and tumor board discussion. These high standards were maintained in patient selection, with 90% of the patients receiving chemotherapy having an ECOG performance status of 0-1. In addition, real-world evidence can validate and extend the results of randomized prospective studies to determine whether they are generalizable. Even regulatory agencies, such as the U.S. Food and Drug Administration, are progressively becoming more interested in data based on real-world evidence. 15
In conclusion, our study shows that adjuvant chemotherapy improves both OS and RFS in patients with NSCLC in a real-world setting. However, the cisplatin-vinorelbine regimen was not only associated with alarming rates of treatment-related grade 3-4 toxicity but also with a remarkably high risk of treatment-related deaths. Our results endorse the relevance of real-world data to current daily practices and public health policies in patients with NSCLC, especially for treatment with curative intent.
Financial support: None.
2 Study carrried out at the Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. | CISPLATIN, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC | 33656100 | 19,030,754 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer.
OBJECTIVE
Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting.
METHODS
This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting.
RESULTS
The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity.
CONCLUSIONS
These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.
INTRODUCTION
Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths both in men and women worldwide, with an estimated 1.7 million deaths in 2018. 1 Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. 2 Clinical outcomes and treatment strategies for NSCLC are directly related to stage at diagnosis. Unfortunately, only 25% of the patients with NSCLC have non-metastatic disease at diagnosis, and recurrence rates are often high even when patients are treated with curative intent. 3
In order to improve patient outcomes, adjuvant cisplatin-based chemotherapy after surgical resection has been extensively studied in the last decades. 4 - 8 The Adjuvant Navelbine International Trialist Association (ANITA) trial 4 demonstrated that cisplatin and vinorelbine significantly improve five-year survival rates (by 8,6%; p = 0,017) in patients with stage IB-IIIA NSCLC. However, a subgroup analysis indicated that the benefit is mainly seen in patients with stage II or IIIA disease. 4 )
The benefit of adjuvant chemotherapy in NSCLC was confirmed in a meta-analysis evaluating more than 4.500 patients in five clinical trials. 5 It showed that platinum-based adjuvant chemotherapy resulted in a 5.4% absolute improvement in overall survival (OS) in patients with stage II or III NSCLC (hazard ratio [HR] = 0.89; 95% CI: 0.82-0.96; p = 0.005). 5 Based on these results, platinum-based adjuvant chemotherapy has become the standard of care for patients with completely resected stage II or IIIA NSCLC, and the most commonly used regimen is a combination of cisplatin and vinorelbine. 4 - 8
Although effectiveness of the cisplatin-vinorelbine regimen has been well established, the combination of cisplatin and vinorelbine is associated with clinically relevant toxicity. High rates of grade 3-4 adverse events can compromise treatment adherence, leading to dose reductions and delays, as well as to treatment discontinuation, which is known to be associated with worse outcomes. 4 - 8 Studies providing real-world data on long-term efficacy and safety of adjuvant chemotherapy in NSCLC are scarce and have heterogeneous methods and outcomes. Therefore, the primary objective of the present study was to evaluate the effectiveness and safety of adjuvant chemotherapy for NSCLC patients in a real-world setting.
METHODS
Study design and participants
In this retrospective cohort study, patients undergoing surgical treatment for localized NSCLC were consecutively evaluated and treated between June of 2009 and January of 2018 at the Instituto do Câncer do Estado de São Paulo (ICESP), located in the city of São Paulo, Brazil. The ICESP has a dedicated multidisciplinary thoracic oncology team responsible for evaluating and discussing the cases of patients considered candidates for surgery with curative intent.
We included patients with histologically confirmed NSCLC and TNM stage I-III NSCLC 3 undergoing surgery with curative intent. In accordance with the institutional guidelines, all patients were submitted to pre-operative staging with CT or PET/CT to exclude metastases and with mediastinoscopy or EBUS for mediastinal staging, when indicated. Exclusion criteria included metastatic disease, primary tumor not amenable to complete resection, and a concurrent diagnosis of other malignancies. Data on clinical and demographic characteristics, as well as on treatment received, toxicity, and oncologic outcomes were obtained from electronic medical records. The study was approved by the local research ethics committee (ID 1011/16).
Treatment
The thoracic surgery team defined the type of surgery required to achieve a tumor-free resection margins (lobectomy or pneumonectomy and lymph node dissection) by using an open surgery or video-assisted thoracic surgery, in accordance with the International Association for the Study of Lung Cancer recommendations. 2 , 3
Adjuvant chemotherapy, radiation therapy, or both were prescribed at the discretion of the physicians involved, in accordance with institutional guidelines or by tumor board consensus. At our institution during the study period, adjuvant chemotherapy was recommended for patients with completely resected stage II-III NSCLC and was considered on a case-by-case basis in patients with stage IB NSCLC. In addition, patients must have an ECOG performance status of 0-1 and adequate hepatic, renal, and hematological function. Standard adjuvant chemotherapy as defined by institutional guidelines is cisplatin (80 mg/m2 on day 1) and vinorelbine (30 mg/m2 on days 1, 8, and 15) every three weeks for four cycles. Alternative platinum-based chemotherapy regimens are allowed in specific settings. Although adjuvant radiation therapy is not part of our routine protocol, it was considered on a case-by-case basis in patients with positive margins or N2 lymph node status.
Statistical analysis
Patient characteristics and treatment-related toxicities were summarized by descriptive statistics. Continuous variables were expressed as median and range, whereas categorical variables were presented as absolute numbers and proportions. Differences in continuous variables between the groups were evaluated by Student’s t-test. Categorical variables were compared between groups with the use of Fisher’s exact test.
The Kaplan-Meier method was used in order to estimate survival function, and curves were compared by the log-rank test. The primary outcome was OS, defined as the time from the date of surgery to the date of death from any cause or the date of the last medical visit. Recurrence-free survival (RFS) was also analyzed and defined as the time from surgery to disease recurrence or death. Patients presenting with no events of interest were censored at the last follow-up date.
Potential prognostic factors were evaluated by univariate and multivariate analysis with Cox proportional hazards regression, which provided the HR and 95% CI. Prognostic factors evaluated in the univariate analysis included age, gender, TNM stage, lymph node status, histology, and use of adjuvant chemotherapy. For the multivariate model, we included the use of adjuvant chemotherapy and factors showing p ≤ 0.10 in the univariate analysis as long as they were not associated with each other. The chi-square test was used in order to evaluate the association between variables.
Statistical analyses were conducted with the Stata statistical software package, version 15.1 (StataCorp LP, College Station, TX, USA). The level of significance was set at 5% (p < 0.05).
RESULTS
Patient characteristics
The study included 231 consecutive patients who met the eligibility criteria. The median follow-up time was 24 months. Of the 231 patients, 80 patients received adjuvant chemotherapy, and 151 were followed after surgical treatment (controls). Of the 80 patients who received adjuvant chemotherapy, 55 patients (68%) received the cisplatin-vinorelbine regimen. Alternative regimens included carboplatin and paclitaxel (n = 17; 21.2%), cisplatin and gemcitabine (n = 5; 6.2%), cisplatin and paclitaxel (n = 1; 1.2%), and carboplatin and vinorelbine (n = 1; 1.2%). Among the patients who received cisplatin and vinorelbine, the median cumulative dose of cisplatin was 286 mg/m2 (range: 72-320 mg/m2), and that of vinorelbine was 292 mg/m2 (range: 60-360 mg/m2).
Patients in the adjuvant chemotherapy group were younger than those in the control group (median age: 63.0 years vs. 67.6 years; p < 0.001) and more frequently underwent pneumonectomy (15.0% vs. 7.9%; p < 0.005). The proportion of early stage disease was higher in the control group, with stage I NSCLC in 56.3% (p < 0.001) and negative lymph nodes (N0) in 67.5% (p < 0.001). Of the patients who received adjuvant chemotherapy, only 2.5% had stage I NSCLC, and 31.2% had negative lymph nodes (N0). Table 1 summarizes the characteristics of the study participants.
Table 1 Characteristics of the patients included in the study (N = 231).a
Characteristic Group P
Adjuvant chemotherapy No adjuvant chemotherapy
(n = 80) (n = 151)
Age, years 63.0 [45.3-79.1] 68.3 [34.0-87.9] < 0.001*
Sex
Male
Female
36 (45.0)
44 (55.0)
73 (48.3)
78 (51.7) 0.388†
Type of surgery
Pneumonectomy
Lobectomy
Other
12 (15.0)
61 (76.2)
7 (8.7)
12 (7.9)
134 (88.7)
5 (3.3) 0.005†
Histology
SCC
Adenocarcinoma
Other
Not available
21 (26.2)
53 (66.2)
6 (7.5)
0 (0)
48 (31.8)
92 (60.9)
10 (6.6)
1 (0.7) 0.747†
Stage
I
II
III
Not available
2 (2.5)
44 (54.9)
34 (42.5)
0 (0)
85 (56.3)
41 (27.1)
24 (15.9)
1 (0.7) < 0.001†
Lymph node status
N0
N1
N2
Not available
25 (31.2)
27 (33.7)
27 (33.7)
1 (1.2)
102 (67.5)
17 (11.3)
14 (9.3)
18 (11.9) < 0.001†
ECOG-PS before chemotherapy
0
1
2
Not available
22 (27.5)
48 (60.0)
1 (1.2)
9 (11.2)
-
-
Radiation therapy
Yes
13 (16.2)
5 (3.3)
SCC: squamous cell carcinoma; and PS: performance status. aValues expressed as median [range] or n (%). *Student’s t-test. †Fisher’s exact test.
Effectiveness
In the univariate analysis, factors associated with shorter OS were TNM stage (stage II vs. stage I: HR = 2.57; 95% CI: 1.40-4.71; p = 0.002; and stage III vs. stage I: HR = 3.81; 95% CI: 2.06-7.07; p < 0.001) and lymph node status (N2 vs. N0: HR = 1.82; 95% CI: 1.07-3.11; p = 0.027). Adjuvant chemotherapy use and TNM stage were included in the multivariate model. Lymph node status was not included, because it is part of the TNM stage (p < 0.001).
The multivariate analysis confirmed that TNM stage was a negative prognostic factor for OS (stage II vs. stage I: HR = 3.93; 95% CI: 2.06-7.49; p < 0.001; and stage III vs. stage I: HR = 6.31; 95% CI: 3.23-12.35; p < 0.001), whereas adjuvant chemotherapy use was associated with longer OS in comparison with the control group (HR = 0.43; 95% CI: 0.25-0.72; p = 0.001). The results of univariate and multivariate Cox regression analyses are presented in Table 2.
Table 2 Factors associated with overall survival after surgery for resection of non-small cell lung cancer (Cox regression).
Factor Univariate analysis Multivariate analysis
HR (95% CI) p HR (95% CI) p
Adjuvant chemotherapy (yes vs. no) 0.97 (0.60-1.55) 0.909 0.43 (0.25-0.72) 0.001
Age (> 60 years vs. ≤ 60 years) 1.26 (0.76-2.08) 0.367
Sex (male vs. female) 1.44 (0.90-2.29) 0.123
TNM stage
I
II
III
Reference
2.57 (1.40-4.71)
3.81 (2.06-7.07)
0.002
0.000
Reference
3.93 (2.06-7.49)
6.31 (3.23-12.35)
< 0.001
< 0.001
Lymph node status
N0
N1
N2
Reference
0.93 (0.48-1.82)
1.82 (1.07-3.11)
0.854
0.027
Histology (SCC vs. adenocarcinoma) 1.38 (0.84-2.27) 0.192
HR: hazard ratio; and SCC: squamous cell carcinoma.
During the study follow-up period, 97 patients (67%) had disease recurrence or died. Given the discrepancy between the study groups regarding tumor stage and the importance of this factor for oncologic outcomes, survival analyses were carried out according to tumor stage. Among stage II NSCLC patients, those who received adjuvant chemotherapy had longer RFS than did those who did not (median RFS: not reached vs. 25.5 months; HR = 0.50; 95% CI: 0.26-0.95; p = 0.036). Adjuvant chemotherapy was also associated with longer OS. The median OS was not reached in the adjuvant chemotherapy group, whereas, in the control group, it was 33.8 months (HR = 0.42; 95% CI: 0.21-0.85; p = 0.017). Five-year OS rates were 62.1% (95% CI: 42.5-76.7%) and 12.3% (95% CI: 0.8-39.4%) in the adjuvant chemotherapy and control groups, respectively. The Kaplan-Meier curves for RFS and OS in stage II NSCLC patients are shown in Figure 1.
Figure 1 Recurrence-free survival (A) and overall survival (B) curves in patients with stage II non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients with stage III NSCLC who received adjuvant chemotherapy had longer RFS than did those in the control group, the absolute difference in the median RFS between the two groups being approximately 30 months (median RFS: 36.5 months vs. 6.9 months; HR = 0.32; 95% CI: 0.16-0.64; p < 0.001). There was a trend toward longer OS in the adjuvant chemotherapy group in comparison with the control group (median OS: 36.5 months vs. 20.5 months; HR = 0.48; 95% CI: 0.22-1.03; p = 0.060). Five-year OS rates were 37.9% (95% CI: 17.0-58.8%) and 31.8% (95% CI: 10.8-55.4%) in the adjuvant chemotherapy and control groups, respectively. Figure 2 presents the RFS and OS curves for patients with stage III NSCLC.
Figure 2 Recurrence-free survival (A) and overall survival (B) curves in patients with stage III non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients who received adjuvant chemotherapy with cisplatin and vinorelbine were compared with controls, and RFS and OS were found to be similar between the two (Figures S1 and S2 in the supplementary material).
Safety
Because the cisplatin and vinorelbine regimen is considered an acceptable chemotherapy regimen and because it was used by most of the patients who received adjuvant chemotherapy in the present study, the safety profile of this regimen was evaluated. Moreover, previous randomized studies and clinical experience have suggested a high toxicity rate. 4 - 8
Of the patients who received adjuvant chemotherapy with cisplatin and vinorelbine, 49 (89%) experienced grade 3-4 toxicities, hospitalization being required in 27 (49%). Sixteen patients (29%) had grade 3-4 febrile neutropenia. In addition, 5 patients (9%) died of treatment toxicity (grade 5 toxicity; Table 3).
Table 3 Characteristics of the patients who died of adjuvant treatment toxicity.
Patient Sex Age, years ECOG-PS Staging Chemotherapy regimen Toxicity
1 Male 71 1 IIIA cisplatin + vinorelbine FN
2 Female 61 0 IIA cisplatin + vinorelbine FN + AKI
3 Male 70 1 IIIA cisplatin + vinorelbine FN + AKI
4 Male 72 1 IIB cisplatin + vinorelbine FN + AKI
5 Male 63 1 IIB cisplatin + vinorelbine FN + AKI
PS: performance status; FN: febrile neutropenia; and AKI: acute kidney injury.
Twenty-five patients discontinued the adjuvant cisplatin and vinorelbine regimen, treatment toxicity being the main reason for treatment discontinuation (in 68%). Table 4 summarizes the safety profile of adjuvant cisplatin and vinorelbine regimen in comparison with the safety results of the pivotal ANITA trial. 4
Table 4 Safety profile of adjuvant chemotherapy with cisplatin and vinorelbine in patients with non-small cell lung cancer after surgery.
Profile Present study ANITA triala
Grade 3-4 toxicity 89% N/A
Grade 5 toxicity 9% 2%
Grade 3-4 febrile neutropenia 29% 9%
Toxicity as reason for chemotherapy discontinuation 68% 34%
Hospitalization due to toxicity 49% N/A
a Results based on Douillard et al. 4 ) ANITA: Adjuvant Navelbine International Trialist Association.
DISCUSSION
Our findings reinforce the survival benefit of adjuvant chemotherapy in patients with NSCLC, both in terms of OS and RFS. A meaningful OS benefit was observed in patients with stage II or III NSCLC. The benefit of adjuvant chemotherapy in NSCLC patients has already been demonstrated in various randomized phase III trials. 4 , 6 - 8 In addition, a meta-analysis evaluating 5,584 patients of five clinical trials showed a 5.4% absolute OS gain with cisplatin-based chemotherapy. Among different chemotherapy regimens, cisplatin plus vinorelbine was marginally better than other drug combinations. Furthermore, the cisplatin-vinorelbine combination was the most commonly used regimen, being the largest (41%) and most homogenous study subgroup. 5 When this regimen was separately analyzed, a significant survival benefit was found (absolute benefit, 8.9% at five years; HR = 0.80; 95% CI: 0.70-0.91; p < 0.001). 9 However, among 6,430 patients of 16 clinical trials included in another meta-analysis, 10 which evaluated the role of adjuvant cisplatin-based chemotherapy in NSCLC patients, an increased risk of non-lung cancer-related deaths was observed in those receiving chemotherapy (relative risk = 1.3, p = 0.002).
More recently, Kenmotsu et al. 11 evaluated adjuvant cisplatin-pemetrexed vs. cisplatin-vinorelbine in the NSCLC setting, and, although the superiority of the pemetrexed-containing regimen over the vinorelbine-containing regimen was not demonstrated, both regimens had similar RFS and OS, pemetrexed showing better tolerability and less toxicity. Therefore, the benefits and risks associated with cisplatin-based adjuvant chemotherapy should be taken into account. Although predictive biomarkers of OS benefits from adjuvant treatments (chemotherapy and, possibly in the future, immunotherapy and targeted therapies) are of utmost importance for patient selection, they have yet to be identified and validated.
Notably, randomized phase III trials generally enroll a carefully selected population; only a small number of elderly patients are included, with few comorbidities and good performance status, and this does not represent a real-world setting. Therefore, studies addressing real-world evidence are required to evaluate the benefits and risks of the interventions used in clinical trials. 12 . Kolek et al. 13 reported better survival with adjuvant treatment in this setting, with the longest survival in the cisplatin-vinorelbine cohort. Morgensztern et al. 14 presented the results of 19,691 patients with NSCLC and showed a 4.2% treatment-related mortality rate in six months, reinforcing the importance of and need for real-world data.
Another important issue to be discussed is that, although effectiveness was similar, the incidence of toxicity and hospital admissions was consistently higher in the patients treated with the cisplatin-vinorelbine combination. The outcomes in real-world studies should be carefully analyzed. In the ANITA trial, 4 9% of the patients presented with grade 3-4 febrile neutropenia, and 2% died of treatment-related toxicity, in contrast to a 29% incidence of febrile neutropenia and a 9% mortality rate in our study, which were excessively high for an adjuvant treatment setting. Given that the aim of adjuvant treatment is to improve OS, the difference in the mortality rate between the two studies is noteworthy and potentially exceeds the OS benefit yielded by this treatment. It is of note that 60% of our patients had an ECOG performance status of 1, whereas, in the ANITA trial, 47% had an ECOG performance status of 1, 4 a difference that could explain the higher toxicity observed in our study.
Given the retrospective nature of the present study, selection bias cannot be ruled out. Chemotherapy was prescribed at the discretion of the physicians involved, and the patients who did not receive adjuvant chemotherapy after surgery could have had a worse prognosis a priori. Nevertheless, an indirect comparison reveals that chemotherapy-treated patients show median OS similar to that seen in historical controls. 4 - 8 Despite the retrospective design and the small sample size, which is prone to treatment bias, our analysis has important strengths. The median cumulative doses of cisplatin and vinorelbine in our study were very similar to those in the ANITA trial. 4 Moreover, our patients were treated at a large cancer center by skilled thoracic oncologists, following standard guidelines and tumor board discussion. These high standards were maintained in patient selection, with 90% of the patients receiving chemotherapy having an ECOG performance status of 0-1. In addition, real-world evidence can validate and extend the results of randomized prospective studies to determine whether they are generalizable. Even regulatory agencies, such as the U.S. Food and Drug Administration, are progressively becoming more interested in data based on real-world evidence. 15
In conclusion, our study shows that adjuvant chemotherapy improves both OS and RFS in patients with NSCLC in a real-world setting. However, the cisplatin-vinorelbine regimen was not only associated with alarming rates of treatment-related grade 3-4 toxicity but also with a remarkably high risk of treatment-related deaths. Our results endorse the relevance of real-world data to current daily practices and public health policies in patients with NSCLC, especially for treatment with curative intent.
Financial support: None.
2 Study carrried out at the Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. | CISPLATIN, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC | 33656100 | 19,030,754 | 2021 |
What was the outcome of reaction 'Acute kidney injury'? | Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer.
OBJECTIVE
Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting.
METHODS
This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting.
RESULTS
The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity.
CONCLUSIONS
These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.
INTRODUCTION
Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths both in men and women worldwide, with an estimated 1.7 million deaths in 2018. 1 Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. 2 Clinical outcomes and treatment strategies for NSCLC are directly related to stage at diagnosis. Unfortunately, only 25% of the patients with NSCLC have non-metastatic disease at diagnosis, and recurrence rates are often high even when patients are treated with curative intent. 3
In order to improve patient outcomes, adjuvant cisplatin-based chemotherapy after surgical resection has been extensively studied in the last decades. 4 - 8 The Adjuvant Navelbine International Trialist Association (ANITA) trial 4 demonstrated that cisplatin and vinorelbine significantly improve five-year survival rates (by 8,6%; p = 0,017) in patients with stage IB-IIIA NSCLC. However, a subgroup analysis indicated that the benefit is mainly seen in patients with stage II or IIIA disease. 4 )
The benefit of adjuvant chemotherapy in NSCLC was confirmed in a meta-analysis evaluating more than 4.500 patients in five clinical trials. 5 It showed that platinum-based adjuvant chemotherapy resulted in a 5.4% absolute improvement in overall survival (OS) in patients with stage II or III NSCLC (hazard ratio [HR] = 0.89; 95% CI: 0.82-0.96; p = 0.005). 5 Based on these results, platinum-based adjuvant chemotherapy has become the standard of care for patients with completely resected stage II or IIIA NSCLC, and the most commonly used regimen is a combination of cisplatin and vinorelbine. 4 - 8
Although effectiveness of the cisplatin-vinorelbine regimen has been well established, the combination of cisplatin and vinorelbine is associated with clinically relevant toxicity. High rates of grade 3-4 adverse events can compromise treatment adherence, leading to dose reductions and delays, as well as to treatment discontinuation, which is known to be associated with worse outcomes. 4 - 8 Studies providing real-world data on long-term efficacy and safety of adjuvant chemotherapy in NSCLC are scarce and have heterogeneous methods and outcomes. Therefore, the primary objective of the present study was to evaluate the effectiveness and safety of adjuvant chemotherapy for NSCLC patients in a real-world setting.
METHODS
Study design and participants
In this retrospective cohort study, patients undergoing surgical treatment for localized NSCLC were consecutively evaluated and treated between June of 2009 and January of 2018 at the Instituto do Câncer do Estado de São Paulo (ICESP), located in the city of São Paulo, Brazil. The ICESP has a dedicated multidisciplinary thoracic oncology team responsible for evaluating and discussing the cases of patients considered candidates for surgery with curative intent.
We included patients with histologically confirmed NSCLC and TNM stage I-III NSCLC 3 undergoing surgery with curative intent. In accordance with the institutional guidelines, all patients were submitted to pre-operative staging with CT or PET/CT to exclude metastases and with mediastinoscopy or EBUS for mediastinal staging, when indicated. Exclusion criteria included metastatic disease, primary tumor not amenable to complete resection, and a concurrent diagnosis of other malignancies. Data on clinical and demographic characteristics, as well as on treatment received, toxicity, and oncologic outcomes were obtained from electronic medical records. The study was approved by the local research ethics committee (ID 1011/16).
Treatment
The thoracic surgery team defined the type of surgery required to achieve a tumor-free resection margins (lobectomy or pneumonectomy and lymph node dissection) by using an open surgery or video-assisted thoracic surgery, in accordance with the International Association for the Study of Lung Cancer recommendations. 2 , 3
Adjuvant chemotherapy, radiation therapy, or both were prescribed at the discretion of the physicians involved, in accordance with institutional guidelines or by tumor board consensus. At our institution during the study period, adjuvant chemotherapy was recommended for patients with completely resected stage II-III NSCLC and was considered on a case-by-case basis in patients with stage IB NSCLC. In addition, patients must have an ECOG performance status of 0-1 and adequate hepatic, renal, and hematological function. Standard adjuvant chemotherapy as defined by institutional guidelines is cisplatin (80 mg/m2 on day 1) and vinorelbine (30 mg/m2 on days 1, 8, and 15) every three weeks for four cycles. Alternative platinum-based chemotherapy regimens are allowed in specific settings. Although adjuvant radiation therapy is not part of our routine protocol, it was considered on a case-by-case basis in patients with positive margins or N2 lymph node status.
Statistical analysis
Patient characteristics and treatment-related toxicities were summarized by descriptive statistics. Continuous variables were expressed as median and range, whereas categorical variables were presented as absolute numbers and proportions. Differences in continuous variables between the groups were evaluated by Student’s t-test. Categorical variables were compared between groups with the use of Fisher’s exact test.
The Kaplan-Meier method was used in order to estimate survival function, and curves were compared by the log-rank test. The primary outcome was OS, defined as the time from the date of surgery to the date of death from any cause or the date of the last medical visit. Recurrence-free survival (RFS) was also analyzed and defined as the time from surgery to disease recurrence or death. Patients presenting with no events of interest were censored at the last follow-up date.
Potential prognostic factors were evaluated by univariate and multivariate analysis with Cox proportional hazards regression, which provided the HR and 95% CI. Prognostic factors evaluated in the univariate analysis included age, gender, TNM stage, lymph node status, histology, and use of adjuvant chemotherapy. For the multivariate model, we included the use of adjuvant chemotherapy and factors showing p ≤ 0.10 in the univariate analysis as long as they were not associated with each other. The chi-square test was used in order to evaluate the association between variables.
Statistical analyses were conducted with the Stata statistical software package, version 15.1 (StataCorp LP, College Station, TX, USA). The level of significance was set at 5% (p < 0.05).
RESULTS
Patient characteristics
The study included 231 consecutive patients who met the eligibility criteria. The median follow-up time was 24 months. Of the 231 patients, 80 patients received adjuvant chemotherapy, and 151 were followed after surgical treatment (controls). Of the 80 patients who received adjuvant chemotherapy, 55 patients (68%) received the cisplatin-vinorelbine regimen. Alternative regimens included carboplatin and paclitaxel (n = 17; 21.2%), cisplatin and gemcitabine (n = 5; 6.2%), cisplatin and paclitaxel (n = 1; 1.2%), and carboplatin and vinorelbine (n = 1; 1.2%). Among the patients who received cisplatin and vinorelbine, the median cumulative dose of cisplatin was 286 mg/m2 (range: 72-320 mg/m2), and that of vinorelbine was 292 mg/m2 (range: 60-360 mg/m2).
Patients in the adjuvant chemotherapy group were younger than those in the control group (median age: 63.0 years vs. 67.6 years; p < 0.001) and more frequently underwent pneumonectomy (15.0% vs. 7.9%; p < 0.005). The proportion of early stage disease was higher in the control group, with stage I NSCLC in 56.3% (p < 0.001) and negative lymph nodes (N0) in 67.5% (p < 0.001). Of the patients who received adjuvant chemotherapy, only 2.5% had stage I NSCLC, and 31.2% had negative lymph nodes (N0). Table 1 summarizes the characteristics of the study participants.
Table 1 Characteristics of the patients included in the study (N = 231).a
Characteristic Group P
Adjuvant chemotherapy No adjuvant chemotherapy
(n = 80) (n = 151)
Age, years 63.0 [45.3-79.1] 68.3 [34.0-87.9] < 0.001*
Sex
Male
Female
36 (45.0)
44 (55.0)
73 (48.3)
78 (51.7) 0.388†
Type of surgery
Pneumonectomy
Lobectomy
Other
12 (15.0)
61 (76.2)
7 (8.7)
12 (7.9)
134 (88.7)
5 (3.3) 0.005†
Histology
SCC
Adenocarcinoma
Other
Not available
21 (26.2)
53 (66.2)
6 (7.5)
0 (0)
48 (31.8)
92 (60.9)
10 (6.6)
1 (0.7) 0.747†
Stage
I
II
III
Not available
2 (2.5)
44 (54.9)
34 (42.5)
0 (0)
85 (56.3)
41 (27.1)
24 (15.9)
1 (0.7) < 0.001†
Lymph node status
N0
N1
N2
Not available
25 (31.2)
27 (33.7)
27 (33.7)
1 (1.2)
102 (67.5)
17 (11.3)
14 (9.3)
18 (11.9) < 0.001†
ECOG-PS before chemotherapy
0
1
2
Not available
22 (27.5)
48 (60.0)
1 (1.2)
9 (11.2)
-
-
Radiation therapy
Yes
13 (16.2)
5 (3.3)
SCC: squamous cell carcinoma; and PS: performance status. aValues expressed as median [range] or n (%). *Student’s t-test. †Fisher’s exact test.
Effectiveness
In the univariate analysis, factors associated with shorter OS were TNM stage (stage II vs. stage I: HR = 2.57; 95% CI: 1.40-4.71; p = 0.002; and stage III vs. stage I: HR = 3.81; 95% CI: 2.06-7.07; p < 0.001) and lymph node status (N2 vs. N0: HR = 1.82; 95% CI: 1.07-3.11; p = 0.027). Adjuvant chemotherapy use and TNM stage were included in the multivariate model. Lymph node status was not included, because it is part of the TNM stage (p < 0.001).
The multivariate analysis confirmed that TNM stage was a negative prognostic factor for OS (stage II vs. stage I: HR = 3.93; 95% CI: 2.06-7.49; p < 0.001; and stage III vs. stage I: HR = 6.31; 95% CI: 3.23-12.35; p < 0.001), whereas adjuvant chemotherapy use was associated with longer OS in comparison with the control group (HR = 0.43; 95% CI: 0.25-0.72; p = 0.001). The results of univariate and multivariate Cox regression analyses are presented in Table 2.
Table 2 Factors associated with overall survival after surgery for resection of non-small cell lung cancer (Cox regression).
Factor Univariate analysis Multivariate analysis
HR (95% CI) p HR (95% CI) p
Adjuvant chemotherapy (yes vs. no) 0.97 (0.60-1.55) 0.909 0.43 (0.25-0.72) 0.001
Age (> 60 years vs. ≤ 60 years) 1.26 (0.76-2.08) 0.367
Sex (male vs. female) 1.44 (0.90-2.29) 0.123
TNM stage
I
II
III
Reference
2.57 (1.40-4.71)
3.81 (2.06-7.07)
0.002
0.000
Reference
3.93 (2.06-7.49)
6.31 (3.23-12.35)
< 0.001
< 0.001
Lymph node status
N0
N1
N2
Reference
0.93 (0.48-1.82)
1.82 (1.07-3.11)
0.854
0.027
Histology (SCC vs. adenocarcinoma) 1.38 (0.84-2.27) 0.192
HR: hazard ratio; and SCC: squamous cell carcinoma.
During the study follow-up period, 97 patients (67%) had disease recurrence or died. Given the discrepancy between the study groups regarding tumor stage and the importance of this factor for oncologic outcomes, survival analyses were carried out according to tumor stage. Among stage II NSCLC patients, those who received adjuvant chemotherapy had longer RFS than did those who did not (median RFS: not reached vs. 25.5 months; HR = 0.50; 95% CI: 0.26-0.95; p = 0.036). Adjuvant chemotherapy was also associated with longer OS. The median OS was not reached in the adjuvant chemotherapy group, whereas, in the control group, it was 33.8 months (HR = 0.42; 95% CI: 0.21-0.85; p = 0.017). Five-year OS rates were 62.1% (95% CI: 42.5-76.7%) and 12.3% (95% CI: 0.8-39.4%) in the adjuvant chemotherapy and control groups, respectively. The Kaplan-Meier curves for RFS and OS in stage II NSCLC patients are shown in Figure 1.
Figure 1 Recurrence-free survival (A) and overall survival (B) curves in patients with stage II non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients with stage III NSCLC who received adjuvant chemotherapy had longer RFS than did those in the control group, the absolute difference in the median RFS between the two groups being approximately 30 months (median RFS: 36.5 months vs. 6.9 months; HR = 0.32; 95% CI: 0.16-0.64; p < 0.001). There was a trend toward longer OS in the adjuvant chemotherapy group in comparison with the control group (median OS: 36.5 months vs. 20.5 months; HR = 0.48; 95% CI: 0.22-1.03; p = 0.060). Five-year OS rates were 37.9% (95% CI: 17.0-58.8%) and 31.8% (95% CI: 10.8-55.4%) in the adjuvant chemotherapy and control groups, respectively. Figure 2 presents the RFS and OS curves for patients with stage III NSCLC.
Figure 2 Recurrence-free survival (A) and overall survival (B) curves in patients with stage III non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients who received adjuvant chemotherapy with cisplatin and vinorelbine were compared with controls, and RFS and OS were found to be similar between the two (Figures S1 and S2 in the supplementary material).
Safety
Because the cisplatin and vinorelbine regimen is considered an acceptable chemotherapy regimen and because it was used by most of the patients who received adjuvant chemotherapy in the present study, the safety profile of this regimen was evaluated. Moreover, previous randomized studies and clinical experience have suggested a high toxicity rate. 4 - 8
Of the patients who received adjuvant chemotherapy with cisplatin and vinorelbine, 49 (89%) experienced grade 3-4 toxicities, hospitalization being required in 27 (49%). Sixteen patients (29%) had grade 3-4 febrile neutropenia. In addition, 5 patients (9%) died of treatment toxicity (grade 5 toxicity; Table 3).
Table 3 Characteristics of the patients who died of adjuvant treatment toxicity.
Patient Sex Age, years ECOG-PS Staging Chemotherapy regimen Toxicity
1 Male 71 1 IIIA cisplatin + vinorelbine FN
2 Female 61 0 IIA cisplatin + vinorelbine FN + AKI
3 Male 70 1 IIIA cisplatin + vinorelbine FN + AKI
4 Male 72 1 IIB cisplatin + vinorelbine FN + AKI
5 Male 63 1 IIB cisplatin + vinorelbine FN + AKI
PS: performance status; FN: febrile neutropenia; and AKI: acute kidney injury.
Twenty-five patients discontinued the adjuvant cisplatin and vinorelbine regimen, treatment toxicity being the main reason for treatment discontinuation (in 68%). Table 4 summarizes the safety profile of adjuvant cisplatin and vinorelbine regimen in comparison with the safety results of the pivotal ANITA trial. 4
Table 4 Safety profile of adjuvant chemotherapy with cisplatin and vinorelbine in patients with non-small cell lung cancer after surgery.
Profile Present study ANITA triala
Grade 3-4 toxicity 89% N/A
Grade 5 toxicity 9% 2%
Grade 3-4 febrile neutropenia 29% 9%
Toxicity as reason for chemotherapy discontinuation 68% 34%
Hospitalization due to toxicity 49% N/A
a Results based on Douillard et al. 4 ) ANITA: Adjuvant Navelbine International Trialist Association.
DISCUSSION
Our findings reinforce the survival benefit of adjuvant chemotherapy in patients with NSCLC, both in terms of OS and RFS. A meaningful OS benefit was observed in patients with stage II or III NSCLC. The benefit of adjuvant chemotherapy in NSCLC patients has already been demonstrated in various randomized phase III trials. 4 , 6 - 8 In addition, a meta-analysis evaluating 5,584 patients of five clinical trials showed a 5.4% absolute OS gain with cisplatin-based chemotherapy. Among different chemotherapy regimens, cisplatin plus vinorelbine was marginally better than other drug combinations. Furthermore, the cisplatin-vinorelbine combination was the most commonly used regimen, being the largest (41%) and most homogenous study subgroup. 5 When this regimen was separately analyzed, a significant survival benefit was found (absolute benefit, 8.9% at five years; HR = 0.80; 95% CI: 0.70-0.91; p < 0.001). 9 However, among 6,430 patients of 16 clinical trials included in another meta-analysis, 10 which evaluated the role of adjuvant cisplatin-based chemotherapy in NSCLC patients, an increased risk of non-lung cancer-related deaths was observed in those receiving chemotherapy (relative risk = 1.3, p = 0.002).
More recently, Kenmotsu et al. 11 evaluated adjuvant cisplatin-pemetrexed vs. cisplatin-vinorelbine in the NSCLC setting, and, although the superiority of the pemetrexed-containing regimen over the vinorelbine-containing regimen was not demonstrated, both regimens had similar RFS and OS, pemetrexed showing better tolerability and less toxicity. Therefore, the benefits and risks associated with cisplatin-based adjuvant chemotherapy should be taken into account. Although predictive biomarkers of OS benefits from adjuvant treatments (chemotherapy and, possibly in the future, immunotherapy and targeted therapies) are of utmost importance for patient selection, they have yet to be identified and validated.
Notably, randomized phase III trials generally enroll a carefully selected population; only a small number of elderly patients are included, with few comorbidities and good performance status, and this does not represent a real-world setting. Therefore, studies addressing real-world evidence are required to evaluate the benefits and risks of the interventions used in clinical trials. 12 . Kolek et al. 13 reported better survival with adjuvant treatment in this setting, with the longest survival in the cisplatin-vinorelbine cohort. Morgensztern et al. 14 presented the results of 19,691 patients with NSCLC and showed a 4.2% treatment-related mortality rate in six months, reinforcing the importance of and need for real-world data.
Another important issue to be discussed is that, although effectiveness was similar, the incidence of toxicity and hospital admissions was consistently higher in the patients treated with the cisplatin-vinorelbine combination. The outcomes in real-world studies should be carefully analyzed. In the ANITA trial, 4 9% of the patients presented with grade 3-4 febrile neutropenia, and 2% died of treatment-related toxicity, in contrast to a 29% incidence of febrile neutropenia and a 9% mortality rate in our study, which were excessively high for an adjuvant treatment setting. Given that the aim of adjuvant treatment is to improve OS, the difference in the mortality rate between the two studies is noteworthy and potentially exceeds the OS benefit yielded by this treatment. It is of note that 60% of our patients had an ECOG performance status of 1, whereas, in the ANITA trial, 47% had an ECOG performance status of 1, 4 a difference that could explain the higher toxicity observed in our study.
Given the retrospective nature of the present study, selection bias cannot be ruled out. Chemotherapy was prescribed at the discretion of the physicians involved, and the patients who did not receive adjuvant chemotherapy after surgery could have had a worse prognosis a priori. Nevertheless, an indirect comparison reveals that chemotherapy-treated patients show median OS similar to that seen in historical controls. 4 - 8 Despite the retrospective design and the small sample size, which is prone to treatment bias, our analysis has important strengths. The median cumulative doses of cisplatin and vinorelbine in our study were very similar to those in the ANITA trial. 4 Moreover, our patients were treated at a large cancer center by skilled thoracic oncologists, following standard guidelines and tumor board discussion. These high standards were maintained in patient selection, with 90% of the patients receiving chemotherapy having an ECOG performance status of 0-1. In addition, real-world evidence can validate and extend the results of randomized prospective studies to determine whether they are generalizable. Even regulatory agencies, such as the U.S. Food and Drug Administration, are progressively becoming more interested in data based on real-world evidence. 15
In conclusion, our study shows that adjuvant chemotherapy improves both OS and RFS in patients with NSCLC in a real-world setting. However, the cisplatin-vinorelbine regimen was not only associated with alarming rates of treatment-related grade 3-4 toxicity but also with a remarkably high risk of treatment-related deaths. Our results endorse the relevance of real-world data to current daily practices and public health policies in patients with NSCLC, especially for treatment with curative intent.
Financial support: None.
2 Study carrried out at the Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. | Fatal | ReactionOutcome | CC BY-NC | 33656100 | 19,030,754 | 2021 |
What was the outcome of reaction 'Febrile neutropenia'? | Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer.
OBJECTIVE
Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting.
METHODS
This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting.
RESULTS
The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin-vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin-vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity.
CONCLUSIONS
These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.
INTRODUCTION
Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths both in men and women worldwide, with an estimated 1.7 million deaths in 2018. 1 Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. 2 Clinical outcomes and treatment strategies for NSCLC are directly related to stage at diagnosis. Unfortunately, only 25% of the patients with NSCLC have non-metastatic disease at diagnosis, and recurrence rates are often high even when patients are treated with curative intent. 3
In order to improve patient outcomes, adjuvant cisplatin-based chemotherapy after surgical resection has been extensively studied in the last decades. 4 - 8 The Adjuvant Navelbine International Trialist Association (ANITA) trial 4 demonstrated that cisplatin and vinorelbine significantly improve five-year survival rates (by 8,6%; p = 0,017) in patients with stage IB-IIIA NSCLC. However, a subgroup analysis indicated that the benefit is mainly seen in patients with stage II or IIIA disease. 4 )
The benefit of adjuvant chemotherapy in NSCLC was confirmed in a meta-analysis evaluating more than 4.500 patients in five clinical trials. 5 It showed that platinum-based adjuvant chemotherapy resulted in a 5.4% absolute improvement in overall survival (OS) in patients with stage II or III NSCLC (hazard ratio [HR] = 0.89; 95% CI: 0.82-0.96; p = 0.005). 5 Based on these results, platinum-based adjuvant chemotherapy has become the standard of care for patients with completely resected stage II or IIIA NSCLC, and the most commonly used regimen is a combination of cisplatin and vinorelbine. 4 - 8
Although effectiveness of the cisplatin-vinorelbine regimen has been well established, the combination of cisplatin and vinorelbine is associated with clinically relevant toxicity. High rates of grade 3-4 adverse events can compromise treatment adherence, leading to dose reductions and delays, as well as to treatment discontinuation, which is known to be associated with worse outcomes. 4 - 8 Studies providing real-world data on long-term efficacy and safety of adjuvant chemotherapy in NSCLC are scarce and have heterogeneous methods and outcomes. Therefore, the primary objective of the present study was to evaluate the effectiveness and safety of adjuvant chemotherapy for NSCLC patients in a real-world setting.
METHODS
Study design and participants
In this retrospective cohort study, patients undergoing surgical treatment for localized NSCLC were consecutively evaluated and treated between June of 2009 and January of 2018 at the Instituto do Câncer do Estado de São Paulo (ICESP), located in the city of São Paulo, Brazil. The ICESP has a dedicated multidisciplinary thoracic oncology team responsible for evaluating and discussing the cases of patients considered candidates for surgery with curative intent.
We included patients with histologically confirmed NSCLC and TNM stage I-III NSCLC 3 undergoing surgery with curative intent. In accordance with the institutional guidelines, all patients were submitted to pre-operative staging with CT or PET/CT to exclude metastases and with mediastinoscopy or EBUS for mediastinal staging, when indicated. Exclusion criteria included metastatic disease, primary tumor not amenable to complete resection, and a concurrent diagnosis of other malignancies. Data on clinical and demographic characteristics, as well as on treatment received, toxicity, and oncologic outcomes were obtained from electronic medical records. The study was approved by the local research ethics committee (ID 1011/16).
Treatment
The thoracic surgery team defined the type of surgery required to achieve a tumor-free resection margins (lobectomy or pneumonectomy and lymph node dissection) by using an open surgery or video-assisted thoracic surgery, in accordance with the International Association for the Study of Lung Cancer recommendations. 2 , 3
Adjuvant chemotherapy, radiation therapy, or both were prescribed at the discretion of the physicians involved, in accordance with institutional guidelines or by tumor board consensus. At our institution during the study period, adjuvant chemotherapy was recommended for patients with completely resected stage II-III NSCLC and was considered on a case-by-case basis in patients with stage IB NSCLC. In addition, patients must have an ECOG performance status of 0-1 and adequate hepatic, renal, and hematological function. Standard adjuvant chemotherapy as defined by institutional guidelines is cisplatin (80 mg/m2 on day 1) and vinorelbine (30 mg/m2 on days 1, 8, and 15) every three weeks for four cycles. Alternative platinum-based chemotherapy regimens are allowed in specific settings. Although adjuvant radiation therapy is not part of our routine protocol, it was considered on a case-by-case basis in patients with positive margins or N2 lymph node status.
Statistical analysis
Patient characteristics and treatment-related toxicities were summarized by descriptive statistics. Continuous variables were expressed as median and range, whereas categorical variables were presented as absolute numbers and proportions. Differences in continuous variables between the groups were evaluated by Student’s t-test. Categorical variables were compared between groups with the use of Fisher’s exact test.
The Kaplan-Meier method was used in order to estimate survival function, and curves were compared by the log-rank test. The primary outcome was OS, defined as the time from the date of surgery to the date of death from any cause or the date of the last medical visit. Recurrence-free survival (RFS) was also analyzed and defined as the time from surgery to disease recurrence or death. Patients presenting with no events of interest were censored at the last follow-up date.
Potential prognostic factors were evaluated by univariate and multivariate analysis with Cox proportional hazards regression, which provided the HR and 95% CI. Prognostic factors evaluated in the univariate analysis included age, gender, TNM stage, lymph node status, histology, and use of adjuvant chemotherapy. For the multivariate model, we included the use of adjuvant chemotherapy and factors showing p ≤ 0.10 in the univariate analysis as long as they were not associated with each other. The chi-square test was used in order to evaluate the association between variables.
Statistical analyses were conducted with the Stata statistical software package, version 15.1 (StataCorp LP, College Station, TX, USA). The level of significance was set at 5% (p < 0.05).
RESULTS
Patient characteristics
The study included 231 consecutive patients who met the eligibility criteria. The median follow-up time was 24 months. Of the 231 patients, 80 patients received adjuvant chemotherapy, and 151 were followed after surgical treatment (controls). Of the 80 patients who received adjuvant chemotherapy, 55 patients (68%) received the cisplatin-vinorelbine regimen. Alternative regimens included carboplatin and paclitaxel (n = 17; 21.2%), cisplatin and gemcitabine (n = 5; 6.2%), cisplatin and paclitaxel (n = 1; 1.2%), and carboplatin and vinorelbine (n = 1; 1.2%). Among the patients who received cisplatin and vinorelbine, the median cumulative dose of cisplatin was 286 mg/m2 (range: 72-320 mg/m2), and that of vinorelbine was 292 mg/m2 (range: 60-360 mg/m2).
Patients in the adjuvant chemotherapy group were younger than those in the control group (median age: 63.0 years vs. 67.6 years; p < 0.001) and more frequently underwent pneumonectomy (15.0% vs. 7.9%; p < 0.005). The proportion of early stage disease was higher in the control group, with stage I NSCLC in 56.3% (p < 0.001) and negative lymph nodes (N0) in 67.5% (p < 0.001). Of the patients who received adjuvant chemotherapy, only 2.5% had stage I NSCLC, and 31.2% had negative lymph nodes (N0). Table 1 summarizes the characteristics of the study participants.
Table 1 Characteristics of the patients included in the study (N = 231).a
Characteristic Group P
Adjuvant chemotherapy No adjuvant chemotherapy
(n = 80) (n = 151)
Age, years 63.0 [45.3-79.1] 68.3 [34.0-87.9] < 0.001*
Sex
Male
Female
36 (45.0)
44 (55.0)
73 (48.3)
78 (51.7) 0.388†
Type of surgery
Pneumonectomy
Lobectomy
Other
12 (15.0)
61 (76.2)
7 (8.7)
12 (7.9)
134 (88.7)
5 (3.3) 0.005†
Histology
SCC
Adenocarcinoma
Other
Not available
21 (26.2)
53 (66.2)
6 (7.5)
0 (0)
48 (31.8)
92 (60.9)
10 (6.6)
1 (0.7) 0.747†
Stage
I
II
III
Not available
2 (2.5)
44 (54.9)
34 (42.5)
0 (0)
85 (56.3)
41 (27.1)
24 (15.9)
1 (0.7) < 0.001†
Lymph node status
N0
N1
N2
Not available
25 (31.2)
27 (33.7)
27 (33.7)
1 (1.2)
102 (67.5)
17 (11.3)
14 (9.3)
18 (11.9) < 0.001†
ECOG-PS before chemotherapy
0
1
2
Not available
22 (27.5)
48 (60.0)
1 (1.2)
9 (11.2)
-
-
Radiation therapy
Yes
13 (16.2)
5 (3.3)
SCC: squamous cell carcinoma; and PS: performance status. aValues expressed as median [range] or n (%). *Student’s t-test. †Fisher’s exact test.
Effectiveness
In the univariate analysis, factors associated with shorter OS were TNM stage (stage II vs. stage I: HR = 2.57; 95% CI: 1.40-4.71; p = 0.002; and stage III vs. stage I: HR = 3.81; 95% CI: 2.06-7.07; p < 0.001) and lymph node status (N2 vs. N0: HR = 1.82; 95% CI: 1.07-3.11; p = 0.027). Adjuvant chemotherapy use and TNM stage were included in the multivariate model. Lymph node status was not included, because it is part of the TNM stage (p < 0.001).
The multivariate analysis confirmed that TNM stage was a negative prognostic factor for OS (stage II vs. stage I: HR = 3.93; 95% CI: 2.06-7.49; p < 0.001; and stage III vs. stage I: HR = 6.31; 95% CI: 3.23-12.35; p < 0.001), whereas adjuvant chemotherapy use was associated with longer OS in comparison with the control group (HR = 0.43; 95% CI: 0.25-0.72; p = 0.001). The results of univariate and multivariate Cox regression analyses are presented in Table 2.
Table 2 Factors associated with overall survival after surgery for resection of non-small cell lung cancer (Cox regression).
Factor Univariate analysis Multivariate analysis
HR (95% CI) p HR (95% CI) p
Adjuvant chemotherapy (yes vs. no) 0.97 (0.60-1.55) 0.909 0.43 (0.25-0.72) 0.001
Age (> 60 years vs. ≤ 60 years) 1.26 (0.76-2.08) 0.367
Sex (male vs. female) 1.44 (0.90-2.29) 0.123
TNM stage
I
II
III
Reference
2.57 (1.40-4.71)
3.81 (2.06-7.07)
0.002
0.000
Reference
3.93 (2.06-7.49)
6.31 (3.23-12.35)
< 0.001
< 0.001
Lymph node status
N0
N1
N2
Reference
0.93 (0.48-1.82)
1.82 (1.07-3.11)
0.854
0.027
Histology (SCC vs. adenocarcinoma) 1.38 (0.84-2.27) 0.192
HR: hazard ratio; and SCC: squamous cell carcinoma.
During the study follow-up period, 97 patients (67%) had disease recurrence or died. Given the discrepancy between the study groups regarding tumor stage and the importance of this factor for oncologic outcomes, survival analyses were carried out according to tumor stage. Among stage II NSCLC patients, those who received adjuvant chemotherapy had longer RFS than did those who did not (median RFS: not reached vs. 25.5 months; HR = 0.50; 95% CI: 0.26-0.95; p = 0.036). Adjuvant chemotherapy was also associated with longer OS. The median OS was not reached in the adjuvant chemotherapy group, whereas, in the control group, it was 33.8 months (HR = 0.42; 95% CI: 0.21-0.85; p = 0.017). Five-year OS rates were 62.1% (95% CI: 42.5-76.7%) and 12.3% (95% CI: 0.8-39.4%) in the adjuvant chemotherapy and control groups, respectively. The Kaplan-Meier curves for RFS and OS in stage II NSCLC patients are shown in Figure 1.
Figure 1 Recurrence-free survival (A) and overall survival (B) curves in patients with stage II non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients with stage III NSCLC who received adjuvant chemotherapy had longer RFS than did those in the control group, the absolute difference in the median RFS between the two groups being approximately 30 months (median RFS: 36.5 months vs. 6.9 months; HR = 0.32; 95% CI: 0.16-0.64; p < 0.001). There was a trend toward longer OS in the adjuvant chemotherapy group in comparison with the control group (median OS: 36.5 months vs. 20.5 months; HR = 0.48; 95% CI: 0.22-1.03; p = 0.060). Five-year OS rates were 37.9% (95% CI: 17.0-58.8%) and 31.8% (95% CI: 10.8-55.4%) in the adjuvant chemotherapy and control groups, respectively. Figure 2 presents the RFS and OS curves for patients with stage III NSCLC.
Figure 2 Recurrence-free survival (A) and overall survival (B) curves in patients with stage III non-small cell lung cancer, comparing those who received adjuvant chemotherapy with those who did not (controls). HR: hazard ratio; and CT: chemotherapy.
Patients who received adjuvant chemotherapy with cisplatin and vinorelbine were compared with controls, and RFS and OS were found to be similar between the two (Figures S1 and S2 in the supplementary material).
Safety
Because the cisplatin and vinorelbine regimen is considered an acceptable chemotherapy regimen and because it was used by most of the patients who received adjuvant chemotherapy in the present study, the safety profile of this regimen was evaluated. Moreover, previous randomized studies and clinical experience have suggested a high toxicity rate. 4 - 8
Of the patients who received adjuvant chemotherapy with cisplatin and vinorelbine, 49 (89%) experienced grade 3-4 toxicities, hospitalization being required in 27 (49%). Sixteen patients (29%) had grade 3-4 febrile neutropenia. In addition, 5 patients (9%) died of treatment toxicity (grade 5 toxicity; Table 3).
Table 3 Characteristics of the patients who died of adjuvant treatment toxicity.
Patient Sex Age, years ECOG-PS Staging Chemotherapy regimen Toxicity
1 Male 71 1 IIIA cisplatin + vinorelbine FN
2 Female 61 0 IIA cisplatin + vinorelbine FN + AKI
3 Male 70 1 IIIA cisplatin + vinorelbine FN + AKI
4 Male 72 1 IIB cisplatin + vinorelbine FN + AKI
5 Male 63 1 IIB cisplatin + vinorelbine FN + AKI
PS: performance status; FN: febrile neutropenia; and AKI: acute kidney injury.
Twenty-five patients discontinued the adjuvant cisplatin and vinorelbine regimen, treatment toxicity being the main reason for treatment discontinuation (in 68%). Table 4 summarizes the safety profile of adjuvant cisplatin and vinorelbine regimen in comparison with the safety results of the pivotal ANITA trial. 4
Table 4 Safety profile of adjuvant chemotherapy with cisplatin and vinorelbine in patients with non-small cell lung cancer after surgery.
Profile Present study ANITA triala
Grade 3-4 toxicity 89% N/A
Grade 5 toxicity 9% 2%
Grade 3-4 febrile neutropenia 29% 9%
Toxicity as reason for chemotherapy discontinuation 68% 34%
Hospitalization due to toxicity 49% N/A
a Results based on Douillard et al. 4 ) ANITA: Adjuvant Navelbine International Trialist Association.
DISCUSSION
Our findings reinforce the survival benefit of adjuvant chemotherapy in patients with NSCLC, both in terms of OS and RFS. A meaningful OS benefit was observed in patients with stage II or III NSCLC. The benefit of adjuvant chemotherapy in NSCLC patients has already been demonstrated in various randomized phase III trials. 4 , 6 - 8 In addition, a meta-analysis evaluating 5,584 patients of five clinical trials showed a 5.4% absolute OS gain with cisplatin-based chemotherapy. Among different chemotherapy regimens, cisplatin plus vinorelbine was marginally better than other drug combinations. Furthermore, the cisplatin-vinorelbine combination was the most commonly used regimen, being the largest (41%) and most homogenous study subgroup. 5 When this regimen was separately analyzed, a significant survival benefit was found (absolute benefit, 8.9% at five years; HR = 0.80; 95% CI: 0.70-0.91; p < 0.001). 9 However, among 6,430 patients of 16 clinical trials included in another meta-analysis, 10 which evaluated the role of adjuvant cisplatin-based chemotherapy in NSCLC patients, an increased risk of non-lung cancer-related deaths was observed in those receiving chemotherapy (relative risk = 1.3, p = 0.002).
More recently, Kenmotsu et al. 11 evaluated adjuvant cisplatin-pemetrexed vs. cisplatin-vinorelbine in the NSCLC setting, and, although the superiority of the pemetrexed-containing regimen over the vinorelbine-containing regimen was not demonstrated, both regimens had similar RFS and OS, pemetrexed showing better tolerability and less toxicity. Therefore, the benefits and risks associated with cisplatin-based adjuvant chemotherapy should be taken into account. Although predictive biomarkers of OS benefits from adjuvant treatments (chemotherapy and, possibly in the future, immunotherapy and targeted therapies) are of utmost importance for patient selection, they have yet to be identified and validated.
Notably, randomized phase III trials generally enroll a carefully selected population; only a small number of elderly patients are included, with few comorbidities and good performance status, and this does not represent a real-world setting. Therefore, studies addressing real-world evidence are required to evaluate the benefits and risks of the interventions used in clinical trials. 12 . Kolek et al. 13 reported better survival with adjuvant treatment in this setting, with the longest survival in the cisplatin-vinorelbine cohort. Morgensztern et al. 14 presented the results of 19,691 patients with NSCLC and showed a 4.2% treatment-related mortality rate in six months, reinforcing the importance of and need for real-world data.
Another important issue to be discussed is that, although effectiveness was similar, the incidence of toxicity and hospital admissions was consistently higher in the patients treated with the cisplatin-vinorelbine combination. The outcomes in real-world studies should be carefully analyzed. In the ANITA trial, 4 9% of the patients presented with grade 3-4 febrile neutropenia, and 2% died of treatment-related toxicity, in contrast to a 29% incidence of febrile neutropenia and a 9% mortality rate in our study, which were excessively high for an adjuvant treatment setting. Given that the aim of adjuvant treatment is to improve OS, the difference in the mortality rate between the two studies is noteworthy and potentially exceeds the OS benefit yielded by this treatment. It is of note that 60% of our patients had an ECOG performance status of 1, whereas, in the ANITA trial, 47% had an ECOG performance status of 1, 4 a difference that could explain the higher toxicity observed in our study.
Given the retrospective nature of the present study, selection bias cannot be ruled out. Chemotherapy was prescribed at the discretion of the physicians involved, and the patients who did not receive adjuvant chemotherapy after surgery could have had a worse prognosis a priori. Nevertheless, an indirect comparison reveals that chemotherapy-treated patients show median OS similar to that seen in historical controls. 4 - 8 Despite the retrospective design and the small sample size, which is prone to treatment bias, our analysis has important strengths. The median cumulative doses of cisplatin and vinorelbine in our study were very similar to those in the ANITA trial. 4 Moreover, our patients were treated at a large cancer center by skilled thoracic oncologists, following standard guidelines and tumor board discussion. These high standards were maintained in patient selection, with 90% of the patients receiving chemotherapy having an ECOG performance status of 0-1. In addition, real-world evidence can validate and extend the results of randomized prospective studies to determine whether they are generalizable. Even regulatory agencies, such as the U.S. Food and Drug Administration, are progressively becoming more interested in data based on real-world evidence. 15
In conclusion, our study shows that adjuvant chemotherapy improves both OS and RFS in patients with NSCLC in a real-world setting. However, the cisplatin-vinorelbine regimen was not only associated with alarming rates of treatment-related grade 3-4 toxicity but also with a remarkably high risk of treatment-related deaths. Our results endorse the relevance of real-world data to current daily practices and public health policies in patients with NSCLC, especially for treatment with curative intent.
Financial support: None.
2 Study carrried out at the Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. | Fatal | ReactionOutcome | CC BY-NC | 33656100 | 19,030,754 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Deep vein thrombosis'. | Splenic vein stenting for recurrent chylous ascites in sinistral portal hypertension: a case report.
BACKGROUND
Sinistral portal hypertension results from obstruction or stenosis of the splenic vein and is characterized by normal portal vein pressures and liver function tests. Gastrointestinal bleeding is the most common presentation and indication for treatment. Although sinistral portal hypertension-related chylous ascites is rare, several cases have described successful treatment with portal venous, rather than splenic venous, recanalization. Splenectomy is effective in the treatment of sinistral portal hypertension-related bleeding, although recent studies have evaluated splenic vein stenting and splenic arterial embolization as minimally-invasive treatment alternatives. Splenic vein stenting may be a viable option for other presentations of sinistral portal hypertension.
METHODS
A 59-year-old gentleman with a history of necrotizing gallstone pancreatitis was referred to interventional radiology for management of recurrent chylous ascites. Analysis of ascites demonstrated a triglyceride level of 1294 mg/dL. Computed tomography revealed splenic and superior mesenteric venous stricture. The patient elected to undergo minimally invasive transhepatic portal venography, which confirmed the presence of splenic vein and superior mesenteric vein stenosis. Venography of the splenic vein showed reversal of portal venous flow, multiple collaterals, and a pressure gradient of 14 mmHg. Two 10 mm × 40 mm Cordis stents were placed, which decreased the pressure gradient to 7 mmHg and resolved the portosystemic collaterals. At 6 months follow-up, the patient had no recurrent episodes of ascites.
CONCLUSIONS
The current case highlights the successful treatment of sinistral portal hypertension-related intractable chylous ascites treated with transhepatic splenic vein stenting. Splenic venous stent patency rates of 92.9% at 12 months have been reported. Rebleeding rates of 7.1% for splenic vein stenting, 16% for splenectomy, and 47.8% for splenic arterial embolization have been reported in the treatment of sinistral portal hypertension-related gastrointestinal bleeding. The literature regarding splenic vein stenting for sinistral portal hypertension-related ascites is less robust. Technical and clinical success in the current case suggests that splenic vein recanalization may be a safe and viable option in other sinistral portal hypertension-related symptomatology.
METHODS
Level 4, Case Report.
Introduction
Sinistral portal hypertension (SPH) results from obstruction or stenosis of the splenic vein and is characterized by normal portal vein pressures and liver function tests (El Kininy et al. 2017). Gastrointestinal bleeding (GIB) is the most common presentation and indication for treatment (El Kininy et al. 2017). Although SPH-related chylous ascites is rare, several cases describe successful treatment with portal venous recanalization (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003). Splenectomy is effective in the treatment of SPH-related GIB, although recent studies have evaluated splenic vein stenting (SVS) and splenic arterial embolization (SAE) as minimally-invasive treatment alternatives (Ghelfi et al. 2016; Luo et al. 2014; Stein and Link 1999; Wei et al. 2020). Herein, a case of SPH-related recurrent chylous ascites successfully treated with SVS is described.
Case report
IRB approval was not required by our institution for this case report. A 59-year-old gentleman with a history of necrotizing gallstone pancreatitis and atrial fibrillation was referred to interventional radiology for management of recurrent chylous ascites. The patient had gallstone pancreatitis 2 years prior to referral, which was complicated by the formation of recurrent and refractory infected pancreatic pseudocysts requiring repeat percutaneous and endoscopic drainage as well as a cyst-gastrostomy. During admission for cyst-gastrostomy, the patient developed bilateral sub-massive pulmonary embolism and left popliteal deep venous thrombosis while on warfarin, necessitating placement of an inferior vena cava filter. In addition, the patient reported a remote history of suspected GIB prophylactically treated with coil embolization of the gastroduodenal artery.
One month prior to referral, the patient developed chylous ascites requiring repeat paracentesis. Analysis of ascites demonstrated milky white fluid, with 89% neutrophils, 11% mononuclear cells, and a triglyceride level of 1294 mg/dL. CT imaging demonstrated focal splenic and superior mesenteric venous stenoses, gastric varices, splenoportal collaterals, and large abdominal ascites. After discussion with the patient, the decision was made to proceed with percutaneous transhepatic venography with potential venoplasty and stenting.
Under moderate sedation, ultrasound-guided transhepatic right portal access was obtained with a 21 gauge chiba needle. As the procedure involved a transhepatic approach, no intraprocedural heparin was given. Positioning was confirmed with injection of contrast under fluoroscopy. A 0.018″ nitinol (Nitrex) guidewire with a 5 Fr KMP catheter (Cook) was advanced into the portal venous system. Portal venogram was normal, with a pressure of 3 mmHg. Superior mesenteric venogram demonstrated stricture adjacent to the portal confluence and an elevated pressure of 9 mmHg. Progressive superior mesenteric venoplasty was performed up to 7 mm with a Armada 35 balloon (Abbott Vascular). No change in the pressure gradient of 6 mmHg was demonstrated.
The splenic vein was then selectively catheterized. To confirm positioning within the splenic vein, the splenic artery was selectively catheterized. Digital subtraction angiogram of the splenic artery revealed delayed opacification surrounding the catheter within the splenic vein. Splenic venogram demonstrated reversal of normal portal venous flow, multiple splenoportal venous collaterals, and a splenic venous pressure of 17 mmHg (Fig. 1). Progressive splenic venoplasty was performed with a Armada 35 balloon (Abbott Vascular) up to 1 cm with no angiographic or hemodynamic improvement. Two 10 mm × 40 mm Cordis stents were placed, which resulted in resolution of splenoportal collaterals and a decrease in the pressure gradient to 7 mmHg (Fig. 2). Track embolization was performed using two 8 mm × 14 cm coils and gelfoam slurry. He was maintained on a heparin drip for 1 week before transitioning to 5 mg of apixaban twice daily. The patient developed a post-procedure perihepatic hematoma but was discharged shortly thereafter, having received no additional interventions. He remained free of ascites 6 months after the procedure. Fig. 1 Digital subtraction venography of the splenic vein prior to venoplasty reveals multiple areas of stenosis and robust venous collaterals from portal hypertension
Fig. 2 Digital subtraction venography of the splenic vein after deployment of splenic stents shows increased splenic venous patency with resolution of splenoportal collaterals
Discussion
Splenic vein stenosis most commonly occurs as a sequela of pancreatic disease (Luo et al. 2014; Stein and Link 1999). The patient’s history of pancreatitis with infected pseudocyst was the likely etiology of splenic venous stenosis. The most common clinical presentation of SPH is GIB, and most cases of splenic vein recanalization have treated this presentation (Fernandes et al. 2015). Several case reports have shown successful treatment of chylous ascites with portal venous stenting (PVS) (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003).
Splenectomy is the historical treatment of SPH-related GIB, although SVS and SAE have been advocated as possible life-saving alternatives (Wei et al. 2020; Fernandes et al. 2015). Post-splenectomy sepsis from asplenia carries a reported mortality rate as high as 6% (Loftus et al. 1993). Rebleeding rates as high as 16% have been reported (Loftus et al. 1993). SAE carries the risk of splenic abscess, post-infarction syndrome, and incomplete therapeutic response requiring splenectomy (Fernandes et al. 2015).
Luo et al. (2014) published a report on 11 patients diagnosed with SPH-related GIB who underwent transjugular splenic vein recanalization. Six of these patients were identified as having splenic vein stenosis, and technical success was achieved in each case (Luo et al. 2014). A recent retrospective comparative study between SAE and SVS for SPH-related GIB showed patients treated with SVS were less likely to develop rebleeding, with rebleeding rates of 7.1% and 47.8% in SVS versus SAE groups respectively (Wei et al. 2020). The literature regarding SVS for SPH-related ascites is less robust, with few studies describing treatment with PVS rather than SVS (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003; Stein and Link 1999).
SPH-related chylous ascites is caused by redistribution of gastrointestinal lymphatic flow from increased portosystemic venous pressure (Tsauo et al. 2016). In 2003, Maleux et al. first reported successful treatment of chylous ascites from portal vein stenosis with PVS, attaining resolution of chylous ascites at 1-year follow-up (Maleux et al. 2003). Stein and Link (1999) studied 21 patients with either portal vein, splenic vein, or combined portal and splenic vein stenosis. Fifteen of their patients presented with GIB, and 2 presented with intractable ascites; however, the treatment approach for patients with ascites was not specified (Stein and Link 1999). Lastly, Poo et al. (2018) reported a patient with chylous ascites who had a tight focal stenosis involving the SMV and main portal vein. The patient was treated with PVS and was ascites-free at 1-year follow-up (Poo et al. 2018). Given that the described patient presented with a non-emergent presentation of SPH, SVS was felt to be the safest option in lieu of his multiple comorbidities and preference for minimally-invasive therapy.
While no long-term patency studies of SVS for SPH-related chylous ascites are reported in the literature, comparisons may be tentatively drawn from splenic vein patency rates in SPH-related GIB. Wei et al. (2020) reported a cumulative stent patency rate of 92.9% 12 months after SVS for SPH-related GIB. A single splenic stent dysfunction was their only SVS-related complication (Wei et al. 2020). Both cases of PVS for chylous ascites in the literature reported portal venous patency at 1 year. Maleux et al. (2003) gave their patient 1 month of daily 40 mg low molecular weight heparin followed by long-term daily 160 mg acetylic salicyclic acid, while Poo et al. (2018) gave their patient long-term 75 mg daily aspirin. The patient in the current case was given 1 week of heparin drip while hospitalized, followed by his preprocedural anticoagulation of 5 mg apixaban twice daily. Anticoagulation regimen was determined based upon the patient’s history of atrial fibrillation, rather than maintenance of splenic stent patency and likely would have consisted of a less aggressive regimen in the absence of this history. There are no standardized guidelines regarding anticoagulation after portomesenteric stenting, and some studies have failed to find an association between type of anticoagulation and risk of stent thrombosis (Sheth et al. 2018). At 6 months follow-up, the patient remained free of abdominal ascites.
There has been some debate in the literature regarding a transjugular versus transhepatic approach, with some interventionalists avoiding a transhepatic approach due to the perceived risk of increased bleeding (Luo et al. 2014). Studies have shown success via both approaches, and a transhepatic approach was taken in the current case due to the relative ease of the technique and the patient’s stable bloodwork (El Kininy et al. 2017; Ghelfi et al. 2016; Luo et al. 2014; Stein and Link 1999). Nevertheless, the development of a perihepatic hematoma in the current case exemplifies the importance of weighing a variety of factors when planning an approach.
Conclusions
This case report highlights successful treatment of SPH-related recurrent chylous ascites with transhepatic SVS. While evidence for SVS for SPH-related chylous ascites remains sparse, technical success and resolution of ascites suggest that splenic vein recanalization may be a safe and viable option. Although the current literature is promising, additional scientific studies are needed to assess the role of SVS for other SPH-related symptomatology.
Acknowledgements
Not applicable.
Authors’ contributions
All authors made substantial contributions to the conception of the work. BC drafted the manuscript. JM and RF substantially revised the manuscript. All authors have approved the submitted version and agree to be personally accountable for the author’s own contributions. All authors ensure the integrity of this work.
Authors’ information
Not applicable.
Funding
This study was not supported by any funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. IRB approval was not required by our institution for this case report per HCA Healthcare ethics committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
All authors have no competing interests to disclose.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | WARFARIN | DrugsGivenReaction | CC BY | 33656619 | 19,494,919 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'. | Splenic vein stenting for recurrent chylous ascites in sinistral portal hypertension: a case report.
BACKGROUND
Sinistral portal hypertension results from obstruction or stenosis of the splenic vein and is characterized by normal portal vein pressures and liver function tests. Gastrointestinal bleeding is the most common presentation and indication for treatment. Although sinistral portal hypertension-related chylous ascites is rare, several cases have described successful treatment with portal venous, rather than splenic venous, recanalization. Splenectomy is effective in the treatment of sinistral portal hypertension-related bleeding, although recent studies have evaluated splenic vein stenting and splenic arterial embolization as minimally-invasive treatment alternatives. Splenic vein stenting may be a viable option for other presentations of sinistral portal hypertension.
METHODS
A 59-year-old gentleman with a history of necrotizing gallstone pancreatitis was referred to interventional radiology for management of recurrent chylous ascites. Analysis of ascites demonstrated a triglyceride level of 1294 mg/dL. Computed tomography revealed splenic and superior mesenteric venous stricture. The patient elected to undergo minimally invasive transhepatic portal venography, which confirmed the presence of splenic vein and superior mesenteric vein stenosis. Venography of the splenic vein showed reversal of portal venous flow, multiple collaterals, and a pressure gradient of 14 mmHg. Two 10 mm × 40 mm Cordis stents were placed, which decreased the pressure gradient to 7 mmHg and resolved the portosystemic collaterals. At 6 months follow-up, the patient had no recurrent episodes of ascites.
CONCLUSIONS
The current case highlights the successful treatment of sinistral portal hypertension-related intractable chylous ascites treated with transhepatic splenic vein stenting. Splenic venous stent patency rates of 92.9% at 12 months have been reported. Rebleeding rates of 7.1% for splenic vein stenting, 16% for splenectomy, and 47.8% for splenic arterial embolization have been reported in the treatment of sinistral portal hypertension-related gastrointestinal bleeding. The literature regarding splenic vein stenting for sinistral portal hypertension-related ascites is less robust. Technical and clinical success in the current case suggests that splenic vein recanalization may be a safe and viable option in other sinistral portal hypertension-related symptomatology.
METHODS
Level 4, Case Report.
Introduction
Sinistral portal hypertension (SPH) results from obstruction or stenosis of the splenic vein and is characterized by normal portal vein pressures and liver function tests (El Kininy et al. 2017). Gastrointestinal bleeding (GIB) is the most common presentation and indication for treatment (El Kininy et al. 2017). Although SPH-related chylous ascites is rare, several cases describe successful treatment with portal venous recanalization (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003). Splenectomy is effective in the treatment of SPH-related GIB, although recent studies have evaluated splenic vein stenting (SVS) and splenic arterial embolization (SAE) as minimally-invasive treatment alternatives (Ghelfi et al. 2016; Luo et al. 2014; Stein and Link 1999; Wei et al. 2020). Herein, a case of SPH-related recurrent chylous ascites successfully treated with SVS is described.
Case report
IRB approval was not required by our institution for this case report. A 59-year-old gentleman with a history of necrotizing gallstone pancreatitis and atrial fibrillation was referred to interventional radiology for management of recurrent chylous ascites. The patient had gallstone pancreatitis 2 years prior to referral, which was complicated by the formation of recurrent and refractory infected pancreatic pseudocysts requiring repeat percutaneous and endoscopic drainage as well as a cyst-gastrostomy. During admission for cyst-gastrostomy, the patient developed bilateral sub-massive pulmonary embolism and left popliteal deep venous thrombosis while on warfarin, necessitating placement of an inferior vena cava filter. In addition, the patient reported a remote history of suspected GIB prophylactically treated with coil embolization of the gastroduodenal artery.
One month prior to referral, the patient developed chylous ascites requiring repeat paracentesis. Analysis of ascites demonstrated milky white fluid, with 89% neutrophils, 11% mononuclear cells, and a triglyceride level of 1294 mg/dL. CT imaging demonstrated focal splenic and superior mesenteric venous stenoses, gastric varices, splenoportal collaterals, and large abdominal ascites. After discussion with the patient, the decision was made to proceed with percutaneous transhepatic venography with potential venoplasty and stenting.
Under moderate sedation, ultrasound-guided transhepatic right portal access was obtained with a 21 gauge chiba needle. As the procedure involved a transhepatic approach, no intraprocedural heparin was given. Positioning was confirmed with injection of contrast under fluoroscopy. A 0.018″ nitinol (Nitrex) guidewire with a 5 Fr KMP catheter (Cook) was advanced into the portal venous system. Portal venogram was normal, with a pressure of 3 mmHg. Superior mesenteric venogram demonstrated stricture adjacent to the portal confluence and an elevated pressure of 9 mmHg. Progressive superior mesenteric venoplasty was performed up to 7 mm with a Armada 35 balloon (Abbott Vascular). No change in the pressure gradient of 6 mmHg was demonstrated.
The splenic vein was then selectively catheterized. To confirm positioning within the splenic vein, the splenic artery was selectively catheterized. Digital subtraction angiogram of the splenic artery revealed delayed opacification surrounding the catheter within the splenic vein. Splenic venogram demonstrated reversal of normal portal venous flow, multiple splenoportal venous collaterals, and a splenic venous pressure of 17 mmHg (Fig. 1). Progressive splenic venoplasty was performed with a Armada 35 balloon (Abbott Vascular) up to 1 cm with no angiographic or hemodynamic improvement. Two 10 mm × 40 mm Cordis stents were placed, which resulted in resolution of splenoportal collaterals and a decrease in the pressure gradient to 7 mmHg (Fig. 2). Track embolization was performed using two 8 mm × 14 cm coils and gelfoam slurry. He was maintained on a heparin drip for 1 week before transitioning to 5 mg of apixaban twice daily. The patient developed a post-procedure perihepatic hematoma but was discharged shortly thereafter, having received no additional interventions. He remained free of ascites 6 months after the procedure. Fig. 1 Digital subtraction venography of the splenic vein prior to venoplasty reveals multiple areas of stenosis and robust venous collaterals from portal hypertension
Fig. 2 Digital subtraction venography of the splenic vein after deployment of splenic stents shows increased splenic venous patency with resolution of splenoportal collaterals
Discussion
Splenic vein stenosis most commonly occurs as a sequela of pancreatic disease (Luo et al. 2014; Stein and Link 1999). The patient’s history of pancreatitis with infected pseudocyst was the likely etiology of splenic venous stenosis. The most common clinical presentation of SPH is GIB, and most cases of splenic vein recanalization have treated this presentation (Fernandes et al. 2015). Several case reports have shown successful treatment of chylous ascites with portal venous stenting (PVS) (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003).
Splenectomy is the historical treatment of SPH-related GIB, although SVS and SAE have been advocated as possible life-saving alternatives (Wei et al. 2020; Fernandes et al. 2015). Post-splenectomy sepsis from asplenia carries a reported mortality rate as high as 6% (Loftus et al. 1993). Rebleeding rates as high as 16% have been reported (Loftus et al. 1993). SAE carries the risk of splenic abscess, post-infarction syndrome, and incomplete therapeutic response requiring splenectomy (Fernandes et al. 2015).
Luo et al. (2014) published a report on 11 patients diagnosed with SPH-related GIB who underwent transjugular splenic vein recanalization. Six of these patients were identified as having splenic vein stenosis, and technical success was achieved in each case (Luo et al. 2014). A recent retrospective comparative study between SAE and SVS for SPH-related GIB showed patients treated with SVS were less likely to develop rebleeding, with rebleeding rates of 7.1% and 47.8% in SVS versus SAE groups respectively (Wei et al. 2020). The literature regarding SVS for SPH-related ascites is less robust, with few studies describing treatment with PVS rather than SVS (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003; Stein and Link 1999).
SPH-related chylous ascites is caused by redistribution of gastrointestinal lymphatic flow from increased portosystemic venous pressure (Tsauo et al. 2016). In 2003, Maleux et al. first reported successful treatment of chylous ascites from portal vein stenosis with PVS, attaining resolution of chylous ascites at 1-year follow-up (Maleux et al. 2003). Stein and Link (1999) studied 21 patients with either portal vein, splenic vein, or combined portal and splenic vein stenosis. Fifteen of their patients presented with GIB, and 2 presented with intractable ascites; however, the treatment approach for patients with ascites was not specified (Stein and Link 1999). Lastly, Poo et al. (2018) reported a patient with chylous ascites who had a tight focal stenosis involving the SMV and main portal vein. The patient was treated with PVS and was ascites-free at 1-year follow-up (Poo et al. 2018). Given that the described patient presented with a non-emergent presentation of SPH, SVS was felt to be the safest option in lieu of his multiple comorbidities and preference for minimally-invasive therapy.
While no long-term patency studies of SVS for SPH-related chylous ascites are reported in the literature, comparisons may be tentatively drawn from splenic vein patency rates in SPH-related GIB. Wei et al. (2020) reported a cumulative stent patency rate of 92.9% 12 months after SVS for SPH-related GIB. A single splenic stent dysfunction was their only SVS-related complication (Wei et al. 2020). Both cases of PVS for chylous ascites in the literature reported portal venous patency at 1 year. Maleux et al. (2003) gave their patient 1 month of daily 40 mg low molecular weight heparin followed by long-term daily 160 mg acetylic salicyclic acid, while Poo et al. (2018) gave their patient long-term 75 mg daily aspirin. The patient in the current case was given 1 week of heparin drip while hospitalized, followed by his preprocedural anticoagulation of 5 mg apixaban twice daily. Anticoagulation regimen was determined based upon the patient’s history of atrial fibrillation, rather than maintenance of splenic stent patency and likely would have consisted of a less aggressive regimen in the absence of this history. There are no standardized guidelines regarding anticoagulation after portomesenteric stenting, and some studies have failed to find an association between type of anticoagulation and risk of stent thrombosis (Sheth et al. 2018). At 6 months follow-up, the patient remained free of abdominal ascites.
There has been some debate in the literature regarding a transjugular versus transhepatic approach, with some interventionalists avoiding a transhepatic approach due to the perceived risk of increased bleeding (Luo et al. 2014). Studies have shown success via both approaches, and a transhepatic approach was taken in the current case due to the relative ease of the technique and the patient’s stable bloodwork (El Kininy et al. 2017; Ghelfi et al. 2016; Luo et al. 2014; Stein and Link 1999). Nevertheless, the development of a perihepatic hematoma in the current case exemplifies the importance of weighing a variety of factors when planning an approach.
Conclusions
This case report highlights successful treatment of SPH-related recurrent chylous ascites with transhepatic SVS. While evidence for SVS for SPH-related chylous ascites remains sparse, technical success and resolution of ascites suggest that splenic vein recanalization may be a safe and viable option. Although the current literature is promising, additional scientific studies are needed to assess the role of SVS for other SPH-related symptomatology.
Acknowledgements
Not applicable.
Authors’ contributions
All authors made substantial contributions to the conception of the work. BC drafted the manuscript. JM and RF substantially revised the manuscript. All authors have approved the submitted version and agree to be personally accountable for the author’s own contributions. All authors ensure the integrity of this work.
Authors’ information
Not applicable.
Funding
This study was not supported by any funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. IRB approval was not required by our institution for this case report per HCA Healthcare ethics committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
All authors have no competing interests to disclose.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | WARFARIN | DrugsGivenReaction | CC BY | 33656619 | 19,494,919 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary embolism'. | Splenic vein stenting for recurrent chylous ascites in sinistral portal hypertension: a case report.
BACKGROUND
Sinistral portal hypertension results from obstruction or stenosis of the splenic vein and is characterized by normal portal vein pressures and liver function tests. Gastrointestinal bleeding is the most common presentation and indication for treatment. Although sinistral portal hypertension-related chylous ascites is rare, several cases have described successful treatment with portal venous, rather than splenic venous, recanalization. Splenectomy is effective in the treatment of sinistral portal hypertension-related bleeding, although recent studies have evaluated splenic vein stenting and splenic arterial embolization as minimally-invasive treatment alternatives. Splenic vein stenting may be a viable option for other presentations of sinistral portal hypertension.
METHODS
A 59-year-old gentleman with a history of necrotizing gallstone pancreatitis was referred to interventional radiology for management of recurrent chylous ascites. Analysis of ascites demonstrated a triglyceride level of 1294 mg/dL. Computed tomography revealed splenic and superior mesenteric venous stricture. The patient elected to undergo minimally invasive transhepatic portal venography, which confirmed the presence of splenic vein and superior mesenteric vein stenosis. Venography of the splenic vein showed reversal of portal venous flow, multiple collaterals, and a pressure gradient of 14 mmHg. Two 10 mm × 40 mm Cordis stents were placed, which decreased the pressure gradient to 7 mmHg and resolved the portosystemic collaterals. At 6 months follow-up, the patient had no recurrent episodes of ascites.
CONCLUSIONS
The current case highlights the successful treatment of sinistral portal hypertension-related intractable chylous ascites treated with transhepatic splenic vein stenting. Splenic venous stent patency rates of 92.9% at 12 months have been reported. Rebleeding rates of 7.1% for splenic vein stenting, 16% for splenectomy, and 47.8% for splenic arterial embolization have been reported in the treatment of sinistral portal hypertension-related gastrointestinal bleeding. The literature regarding splenic vein stenting for sinistral portal hypertension-related ascites is less robust. Technical and clinical success in the current case suggests that splenic vein recanalization may be a safe and viable option in other sinistral portal hypertension-related symptomatology.
METHODS
Level 4, Case Report.
Introduction
Sinistral portal hypertension (SPH) results from obstruction or stenosis of the splenic vein and is characterized by normal portal vein pressures and liver function tests (El Kininy et al. 2017). Gastrointestinal bleeding (GIB) is the most common presentation and indication for treatment (El Kininy et al. 2017). Although SPH-related chylous ascites is rare, several cases describe successful treatment with portal venous recanalization (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003). Splenectomy is effective in the treatment of SPH-related GIB, although recent studies have evaluated splenic vein stenting (SVS) and splenic arterial embolization (SAE) as minimally-invasive treatment alternatives (Ghelfi et al. 2016; Luo et al. 2014; Stein and Link 1999; Wei et al. 2020). Herein, a case of SPH-related recurrent chylous ascites successfully treated with SVS is described.
Case report
IRB approval was not required by our institution for this case report. A 59-year-old gentleman with a history of necrotizing gallstone pancreatitis and atrial fibrillation was referred to interventional radiology for management of recurrent chylous ascites. The patient had gallstone pancreatitis 2 years prior to referral, which was complicated by the formation of recurrent and refractory infected pancreatic pseudocysts requiring repeat percutaneous and endoscopic drainage as well as a cyst-gastrostomy. During admission for cyst-gastrostomy, the patient developed bilateral sub-massive pulmonary embolism and left popliteal deep venous thrombosis while on warfarin, necessitating placement of an inferior vena cava filter. In addition, the patient reported a remote history of suspected GIB prophylactically treated with coil embolization of the gastroduodenal artery.
One month prior to referral, the patient developed chylous ascites requiring repeat paracentesis. Analysis of ascites demonstrated milky white fluid, with 89% neutrophils, 11% mononuclear cells, and a triglyceride level of 1294 mg/dL. CT imaging demonstrated focal splenic and superior mesenteric venous stenoses, gastric varices, splenoportal collaterals, and large abdominal ascites. After discussion with the patient, the decision was made to proceed with percutaneous transhepatic venography with potential venoplasty and stenting.
Under moderate sedation, ultrasound-guided transhepatic right portal access was obtained with a 21 gauge chiba needle. As the procedure involved a transhepatic approach, no intraprocedural heparin was given. Positioning was confirmed with injection of contrast under fluoroscopy. A 0.018″ nitinol (Nitrex) guidewire with a 5 Fr KMP catheter (Cook) was advanced into the portal venous system. Portal venogram was normal, with a pressure of 3 mmHg. Superior mesenteric venogram demonstrated stricture adjacent to the portal confluence and an elevated pressure of 9 mmHg. Progressive superior mesenteric venoplasty was performed up to 7 mm with a Armada 35 balloon (Abbott Vascular). No change in the pressure gradient of 6 mmHg was demonstrated.
The splenic vein was then selectively catheterized. To confirm positioning within the splenic vein, the splenic artery was selectively catheterized. Digital subtraction angiogram of the splenic artery revealed delayed opacification surrounding the catheter within the splenic vein. Splenic venogram demonstrated reversal of normal portal venous flow, multiple splenoportal venous collaterals, and a splenic venous pressure of 17 mmHg (Fig. 1). Progressive splenic venoplasty was performed with a Armada 35 balloon (Abbott Vascular) up to 1 cm with no angiographic or hemodynamic improvement. Two 10 mm × 40 mm Cordis stents were placed, which resulted in resolution of splenoportal collaterals and a decrease in the pressure gradient to 7 mmHg (Fig. 2). Track embolization was performed using two 8 mm × 14 cm coils and gelfoam slurry. He was maintained on a heparin drip for 1 week before transitioning to 5 mg of apixaban twice daily. The patient developed a post-procedure perihepatic hematoma but was discharged shortly thereafter, having received no additional interventions. He remained free of ascites 6 months after the procedure. Fig. 1 Digital subtraction venography of the splenic vein prior to venoplasty reveals multiple areas of stenosis and robust venous collaterals from portal hypertension
Fig. 2 Digital subtraction venography of the splenic vein after deployment of splenic stents shows increased splenic venous patency with resolution of splenoportal collaterals
Discussion
Splenic vein stenosis most commonly occurs as a sequela of pancreatic disease (Luo et al. 2014; Stein and Link 1999). The patient’s history of pancreatitis with infected pseudocyst was the likely etiology of splenic venous stenosis. The most common clinical presentation of SPH is GIB, and most cases of splenic vein recanalization have treated this presentation (Fernandes et al. 2015). Several case reports have shown successful treatment of chylous ascites with portal venous stenting (PVS) (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003).
Splenectomy is the historical treatment of SPH-related GIB, although SVS and SAE have been advocated as possible life-saving alternatives (Wei et al. 2020; Fernandes et al. 2015). Post-splenectomy sepsis from asplenia carries a reported mortality rate as high as 6% (Loftus et al. 1993). Rebleeding rates as high as 16% have been reported (Loftus et al. 1993). SAE carries the risk of splenic abscess, post-infarction syndrome, and incomplete therapeutic response requiring splenectomy (Fernandes et al. 2015).
Luo et al. (2014) published a report on 11 patients diagnosed with SPH-related GIB who underwent transjugular splenic vein recanalization. Six of these patients were identified as having splenic vein stenosis, and technical success was achieved in each case (Luo et al. 2014). A recent retrospective comparative study between SAE and SVS for SPH-related GIB showed patients treated with SVS were less likely to develop rebleeding, with rebleeding rates of 7.1% and 47.8% in SVS versus SAE groups respectively (Wei et al. 2020). The literature regarding SVS for SPH-related ascites is less robust, with few studies describing treatment with PVS rather than SVS (Tsauo et al. 2016; Poo et al. 2018; Maleux et al. 2003; Stein and Link 1999).
SPH-related chylous ascites is caused by redistribution of gastrointestinal lymphatic flow from increased portosystemic venous pressure (Tsauo et al. 2016). In 2003, Maleux et al. first reported successful treatment of chylous ascites from portal vein stenosis with PVS, attaining resolution of chylous ascites at 1-year follow-up (Maleux et al. 2003). Stein and Link (1999) studied 21 patients with either portal vein, splenic vein, or combined portal and splenic vein stenosis. Fifteen of their patients presented with GIB, and 2 presented with intractable ascites; however, the treatment approach for patients with ascites was not specified (Stein and Link 1999). Lastly, Poo et al. (2018) reported a patient with chylous ascites who had a tight focal stenosis involving the SMV and main portal vein. The patient was treated with PVS and was ascites-free at 1-year follow-up (Poo et al. 2018). Given that the described patient presented with a non-emergent presentation of SPH, SVS was felt to be the safest option in lieu of his multiple comorbidities and preference for minimally-invasive therapy.
While no long-term patency studies of SVS for SPH-related chylous ascites are reported in the literature, comparisons may be tentatively drawn from splenic vein patency rates in SPH-related GIB. Wei et al. (2020) reported a cumulative stent patency rate of 92.9% 12 months after SVS for SPH-related GIB. A single splenic stent dysfunction was their only SVS-related complication (Wei et al. 2020). Both cases of PVS for chylous ascites in the literature reported portal venous patency at 1 year. Maleux et al. (2003) gave their patient 1 month of daily 40 mg low molecular weight heparin followed by long-term daily 160 mg acetylic salicyclic acid, while Poo et al. (2018) gave their patient long-term 75 mg daily aspirin. The patient in the current case was given 1 week of heparin drip while hospitalized, followed by his preprocedural anticoagulation of 5 mg apixaban twice daily. Anticoagulation regimen was determined based upon the patient’s history of atrial fibrillation, rather than maintenance of splenic stent patency and likely would have consisted of a less aggressive regimen in the absence of this history. There are no standardized guidelines regarding anticoagulation after portomesenteric stenting, and some studies have failed to find an association between type of anticoagulation and risk of stent thrombosis (Sheth et al. 2018). At 6 months follow-up, the patient remained free of abdominal ascites.
There has been some debate in the literature regarding a transjugular versus transhepatic approach, with some interventionalists avoiding a transhepatic approach due to the perceived risk of increased bleeding (Luo et al. 2014). Studies have shown success via both approaches, and a transhepatic approach was taken in the current case due to the relative ease of the technique and the patient’s stable bloodwork (El Kininy et al. 2017; Ghelfi et al. 2016; Luo et al. 2014; Stein and Link 1999). Nevertheless, the development of a perihepatic hematoma in the current case exemplifies the importance of weighing a variety of factors when planning an approach.
Conclusions
This case report highlights successful treatment of SPH-related recurrent chylous ascites with transhepatic SVS. While evidence for SVS for SPH-related chylous ascites remains sparse, technical success and resolution of ascites suggest that splenic vein recanalization may be a safe and viable option. Although the current literature is promising, additional scientific studies are needed to assess the role of SVS for other SPH-related symptomatology.
Acknowledgements
Not applicable.
Authors’ contributions
All authors made substantial contributions to the conception of the work. BC drafted the manuscript. JM and RF substantially revised the manuscript. All authors have approved the submitted version and agree to be personally accountable for the author’s own contributions. All authors ensure the integrity of this work.
Authors’ information
Not applicable.
Funding
This study was not supported by any funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. IRB approval was not required by our institution for this case report per HCA Healthcare ethics committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
All authors have no competing interests to disclose.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | WARFARIN | DrugsGivenReaction | CC BY | 33656619 | 19,494,919 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant ascites'. | A case of multiple metastatic sarcomatoid renal cell carcinoma with complete response to nivolumab.
Sarcomatoid renal cell carcinoma (SRCC) is associated with poor prognosis. Although there is no standard treatment for SRCC, recent studies have reported the effectiveness of immune checkpoint inhibitors.
An 82-year-old Japanese man presented to our hospital with an incidental right renal tumor. Abdominal computed tomography (CT) showed an exophytic tumor in the right kidney with suspected right iliopsoas muscle invasion. Laparoscopic right radical nephrectomy was performed. Histopathological diagnosis revealed a clear cell RCC with a spindle cell carcinoma component. CT performed 3 months after surgery revealed multiple bilateral lung metastases and local recurrence. Although the patient received tyrosine-kinase inhibitors for treating multiple metastases, the lung metastases continued to gradually increase, and peritonitis carcinomatosis was observed. Thus, the patient was intravenously administered nivolumab once every 2 weeks. After nivolumab administration, lung metastases, local recurrence, and peritonitis carcinomatosis gradually reduced. After 20 months of nivolumab treatment, the patient achieved a complete response of multiple metastases on CT.
Nivolumab may be used as a treatment option for sarcomatoid renal cell carcinoma with multiple metastases.
1 INTRODUCTION
Sarcomatoid renal cell carcinoma (SRCC) accounts for 1% to 5% of all renal neoplasms and is also known as spindle cell carcinoma, anaplastic carcinoma, and carcinosarcoma.1, 2 Renal cell carcinoma (RCC) with a sarcomatoid component is associated with poor prognosis even for patients diagnosed with stage I or II RCC. Most patients with RCC with a sarcomatoid variant showed local recurrence or distant metastases at diagnosis.1, 2 In general, the oncological outcomes of SRCC are unfavorable, and the median survival of SRCC patients has been reported to be between 5 and 12 months.3 In addition, the time from nephrectomy to cancer recurrence was significantly shorter in patients with SRCC than in those with non‐SRCC (18.8 vs 42.9 months; P < .0001).4 Recently, some reports have suggested that immune checkpoint inhibitors (ICIs) are particularly effective for SRCC.5, 6, 7, 8 In this study, we reported a stage IV SRCC patient, who achieved complete response to nivolumab treatment.
2 CASE
An 82‐year‐old Japanese male patient presented with an incidental right renal tumor at our hospital. Abdominal computed tomography (CT) showed an exophytic tumor measuring 6.2 cm × 6.3 cm in the lower pole of the right kidney with suspected right iliopsoas muscle invasion and right adrenal gland metastasis (Figure 1). The patient did not show lymph node involvement or distant metastases at this point.
FIGURE 1 Abdominal computed tomography showing a right renal tumor in the lower pole with suspected invasion to the right iliopsoas muscle (arrow)
Laparoscopic right radical nephrectomy with right adrenalectomy was performed. Histopathological diagnosis revealed clear cell RCC with a spindle cell carcinoma component (40%) (Figure 2A). Immunohistochemistry analysis using anti‐programmed death‐ligand 1 (PD‐L1) antibody (clone 28‐8) showed that PD‐L1 was expressed 25% in tumor positive score (TPS), 20% in immune cells (IC), and 40 in combined positive score (CPS) (Figure 2B).
FIGURE 2 (A) Histopathological findings showing clear cell renal cell carcinoma with a spindle cell carcinoma component. (B) Immunohistochemistry analysis using anti‐programmed death‐ligand 1 (PD‐L1) antibody (clone 28‐8) showed that PD‐L1 was expressed in 40% of the surgical specimens
CT scans 3 months after the surgery revealed multiple bilateral lung metastases and local recurrence. Although we did not perform needle biopsies for metastatic lesions, we considered that multiple metastases most likely developed from the SRCC owing to the patient's clinical course after surgery. The patient was classified as having intermediate risk according to the International Metastatic RCC Database Consortium risk classification and the Memorial Sloan‐Kettering Cancer Center prognostic model because he fulfilled the criteria of the hemoglobin level being below the lower limit of the normal range and less than 1 year from time of diagnosis to systemic therapy.6, 7 The patient had advanced age and was worried that sunitinib‐related adverse events would lower performance status. Therefore, sunitinib was administered at a dose of 25 mg orally once daily for 2 weeks on and 1 week off in each 3‐week cycle. It was well‐tolerated by the patient, who showed only grade 2 adverse events. At that time, five lung metastases were identified as target lesions. However, the diameter of targeted lung metastases increased from 5.6 to 7.4 cm (32% increase) in 2 months after sunitinib administration. Therefore, treatment was switched to axitinib, which was administered 5 mg twice daily. However, lung metastases continued to gradually increase, and peritonitis carcinomatosis was observed 2 months after the initiation of axitinib. Thus, the patient was then administered nivolumab (240 mg) intravenously once every 2 weeks. After nivolumab administration, lung metastases, local recurrence, and peritonitis carcinomatosis reduced gradually. After 20 months of nivolumab treatment (24 months after the diagnosis of RCC), the patient achieved complete response with multiple metastases on CT, and treatment‐related adverse events were not seen during nivolumab administration (Figure 3).
FIGURE 3 Computed tomography (CT) taken before (A–C) and after the administration of nivolumab (D–F) (arrows). (A–C) CT shows lung metastasis (A), local recurrence (B), and peritonitis carcinomatosis (C). (D–F) After 24 months of nivolumab treatment, the patient achieved a complete response with multiple metastases on CT (arrows)
3 DISCUSSION
In recent years, the treatment for metastatic RCC has dramatically changed. The prognosis of RCC patients with lymph node involvement or distant metastases receiving ICIs has also changed. Several patients have shown a decreased number of metastatic sites, and some patients have achieved complete response to ICI treatment. According to a phase III trial comparing nivolumab with everolimus in patients with previously treated advanced RCC (CheckMate 025), median progression‐free survival (PFS) was 4.6 months with nivolumab and 4.4 months with everolimus (P = .11), even though overall survival (OS) in patients who received nivolumab was significantly longer than those who were administered everolimus (P = .0018).9 In an open‐label phase III trial (KEYNOTE‐426), patients with advanced RCC who received pembrolizumab plus axitinib had significantly longer OS and PFS and a higher objective response rate than those who received sunitinib only.8 In the phase III JAVELIN Renal 101 trial, PFS was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first‐line treatments for advanced RCC.10 Based on the results of IMmotion151 trial for untreated metastatic RCC, the median PFS was 11·2 months in the atezolizumab plus bevacizumab group vs 7·7 months in the sunitinib group, in the PD‐L1 positive population (P = .022).11 In CheckMate 9ER, nivolumab plus cabozantinib demonstrated superiority over sunitinib by doubling the PFS time, doubling the OS rate, and significantly improving OS for advanced RCC.12 From these results, combination therapy may have several advantages with oncological outcomes in advanced or metastatic RCC than nivolumab monotherapy.
Conversely, SRCC has a more aggressive disease biology and poorer oncological outcomes than other RCCs.5 In addition, the optimal treatment regimens for SRCC remain unknown according to several guidelines. According to molecular‐targeting therapy for metastatic RCC with sarcomatoid differentiation, Golshayan et al reported that treatment with sunitinib, sorafenib, or bevacizumab, achieved partial response of metastatic disease in 19% of the patients who had mainly clear cell carcinoma with >20% sarcomatoid component in the primary tumors.13 In addition, median tumor shrinkage, PFS, and OS were 2%, 5.3, and 11.8 months, respectively.13 In a phase II trial for SRCC patients who received the combination of capecitabine, gemcitabine, and bevacizumab, the median OS and PFS were 12 and 5.5 months, respectively.14 Recent randomized controlled trials using ICIs for RCC treatment have reported that RCC with a sarcomatoid component clearly showed improved oncological outcomes, including OS or PFS rates.3, 5, 6, 8 The post‐hoc analysis of CheckMate‐214 study evaluated the utility of nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib in patients with SRCC.3 The median OS in patients who received NIVO+IPI was significantly longer than that in those who received sunitinib (P = .0004); PFS benefits with NIVO+IPI were similarly observed (P = .0093).3 While only 23.1% of the SRCC patients who received sunitinib achieved objective response, 60.8% of those who received NIVO+IPI achieved objective response (P < .0001).3 Additionally, the patients who received NIVO+IPI, unlike those who received sunitinib, achieved complete response (18.9% vs 3.1%, respectively). On the other hand, a retrospective study from Roswell Park Comprehensive Cancer Center reported the efficacy of ICIs in patients with metastatic SRCC.15 Although the median OS in patients who received ICs (CPI arm) was 33.8 months compared to 8.8 months in those who received non‐immunotherapy (no CPI arm), 30% of the patients in CPI arm and 25% of those in non CPI arm were alive after a median follow‐up of 35 months.14 Therefore, these results suggest that the combination therapy, including ICIs, may improve oncological outcomes in patients with advanced or metastatic RCC.
The reason why patients who received ICIs showed improved oncological outcomes remains unclear. It is possible that the patient had PD‐L1 expression of 25% in TPS, 20% in IC, and 40 in CPS. Recently, it has been found that there is higher PD‐L1 expression and higher PD1‐ and CD8‐positive cell density in SRCC than in grade 4 clear cell RCC.15 In the CheckMate 214 population, PD‐L1 was a prognostic factor for poor oncological outcomes and was associated with more advanced disease.6, 16 These data may support the use of ICIs in patients with SRCC regardless of the tumor PD‐L1 expression level.3 Further large‐scale clinical or case‐control observational studies are needed to validate the utility of ICIs as a treatment option for SRCC. In addition, molecular analyses may further characterize the immune response in SRCCs.
4 CONCLUSION
We reported an SRCC patient who showed multiple metastases. This was a case of multiple metastatic progressive SRCC, showing a complete response to nivolumab treatment. ICIs may be used a treatment option for SRCC with lymph node involvement or distant metastases.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
AUTHOR CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, M.T., T.K.; Investigation, K.N., K.O., K.I.; Formal Analysis, N.S.,T.M.; Writing‐Original Draft, M.T.; Writing–Review & Editing: T.K.
ETHICS STATEMENT
Informed consent was obtained to publish this report.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request. | AXITINIB | DrugsGivenReaction | CC BY | 33656804 | 20,290,572 | 2021-08 |
What was the outcome of reaction 'Malignant ascites'? | A case of multiple metastatic sarcomatoid renal cell carcinoma with complete response to nivolumab.
Sarcomatoid renal cell carcinoma (SRCC) is associated with poor prognosis. Although there is no standard treatment for SRCC, recent studies have reported the effectiveness of immune checkpoint inhibitors.
An 82-year-old Japanese man presented to our hospital with an incidental right renal tumor. Abdominal computed tomography (CT) showed an exophytic tumor in the right kidney with suspected right iliopsoas muscle invasion. Laparoscopic right radical nephrectomy was performed. Histopathological diagnosis revealed a clear cell RCC with a spindle cell carcinoma component. CT performed 3 months after surgery revealed multiple bilateral lung metastases and local recurrence. Although the patient received tyrosine-kinase inhibitors for treating multiple metastases, the lung metastases continued to gradually increase, and peritonitis carcinomatosis was observed. Thus, the patient was intravenously administered nivolumab once every 2 weeks. After nivolumab administration, lung metastases, local recurrence, and peritonitis carcinomatosis gradually reduced. After 20 months of nivolumab treatment, the patient achieved a complete response of multiple metastases on CT.
Nivolumab may be used as a treatment option for sarcomatoid renal cell carcinoma with multiple metastases.
1 INTRODUCTION
Sarcomatoid renal cell carcinoma (SRCC) accounts for 1% to 5% of all renal neoplasms and is also known as spindle cell carcinoma, anaplastic carcinoma, and carcinosarcoma.1, 2 Renal cell carcinoma (RCC) with a sarcomatoid component is associated with poor prognosis even for patients diagnosed with stage I or II RCC. Most patients with RCC with a sarcomatoid variant showed local recurrence or distant metastases at diagnosis.1, 2 In general, the oncological outcomes of SRCC are unfavorable, and the median survival of SRCC patients has been reported to be between 5 and 12 months.3 In addition, the time from nephrectomy to cancer recurrence was significantly shorter in patients with SRCC than in those with non‐SRCC (18.8 vs 42.9 months; P < .0001).4 Recently, some reports have suggested that immune checkpoint inhibitors (ICIs) are particularly effective for SRCC.5, 6, 7, 8 In this study, we reported a stage IV SRCC patient, who achieved complete response to nivolumab treatment.
2 CASE
An 82‐year‐old Japanese male patient presented with an incidental right renal tumor at our hospital. Abdominal computed tomography (CT) showed an exophytic tumor measuring 6.2 cm × 6.3 cm in the lower pole of the right kidney with suspected right iliopsoas muscle invasion and right adrenal gland metastasis (Figure 1). The patient did not show lymph node involvement or distant metastases at this point.
FIGURE 1 Abdominal computed tomography showing a right renal tumor in the lower pole with suspected invasion to the right iliopsoas muscle (arrow)
Laparoscopic right radical nephrectomy with right adrenalectomy was performed. Histopathological diagnosis revealed clear cell RCC with a spindle cell carcinoma component (40%) (Figure 2A). Immunohistochemistry analysis using anti‐programmed death‐ligand 1 (PD‐L1) antibody (clone 28‐8) showed that PD‐L1 was expressed 25% in tumor positive score (TPS), 20% in immune cells (IC), and 40 in combined positive score (CPS) (Figure 2B).
FIGURE 2 (A) Histopathological findings showing clear cell renal cell carcinoma with a spindle cell carcinoma component. (B) Immunohistochemistry analysis using anti‐programmed death‐ligand 1 (PD‐L1) antibody (clone 28‐8) showed that PD‐L1 was expressed in 40% of the surgical specimens
CT scans 3 months after the surgery revealed multiple bilateral lung metastases and local recurrence. Although we did not perform needle biopsies for metastatic lesions, we considered that multiple metastases most likely developed from the SRCC owing to the patient's clinical course after surgery. The patient was classified as having intermediate risk according to the International Metastatic RCC Database Consortium risk classification and the Memorial Sloan‐Kettering Cancer Center prognostic model because he fulfilled the criteria of the hemoglobin level being below the lower limit of the normal range and less than 1 year from time of diagnosis to systemic therapy.6, 7 The patient had advanced age and was worried that sunitinib‐related adverse events would lower performance status. Therefore, sunitinib was administered at a dose of 25 mg orally once daily for 2 weeks on and 1 week off in each 3‐week cycle. It was well‐tolerated by the patient, who showed only grade 2 adverse events. At that time, five lung metastases were identified as target lesions. However, the diameter of targeted lung metastases increased from 5.6 to 7.4 cm (32% increase) in 2 months after sunitinib administration. Therefore, treatment was switched to axitinib, which was administered 5 mg twice daily. However, lung metastases continued to gradually increase, and peritonitis carcinomatosis was observed 2 months after the initiation of axitinib. Thus, the patient was then administered nivolumab (240 mg) intravenously once every 2 weeks. After nivolumab administration, lung metastases, local recurrence, and peritonitis carcinomatosis reduced gradually. After 20 months of nivolumab treatment (24 months after the diagnosis of RCC), the patient achieved complete response with multiple metastases on CT, and treatment‐related adverse events were not seen during nivolumab administration (Figure 3).
FIGURE 3 Computed tomography (CT) taken before (A–C) and after the administration of nivolumab (D–F) (arrows). (A–C) CT shows lung metastasis (A), local recurrence (B), and peritonitis carcinomatosis (C). (D–F) After 24 months of nivolumab treatment, the patient achieved a complete response with multiple metastases on CT (arrows)
3 DISCUSSION
In recent years, the treatment for metastatic RCC has dramatically changed. The prognosis of RCC patients with lymph node involvement or distant metastases receiving ICIs has also changed. Several patients have shown a decreased number of metastatic sites, and some patients have achieved complete response to ICI treatment. According to a phase III trial comparing nivolumab with everolimus in patients with previously treated advanced RCC (CheckMate 025), median progression‐free survival (PFS) was 4.6 months with nivolumab and 4.4 months with everolimus (P = .11), even though overall survival (OS) in patients who received nivolumab was significantly longer than those who were administered everolimus (P = .0018).9 In an open‐label phase III trial (KEYNOTE‐426), patients with advanced RCC who received pembrolizumab plus axitinib had significantly longer OS and PFS and a higher objective response rate than those who received sunitinib only.8 In the phase III JAVELIN Renal 101 trial, PFS was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first‐line treatments for advanced RCC.10 Based on the results of IMmotion151 trial for untreated metastatic RCC, the median PFS was 11·2 months in the atezolizumab plus bevacizumab group vs 7·7 months in the sunitinib group, in the PD‐L1 positive population (P = .022).11 In CheckMate 9ER, nivolumab plus cabozantinib demonstrated superiority over sunitinib by doubling the PFS time, doubling the OS rate, and significantly improving OS for advanced RCC.12 From these results, combination therapy may have several advantages with oncological outcomes in advanced or metastatic RCC than nivolumab monotherapy.
Conversely, SRCC has a more aggressive disease biology and poorer oncological outcomes than other RCCs.5 In addition, the optimal treatment regimens for SRCC remain unknown according to several guidelines. According to molecular‐targeting therapy for metastatic RCC with sarcomatoid differentiation, Golshayan et al reported that treatment with sunitinib, sorafenib, or bevacizumab, achieved partial response of metastatic disease in 19% of the patients who had mainly clear cell carcinoma with >20% sarcomatoid component in the primary tumors.13 In addition, median tumor shrinkage, PFS, and OS were 2%, 5.3, and 11.8 months, respectively.13 In a phase II trial for SRCC patients who received the combination of capecitabine, gemcitabine, and bevacizumab, the median OS and PFS were 12 and 5.5 months, respectively.14 Recent randomized controlled trials using ICIs for RCC treatment have reported that RCC with a sarcomatoid component clearly showed improved oncological outcomes, including OS or PFS rates.3, 5, 6, 8 The post‐hoc analysis of CheckMate‐214 study evaluated the utility of nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib in patients with SRCC.3 The median OS in patients who received NIVO+IPI was significantly longer than that in those who received sunitinib (P = .0004); PFS benefits with NIVO+IPI were similarly observed (P = .0093).3 While only 23.1% of the SRCC patients who received sunitinib achieved objective response, 60.8% of those who received NIVO+IPI achieved objective response (P < .0001).3 Additionally, the patients who received NIVO+IPI, unlike those who received sunitinib, achieved complete response (18.9% vs 3.1%, respectively). On the other hand, a retrospective study from Roswell Park Comprehensive Cancer Center reported the efficacy of ICIs in patients with metastatic SRCC.15 Although the median OS in patients who received ICs (CPI arm) was 33.8 months compared to 8.8 months in those who received non‐immunotherapy (no CPI arm), 30% of the patients in CPI arm and 25% of those in non CPI arm were alive after a median follow‐up of 35 months.14 Therefore, these results suggest that the combination therapy, including ICIs, may improve oncological outcomes in patients with advanced or metastatic RCC.
The reason why patients who received ICIs showed improved oncological outcomes remains unclear. It is possible that the patient had PD‐L1 expression of 25% in TPS, 20% in IC, and 40 in CPS. Recently, it has been found that there is higher PD‐L1 expression and higher PD1‐ and CD8‐positive cell density in SRCC than in grade 4 clear cell RCC.15 In the CheckMate 214 population, PD‐L1 was a prognostic factor for poor oncological outcomes and was associated with more advanced disease.6, 16 These data may support the use of ICIs in patients with SRCC regardless of the tumor PD‐L1 expression level.3 Further large‐scale clinical or case‐control observational studies are needed to validate the utility of ICIs as a treatment option for SRCC. In addition, molecular analyses may further characterize the immune response in SRCCs.
4 CONCLUSION
We reported an SRCC patient who showed multiple metastases. This was a case of multiple metastatic progressive SRCC, showing a complete response to nivolumab treatment. ICIs may be used a treatment option for SRCC with lymph node involvement or distant metastases.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
AUTHOR CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, M.T., T.K.; Investigation, K.N., K.O., K.I.; Formal Analysis, N.S.,T.M.; Writing‐Original Draft, M.T.; Writing–Review & Editing: T.K.
ETHICS STATEMENT
Informed consent was obtained to publish this report.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request. | Recovered | ReactionOutcome | CC BY | 33656804 | 20,290,572 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Zoledronic acid is effective in the management of migratory osteoporosis unresponsive to conservative treatment and risedronate: A case report.
We describe a case of a 55-year-old woman with migratory osteoporosis (MO) which initially presented as pain with bone marrow edema (BME) evident in magnetic resonance imaging (MRI) of the left ankle and was managed with non-weight-bearing (NWB). The patient was already treated with per os risedronate for postmenopausal osteoporosis. After significant initial improvement, pain and BME relapsed in the left ankle and additionally expanded to insult the foot, while 3 months later the left hip was also affected. Since the combination of NWB, analgesics and risedronate had failed to control the disease, a single infusion of 5mg zoledronic acid (ZA) was administered. One month later the pain in all affected sites was disappeared and BME resolved as shown by MRI performed 3.5 months following ZA infusion. The patient, eventually, returned to her daily routine. This case underlines the effectiveness of ZA in MO and the need for more aggressive treatment in this disease.
Introduction
Transient osteoporosis (TO), also referred as “primary bone marrow edema syndrome”, is a rare metabolic bone disorder with acute or subacute onset, that primarily affects the hip, the knee, the ankle or the foot, causing local bone marrow edema (BME)[1]. Patients are usually middle-aged individuals (preferably males) or pregnant women and the main clinical manifestation is severe lower extremity pain that exacerbates on weight-bearing. The gold standard imaging modality for the diagnosis of TO is magnetic resonance imaging (MRI), in which a homogenous regional signal of increased T2, STIR or decreased T1 intensity is found in the bone marrow. TO is a diagnosis of exclusion, as secondary bone marrow edema can be provoked by many stimuli[1]. Moreover, a TO episode can resemble a flare of an inflammatory arthritis[2]. In about 30% of TO patients a recurrence of the disease in the same area or a migration to another region can occur and this condition is known as migratory osteoporosis (MO)[3-5]. Only scarce data are available about the management of patients with MO. As MO is characterized by locally accelerated bone turnover and subsequent bone loss, bisphosphonates have been used in several MO cases. The severity of the local bone metabolism disturbance in MO indicates that the rationale of using more potent bisphosphonates in these patients might be reasonable. We present here a case of a woman with MO in whom a single zoledronic acid (ZA) infusion alleviated the symptoms and normalized MRI while the combination of weight-bearing avoidance and risedronate had previously failed to prevent two subsequent episodes of the disease. Informed consent was obtained from the patient for publication of her clinical case and accompanying MRI images.
Case Presentation
A 55-year-old postmenopausal woman presented in our clinic in November 2019 complaining for a 2-week, acute-onset, severe pain in her left hip that reflected at the front and the lateral side of the ipsilateral thigh. She was on etoricoxib 90mg daily for the last days, while she was also receiving per os risedronate 75 mg twice monthly for osteoporosis (started on 2015), calcium and vitamin D supplementation (1000 mg/800 IU daily), and a combination of pitavastatin 2 mg/day and ezetimibe 10 mg/day for dyslipidemia. At clinical examination tenderness of the left hip was produced at both active and passive movement of the joint. No other swollen or tender joints or rash was noted. She had no family history of psoriasis, inflammatory bowel disease or inflammatory arthritis. Laboratory testing exhibited normal inflammation markers: ESR 9 mm/h (normal<28 mm/h), CRP 0.37 mg/dL (normal<0.8 mg/dL), and normal bone metabolic profile (serum calcium 9.0 mg/dL; normal range 8.4-10.2 mg/dL; phosphate 3.9 mg/dL; normal range 2.5-4.5 mg/dL; total alkaline phosphatase 101 IU/L; normal range 40-140 IU/L; parathyroid hormone 31.3 pg/mL; normal range 10-55 pg/mL; 25-hydroxyvitamin D3 32.7 ng/mL; normal values>20 ng/mL). Full blood count, liver and renal functional tests were also normal.
In January 2019, three weeks after intense dancing activity, the patient had experienced an episode of acute, severe pain at her left ankle. The pain was produced even by minimum motion and MRI of the left ankle revealed extensive BME of the talus (ankle) (Figure 1A). After evaluation from an orthopedic surgeon, the patient was instructed to use crutches for non-weight-bearing (NWB) and receive paracetamol and/or nonsteroidal anti-inflammatory drugs (NSAIDs) upon pain. The severe pain ameliorated within 1.5 month but did not resolve completely. In May 2019, a follow-up MRI of the left ankle showed resolution of the BME (Figure 1B). As the patient was almost asymptomatic at that time point, she dismissed crutches and returned to her regular daily activities. However, the pain on the left foot relapsed and a third MRI of the left ankle-foot on July 2019 displayed periarticular (subchondral) BME in the bones of the ankle and the foot (Figure 1C). The patient was set again in conservative treatment with NWB and rest for the following two months, till September 2019, with a partial response of pain intensity. One month later, the above reported episode of the left hip insult occurred. To be noted, all these months the patient was taking 500-2000 mg paracetamol daily.
Figure 1 Serial magnetic resonance imaging (MRI) of the left ankle-foot (sagittal T2-weighted) of the patient (A-D). In January 2019, bone marrow edema (BME) was revealed in talus (A, yellow arrow) and conservative treatment with weight-bearing avoidance and analgesics followed. In May 2019, a follow-up MRI showed resolution of the BME (B). After 2 months, the local pain relapsed and a new MRI displayed periarticular (subchondral) BME (yellow arrows) in the bones of the left ankle and the foot (C). Three-and-a-half months after a 5mg zoledronic acid infusion the BME has almost completely resolved (D).
Based on her history and the current clinical condition we considered that MO was the more plausible diagnosis. A MRI of the left hip was performed and revealed typical features of TO (Figure 2A). As the management with crutches, paracetamol/NSAIDs and risedronate had failed to prevent the 2nd and the 3rd episode of MO, we discontinued risedronate and administered an intravenous infusion of ZA 5 mg instead, in November 2019. No adverse events were reported by the patient. The patient denied the further use of crutches. Hip pain disappeared within one month and a follow-up MRI of the left hip and the left ankle and foot 3.5 months later showed that BME resolved (Figures 1D, 2B). Five months after the infusion, the patient has returned to her work and her regular physical activities (e.g. dancing), free of analgesics.
Figure 2 Magnetic resonance imaging (MRI) of the left hip of the patient before (A) and 3.5 months after (B) a zoledronic acid (ZA) infusion (Coronal T2-weighted with fat suppresion). In November 2019, a MRI revealed extensive bone marrow edema (BME) in the left femoral head and neck (A, yellow arrow) and a single 5mg ZA infusion was administered. 3.5 months later, a second MRI of the left hip displayed resolution of BME (B).
Discussion
TO and MO are rare, but possibly underdiagnosed, entities. Sudden limb overuse and low bone mass are known risk factors that are associated with TO development[3,5]. Both were present in our patient, along with compatible age. In such typical cases of TO many authors suggest conservative management for several months[1]: avoidance of weight-bearing, rest and analgesics (paracetamol and NSAIDs). Nevertheless, with this approach symptoms resolve in a mean time of 4-6 months or more[5,6], which is a rather unacceptably long period for a condition that results in prolonged immobilization, reduced self-care and work absenteeism. Moreover, it does not seem to inhibit a future relapse or migration to another joint[4,7]. Although rest can contribute in the recovery from a single episode of TO, this approach might not be suitable for patients with recurrent BME episodes. A next episode of the disease might not present with impressive clinical picture, as indicated by the recurrence of BME in the left foot of our patient.
To date, no drug has been officially approved for MO treatment and due to disease’s rarity available data derive from case reports and case series. Among different pharmacological options for MO, bisphosphonates are the most commonly used. Oral bisphosphonates, such as alendronate, have shown moderate efficacy in MO[4]. Data from real-life clinical experience suggest that oral bisphosphonates in the doses used for postmenopausal osteoporosis might be inadequate to control MO[4,7]. In our case, the patient was already receiving risedronate for four years for post-menopausal osteoporosis when MO manifested. However, risedronate did not prevent its development. Intravenous bisphosphonates, such as pamidronate and ZA, have been proven effective in TO[8] and in MO[4,7,9,10] and have led in pain alleviation within 1 month, considerably sooner than with conservative approach and alendronate. ZA is the most potent bisphosphonate and a single 5mg dose exhibits anti-resorptive effect lasting at least 5 years in post-menopausal osteoporosis[11]. In line with this knowledge, ZA seems to have a long-term effect in MO, preventing disease relapses for at least 3 years[7]. Indeed, our patient remained asymptomatic until her last visit 5 months after the ZA infusion. To the best of our knowledge, management of MO with other potent agents used in the treatment of generalized osteoporosis e.g. denosumab or osteoanabolic treatment has not been tested up to now.
It is true that the high cost of an MRI scan is a deterrent factor in performing such an examination frequently. However, in our patient, repeated MRI scans allowed a more accurate monitoring of disease progression and relapses and facilitated timely and effective management, protecting the patient from prolonged pain and immobilization. Close clinical monitoring of these patients could contribute in early recognition of disease relapse and targeted imaging, as well as in avoidance of unnecessary MRI exams.
In conclusion, this case underlines that conservative approach and risedronate might not be effective in arresting the disease process of MO. NWB and analgesics might not be sufficient for the management of patients that experience multiple episodes of MO and a more aggressive approach should be considered. In such cases, ZA seems to be the most efficacious treatment choice. Close monitoring of TO and MO patients with serial MRI scans could contribute in early intervention and successful management of MO. Finally, as safe conclusion can not be drawn from case reports, prospective single- or multi-center studies are needed to confirm the favorable effect of ZA in MO patients, especially compared to per os bisphosphonates.
The authors have no conflict of interest.
Edited by: G. Lyritis | ACETAMINOPHEN, CALCIUM\VITAMIN D, ETORICOXIB, EZETIMIBE, PITAVASTATIN CALCIUM, RISEDRONATE SODIUM | DrugsGivenReaction | CC BY-NC-SA | 33657764 | 19,285,528 | 2021-03-01 |
What was the dosage of drug 'CALCIUM\VITAMIN D'? | Zoledronic acid is effective in the management of migratory osteoporosis unresponsive to conservative treatment and risedronate: A case report.
We describe a case of a 55-year-old woman with migratory osteoporosis (MO) which initially presented as pain with bone marrow edema (BME) evident in magnetic resonance imaging (MRI) of the left ankle and was managed with non-weight-bearing (NWB). The patient was already treated with per os risedronate for postmenopausal osteoporosis. After significant initial improvement, pain and BME relapsed in the left ankle and additionally expanded to insult the foot, while 3 months later the left hip was also affected. Since the combination of NWB, analgesics and risedronate had failed to control the disease, a single infusion of 5mg zoledronic acid (ZA) was administered. One month later the pain in all affected sites was disappeared and BME resolved as shown by MRI performed 3.5 months following ZA infusion. The patient, eventually, returned to her daily routine. This case underlines the effectiveness of ZA in MO and the need for more aggressive treatment in this disease.
Introduction
Transient osteoporosis (TO), also referred as “primary bone marrow edema syndrome”, is a rare metabolic bone disorder with acute or subacute onset, that primarily affects the hip, the knee, the ankle or the foot, causing local bone marrow edema (BME)[1]. Patients are usually middle-aged individuals (preferably males) or pregnant women and the main clinical manifestation is severe lower extremity pain that exacerbates on weight-bearing. The gold standard imaging modality for the diagnosis of TO is magnetic resonance imaging (MRI), in which a homogenous regional signal of increased T2, STIR or decreased T1 intensity is found in the bone marrow. TO is a diagnosis of exclusion, as secondary bone marrow edema can be provoked by many stimuli[1]. Moreover, a TO episode can resemble a flare of an inflammatory arthritis[2]. In about 30% of TO patients a recurrence of the disease in the same area or a migration to another region can occur and this condition is known as migratory osteoporosis (MO)[3-5]. Only scarce data are available about the management of patients with MO. As MO is characterized by locally accelerated bone turnover and subsequent bone loss, bisphosphonates have been used in several MO cases. The severity of the local bone metabolism disturbance in MO indicates that the rationale of using more potent bisphosphonates in these patients might be reasonable. We present here a case of a woman with MO in whom a single zoledronic acid (ZA) infusion alleviated the symptoms and normalized MRI while the combination of weight-bearing avoidance and risedronate had previously failed to prevent two subsequent episodes of the disease. Informed consent was obtained from the patient for publication of her clinical case and accompanying MRI images.
Case Presentation
A 55-year-old postmenopausal woman presented in our clinic in November 2019 complaining for a 2-week, acute-onset, severe pain in her left hip that reflected at the front and the lateral side of the ipsilateral thigh. She was on etoricoxib 90mg daily for the last days, while she was also receiving per os risedronate 75 mg twice monthly for osteoporosis (started on 2015), calcium and vitamin D supplementation (1000 mg/800 IU daily), and a combination of pitavastatin 2 mg/day and ezetimibe 10 mg/day for dyslipidemia. At clinical examination tenderness of the left hip was produced at both active and passive movement of the joint. No other swollen or tender joints or rash was noted. She had no family history of psoriasis, inflammatory bowel disease or inflammatory arthritis. Laboratory testing exhibited normal inflammation markers: ESR 9 mm/h (normal<28 mm/h), CRP 0.37 mg/dL (normal<0.8 mg/dL), and normal bone metabolic profile (serum calcium 9.0 mg/dL; normal range 8.4-10.2 mg/dL; phosphate 3.9 mg/dL; normal range 2.5-4.5 mg/dL; total alkaline phosphatase 101 IU/L; normal range 40-140 IU/L; parathyroid hormone 31.3 pg/mL; normal range 10-55 pg/mL; 25-hydroxyvitamin D3 32.7 ng/mL; normal values>20 ng/mL). Full blood count, liver and renal functional tests were also normal.
In January 2019, three weeks after intense dancing activity, the patient had experienced an episode of acute, severe pain at her left ankle. The pain was produced even by minimum motion and MRI of the left ankle revealed extensive BME of the talus (ankle) (Figure 1A). After evaluation from an orthopedic surgeon, the patient was instructed to use crutches for non-weight-bearing (NWB) and receive paracetamol and/or nonsteroidal anti-inflammatory drugs (NSAIDs) upon pain. The severe pain ameliorated within 1.5 month but did not resolve completely. In May 2019, a follow-up MRI of the left ankle showed resolution of the BME (Figure 1B). As the patient was almost asymptomatic at that time point, she dismissed crutches and returned to her regular daily activities. However, the pain on the left foot relapsed and a third MRI of the left ankle-foot on July 2019 displayed periarticular (subchondral) BME in the bones of the ankle and the foot (Figure 1C). The patient was set again in conservative treatment with NWB and rest for the following two months, till September 2019, with a partial response of pain intensity. One month later, the above reported episode of the left hip insult occurred. To be noted, all these months the patient was taking 500-2000 mg paracetamol daily.
Figure 1 Serial magnetic resonance imaging (MRI) of the left ankle-foot (sagittal T2-weighted) of the patient (A-D). In January 2019, bone marrow edema (BME) was revealed in talus (A, yellow arrow) and conservative treatment with weight-bearing avoidance and analgesics followed. In May 2019, a follow-up MRI showed resolution of the BME (B). After 2 months, the local pain relapsed and a new MRI displayed periarticular (subchondral) BME (yellow arrows) in the bones of the left ankle and the foot (C). Three-and-a-half months after a 5mg zoledronic acid infusion the BME has almost completely resolved (D).
Based on her history and the current clinical condition we considered that MO was the more plausible diagnosis. A MRI of the left hip was performed and revealed typical features of TO (Figure 2A). As the management with crutches, paracetamol/NSAIDs and risedronate had failed to prevent the 2nd and the 3rd episode of MO, we discontinued risedronate and administered an intravenous infusion of ZA 5 mg instead, in November 2019. No adverse events were reported by the patient. The patient denied the further use of crutches. Hip pain disappeared within one month and a follow-up MRI of the left hip and the left ankle and foot 3.5 months later showed that BME resolved (Figures 1D, 2B). Five months after the infusion, the patient has returned to her work and her regular physical activities (e.g. dancing), free of analgesics.
Figure 2 Magnetic resonance imaging (MRI) of the left hip of the patient before (A) and 3.5 months after (B) a zoledronic acid (ZA) infusion (Coronal T2-weighted with fat suppresion). In November 2019, a MRI revealed extensive bone marrow edema (BME) in the left femoral head and neck (A, yellow arrow) and a single 5mg ZA infusion was administered. 3.5 months later, a second MRI of the left hip displayed resolution of BME (B).
Discussion
TO and MO are rare, but possibly underdiagnosed, entities. Sudden limb overuse and low bone mass are known risk factors that are associated with TO development[3,5]. Both were present in our patient, along with compatible age. In such typical cases of TO many authors suggest conservative management for several months[1]: avoidance of weight-bearing, rest and analgesics (paracetamol and NSAIDs). Nevertheless, with this approach symptoms resolve in a mean time of 4-6 months or more[5,6], which is a rather unacceptably long period for a condition that results in prolonged immobilization, reduced self-care and work absenteeism. Moreover, it does not seem to inhibit a future relapse or migration to another joint[4,7]. Although rest can contribute in the recovery from a single episode of TO, this approach might not be suitable for patients with recurrent BME episodes. A next episode of the disease might not present with impressive clinical picture, as indicated by the recurrence of BME in the left foot of our patient.
To date, no drug has been officially approved for MO treatment and due to disease’s rarity available data derive from case reports and case series. Among different pharmacological options for MO, bisphosphonates are the most commonly used. Oral bisphosphonates, such as alendronate, have shown moderate efficacy in MO[4]. Data from real-life clinical experience suggest that oral bisphosphonates in the doses used for postmenopausal osteoporosis might be inadequate to control MO[4,7]. In our case, the patient was already receiving risedronate for four years for post-menopausal osteoporosis when MO manifested. However, risedronate did not prevent its development. Intravenous bisphosphonates, such as pamidronate and ZA, have been proven effective in TO[8] and in MO[4,7,9,10] and have led in pain alleviation within 1 month, considerably sooner than with conservative approach and alendronate. ZA is the most potent bisphosphonate and a single 5mg dose exhibits anti-resorptive effect lasting at least 5 years in post-menopausal osteoporosis[11]. In line with this knowledge, ZA seems to have a long-term effect in MO, preventing disease relapses for at least 3 years[7]. Indeed, our patient remained asymptomatic until her last visit 5 months after the ZA infusion. To the best of our knowledge, management of MO with other potent agents used in the treatment of generalized osteoporosis e.g. denosumab or osteoanabolic treatment has not been tested up to now.
It is true that the high cost of an MRI scan is a deterrent factor in performing such an examination frequently. However, in our patient, repeated MRI scans allowed a more accurate monitoring of disease progression and relapses and facilitated timely and effective management, protecting the patient from prolonged pain and immobilization. Close clinical monitoring of these patients could contribute in early recognition of disease relapse and targeted imaging, as well as in avoidance of unnecessary MRI exams.
In conclusion, this case underlines that conservative approach and risedronate might not be effective in arresting the disease process of MO. NWB and analgesics might not be sufficient for the management of patients that experience multiple episodes of MO and a more aggressive approach should be considered. In such cases, ZA seems to be the most efficacious treatment choice. Close monitoring of TO and MO patients with serial MRI scans could contribute in early intervention and successful management of MO. Finally, as safe conclusion can not be drawn from case reports, prospective single- or multi-center studies are needed to confirm the favorable effect of ZA in MO patients, especially compared to per os bisphosphonates.
The authors have no conflict of interest.
Edited by: G. Lyritis | UNK, DAILY (1000 MG/800 IU) | DrugDosageText | CC BY-NC-SA | 33657764 | 19,285,528 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | LEUPROLIDE | DrugsGivenReaction | CC BY | 33658071 | 19,511,063 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal growth restriction'. | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | ESTRADIOL, LEUPROLIDE ACETATE, PROGESTERONE | DrugsGivenReaction | CC BY | 33658071 | 19,039,930 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | ESTRADIOL, LEUPROLIDE ACETATE, PROGESTERONE | DrugsGivenReaction | CC BY | 33658071 | 19,039,930 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pre-eclampsia'. | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | ESTRADIOL, LEUPROLIDE ACETATE, PROGESTERONE | DrugsGivenReaction | CC BY | 33658071 | 19,039,930 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature delivery'. | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | ESTRADIOL, LEUPROLIDE ACETATE, PROGESTERONE | DrugsGivenReaction | CC BY | 33658071 | 19,039,930 | 2021-03-03 |
What was the administration route of drug 'LEUPROLIDE ACETATE'? | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | Intramuscular | DrugAdministrationRoute | CC BY | 33658071 | 19,039,930 | 2021-03-03 |
What was the administration route of drug 'LEUPROLIDE'? | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | Intramuscular | DrugAdministrationRoute | CC BY | 33658071 | 19,511,063 | 2021-03-03 |
What was the administration route of drug 'PROGESTERONE'? | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | Intramuscular | DrugAdministrationRoute | CC BY | 33658071 | 19,039,930 | 2021-03-03 |
What was the dosage of drug 'CHORIOGONADOTROPIN ALFA'? | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | 10,000 UNITS | DrugDosageText | CC BY | 33658071 | 19,475,281 | 2021-03-03 |
What was the dosage of drug 'FOLLITROPIN\LUTEINIZING HORMONE'? | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | 150 IU (INTERNATIONAL UNIT) DAILY; | DrugDosageText | CC BY | 33658071 | 19,521,423 | 2021-03-03 |
What was the dosage of drug 'FOLLITROPIN\UROFOLLITROPIN'? | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | 450 IU (INTERNATIONAL UNIT) DAILY; | DrugDosageText | CC BY | 33658071 | 19,521,423 | 2021-03-03 |
What was the dosage of drug 'GONADOTROPHIN, CHORIONIC'? | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | 10,000 UNITS | DrugDosageText | CC BY | 33658071 | 19,521,423 | 2021-03-03 |
What was the outcome of reaction 'Placenta accreta'? | A rare case of extensive placenta accreta in twin pregnancy after GnRH agonist treatment of adenomyosis.
BACKGROUND
Adenomyosis remains an enigma for the reproductive endocrinologist. It is thought to contribute to sub-fertility, and its only curative treatment is hysterectomy. However, studies have documented increased live birth rates in women with adenomyosis who were treated with gonadotropin releasing hormone agonist (GnRHa).
METHODS
Here we present a case of a 52-year-old woman with adenomyosis who had three failed frozen embryo transfers (FETs) prior to initiating a 6-month trial of GnRHa. GnRHa therapy resulted in a decrease in uterine size from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm and a decrease in the junctional zone (JZ) thickness from 19 to 9 mm. Subsequently, she underwent her fourth FET, which resulted in live birth of twins. The delivery was complicated by expansive accretas of both placentas requiring cesarean hysterectomy. The final pathology of the placentas demonstrated an extensive lack of decidualized endometrium that was even absent outside the basal plate.
CONCLUSIONS
GnRHa therapy in patients with adenomyosis may improve implantation rates after FET. Previous molecular studies indicate that genetic variance in the expression of the gonadotropin releasing hormone receptor (GnRHR) could explain the expansive lack of decidualized endometrium after GnRHa therapy. Further investigations are needed to determine if GnRHa therapy contributes to the pathologic process of placenta accreta.
Background
Adenomyosis is a pathologic condition characterized by the presence of endometrial glands and stroma within the myometrium. While histopathology is the gold standard for diagnostic confirmation, improved ultrasound and MRI technology has led to highly sensitive and specific alternative modalities for diagnosis. A recent systematic review showed that the sensitivities for ultrasound and MRI, respectively, were 72 and 77% [1]. MRI specificity is slightly higher at 89% compared to 81% for ultrasound. When diagnosing adenomyosis using either imaging modality, physicians focus on the junctional zone, the heterogeneity of the uterine wall, and asymmetry in the thickness of the uterine walls [2–4].
The growing utilization of non-invasive diagnostic imaging in patients undergoing infertility workup has led to an increased recognition of adenomyosis in this population. Due to its association with sub-fertility and the definitive treatment being hysterectomy, adenomyosis has presented a clinical dilemma for reproductive endocrinologists. Thus far, there are no formal guidelines for fertility-sparing treatment of adenomyosis, and current methods are largely based on retrospective case series and case reports [5–9]. Surgical resection, typically reserved for focal lesions, carries an increased risk of uterine rupture [6, 9]. Fertility centers can also treat focal and diffuse adenomyosis with medical therapy, which typically consists of gonadotropin releasing hormone agonist (GnRHa) for 3 to 6 months prior to fresh or frozen embryo transfer [5, 6, 10]. By inducing apoptosis and reducing angiogenesis, GnRHa is thought to decrease the size of the ectopic endometrial glands constituting adenomyosis [5, 11]. Here we present a successful twin live birth in a 52-year-old patient with three prior failed frozen embryo transfers (FETs) who, after GnRHa therapy, underwent FET and achieved clinical pregnancy.
Case description
The patient presented to our fertility clinic at age 48 as a nulligravida desiring pregnancy. She had a history of fibroids for which she had undergone a myomectomy at an outside institution. The patient reported that the surgeon removed nine fibroids. Of note, the operative report was unavailable for review so the type of myomectomy, size of myomas, and depth of myometrial invasion were unable to be confirmed. After surgery, she was told that she would require pre-labor cesarean delivery if she became pregnant. She reported regular monthly menses and no medical comorbidities. Initial evaluation at our clinic included transvaginal ultrasound (TVUS), antral follicle count (AFC) as well as anti-Mullerian hormone measurement (AMH) and assessment for metabolic syndrome. TVUS revealed three intramural fibroids (the largest 2.5 cm in diameter), none of which appeared to be impacting the endometrial cavity. Her AFC was 3, AMH was 0.52 ng/mL, thyroid function and insulin resistance testing were normal.
At her follow-up visit, a saline-infused sonohysterogram (SIS) was attempted but only partially successful due to cervical stenosis. A left hydrosalpinx was visualized, and diagnostic laparoscopy was pursued. In the operating room, cervical dilation was performed. Subsequently, chromotubation revealed non-patent fallopian tubes, and due to extensive adhesive disease, bilateral Filshie clips were placed in lieu of salpingectomy. No evidence of endometriosis was seen during her laparoscopy, and the adhesive disease was thought to be due to her prior myomectomy. She had a repeat SIS which was successful and a normal endometrial cavity was seen. None of the previously seen fibroids were noted to have a submucosal component. A mock embryo transfer was performed without complication.
In spite of our recommendation to pursue donor eggs, the patient highly desired a trial of in-vitro fertilization (IVF) using autologous oocytes. She underwent ovarian stimulation using 450 IU of Bravelle (urofollitopin) and 150 IU of Menopur (menotropin) daily. GnRH antagonist 0.25 mg was started on stimulation day (SD) 4 to prevent premature follicle maturation. She was triggered on SD8 with 10,000 units of human chorionic gonadotropin when there were 3 follicles > 17 mm in size and estradiol peaked at 922 pg/mL. Four oocytes were retrieved from this cycle, but only one was mature. Intracytoplasmic sperm injection (ICSI) was performed on the mature oocyte; however, there was failed fertilization. After this outcome, the patient desired an emotional break from the IVF process.
Fifteen months later, the patient returned to our clinic to resume fertility treatment. At this point, she agreed to use fresh donor oocytes and undergo FET. The 24 year-old donor underwent an uncomplicated ovarian stimulation and oocyte retrieval. A total of 45 mature oocytes were retrieved. Following ICSI, there were 39 two pronuclear embryos that fertilized normally and were cultured to blastocyst-stage in single step media. Eighteen blastocysts were biopsied and vitrified. Fifteen of the 18 embryos were euploid. The patient underwent another SIS and mock ET, both of which were normal. She started 3 estradiol 0.1 mg patches every other day in preparation for FET. During her ultrasound for a lining check, her endometrial stripe (EMS) was 10 mm, so she started 90 mg of 8% vaginal gel twice daily and 50 mg of intramuscular progesterone daily. Six days after progresterone supplementation, she had her first FET of 1 euploid blastocyst. Her pregnancy test 10 days later was negative.
She decided to pursue another cycle, and after extensive counseling regarding the risks associated with twin pregnancy, the decision was made to proceed with transfer of 2 euploid blastocysts. This transfer resulted in an anembryonic pregnancy, diagnosed by abnormally rising B-HCG and ultrasounds done 2 weeks apart which demonstrated a gestational sac without interval development of a fetal pole. Over the next 2 weeks, her B-HCG was serially monitored, as patient desired expectant management, and her levels were trending downward. The pregnancy failed to evacuate completely after expectant management, and she consented to a suction dilation and curettage. The pathology results were confirmatory of an anembryonic pregnancy.
The patient wished to proceed with another embryo transfer. Prior to this transfer, a pelvic MRI was completed to evaluate if any of her fibroids (described previously) impacted the endometrial cavity. The MRI only showed evidence of adenomyosis as characterized by thickened junction zone (JZ) at 19 mm with multiple 1-2 mm myometrial junctional zone cysts (Fig. 1). Since the endometrial cavity was clear on MRI, the patient underwent a third FET of 2 euploid embryos. Her subsequent pregnancy test was negative.
Fig. 1 An axial T-1 weighted MRI image shows multiple 1-2 cm myometerial junctional zone cysts (arrowheads) and a thickened junctional zone (arrows)
After the third unsuccessful FET, the patient was counseled that her adenomyosis could be contributing to the multiple failed FETs. She was counseled on the options of using a gestational carrier vs. medical management. She decided to pursue medical management using leuprolide acetate (GnRHa) for 6 months prior to another FET. She received monthly intramuscular injections of 3.75 mg of leuprolide acetate. Three weeks after the last injection, another MRI was completed which showed a decrease in the JZ from 19 to 9 mm. Uterine size also decreased from 11.5 × 7.9 × 7.0 cm to 7.8 × 6.2 × 5.9 cm (Figs. 2 and 3). Prior to her next FET, the patient was counseled on the number of embryos to transfer. While single embryo transfer (sET) was recommended, we decided to proceed with double embryo transfer due to her history of multiple failed transfers and personal preference. The same protocol for FET preparation was used, and she underwent her fourth FET of 2 euploid blastocysts after an EMS of 10.2 mm was confirmed.
Fig. 2 Sagital T-2 images before and after GnRHa therapy showing a decrease in junctional zone thickness. a Before GnRHa therapy, the junctional zone is thickened at 19 mm (arrows). b After GnRHa therapy for 6 months, the junctional zone has decreased to 9 mm (arrows)
Fig. 3 Axial T-2 fat-suppresed images of the uterus before and after GnRHa therapy demonstrating a decrease in cystic spaces in the junctional zone. a Cystic spaces (arrows) within the junctional zone consistent with adenomyosis prior to GnRHa therapy. b After GnRHa therapy, the cystic spaces (arrow) and junctional zone have decreased in size
Her initial B-HCG of 1010.3 collected 10 days after FET confirmed pregnancy, and subsequent TVUS several weeks later confirmed viable intrauterine twin pregnancy. She was followed by our fertility center until 10 weeks gestational age (GA) and then transferred to a general obstetrician. Her dichorionic-diamniotic pregnancy was complicated by placenta previa in Twin A for which she had serial ultrasounds. At 27 weeks GA, Twin B was noted to have intrauterine growth restriction (IUGR) < 5th percentile for which she had weekly biophysical profiles. At 31 weeks GA, the patient started developing elevated blood pressures and was transferred to a tertiary care center as the estimated fetal weight of Twin B was less than 1800 g. She was diagnosed with pre-eclampsia without severe features and discharged home after receiving betamethasone for fetal lung maturity. She followed up with the maternal fetal medicine specialists as an outpatient. At 32 weeks, she was admitted for extended maternal fetal monitoring due to worsening pre-eclampsia, IUGR of Twin B < 5th percentile, and placenta previa of Twin A. The patient developed pre-eclampsia with severe features at 33 weeks and was expectantly managed until 34 weeks. She was delivered at 34 weeks via planned primary cesarean due to placenta previa and history of open myomectomy. Cesarean delivery was complicated by extensive accretas of both placentas, which necessitated a supracervical hysterectomy. The patient did not sustain any post-operative complications and has since resumed her daily activities. The neonates also had an uncomplicated hospital stay and are currently meeting all their developmental milestones.
Discussion and conclusions
This case demonstrates that GnRHa therapy for 6 months in patients with adenomyosis may improve implantation rates after FET, which is consistent with prior studies [7, 8]. Through pituitary downregulation, long-term GnRHa therapy has been shown to decrease the size of adenomyotic lesions [11, 12]. Our patient also had a decrease in her uterine size and a decrease in her JZ from 19 mm to 9 mm on MRI. This decrease in JZ could have facilitated implantation as a thickened JZ prior to FET has been associated with low implantation rates [13]. One study showed that a JZ > 12 mm was associated with an implantation rate of 5% during FET whereas JZ < 10 mm was associated with a 45% implantation rate [14]. Thus, one plausible theory for how GnRHa treatment facilitated pregnancy in our patient was through decreasing the JZ.
The question remains if GnRHa treatment for 6 months also led to the extensive lack of decidualized endometrium, which subsequently led to the development of expansive accretas of both placentas. The patient did have other risk factors for placenta accreta such as IVF treatment, advanced maternal age (AMA), and prior myomectomy [15–19]. The degree of her placental disease raises concern for a a global change to the endometrial stratum basalis, as opposed to the focal changes often seen with IVF pregnancies and a history of myomectomy. The description in the pathology report was that the uterus had no decidualized endometrium on the implantation site of placenta A and the implantation site of placenta B only had a focal area of decidualized endometrium. Within the remainder of the uterine specimen, there was only one other focal area of decidualized endometrium, and it was located within the myometrium, consistent with adenomyosis. There was no histologic evidence of placental invasion past the myometrium nor was there any histologic evidence of endometriosis. Although her prior myomectomy could have contributed to the development of a placenta accreta, it is unlikely to be the sole cause as myomectomies tend to cause focal accretas at the endomyometrial incision site [18, 19]. While undergoing IVF treatments and being of AMA are also risk factors for placenta accreta, neither has been associated with an expansive placenta accreta such as this one. The encompassing surface area of affected endometrium indicates a more systemic defect in decidualization.
Although no studies have investigated whether GnRHa therapy can affect endometrial decidualization, molecular studies have demonstrated that GnRHa also directly exerts anti-proliferative effects on the target organ through the gonadotropin releasing hormone receptor (GnRHR) [11, 20]. In these studies, the direct effect of GnRHa was highly variable between different samples which was attributed to the genetic variance in GnRHR capacity and affinity for GnRHa. We hypothesize that our patient had a genetic variance in GnRHR that could be associated with an increased response to GnRHa. Thus, GnRHa downregulated cellular function at the level of the endometrium so profoundly that it subsequently inhibited or delayed the process of endometrial decidualization. Since this may only affect a small subset of the population, it could explain why other studies of GnRHa therapy in patients with adenomyosis have not shown an increased risk for placenta accreta.
Further investigation is necessary since GnRHa therapy is a widely used medication both in IVF protocols, in treatment of endometriosis, and more recently in patients with adenomyosis. Pregnancies conceived after IVF do have an increased risk for subsequent placenta accreta [15, 16]. These studies did not compare GnRH agonist vs GnRH antagonist protocols, but that could be a potential area of study in the future [15, 16, 21, 22]. Although larger studies have shown that endometriosis is associated with increased risk for placenta accreta, smaller studies did not find an association as it was a rare outcome [23–25]. None of these studies reported whether the patients were treated with GnRHa prior to pregnancy. Case literature has reported that adenomyosis could be a pre-disposing factor for placenta accreta; however, larger studies have not validated that finding [26–29]. Thus, larger studies on patients who receive GnRHa therapy prior to conception for any condition (endometriosis, adenomyosis, or IVF) may be able to demonstrate that there is an increased risk of abnormal placentation with GnRHa therapy.
Lastly, in patients with adenomyosis who receive GnRHa therapy prior to FET, we would recommend single embryo transfer and MFM consultation. We discussed with our patient on multiple occasions that sET is the standard of care when transferring euploid embryos. However, given her multiple rounds of IVF and personal preference, a shared decision was made to transfer two euploid embryos. In addition, we would recommend MFM consultation in patients that achieve pregnancy after GnRHa therapy to monitor for the development of abnormal placentation with serial ultrasounds. Targetted monitoring has been shown to increase rates of detection as well as decrease estimated blood loss and maternal hospital stay [30].
Abbreviations
GnRHaGonadotropin releasing hormone agonist
FETsFrozen embryo transfers
JZJunctional zone
TVUSTransvaginal ultrasound
AFCAntral follicle count
AMHAnti-Mullerian hormone
SISSaline-infused sonohysterogram
IVFIn-vitro fertilization
SDStimulation day
ICSIIntracytoplasmic sperm injection
EMSEndometrial stripe
GAGestational age
IUGRIntrauterine growth restriction
GnRHRGonadotropin releasing hormone receptor
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Acknowledgements
We would like to acknowledge Dr. Popek, Director of Perinatal and Placental Pathology, who shared her insight and expertise regarding the unique findings of this case. Also, we would like to thank Dr. Jewel Appleton who provided the images for this case report.
Code availability
N/A
Authors’ contributions
All the authors actively participated in the production of this manuscript. The author(s) read and approved the final manuscript.
Funding
None.
Availability of data and materials
N/A
Ethics approval and consent to participate
Not applicable in case reports or case series. Our institution only requires that written consent be obtained prior to publication. This consent has been obtained.
Informed consent was obtained for this case report from the participant.
Consent for publication
The participant has consented to the submission of the case report to the journal.
Competing interests
The authors declare that they have no conflict of interest. | Recovered | ReactionOutcome | CC BY | 33658071 | 19,475,281 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | A case report of greater saphenous vein thrombosis in a patient with coronavirus (COVID-19) infection.
In December 2019, the World Health Organization (WHO) announced a series of pneumonia cases caused by an unknown origin, discovered in Wuhan, China. A dangerous virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a disease named acute respiratory syndrome, which was later popularly called coronavirus infection (COVID-19). Patients with acute COVID-19 are at high risk of thrombosis in various blood vessels due to hypercoagulability, blood stasis, and endothelial damage. In this study, we present a case report of a patient with COVID-19, who was hospitalized in one of the hospitals in Sanandaj, Iran. There were symptoms of fever, chills, muscle aches, cough, and tachycardia. Laboratory tests showed high levels of CRP, ESR, Ferritin CLIA, LDH and D-Dimer in this patient. Doppler ultrasound of the patient also revealed an abnormal finding, thrombosis in the right greater saphenous vein. This suggests that COVID-19 may lead to other negative effects through damage to blood vessels.
Introduction
Coronavirus has been widespread around the world since early 2020. The disease is highly contagious and, in severe cases, can lead to acute respiratory syndrome or organ failure [1, 2]. In January 2020, the World Health Organization (WHO) announced the outbreak of the disease as a “public health emergency of international concern” [3]. To date, the virus has led to an unprecedented global health crisis that has resulted in over 2 million death worldwide [4].
Several studies have shown that superficial vein thrombosis (SVT) is a common venous disease that appears to be medically benign but can cause serious complications and may be associated with complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE) [5, 6]. The prevalence of SVT is estimated to be about 3 to 11%, while the incidence of thrombosis in the greater saphenous vein (GSV) is about 60 to 80% of the time [7, 8]. The proximity of the greater saphenous vein to the saphenofemoral junction (SFJ) increases the possibility of displacement of blood clots and their entry into the deep venous system and as a result makes SVT a serious concern [9].
There is a risk for venous and arterial thrombosis in patients with SARS-Cov2 due to excessive coagulation status, blood stasis, and damage to vascular endothelial cells in this condition [10]. As the clinical signs of venous and arterial thrombosis are ambiguous, it is very important to use imaging techniques such as Doppler ultrasound and computed tomography (CT) angiography to prevent catastrophic complications such as pulmonary embolism and mortality [11]. In this case report, the course of a patient with coronavirus is described.
Case presentation
A 40-year-old man with one-week symptoms of cough, fever, fatigue, muscle aches, diarrhea, palpitations, and shortness of breath but no chest pain was admitted to Tohid Hospital, Sanandaj, Iran. Before admission, the patient was diagnosed with COVID-19 by an infectious disease specialist based on the initial symptoms. Both CT scans (Fig. 1) and the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed the infection. The patient had no history of underlying diseases such as diabetes, heart disease, hypertension, or cancer. At the hospital’s emergency department, the physical examinations showed that the patient had an irregular heart rate of 145 beats/min, blood pressure of 82/75 mmHg, temperature of 38.4 °C, respiratory rate of 26 breaths/min, and oxygen saturation of 89%. Paraclinical and laboratory results showed that routine blood tests, renal function, and electrolytes were completely normal. The influenza A and B antigen tests were also negative. However, the other laboratory findings were all abnormal, which are briefly listed in Table 1. In CT scans of the lungs (Fig. 1), bronchovascular marking is evident. Additionally, multiple foci of parenchymal turbidity and ground-glass opacity were observed with greater density at the margins and at the base of the lungs. Therefore, the patient was started on medical treatment with Naproxen, Hydroxychloroquine, Famotidine, Zinc, Neurobion, and anticoagulants by injecting heparin and taking acetylsalicylic acid tablets. Fig. 1 Axial without contrast-enhanced chest computed tomography (CT) image showing a coronavirus disease (COVID-19) infection
Table 1 The results of laboratory findings
Test Name Unit Reference range Results Flag
1 BUN mg/dl 6–20 32 Hi
2 CPK IU/L male: 0–171 55
3 LDH U/L 235–470 510 Hi
4 Na(ser) mEq/L 138–145 134 LOW
5 K(ser) mEq/L 3.6–5.9 3.8
6 Cr mg/dl male:0.8–1.3 mg/dl 0.7 LOW
7 CRP mg/l 0–6 30 Hi
8 ESR mm 5–12 18 Hi
9 Ferritin CLIA ng/mL 50–434 511 Hi
10 D-Dimer(CLIA-Siemens) ng/mL < 885 > 7500 Hi
Three days after hospitalization, Doppler ultrasound was performed on the lower limb due to numbness and tingling (paresthesia) in the right leg, in addition to swelling, redness, pain, and sensitivity to touch. Examination of the main veins of both lower limbs showed no evidence of occlusion in the external iliac, common femoral, popliteal, anterior and posterior tibialis, and peroneal. However, more detailed examination revealed that thrombosis was evident at the beginning of the greater saphenous vein of the right leg from distal to proximal (Fig. 2). The patient was discharged after 12 days of hospitalization with complete recovery from COVID-19. The anticoagulation treatment for the GSV thrombosis was continued for the patient, and no negative side effect caused by SVT was reported after the treatment. Fig. 2 Doppler ultrasound images of the lower right limb showing a superficial vein thrombosis (SVT). Anterior accessory saphenous vein (AASV), great saphenous vein (GSV), common femoral vein (CFV), and common femoral artery (CFA) in the Doppler ultrasound images of the lower right limb
Discussion
In this case report, we presented a patient with COVID-19 who was hospitalized in Tohid Hospital, Sanandaj, Iran and later was diagnosed with a thrombosis in his right GSV. This patient had common COVID-19 symptoms such as fever, dry cough, shortness of breath, and muscle pain [12] but no risk factor for SVT. Paraclinical tests and CT scans of the chest confirmed the COVID-19 diagnosis, and although there was no obvious evidence of SVT, detailed examination by Doppler ultrasound revealed a thrombosis in the patient’s GSV.
Studies have shown that the most important and stable hemostatic disorders associated with COVID-19 include mild thrombocytopenia [13] and an increase in D-dimer amount [14]. There is evidence showing thrombotic abnormalities, in addition to abnormalities in the function of various organs in patients with COVID-19 [15], which lead to higher mortality. However, as far as we can ascertain there are few reports of SVT and its side effects in patients with COVID-19.
Pathophysiologically, patients with COVID-19 may have a higher risk for developing venous thrombosis, usually due to diarrhea, hypotension, recurrent long-term infections, and dehydration [16]. Therefore, in patients with coronavirus, assessing the risk of DVT and SVT are essential to reduce complications and mortality risk. Studies have shown that patients prone to DVT usually have one of the following criteria: age over 75, respiratory and heart failure, history of previous thrombosis, acute onset of chronic pulmonary obstruction, acute cerebral infarction, malignant tumor, limb varicose veins, obesity, chronic kidney disease, inflammatory bowel disease, and more than 3 days of bed rest [17].
In one study on a patient with COVID-19, CT images of angiography showed signs of acute cerebral infarction and DVT in both lower limbs [18]. In our case report, the patient was suspected of having thromboembolism due to having similar lesions on his leg, however after a CT scan of his chest, his diagnosis with COVID-19 was confirmed, while there was no evidence of pulmonary thromboembolism. The physicians at the hospital also suspected SVT and DVT due to numbness, swelling, and pain in the right leg, which were examined by Doppler ultrasound of all blood vessels, including the common iliac, small saphenous, and greater saphenous. Since many studies have reported respiratory distress along with other clinical evidence of venous thrombosis, pulmonary embolism should be suspected [19, 20].
A recent study on the intensive care unit (ICU) patients with COVID-19 found that the rate of thrombotic disorders in these patients is 31% [21]. Further, medical images have shown that 27% of such thrombotic disorders are due to venous thromboembolism, 3.7% to arterial thrombosis, and 81% to pulmonary embolism, which is the most common complication of thrombosis in ICU patients [21]. The possible reasons for venous thrombosis may include the fact that COVID-19 attacks the human body via the 2-angiotensin converting enzyme, which is found in various blood vessels and organs of the body [22]. Ultimately, coronaviruses cause cytokine waterfalls, including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα in the body, which can increase the risk of complications such as blood clots. This cytokine storm can be associated with the severity of the disease and its negative consequences [23, 24]. Blood clots formed in DVT may also have a variety of causes, including vascular damage, surgery, special medications, and limited mobility [25], but the exact cause of COVID-19-induced DVT is still unknown [26].
Conclusion
COVID-19 is an emerging source of venous thrombosis due to factors such as excessive coagulation, blood stasis, and endothelial damage. The main mechanism of SVT and DVT formation due to COVID-19 is unknown and has not yet been examined. Although COVID-19 cases presented with SVT and DVT are rare, recognizing SVT and DVT as potential complications of COVID 19 infection will be of great value. Imaging techniques such as CT, MRI, and ultrasound can confirm the diagnosis of SVT and DVT. Due to the possibility of COVID-19 infection in patients presenting with venous thrombosis or other thromboembolic diseases, it seems important to consider the presence of COVID-19 in their diagnosis.
Acknowledgements
The authors thank all the teaching and medical staff of Kurdistan University of Medical Sciences for their effort in eradicating the virus around the clock.
Authors’ contributions
MBHS supervised the study and wrote the manuscript; PF collected the clinical data; MA and FF analyzed the data and images; and NHS reviewed the manuscript. The author(s) read and approved the final manuscript.
Funding
No source of funding.
Availability of data and materials
I have presented the data of the patient in the manuscript as a Table. I have submitted the figures separately as figures.
Declarations
Ethical approval and consent to participate
This research has been confirmed by the Research Center of Kurdistan University of Medical Sciences and Ethics Committee with the file number IR.MUK.REC.1399.087.
Consent for publication
Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article which was approved by the Research Center of Kurdistan University of Medical Sciences.
Competing interests
All authors declare that there is no conflict of interest that prejudices the impartiality of this scientific work.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ASPIRIN, CYANOCOBALAMIN\PYRIDOXINE\THIAMINE, FAMOTIDINE, HEPARIN SODIUM, HYDROXYCHLOROQUINE, NAPROXEN, ZINC | DrugsGivenReaction | CC BY | 33658082 | 20,196,642 | 2021-03-03 |
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