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Limitations | Our study has several limitations. The Camden Core Model did not establish a priori criteria to define full intervention exposure at the time of trial implementation. We used a combination of data distributions and guidance from program designers to select the engagement definition used for this analysis and tested several variations in sensitivity analyses. Although our study provided insight into the characteristics of patients who were less likely to be engaged, we were unable to assess causes of variable intervention exposure. Our results should not be interpreted to suggest that unengaged patients would have achieved outcomes comparable with engaged patients had they received a more complete intervention dose.We analyzed readmissions at 180 days as the primary outcome for consistency with the original evaluation. However, the focus on this singular outcome measure as the primary value mechanism for complex care may distract from a broader range of potential benefits. While there are patients for whom reducing hospitalizations is an appropriate goal of complex care management, for others, frequent hospitalizations result from exceptional circumstances that are not resolved irrespective of intensive intervention. | PMC10498327 | ||
Conclusions | The conclusion from the original randomized clinical trial of the Camden Core Model that the intervention did not work may have been premature, because the estimated treatment effect in the ITT analysis was averaged over a population including patients who received low-intensity and short-term intervention. In this reanalysis of the Health Care Hotspotting trial, the distillation method helped identify individuals for whom intervention delivery was successful and whether the intervention worked when it could be delivered more fully. Both questions are essential to producing policy relevant results in evaluations of care management programs. | PMC10498327 | ||
Objective | Cushing’s disease | POLAND | Edited by: Renato Cozzi, Endocrinology Unit Ospedale Niguarda, ItalyReviewed by: Przemyslaw Witek, Warsaw Medical University, Poland; Athanasios Fountas, General Hospital of Athens G. Genimatas, Greece†Present addresses: Alberto M. Pedroncelli, Chief Medical Office, Camurus AB, Lund, SwedenRicardo Maamari, Global Medical Affairs, Mayne Pharma, Raleigh, NC, United States‡These authors have contributed equally to this workThis study evaluated short- and long-term efficacy and safety of the second-generation somatostatin receptor ligand pasireotide alone or in combination with dopamine agonist cabergoline in patients with Cushing’s disease (CD). | PMC10593462 |
Study design | This is an open-label, multicenter, non-comparative, Phase II study comprising 35-week core phase and an optional extension phase. All patients started with pasireotide, and cabergoline was added if cortisol remained elevated. Eligible patients had active CD, with or without prior surgery, were pasireotide naïve at screening or had discontinued pasireotide for reasons other than safety. Primary endpoint was proportion of patients with a mean urinary free cortisol (mUFC) level not exceeding the upper limit of normal (ULN) at week 35 with missing data imputed using last available post-baseline assessments. | PMC10593462 | ||
Results | Hyperglycemia, nausea, diarrhea, cholelithiasis, hypercortisolism | ADVERSE EVENTS, HYPERGLYCEMIA, HYPERCORTISOLISM, CHOLELITHIASIS | Of 68 patients enrolled, 26 (38.2%) received pasireotide monotherapy and 42 (61.8%) received pasireotide plus cabergoline during the core phase. Thirty-four patients (50.0%; 95% CI 37.6–62.4) achieved the primary endpoint, of whom 17 (50.0%) received pasireotide monotherapy and 17 (50.0%) received combination therapy. Proportion of patients with mUFC control remained stable during the extension phase up to week 99. Treatment with either mono or combination therapy provided sustained improvements in clinical symptoms of hypercortisolism up to week 99. Hyperglycemia and nausea (51.5% each), diarrhea (44.1%) and cholelithiasis (33.8%) were the most frequent adverse events. | PMC10593462 |
Conclusion | hypercortisolism | HYPERCORTISOLISM | Addition of cabergoline in patients with persistently elevated mUFC on maximum tolerated doses of pasireotide is an effective and well-tolerated long-term strategy for enhancing control of hypercortisolism in some CD patients. | PMC10593462 |
Clinical trial registration | PMC10593462 | |||
Introduction | pituitary tumor, Cushing’s disease | PITUITARY TUMOR, SECONDARY, OVERPRODUCTION OF CORTISOL | Cushing’s disease (CD) is a rare condition arising from chronic overproduction of cortisol, secondary to an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor (Pasireotide is a second-generation, multireceptor-targeted somatostatin receptor ligand (SRLs), with affinity for 4 of the 5 known somatostatin receptor subtypes (SSTRs) (Cabergoline, a potent dopamine agonist with high affinity for dopamine type 2 receptors (D2), is commonly used off-label for the treatment of CD (The current study aims to report the efficacy and safety of prolonged treatment with pasireotide alone or in combination with cabergoline from the largest prospective, multicentre study to date of a pituitary-targeting combination treatment regimen in patients with CD (NCT01915303). | PMC10593462 |
Materials and methods | PMC10593462 | |||
Patients | Adults (≥18 years) with a confirmed diagnosis of CD or | PMC10593462 | ||
Study design | This was a single-arm, open-label, multicenter, non-comparative, Phase II study. After 4 weeks of screening, patients were treated in a stepwise approach during the core phase. Patients received subcutaneous pasireotide 0.6 mg twice daily (bid) for 8 weeks. Patients with a mUFC level exceeding ULN after 8 weeks received pasireotide 0.9 mg bid for another 8 weeks. If mUFC level remained elevated with pasireotide 0.9 mg bid, oral cabergoline 0.5 mg once daily (qd) was added for 8 weeks and could be increased to 1.0 mg qd for another 8 weeks (Collection of extension data commenced from week 43, and patients continued their current study treatment up to study end (4 September 2019; date of last patient visit), week 257. Data beyond week 99 are not reported here because of small patient numbers. | PMC10593462 | ||
End points and assessments | hirsutism | HIRSUTISM | The primary endpoint of the study was the proportion of patients with mUFC ≤ULN at week 35. Secondary endpoints (reported at 4-week intervals up to week 35 and 8-week intervals from week 43 to the date of the last patient visit) included changes from baseline in mUFC, plasma ACTH, serum cortisol, total cholesterol, and clinical signs (systolic/diastolic blood pressure, body mass index (BMI), weight, waist circumference, facial rubor, hirsutism, striae, supraclavicular and dorsal fat pads) and symptoms (CushingQoL). Treatment escape was defined as an increase in one UFC above the normal range during follow-up of complete responders ( | PMC10593462 |
Statistical analyses | No formal hypothesis testing was performed because of the exploratory design of the study. Efficacy analyses were conducted on full analysis set, i.e., all patients to whom study treatment was assigned. Safety analyses were conducted on all patients who received ≥1 dose of pasireotide per day during the study. For patients with missing mUFC value at week 35, including those who discontinued, the last available assessment was carried forward. Details on the | PMC10593462 | ||
Results | PMC10593462 | |||
Study population | ADVERSE EVENTS, RECURRENT DISEASE | A total of 68 patients were enrolled in the study. At baseline, 66 (97.1%) patients were pasireotide naïve, while 2 (2.9%) were treated with pasireotide previously with 4 weeks of washout period prior to screening (Patient demographics and baseline characteristics.*Persistent or recurrent disease refers to patients with previous surgery or on medication who did not respond or experienced escape. mUFC, mean urine free cortisol; SD, standard deviation; ULN, upper limit of normal.Patient disposition. *If the study drugs were locally available at the end of the core phase, patients could switch over to the commercial supply and exit the extension phase. Only in countries where the drug was not locally available were patients given the option to enter the extension phase. Percentage for patients not entering the extension phase was calculated from the total number of patients enrolled in the study.Twenty-nine (42.6%) patients continued treatment in the extension phase; 10 (34.5%) received pasireotide monotherapy and 19 (65.5%) received combination therapy. Twelve (41.4%) patients completed the extension phase, while 17 (58.6%) discontinued treatment before study end, most commonly for unsatisfactory therapeutic effect (n=8). The most common reason for discontinuation was adverse events (AEs): 5 (17.2%) patients with pasireotide monotherapy and 2 (5.1%) patients with combination therapy. | PMC10593462 | |
Efficacy: biochemical response | hypercortisolism | HYPERCORTISOLISM | Overall, 34/68 (50.0%; 95% CI 37.6–62.4) patients achieved the primary endpoint, of whom 17 (50.0%) were receiving pasireotide monotherapy and 17 (50.0%) were receiving combination therapy. Patients with mild hypercortisolism (mUFC 1.0–<2.0 x ULN) at baseline were more likely to respond to both pasireotide monotherapy and combination therapy (n=15; 22.1%, Patients achieving mUFC ≤ULN at week 35. For the overall study population (n=68), mUFC rapidly decreased from 501.6 nmol/24h (3.6 x ULN; SD: 488.66 nmol/24h) to 242.1 nmol/24h (1.8 x ULN; SD: 203.47 nmol/24h) at week 4 and mUFC remained below baseline levels up to week 35 (184.8 nmol/24h; 1.3 x ULN; SD:140.13 nmol/24h). For patients who received pasireotide monotherapy (n=26), mUFC( ± SD) decreased from baseline (442.1± 557.13 nmol/24h [n=26]; 3.2 x ULN) to week 35 (136.6 ± 127.77 nmol/24h [n=14]; 1 x ULN) and at the end of the study (111.2 ± 40.39 nmol/24h [n=5]; 0.8 x ULN) using the last-observation-carried-forward (LOCF). For those who did not normalize on pasireotide monotherapy (n=42), mUFC ( ± SD) decreased from baseline, i.e., last observation before starting cabergoline (280.20 ± 129.03 nmol/24h [n=40]; 2.0 x ULN) to week 35 (206.6 ± 141.96 nmol/24h [n=31]; 1.5 x ULN) and at the end of the study (219.60 ± 83.78 nmol/24h [n=7]; 1.6 x ULN) using the LOCF. During the core phase, mean serum cortisol decreased from 738.6 nmol/L (1.3 x ULN) at baseline to 538.2 nmol/L (0.95 x ULN) and ACTH levels from 16.3 pmol/L (2.7 x ULN) to 11.0 pmol/L (1.8 x ULN) at week 35.During the extension phase, 25 patients had a mUFC assessment; of whom 12 (48%) had a mUFC ≤ULN at the end of the extension phase. During the extension phase, mUFC levels decreased slightly and fluctuated above and below the ULN up to the week 139 (Mean actual change over time in Twenty-one of 38 (55%) patients achieved control with combination therapy at some point during the core or extension study, of whom 13 (62%) experienced escape (at least one UFC >ULN after previous control). The time to achieve control after starting cabergoline ranged from 14−;343 days. Notably, one patient received pasireotide 0.6 mg bid initially, dose increased to 0.9 mg bid at Week 17, followed by addition of cabergoline 0.5 mg od at Week 31. The patient achieved biochemical control (mUFC value of 120.15 nmol/24h) on the same day of the start of combination therapy. Clinically it is highly unlikely that biochemical control was achieved with single dose of cabergoline administration. Therefore, it could be considered that normalization was achieved while receiving pasireotide monotherapy. Also, the physician might have prescribed combination therapy before receiving the mUFC value of the (urinary) sample delivered on the morning of combination therapy initiation (while the patient was still on monotherapy). The patient continued combination therapy and maintained biochemical control up to Week 35 and beyond. Furthermore, at Week 59 the cabergoline dose was increased to 1.0 mg/day due to mUFC >ULN at previous visit (Week 51). The patient remained on pasireotide 0.9 mg bid/cabergoline 1.0 mg od combination therapy until the study end.The median time to escape after achieving control with the addition of cabergoline was 58 days (range 28−;344). 10/13patients regained biochemical control with combination therapy. No patients on pasireotide alone experienced escape, probably due to the short observation time. | PMC10593462 |
Clinical signs and symptoms of CD | Relative to baseline, pasireotide monotherapy was accompanied by reductions in median blood pressure, weight, BMI, waist circumference, and total cholesterol. Overall improvement in clinical measures persisted over time (Mean( ± SD) standardized CushingQoL score was 41.6(± 20.2) at baseline and increased to 47.6(± 20.8) at week 35 ( | PMC10593462 | ||
Safety and tolerability | Hyperglycemia, death, multi-organ dysfunction, hyperglycemia, hyperglycemia-related AEs, deaths | HYPERGLYCEMIA, UNCONTROLLED HYPERTENSION, ADVERSE EVENTS, HYPERGLYCEMIA, ADVERSE EVENT, SYNDROME | Median duration of exposure to pasireotide was 35.0 weeks (range 0−;268), with a median dose of 1.53 mg/day (range 0.29−;1.80). Median duration of exposure to cabergoline was 16.9 weeks (range 1−;215), with a median dose of 0.50 mg/day (range 0.44−;0.97).All patients (N=68) reported at least one AE and 28/68 (41.2%) patients had a grade 3/4 AE (Summary of adverse events (≥10%), overall and by treatment regimen.*Excluding hematological and biological AEs.
Hyperglycemia is self-monitored fasting blood glucose value of >130 mg/dL AE, adverse event; GGT, gamma-glutamyl transferase.The most common AEs leading to discontinuation were increased gamma-glutamyl transferase (GGT) and hyperglycemia (two patients each, 2.9%). Twenty-three (33.8%) patients had ≥1 AE leading to dose adjustment or interruption. Details on special safety assessments such as hyperglycemia-related AEs, blood glucose, HbA1c, IGF-1 as well as hematological and biochemical abnormalities are presented in the Three (4.4%) patients died during the study, two (2.9%) during the core phase and one (1.5%) during the extension. All deaths were considered unrelated to study medication. The causes during the core phase were multi-organ dysfunction syndrome for one patient aged 79 years and unknown for the other aged 34 years. Uncontrolled hypertension was reported as the cause of death for the patient aged 47 during the extension phase. | PMC10593462 |
Discussion | pituitary tumor, tumor, mild/moderate, hypercortisolemia, hypercortisolism | PITUITARY TUMOR, TUMOR, DISEASE, HYPERCORTISOLEMIA, HYPERCORTISOLISM | The severe morbidity and increased mortality with uncontrolled CD highlight the importance of identifying an effective medical strategy. This study explored the potential of a synergistic benefit of the addition of cabergoline to pasireotide treatment in patients with CD.Complete normalization of cortisol production is required to reverse the risks of morbidity and mortality in patients with CD (This study confirms previous reports that patients with mild hypercortisolism at baseline were more likely to achieve mUFC control with pasireotide monotherapy than patients with moderate or severe hypercortisolism (Improvements in clinical signs and symptoms with pasireotide monotherapy were consistent with published data (The overall safety profile was consistent with that expected for pasireotide, with most AEs being mild/moderate (Both pasireotide and cabergoline are pituitary-targeted agents that act directly on the source of the disease via inhibition of ACTH release by the corticotroph tumor, which may be an advantage over steroid synthesis inhibitors. This study further confirms previous data reporting the benefits of pasireotide in combination with cabergoline in patients with CD (Although clinicians have several therapeutic options at their disposal to treat hypercortisolemia associated with CD, the optimal treatment approach should be based on the individual clinical situation and the benefit–risk considerations for each patient. In this study, 13 patients had history of pituitary radiation, with a duration of at least 2.6 years (median 3.3 years) between the last radiation treatment and the observed response date. However, only 7/13 patients achieved the therapeutic target. Although there was a gap of > 2 years, we cannot exclude the role of radiation in normalizing UFC. Contrastingly, 6/13 patients treated with radiation did not achieve mUFC ≤ULN (responders) at Week 35. The impact of the adjuvant radiation therapy remains unclear.The strengths of this study are that this is the largest and longest prospective study with pituitary-directed pharmacotherapy, to date, evaluating the addition of cabergoline to pasireotide in patients with CD, and this stepwise approach reflects real-world clinical practice (Other limitations include protocol deviations in including 3 patients with normal UFC at baseline (one patient was uncontrolled at rescreen, and one was discontinued at 2 weeks - both classified asnon-responders), lack of data on impact of radiation therapy without study drug in patients who gained biochemical control with adjuvant radiation therapy, lack of pituitary magnetic resonance imaging to detect pituitary tumor changes, lack of data about effective cabergoline dose and absence of cardiac valve assessment for mild to moderate severity in the medium term. Both pasireotide and cabergoline can induce tumor shrinkage in CD ( | PMC10593462 |
Conclusions | This is the first study demonstrating that pituitary-targeted combination treatment with pasireotide and cabergoline doubled the number of patients who attained mUFC ≤ULN. Both short- and long-term safety profile are consistent with known data for pasireotide and cabergoline. The low rate of discontinuation due to AEs suggests that pasireotide alone or as combination treatment is generally well-tolerated if appropriately monitored, even with prolonged treatment. The addition of cabergoline to pasireotide treatment in patients with persistently elevated mUFC could be an effective long-term strategy for enhancing the control of CD in a subset of patients, with close monitoring for possible escape. | PMC10593462 | ||
Data availability statement | The original contributions presented in the study are included in the article/ | PMC10593462 | ||
Ethics statement | Ethische | DELHI | The studies involving humans were approved by Hospital Britanico, Buenos Aires, Argentina; Ethische commissie University Hospitals Leuven, Leuven, Belgium; Universitair Ziekenhuis Gent, Gent, Belgium; Comite de Etica em Pesquisa Hospital Moinhos de Vento, Porto Alegre-RS, Brazil; Comitê de Ética em Pesquisa do Hospital de Clínicas, Universidade Federal do Paraná, Curitiba-PR, Brazil; Comissão de Ética para Análise de Projetos de Pesquisa, São Paulo - SP, Brazil; Ethics Committee for clinical trials, Sofia, Bulgaria; Comité Corporativo de Ética en Investigación, Bogotá DC, Colombia; Comite De Protection Des Personnes, Groupe Hospitalier Pellegrin - Bat, Bordeaux Cedex, France; Friedrich-Alexander Universitat Erlangen-Nurnberg, Medizinische Fakultat, Erlangen, Germany;National Ethics Committee, Cholargos, Athens, Greece; Ethics Committee for Clinical Pharmacology (ECCP), Budapest, Hungary; Institute Ethics Committee, New Delhi, India; Institutional Review Board (IRB) Ethics Committee Silver, Christian Medical College, Vellore, Tamil Nadu, India; Institute Ethics Committee, PGIMER, Chandigarh, India; Comitato Etico Dell’irccs Istituto Auxologico Italiano Di Milano, Milano, Italy; Comitato Etico Universita’ Federico Ii Di Napoli, Napoli, Italy; Jawatankuasa Etika & Penyelidikan Perubatan (Medical Research and Ethics Committee), d/a Institut Pengurusan Keshatan Jalan Rumah Sakit, Kuala Lumpur, Malaysia; Institutd Nacional De Neurologia Y Neurocirugia, Mexico City, Mexico; Clinica Bajio (CLINBA), Guanajuato, Mexico; Medische Ethische Toetsings Commissie, Rotterdam; Netherlands; CEIm Provincial de Málaga, Málaga, Spain; Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey; WIRB, Puyallup, WA, USA; Research Integrity Office, Oregon Health & Science University Portland, OR USA. The studies were conducted in accordance with local legislations and institutional requirements. The participants provided their written informed consent to participate in this study. | PMC10593462 |
Author contributions | All authors directly participated in the planning, execution, or analysis, and have had full control of complete primary data, and hold responsibility for data integrity and accuracy. All authors contributed to the article and approved the submitted version. | PMC10593462 | ||
Acknowledgments | BROWN | We thank Julie Brown, Mudskipper Business Ltd, and Manojkumar Patel and Sashi Kiran Goteti, Novartis Healthcare Private Limited, for medical editorial assistance with this manuscript. We would also like to thank all investigators, sub-investigators, study nurses and coordinators, and patients who have made this study possible. | PMC10593462 | |
Conflict of interest | Neuroendocrine CAH, RP | OSTEOPOROSIS, RARE DISEASE | HP and RM were Novartis employees and owned Novartis stocks. AMP was employed by Novartis and Recordati. AC is a Novartis employee and owns Novartis stocks. RF received research grants from Strongbridge and Corcept, consulting fee from Recordati, honoraria and financial support for meetings and/or travel from HRA Pharma and Recordati, and attended advisory boards for Recordati. MF has received research support to Oregon Health & Science University as a principal investigator from Recordati and Xeris Strongbridge and has performed occasional scientific consultancy for Recordati, HRA Pharma, Sparrow, and Xeris Strongbridge. PK attended advisory boards for Recordati. MB’s institution received consulting fee and attended advisory boards from Recordati. DG-D received research grants from Recordati Rare Disease and Bayer, consulting fee from Abbott-Lafrancol, Biotoscana, PTC lab, Glaxo/Helou, Recordati Rare Disease, and Bayer, honoraria from Valentech Pharma, Sanofi, and Bayer, travel grants from Recordati Rare Disease, advocacy groups and other leadership roles from Asociación Colombiana de Endocrinologia and Asociación Colombiana de Osteoporosis y Metabolismo, and other financial and non-financial interests include Asociacion Colombiana de Endocrinologia y Metabolismo, Hospital Universitario Fundación Santa Fé de Bogota, and Asociación Colombiana de Osteoporosis y Metabolismo. CB received research grants from Novartis and Recordati, and consulting and speaker fee from Novartis. BB served as the principal investigator for grants to Massachusetts General Hospital from Cortendo/Strongbridge Xeris, Millendo, and Novartis and has occasionally consulted for Cortendo/Strongbridge Xeris, HRA Pharma, Novartis Recordati, and Sparrow. RP and his institution received research grants and honoraria from Pfizer, Ipsen, Novartis, Merck Serono, IBSA Farmaceutici, Corcept, Shire, HRA Pharma, ICON, Covance, Neuroendocrine CAH, Camurus, Recordati, Janssen Cilag, and CMED Clinical Services, received consulting fee from Recordati Rare Disease, Organon Italia, Siunergos Pharma, Corcept, S&R Farmaceutici S.p.A., DAMOR Farmaceutici, and Pfizer, attended advisory boards from Crinetics Pharmaceuticals, Recordati Rare Disease, Pfizer, and HRA Pharma.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The authors declare that this study received funding from Novartis Pharma AG. Novartis was involved in the study design, analysis, interpretation of data, and providing financial support for medical editorial assistance of this article. | PMC10593462 |
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10593462 | ||
Supplementary material | The Supplementary Material for this article can be found online at: Click here for additional data file. | PMC10593462 | ||
References | PMC10593462 | |||
Background: | RECRUITMENT, ACUTE RESPIRATORY DISTRESS SYNDROME, POSITIVE | Positive end-expiratory pressure (PEEP) benefits in acute respiratory distress syndrome are driven by lung dynamic strain reduction. This depends on the variable extent of alveolar recruitment. The recruitment-to-inflation ratio estimates recruitability across a 10–cm H | PMC10723770 | |
Methods: | COVID-19 ACUTE RESPIRATORY DISTRESS SYNDROME | Twenty patients with moderate-to-severe COVID-19 acute respiratory distress syndrome underwent a decremental PEEP trial (PEEP 15 to 13 to 10 to 8 to 5 cm H | PMC10723770 | |
Results: | Between 15 and 5 cm H | PMC10723770 | ||
Conclusions: | COVID-19 ACUTE RESPIRATORY DISTRESS SYNDROME | Both global and granular recruitment-to-inflation ratio accurately estimate PEEP-induced changes in lung dynamic strain. However, the effect of 10 cm HIn a cohort of patients with moderate to severe COVID-19 acute respiratory distress syndrome, the authors determined respiratory mechanics and end-expiratory lung volume by nitrogen dilution over a 10–cm H | PMC10723770 | |
Visual Abstract: | PMC10723770 | |||
Editor’s Perspective | PMC10723770 | |||
What We Already Know about This Topic | acute respiratory distress syndrome, baby lung overinflation | RECRUITMENT, ACUTE RESPIRATORY DISTRESS SYNDROME | The ability to determine the optimal positive end-expiratory pressure (PEEP) for patients with acute respiratory distress syndrome may have important clinical ramifications.The optimal PEEP in such patients aims at reducing lung dynamic strain while avoiding baby lung overinflation. The balance between these two effects depends on the variable extent of lung recruitment.The recruitment-to-inflation ratio over a 10–cm HWhether the recruitment-to-inflation ratio is uniform or not across a 10–cm H | PMC10723770 |
What This Article Tells Us That Is New | ventilator-induced lung injury, ARDS | COVID-19 ACUTE RESPIRATORY DISTRESS SYNDROME, ARDS, RECRUITMENT, ACUTE RESPIRATORY DISTRESS SYNDROME | In a cohort of patients with moderate to severe COVID-19 acute respiratory distress syndrome, the authors determined respiratory mechanics and end-expiratory lung volume by nitrogen dilution over a 10–cm HThe global effect displayed a linear correlation of both global and granular recruitment-to-inflation ratio with dynamic strain reduction. However, granular recruitment-to-inflation ratio showed high intraindividual variability, suggesting nonuniform recruitability across a 10–cm HA nonlinear quadratic relationship was noted between granular recruitment-to-inflation ratio and PEEP.These pilot data suggest that the recruitment-to-inflation ratio measured across a 10–cm HMechanical ventilation represents the mainstay of supportive therapy in the acute respiratory distress syndrome (ARDS), aiming at maintaining gas exchange while limiting the occurrence of ventilator-induced lung injury.A high interindividual heterogeneity in the potential for lung recruitment with PEEP has been described.Measurement of end-expiratory lung volume through the nitrogen dilution technique looks promising in this contextThe recruitment-to-inflation ratio is assessed through a simplified maneuver and estimates the potential for lung recruitment within a 10–cm HWe report the results of a physiologic study conducted in moderate-to-severe COVID-19 ARDS to determine the behavior of recruitment-to-inflation ratio across the conventionally tested 15– to 5–cm H | PMC10723770 |
Materials and Methods | This prospective, physiologic study was conducted in the intensive care unit (ICU) of a tertiary care university hospital between April and June 2021. Approval was obtained by local institutional review board, Comitato Etico Policlinico Gemelli. Written informed consent was obtained by patients’ legal representatives according to committee recommendations (ID UCSC915920/20). Withdrawal of consent to study participation or data analysis by patients or their legal representatives was allowed at any time during the study. | PMC10723770 | ||
Patients | ARDS | ARDS | Consecutive patients admitted to the ICU between April and July 2021 and fulfilling moderate-to-severe ARDS criteria | PMC10723770 |
Procedures and Measurements | Neuromuscular blockade | NEUROMUSCULAR BLOCKADE | All patients were in the semirecumbent position (30° to 45° head-of-the-bed elevation) and sedated according to standard practice. Neuromuscular blockade was accomplished by cisatracurium continuous infusion at the dose of 35 mg · hStudy procedures are summarized in figure Flow chart of the study protocol. After assessment of eligibility, a single-breath derecruitment maneuver, followed by slow inflation, was performed to assess the presence of airway closure. Patients presenting with airway closure were excluded. After enrollment, each patient was ventilated at positive end-expiratory pressure (PEEP) 15 cm HAt the end of the PEEP trial (PEEP5FRC = EELVFor each derecruitment step ( | PMC10723770 |
Alveolar Recruitment and PEEP-induced Inflation | PEEP-related total volume (PEEPvol) was computed as the difference between end-expiratory lung volume at higher PEEP (EELVVRecruited volume was then normalized to the change in PEEP (Crec = VRecruitment-to-inflation ratio = Crec/CrsThe same parameters were also computed across the whole tested PEEP range by using 15 cm H | PMC10723770 | ||
Strain Indices. | RECRUITMENT | Aerated lung volume (FRC + recruitment) at each PEEP level was calculated as the sum of FRC (After the study end, ventilation was resumed as clinically indicated by the attending physician.Of note, although physiologic measurements were derived from derecruitment PEEP trials, we refer to the terms “recruitment” and “recruitability” when describing our results. This approach is consistent with what previously done in similar investigations, | PMC10723770 | |
Endpoints | Study endpoints were (1) to assess the behavior of the recruitment-to-inflation ratio across the traditionally tested 15 to 5 cm H | PMC10723770 | ||
Sample Size Calculation and Statistical Analysis | Given the physiologic design of the study, consistent with previous investigations with similar design on the topic,Continuous data are expressed as median [interquartile range], and dichotomous variables are displayed as frequencies (%). Paired comparisons between study steps were performed with the Wilcoxon rank sum test: mean differences (95% CI] are displayed for most significant results. Intraindividual variability was rated with the coefficient of variability (ratio of the SD to the meanDifferences between repeated variables were assessed with repeated ANOVA.Results with a two-tailed | PMC10723770 | ||
Mathematical Modeling | RECRUITMENT | As an exploratory analysis, recruitment-to-inflation ratio values obtained in each derecruitment step were regressed (by nonlinear ordinary least-squares) against average step PEEP with a quadratic (parabolic) model, constrained to pass through the point (0,0), assuming essentially no recruitment at extremely low PEEP values. A goodness-of-fit test (chi-square) was conducted on each fit. Such an analysis was not prespecified and was included in the analysis during the peer review process.The rationale of performing such an exploratory analysis by introducing a nonlinear model is that of quantitatively identifying (where possible) the increasing and then decreasing recruitment at progressively increasing PEEP. This behavior is assumed to occur on physiologic principles: at zero end-expiratory pressure, by definition, there is no recruitment; recruitment must tend toward zero at very high PEEP as the maximal capacity of the lung–chest wall is reached on the pressure–volume curve of the respiratory system, corresponding to an ever-decreasing complianceIt should also be appreciated that this approach essentially makes statements about only one (out of possibly many) class of patients, whose data behave in possibly different ways. Indeed, only patients conforming to the increasing and then decreasing pattern are eventually characterized. A formal assessment of what classes actually exist and what (meta)parameters characterize each class ( | PMC10723770 | |
Results | ARDS | ARDS, POSITIVE | Twenty-six patients were screened for enrollment. Six patients (23%) showed intrinsic PEEP or airway closure with airway opening pressure greater than 5 cm HTwenty COVID-19 ARDS patients were studied. Demographics and clinical characteristics at enrollment are displayed in Supplementary table 1 (The median PaStudy variables recorded at PEEP 15 cm HRespiratory Mechanics and Gas Exchange of Enrolled Patients across the Decremental Positive End-expiratory Pressure TrialLung Volumes and Strain Indices Measured in Each Positive End-expiratory Pressure Step | PMC10723770 |
Potential for Lung Recruitment | Between PEEP 5 and 15 cm HCrec and recruitment-to-inflation ratio in the four PEEP ranges along with global Crec and recruitment-to-inflation ratio measured between PEEP 15 and 5 cm H(Average recruitment-to-inflation ratio measured in the four narrow PEEP ranges (median, 1.11 [0.38 to 1.52]) was highly correlated (r = 0.92) with the recruitment-to-inflation ratio measured between PEEP 15 and 5 cm H( | PMC10723770 | ||
Respiratory Mechanics and Lung Strain | As compared to PEEP 5 cm HAs expected, dynamic strain at PEEP 15 cm H | PMC10723770 | ||
Lung Strain Indices | RECRUITMENT | Respiratory system compliance and aerated lung volume (FRC + recruitment) were linearly correlated at PEEP 5 cm HThe reduction dynamic and total strain and the increase in static strain produced by the 10–cm HRelationship between the PEEP-induced percent change in dynamic strain, static strain, and total strain, and the corresponding recruitment-to-inflation ratio measured between 5 and 15 cm HAlso, reduction in dynamic and total strain and the increase in static strain produced by narrower PEEP levels tested in the decremental PEEP trial were closely related to the corresponding recruitment-to-inflation ratio measured (dynamic strain, r = –0.89; static strain, r = –0.36; total strain, r = –0.84; fig. Changes in respiratory system compliance, driving pressure, and Pa | PMC10723770 | |
Discussion | lung injury, derecruitment, ventilator-induced lung injury, ARDS | LUNG HYPERINFLATION, ARDS, RECRUITMENT | The results of the current physiologic study conducted on patients with early moderate-to-severe COVID-19 ARDS can be summarized as follows:Recruitment-to-inflation ratio calculated between 15 and 5 cm HRespiratory mechanics changes induced by PEEP are ineffective estimates of the changes produced on lung strain (Supplementary figure 2, Recruitment-to-inflation ratio, calculated both between PEEP 15 to 5 cm HBecause of the nonuniform behavior of recruitment-to-inflation ratio In ARDS, it is widely accepted that PEEP setting should aim at a balance between alveolar recruitment (A drawback of “universal” strategies driving the setting of high or low PEEP is that the potential for lung recruitment has great interindividual variability, with high PEEP enhancing lung injury in patients with low recruitability, and low PEEP not fully exerting its beneficial effects in recruitable patients.The recently developed recruitment-to-inflation ratio may offer a simple, timely, and reproducible assessment of recruitability at the bedside.Our study demonstrates the reliability of the recruitment-to-inflation ratio measured between PEEP 15 and PEEP 5 cm HHigh recruitment-to-inflation ratio values (The further modeling analysis presented in our manuscript showed a nonlinear fit of the recruitment-to-inflation ratio Our study may have important clinical implications:Dynamic strain is the key mechanism of lung injury during ARDS.The recruitment-to-inflation ratio measured in the 15– to 5–cm HIn selected patients (those with an intermediate recruitment-to-inflation ratio), sequential end-expiratory lung volume measurement enabling recruitment-to-inflation ratio calculation within narrower ranges during a decremental PEEP trial may enable more granular evaluation of PEEP effects on lung strain. This may aid more precise bedside PEEP titration within the evaluated range, setting PEEP to exploit lung recruitment when it is present while minimizing lung hyperinflation when recruitment does not occur.Our study has limitations:In our study, the recruitment-to-inflation ratio was calculated from the lung volume change due to PEEP measured with the dilution technique, and not estimated by the simplified derecruitment maneuver.Patients with airway closure or intrinsic PEEP were excluded from the study: this has helped avoid further confounding factors that could have required even more complex data analysis and interpretation for this proof-of-concept study.We refer to the terms “recruitment” and “recruitability,” although our results should be more properly referred to as “derecruitment” data. This conceptual shift may represent a limitation, considering the hysteretic behavior of pressure–volume curves. Nonetheless, this approach is consistent with the most recent literature on the topic, as derecruitment is simpler to assess and not significantly different from recruitment when a prolonged high-PEEP stabilizing phase precedes the derecruitment procedure, as in our study.Due to the pandemic surge, all studied patients suffered from ARDS caused by COVID-19. There are no reasons to hypothesize that our approach based on end-expiratory lung volume–guided recruitment-to-inflation ratio assessment within narrow PEEP ranges should not be applicable to ARDS from other causes, since respiratory mechanics in COVID-19 ARDS have been shown to share a high degree of similarity with non–COVID-19 cases.No biologic or imaging techniques were used to support the findings of our study. The latter represents a limitation both due to of the lack of data on the regional distribution of ventilation and because computed tomography scan validation of recruitment evaluation is not present. Nevertheless, the role of dynamic strain as key determinant of ventilator-induced lung injury is well-established,Caution is warranted when interpreting linear correlation data from our study: indeed, due to the lack of an external validation of recruitment such as imaging techniques, correlations between recruitment-to-inflation ratio and the recruitment index Crec/FRC and between recruitment-to-inflation ratio and changes in strain must take into account a possible degree of bias, since a number of parameters are involved in the computation of both elements of the correlation. | PMC10723770 |
Conclusions | Recruitment-to-inflation ratio assessed by reducing PEEP from 15 to 5 cm H | PMC10723770 | ||
Research Support | Support was provided solely from institutional and/or departmental sources. | PMC10723770 | ||
Competing Interests | Dr. Grieco has received payments for travel expenses from Getinge (Göteborg, Sweden), and personal fees from GE Healthcare (Chicago, Illinois), Intersurgical (Mirandola, Italy), Fisher & Paykel Healthcare (Auckland, New Zealand), and Merck Sharp & Dohme (Rahway, New Jersey). Dr. Maggiore is the principal investigator of the Re-intubation after nasal high-flow (RINO) trial ( | PMC10723770 | ||
Supplemental Digital Content | Supplementary Figure 1: Relationship between aerated lung size and respiratory system compliance and dynamic strain and driving pressure measured at low (Supplementary Figure 2: Respiratory system compliance, driving pressure, and PaSupplementary Table 1: Demographics and baseline characteristics of enrolled patients. Supplementary Table 2: Nonlinear fit of the relationship between recruitment-to-inflation ratio and positive end-expiratory pressure. | PMC10723770 | ||
Supplementary Material | The article processing charge was funded through the authors’ institution.This article is featured in “This Month in Anesthesiology,” page A1.This article is accompanied by an editorial on p. 719.Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (D.L.G. and G.P. contributed equally to this article. | PMC10723770 | ||
References | PMC10723770 | |||
1. Introduction | muscle mass, deaths | VIRUS | The COVID-19 pandemic limited older adults’ access to preventative and diagnostic services and negatively affected accessibility to age-appropriate exercise programs. The purpose of this study was to assess the feasibility of conducting guided virtual functional fitness assessments before and after participation in an 8-week virtual, live fitness program (Vivo) designed for older adults. It was hypothesized there would be no significant difference between in-person and virtual functional fitness assessments and function would improve following the program. Thirteen community-dwelling older adults were recruited, screened, and randomly assigned to in-person-first or virtual-first fitness assessment groups. Validated assessments were delivered using standardized scripts by trained researchers and included Short Physical Performance Battery (SPPB) balance, a 30 s Chair Stand Test, 8 Foot Up-and-Go Test, 30 s Arm Curl Test, and 2 min Step Test. The eight-week, twice-a-week live virtual fitness program involved cardiovascular, balance, agility, Dual-Task, and strength training. Results showed no significant differences between all but one assessment measures, and several measures improved following the eight-week program. Fidelity checks demonstrated the high fidelity of program delivery. These findings illustrate that virtual assessments can be a feasible method to measure functional fitness in community-dwelling older adults.In December of 2019, the SARS-Cov-2 virus, better known as COVID-19, rapidly spread across the world. The relationship of morbidity and mortality and COVID-19 among older adults has been thoroughly researched. Similar to the United States, the countries of Korea and Italy documented that over 80% of the deaths due to COVID-19 were in people aged ≥ 60 years [In addition to the COVID-19 pandemic, aging leads to many functional declines, including losses of muscle mass and muscle performance, characterized as a loss of muscle strength and power [Despite the well-known benefits of resistance training, only an estimated 8.7% of older adults in the United States meet the recommended amount of resistance training on a weekly basis [Fortunately, virtual fitness programs have provided opportunities to participate in physical activity from a person’s home and provide older adults with an accessible option to exercise that they may otherwise not have pursued. Costs for virtual fitness programs (i.e., internet access plans, webcams for computers/tablets) are similar to that of a fitness club (i.e., membership costs). However, there are limited published studies on the use of virtually delivered functional fitness assessments; yet, they have been promising [Therefore, the purpose of this study was to assess the feasibility of conducting virtual functional fitness assessments and an eight-week virtual fitness training program specifically developed for community-dwelling older adults with low-to-moderate activity levels ( | PMC10252352 |
2. Materials and Methods | PMC10252352 | |||
2.1. Participant Recruitment and Enrollment | RECRUITMENT | Approval for human subjects research was obtained by the Institutional Review Board of the lead researcher’s university prior to the study. A recruitment flyer was distributed to members of a membership-based village organization that assists older adults in maintaining independent living. Inclusion criteria included being 60 years of age and older, community-dwelling, not participating in resistance training twice a week during the past 6 months, and having a laptop or desktop computer with a camera and WiFi. Due to this being a sample of convenience, sample size for statistical power was not calculated for this study, but rather determined by interest and availability of members of the organization during the narrow time window of implementation. Additional participant recruitment and additional program offerings were not possible so it was deemed that sample size would be based on availability rather than statistical power.Prospective participants who indicated interest were scheduled for a two-step screening process, which started with a virtually hosted consent visit with the research team, where informed consent was obtained. The Physical Activity Readiness Questionnaire (PAR-Q+) was used to determine if it was safe for an individual to participate in the exercise program [Following the screening meeting, the participant was officially enrolled into the study and was randomized into one of two groups, which determined the order each participant would receive their pre-test and post-test assessments: virtual first, where participants completed their initial functional fitness assessment battery through a virtual appointment with a trained research staff member or in-person first, where participants completed their initial functional fitness assessment battery during an in-person appointment with a different set of trained research staff. Participants completed the second of their functional fitness assessment batteries between 48 and 72 h after the other assessment’s delivery format. The same order of assessment format for each participant was performed at post-test.Despite modifications made in terms of the set up and instructions to accommodate setting, ensuring participant understanding and safety, the virtual and in-person assessments that the participant performed were the same. All of the assessments were carried out using the same standardized script and were executed in the same order. The in-person and virtual assessments are explained in greater detail below. Participation in all phases of the project was voluntary and participants could drop out of the study at any time and for any reason.In total, 16 participants were initially enrolled into the study. Two did not finish the intervention period and one only completed 50% of the exercise sessions. Thirteen participants completed at least 70% of the exercise sessions and were assessed at both pre-test and post-test timepoints. Participants included ten females and three males with a mean age of 82.56 (±6.96) years and mean weight and height of 67.49 (±20.93) kg and 1.68 (±0.1073) m, respectively. Body mass index mean was 23.51 (±4.81) kg/m | PMC10252352 | |
2.2. In-Person Assessment Process | STAGGERED | Participants were scheduled for a 60 min assessment appointment in a multi-purpose room in a community center where the research team delivered all assessments following standardized communication scripts. Prior to the assessment appointment, the room was arranged for testing with consistent room temperature and lighting. Testing stations in the room were laid out in a sequenced manner around the perimeter of the room. Participants started by completing height and weight measurements using a calibrated scale and a wall stadiometer. Participants then progressed through the functional fitness assessments in the following order: SPPB balance tasks (1 trial for feet together, staggered stance (1 right-foot-forward and 1 left-foot-forward trial) and tandem stance conditions (1 right-foot-forward and 1 left-foot-forward trial), 30-Second Chair Stand Test (1 trial), 8 Foot Up-and-Go Test (Single Task—2 trials), 8 Foot Up-and-Go Test (Dual Task—1 trial), 30 s Arm Curl Test (1 trial), and 2 min Step Test (1 trial). See | PMC10252352 | |
2.3. Virtual Assessment Process | CREST, STAGGERED | Participants were virtually assessed via Zoom by different members of the research team than those who completed the in-person assessments in the same order that assessments were completed in the in-person format. Height and weight were not measured virtually. Researchers utilized the same commonly used, validated assessments listed above to an online administration at the start of COVID-19 with minimal disruption. Each assessment session lasted approximately 60 min in duration. Prior to the virtual assessment, participants were emailed standardized instructions, including equipment needed for the assessments and setup instructions detailing directions for each assessment. Participants were mailed a testing kit, which included a tape measure to accurately measure the distance for the 8 Foot Up-and-Go Test and to measure the midpoint of thigh for the 2 min Step Test, and two resistance bands to perform the 30-Second Arm Curl Test in case dumbbells were not available. At the beginning of the assessment, the assessor ensured proper positioning of the computer and camera, including lighting and sound, and then surveyed the space for trip hazards, ensuring a safe environment for the assessment and for the fitness program. The computer video was positioned so that the assessor could observe the participant performing the full range of motion for each movement, count the number of repetitions and/or keep time, and ensure participant safety. Demonstrations of the movements were performed by the assessor when the assessments were not performed correctly. Participants began the virtual assessment by being guided by a trained assessor on the research team through the SPPB balance tasks (1 trial for feet together), staggered stance (1 right-foot-forward and 1 left-foot-forward trial) and tandem stance conditions (1 right-foot-forward and 1 left-foot-forward trial), 30 Second Chair Stand Test (1 trial), 8 Foot Up-and-Go Test (Single Task—2 trials), 8 Foot Up-and-Go Test (Dual Task—1 trial), and 30 s Arm Curl Test (1 trial), where females were encouraged to use a 5 lb dumbbell and males an 8 lb dumbbell. If dumbbells were not present, a resistance band of light or medium resistance was used. Lastly, participants completed the 2 min Step Test (1 trial). Vital signs were not performed during this test. This test required participants to find a space in the house in front of a wall or door where they had enough room to march in place. Using detailed instructions, including pictures, and with oversight from the assessor on camera to confirm proper measurement while on camera, the participant measured the midpoint of their thigh, half way between the top of their iliac crest and the middle of the patella. A piece of tape was placed on the participant’s thigh, indicating the midpoint. Then, the participant walked over the flat surface (wall or door), placing the thigh with the piece of tape nearest to the surface. The participant then transferred the piece of tape from their thigh to the wall at the same height indicating the midpoint of the participant’s thigh and the height at which to lift the knee during the assessment. The assessor used a handheld counter to count the number of times the right knee was lifted to the height of the tape mark during the two minutes. Additional assessment details can be found in | PMC10252352 | |
2.4. Implementation of the Virtual Fitness Training Program | The virtual fitness training program was delivered by Vivo (The 8-week fitness program consisted of two 45 min sessions per week. Sessions were delivered via Zoom. Each session consisted of a 15 min warm up involving cognitive dual tasks, dynamic mobility exercises for the ankle, hip, spine, and shoulders, and balance exercises; three sets of three to five strength- or cardio-based exercises; and a 10 min cool down involving full-body dynamic stretching. Each exercise included variations ranging from level 1 to level 4 for participants to choose based on their comfortability or fitness level, and this allowed trainers to provide an individualized experience to each participant. The American College of Sports Medicine recommends that activity intensity for older adults be defined relative to an individual’s fitness within the context of perceived physical exertion [ | PMC10252352 | ||
2.5. Assessment of Exercise Fidelity | Fitness training program fidelity was monitored via four live or recorded exercise sessions. Researchers evaluated the class elements based on an observation checklist in order to assess the effectiveness of program delivery of each of the trainers. Fidelity checks included critiques of the trainers’ level of preparedness in gathering materials prior to the session; the clarity of their overview of the workout; effective delivery of the warmup, workout, as well as cool down; and their positive encouragement of participants during the session. Researchers determined a final fidelity score out of 26 based on the total number of boxes checked. Each of the four exercise classes were checked for fidelity by two independent observers and scored above a 22 on both checklists, indicating excellent fidelity. | PMC10252352 | ||
2.6. Statistical Analysis | Descriptive statistics were calculated to summarize all dependent variables and two-tail dependent t-tests were conducted to determine if differences existed between in-person and virtual assessment variables. Additionally, one-tailed dependent t-tests were performed to determine if differences existed between pre-test and post-test timepoints for in-person functional fitness assessment measures. A probability value of ≤0.05 was used to determine significance. Based on calculated attendance, only participants who attended 70% or more of the training sessions were included in the data analyses. | PMC10252352 | ||
3. Results | PMC10252352 | |||
In-Person and Virtual Functional Fitness Assessments | In-person and virtual functional fitness assessment measures for both pre- and post-test are shown in Significant differences were found in several of the in-person functional fitness assessments when comparing pre-test to post-test timepoints. Both lower and upper-body strength improved as measured by the 30 s Chair Stand Test (11.08 ± 2.25 versus 13.15 ± 2.12 repetitions, | PMC10252352 | ||
4. Discussion | anxiety | ADVERSE EVENTS | Functional fitness measures are commonly used in clinical and research settings to determine one’s functional abilities. With COVID-19 and the need to socially distance and isolate, alternative ways to conduct these measurements were necessary, as coming into a clinic or a research facility may not have been an option. While the research on the validity of virtual assessments compared to in-person assessments has been limited, our primary finding supports that virtual assessments can successfully obtain fitness measures for participants. In-person assessment may be the gold standard of fitness testing, but the advantages of virtual assessments should not be overlooked. Some of the benefits include reduced travel time to/from a clinic or research facility and decreased anxiety of visiting a hospital or facility that may be crowded or difficult to navigate. Live virtual assessments still are 1:1 interactions between the assessor and the participant and give uninterrupted time for the participant to ask questions, build rapport between the parties, and give the assessor an opportunity to observe the participant’s home environment, which may reveal potential hazards or suboptimal arrangements [The disadvantages of virtual assessments include the difficulty of ensuring the exact procedures. Detailed instructions help to describe the assessments, provide illustrations and step-by-step set-up procedures, and provide guidance on how the assessment will be performed. The assessor must be well-trained to ensure proper set-up and closely monitor the participant’s movement throughout the assessment for proper scoring. However, with preparation, this study clearly demonstrates that virtual assessments are feasible and can be conducted with high success rates.When comparing the in-person with the virtual assessment variables at matching timepoints, this study found that only the 2 min Step Test at pre-test was significantly different. While the setup and instructions for the assessments were the same, there were significantly more steps taken in the in-person modality to ensure proper set up and understanding than the virtual modality. There has been excellent intra- and inter-reliability demonstrated when previous research has delivered the 2 min Step Test in person [During COVID-19, virtual exercise training provided a method of keeping older adults physically active and engaged. As previously mentioned, the COVID-19 pandemic led to a decrease in physical activity in older adults due to several barriers, but especially due to the lack of in-person fitness training opportunities, as gyms and other facilities were closed. The results of this study show it is feasible to deliver a virtual fitness training to community-dwelling older adults and achieve improvements in overall functional fitness from baseline to post-assessment measurements. Virtual fitness training programs have benefits that should not be overlooked, including increased accessibility and convenience, social engagement through camera and microphone features on video meeting platforms such as Zoom, and individualized attention from a certified fitness professional. Participants indicated that the program of choice for this study, Vivo (A recent meta-analysis examining training programs for functional fitness in older adults, with a wide range of durations ranging from six months to over two years, showed overall improvements in muscle strength and lower-body strength [Findings from this study suggest that virtual functional fitness measures are feasible in older adults and are comparable to in-person functional assessments. While safety of participants and technological issues are primary concerns with virtual programming, this study resulted in minimal technological problems and no reported adverse events. A limitation of this study was that the program was delivered to a sample of older adults living in a higher-income suburb of a large American city. There are known to be associations between access to technology, utilization of virtual healthcare, advancing age, rural residency, and lower socioeconomic status [Additionally, the small sample size and short duration of the study may explain why some functional measures approached clinically meaningful changes and others did not. Future studies of larger size and longer duration should explore factors that may influence meaningful changes in these assessments. Another limitation of this study may have been related to the participant selection. Those who volunteered for the virtual fitness training program, may have been more confident in their technology abilities and therefore, more likely to be successful in the study. Future studies may consider expanding the inclusion criteria to include those with a wide range of technology abilities to help determine the successful delivery of virtual assessments and virtual fitness training in older adults. | PMC10252352 |
5. Conclusions | The COVID-19 pandemic provided an opportunity to determine the feasibility of utilizing virtual functional fitness assessments when in-person functional fitness assessments were not an option. This study successfully delivered virtual functional fitness assessments, showing no difference between them and the in-person functional fitness assessments except for the baseline 2 min Step Test measurement. This study also showed functional improvements in several aspects of functional fitness following 8 weeks of the virtual fitness training program. | PMC10252352 | ||
Author Contributions | Conceptualization, C.T., K.N.P.S. and E.C.K.; methodology, C.T.; software, C.T., J.C., E.J. and J.P.; validation, C.T., J.C, E.J. and J.P.; formal analysis, C.T., J.C., E.J. and J.P.; writing—original draft preparation, C.T., J.C., E.J. and J.P.; writing—review and editing, K.N.P.S. and E.C.K.; funding acquisition, C.T. All authors have read and agreed to the published version of the manuscript. | PMC10252352 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of University of San Francisco (protocol code 1790, 7 August 2023). | PMC10252352 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10252352 | ||
Data Availability Statement | Data and data analyses are available and may be reviewed by following this Google Drive link and then requesting access by contacting Christian Thompson at | PMC10252352 | ||
Conflicts of Interest | Thompson and Starr are scientific advisors for Vivo and Kemp is an employee of Vivo, and they were in these roles at the time of research and analysis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10252352 | ||
References | Functional fitness assessment measures.In-person and virtual assessment descriptive statistics for all subjects (n = 13).Note: * indicates significant difference (≤0.05) between pre-test and post-test measurements. | PMC10252352 | ||
Background | hypotensive, Postoperative cognitive dysfunction | HYPOTENSIVE, COMPLICATION | Postoperative cognitive dysfunction is a noteworthy complication of deliberate hypotensive anesthesia. The aim of this work was to compare the effect of deliberate hypotensive anesthesia using nitroglycerine versus phentolamine on event-related potentials and cognitive function in patients undergoing septoplasty surgery. | PMC10155363 |
Methods | This prospective randomized controlled trial was conducted on 80 patients indicated for septoplasty under general anesthesia; 40 patients received intra-operative Nitroglycerine and 40 patients received intra-operative Phentolamine. Cognitive assessment (using Paired Associate Learning test (PALT) and Benton Visual Retention test (BVRT)) and P300 recording were done for all included patients pre-operatively and one week postoperatively. | PMC10155363 | ||
Results | The scores of PALT and Benton BVRT significantly declined one week following surgery in both Nitroglycerine and Phentolamine groups. There was no statistically significant difference between Nitroglycerine and Phentolamine groups in the postoperative decline in either PALT or BVRT (P-value = 0.342, 0.662 respectively). The values of P300 latency showed a significant delay one week following surgery in both Nitroglycerine and Phentolamine groups (P-value ≤ 0.001, 0.001), but in Nitroglycerine group, the delay is significantly higher than in Phentolamine group (P-value = 0.003). The values of P300 amplitude significantly decreased one week following surgery in both Nitroglycerine and Phentolamine groups (P-value ≤ 0.001, 0.001), but there was no statistically significant difference between Nitroglycerine and Phentolamine groups (P-value = 0.099). | PMC10155363 | ||
Conclusion | hypotensive | HYPOTENSIVE | Phentolamine is preferred over nitroglycerin in deliberate hypotensive anesthesia because it has less harmful effect on cognitive function than nitroglycerin. | PMC10155363 |
Keywords | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10155363 | ||
Introduction | POCD, hypotensive, hypotension, Postoperative cognitive dysfunction | HYPOTENSIVE, VASODILATATION | Postoperative cognitive dysfunction (POCD) has gained much attention in the past years. Despite the great strides in anesthesia and surgical techniques over the past decades, POCD is still highly prevalent [Deliberate hypotensive anesthesia is necessary during maxillofacial and septoplasty surgery for drying surgical field, ease in operation procedure and shortening of the duration of surgery. However, deliberate hypotensive anesthesia is associated with increased risk of impaired perfusion to important organs, such as the brain [The mechanism of the hypotensive action of phentolamine is mediated through its nonselective α-adrenergic antagonist activity, resulting in a decrease in peripheral vascular resistance and vasodilatation. [Neuropsychological tools are classically used to investigate POCD. The optimal cognitive battery is one that includes highly sensitive different tests, each targeting a specific cognitive area [This work aimed to compare the effect of deliberate hypotensive anesthesia using nitroglycerine versus phentolamine on ERPs and cognitive function in patients undergoing septoplasty surgery to select the most appropriate agent to induce hypotension. | PMC10155363 |
Methods | PMC10155363 | |||
Study design and population | MAY | This prospective randomized controlled trial was conducted on 80 patients indicated for septoplasty under general anesthesia. Patients were randomly assigned into one of two groups; the first group (40 patients) received intra-operative Nitroglycerine (Nitroglycerine group) and the second group (40 patients) received intra-operative Phentolamine (Phentolamine group). Randomization was carried out using a closed opaque envelope technique where the physician picked up a sealed envelope containing a card having the name of the group to which the patient was randomly selected. Whatever group was written on the card, the patient was scheduled to it.The patients were recruited from Otorhinolaryngology surgery department, Beni-Suef University Hospital, from January 2020 to May 2021. The study was registered in ClinicalTrials.gov on 1/10/2019, and this is the identification number NCT04110808. | PMC10155363 | |
Eligibility criteria | allergic, mean arterial blood pressure, hypotension, metabolic illness, hypotensive, visual or auditory dysfunction | HYPOTENSIVE, NEURODEGENERATIVE DISORDER | The study included American Society of Anesthesiologists I, II (ASA I, II) patients who were candidate for septoplasty. The age range was between 20 and 50 years. The following patients were excluded from the study: patients who developed intraoperative hypotension with mean arterial blood pressure (MAP) less than 60 mmHg, patients with a history of neurodegenerative disorder, patients with a concomitant medical or metabolic illness known to affect cognition, patients with visual or auditory dysfunction that might affect their ability to respond to cognitive assessment, and patients who were allergic to any of the anesthetic or hypotensive drugs used in the study. | PMC10155363 |
Neurophysiological assessment | head movements | P300 recording was done for all included patients pre-operatively and one week postoperatively by an expert neurophysiologist who was blinded to the intraoperative drugs used. The used device was Galileo Series preamplifiers acquisition system (EBN, Florence, Italy). Bioelectrical activity of the brain was recorded by using gold electrodes and a conductive EEG paste (Elefix). Three active electrodes were positioned at the central line of the scalp frontally (Fz), centrally (Cz), and parietally (Pz) according to the international 10–20 system. While reference electrodes were placed on the earlobes, the ground electrode was positioned at the forehead. Impedance of all electrodes in all recordings was under 5 kΩ. The patients were instructed to keep their eyes closed and avoid head movements in order to reduce eye and muscle artifacts during P300 recording. All participants underwent auditory oddball paradigm task testing. They were instructed to listen to the series of tones with closed eyes. The auditory stimuli were pure tones presented binaurally at random intervals ranging between 3 and 4 s. All tones were 100 ms in duration with a rise–fall time of 10ms and were adjusted in intensity to a 70-dB sound pressure level. The pitches of frequent (standard) and infrequent (target) tones were 1000 and 3000 Hz, respectively, with a total number of 200 tones and a presentation probability for the infrequent tones of (0.2). The patients were asked to identify the infrequent tones in one task by raising the right index finger of the dominant hand in response to the infrequent tones as targets during 15-minute session.The ERP data were averaged with the sweep beginning 100 ms before the stimuli and lasting until 900 ms after stimulus onset in a common average montage containing 3 channels of midline electrode locations Fz, Cz, and Pz according to the international 10–20 system of EEG electrode placement. The P300 latency was identified as the largest positive peak at range of 250–700 ms occurring after the N1, P2, and N2 ERP components obtained from the ‘‘target’’ stimulus presentation. The peak amplitudes were evaluated as the differences between the P300 peak and the mean baseline automatically calculated by a computer [ | PMC10155363 | |
Anesthetic technique | hypotensive, hypotension | HYPOTENSIVE, MUSCLE RELAXATION | At the operating room, standard patient monitoring was established (electrocardiography, pulse oximetry, end-tidal carbon dioxide (ET CO2 ), and noninvasive arterial blood pressure monitoring). Two intravenous cannulas were placed; 18 and 20 gauge.Induction of anesthesia was done by injecting 2 mg/kg propofol, 2 µg/kg fentanyl & 0.5 mg/kg atracurium. The patients were ventilated via face mask with 100% oxygen at a rate of 6 L/min and isoflurane 1.2%. After few minutes, the patients were intubated using a cuffed oral tube. Maintenance of anesthesia was done using isoflurane 1.2% in a mixture of 70% oxygen and 30% air. Muscle relaxation was continued with atracurium 0.1 mg/kg every 20 min. All patients were mechanically ventilated to maintain ET CO2 between 35 and 40 mmHg. An intra-arterial canula was inserted in the radial artery for invasive arterial blood pressure monitoring.The patients were randomly allocated to one of the two groups; either Phentolamine or Nitroglycerine groups. In Phentolamine group (40 patients), the patients received deliberate hypotensive anesthesia with phentolamine infusion via syringe pump by adding 20 mg (2ml) of Phentolamine to 48 ml of normal saline, making it to a final concentration of 0.4 mg/ml at the rate of 0.1-2 mg/min according to the patients desired target blood pressure. In Nitroglycerine group (40 patients), the patients received deliberate hypotensive anesthesia with nitroglycerine infusion via syringe pump by adding 10 mg (10ml) of Nitroglycerin to 40ml of normal saline, making it to a final concentration of 200 µg/ml at the rate of 0.5–10 µg/kg/min according to the patients desired target blood pressure.MAP was gradually reduced in both groups to maintain a target MAP of 60–70 mmHg and systolic blood pressure ≥ 85 mmHg. Patients who developed hypotension (MAP less than 55 mmHg) were managed by discontinuation of the hypotensive drug and administration of intravenous fluid. Ephedrine (10 mg) was given IV when the MAP did not improve, and these patients were excluded from the study.Infusion of the hypotensive agent was stopped 10 min before the anticipated end of surgery. Any residual neuromuscular block was antagonized with neostigmine 0.04 mg/kg and atropine 0.02 mg/kg IV. The patients were extubated after fulfilling the criteria of recovery and transferred to the recovery room. | PMC10155363 |
Sampling | hypotensive | HYPOTENSIVE | Because our study was the first study to compare the effect of deliberate hypotensive anesthesia using nitroglycerine versus phentolamine on P300, we calculated the sample size based on the results of a pilot study we performed before starting our study. The sample size calculation was done using G*Power version 3.1.9.7 Software. The probability of type I error (α) was 5%, effect size = 0.821, df = 78, critical t = 1.99, noncentrality parameter λ = 3.673, A total sample size of 40 patients in each group was required to achieve a statistical power (1–β) 95%. | PMC10155363 |
Statistical analysis | IBM SPSS (Statistical Package of Social Science) Version 25 was used to analyze the data. Categorical variables such as sex were expressed as numbers and percentages. Quantitative variables such as age, years of education, PALT, BVRT, P300 latency, and amplitude were expressed as the median and interquartile range (IQR). Chi-squared test was used for comparison between Nitroglycerine and Phentolamine groups in sex, whereas Mann-Whitney test was used for comparison between Nitroglycerine and Phentolamine groups in age, years of education, PALT, BVRT, P300 latency, and amplitude. Wilcoxon test was used to compare pre and post-operative PALT, BVRT, P300 latency, and amplitude in each of Nitroglycerine and Phentolamine groups. A mixed ANOVA test was used to compare pre and post-operative PALT, BVRT, P300 latency, and amplitude in Nitroglycerine versus Phentolamine groups. P-value ≤ 0.05 was considered statistically significant. All tests were two-tailed. | PMC10155363 | ||
Results | PMC10155363 | |||
Demographics, preoperative psychometric tests, and P300 latency and amplitude | Visual Retention | This prospective randomized controlled trial was conducted on 80 patients indicated for septoplasty under general anesthesia. Forty patients received intra-operative Nitroglycerine (Nitroglycerine group), and 40 patients received intra-operative Phentolamine (Phentolamine group). Consort flow diagram is illustrated in Fig. (1). The median value for age in the Nitroglycerine group was 29 years with IQR (25.25-35) years, and in the Phentolamine group was 33.5 years with IQR (27–38) years. 20 (50%) patients in the Nitroglycerine group were males, and 20 (50%) were females. Whereas 25 (62.5%) patients in the Phentolamine group were males and 15 (37.5%) were females. There was no statistically significant difference between both groups in either age or sex (P-value = 0.193, 0.26 respectively) (Table
CONSORT 2010 Flow Diagram
Demographics, pre-operative psychometric tests, and pre-operative P300 latency and amplitude in patients in Nitroglycerine and Phentolamine groupsPre-operative PALT[Median (IQR)]Values are expressed as median (Q1-Q3), number (%)PALT: Paired Associate Learning Test, BVRT: Benton Visual Retention TestMann-Whitney test was used for comparison between quantitative variables, Chi-squared test was used for comparison between categorical variables, P-value > 0.05 is considered in-significant | PMC10155363 | |
Effect of nitroglycerine versus phentolamine on the scores of psychometric tests | Visual Retention, groups,*P-value ≤ | The scores of PALT significantly declined one week following surgery in both Nitroglycerine and Phentolamine groups (P-value = 0.034, 0.018 respectively). Also, the scores of BVRT significantly declined one week following surgery in both Nitroglycerine and Phentolamine groups (P-value = 0.013, 0.025 respectively). There was no statistically significant difference between Nitroglycerine and Phentolamine groups in the postoperative decline in either PALT or BVRT (P-value = 0.342, 0.662 respectively) (Table
Pre and post-operative psychometric tests in patients in Nitroglycerine and Phentolamine groupsValues are expressed as median (Q1-Q3)PALT: Paired Associate Learning Test, BVRT: Benton Visual Retention TestWilcoxon test was used for comparison between pre and post-operative quantitative variables, Mixed ANOVA test was used for comparing pre and post-operative quantitative variables in the two groups,*P-value ≤ 0.05 is considered significantThere were no statistically significant differences between Nitroglycerine and Phentolamine groups in the percent of change in either PALT or BVRT (P-value = 0.689, 0.675 respectively) (Table
Percent of change in PALT and BVRT in both Nitroglycerine and Phentolamine groupsPercent of change in PALT[Median (IQR)]Values are expressed as median (Q1-Q3)PALT: Paired Associate Learning Test, BVRT: Benton Visual Retention TestMann-Whitney test was used for comparison between Nitroglycerine and Phentolamine groupsP-value > 0.05 is considered in-significant | PMC10155363 | |
Effect of nitroglycerine versus phentolamine on P300 latency and amplitude | groups,*P-value ≤ | The values of P300 latency showed a significant delay one week following surgery in both Nitroglycerine and Phentolamine groups (P-value ≤ 0.001, 0.001), but in Nitroglycerine group, the delay is significantly higher than in Phentolamine group (P-value = 0.003). The values of P300 amplitude significantly decreased one week following surgery in both Nitroglycerine and Phentolamine groups (P-value ≤ 0.001, 0.001). There was no statistically significant difference between Nitroglycerine and Phentolamine groups in the postoperative decrease in P300 amplitude (P-value = 0.099) (Table
Pre and post-operative P300 latency and amplitude, in patients in Nitroglycerine and Phentolamine groupsValues are expressed as median (Q1-Q3)Wilcoxon test was used for comparison between pre and post-operative quantitative variables, Mixed ANOVA test was used for comparing pre and post-operative quantitative variables in the two groups,*P-value ≤ 0.05 is considered significantThe percent of change in P300 latency was significantly higher in Nitroglycerine group in comparison to Phentolamine group (P-value ≤ 0.001), but there was no statistically significant difference between Nitroglycerine and Phentolamine groups in the percent of change in P300 amplitude (P-value = 0.482) (Table
Percent of change in P300 latency and amplitude in both Nitroglycerine and Phentolamine groupsValues are expressed as median (Q1-Q3)Mann-Whitney test was used for comparison between Nitroglycerine and Phentolamine groups*P-value ≤ 0.05 is considered significant | PMC10155363 | |
Discussion | cerebrovascular insufficiency, neuroapoptosis, cerebral hypoperfusion, stroke, POCD, hypotensive, cognitive domain | CEREBROVASCULAR INSUFFICIENCY, NEURODEGENERATION, STROKE, BRAIN, HYPOTENSIVE, CORTEX | Since deliberate hypotensive anesthesia is appropriate for patients who will undergo certain surgical procedures, including septoplasty surgery[In the presence of contradictions in the results of previous studies, whether or not hypotensive anesthesia causes POCD [It is well-established that temporal lobe structures, especially the CA1 region of the hippocampus, are one of the most susceptible brain regions to cerebral hypoperfusion [Noteworthy, the results of neuropsychological tests might be confounded by some participant-related factors, including educational level, emotional state, and visual/auditory functions [As far as we know, this study is the first to investigate the effect of deliberate hypotensive anesthesia on Event-related potentials. Brain regions, such as the frontal cortex and the hippocampus, generate the P300 wave [Information processing speed is another cognitive domain commonly affected in POCD other than memory [Cerebral autoregulation is a compensatory mechanism that maintains cerebral blood flow constant despite a change in cerebral perfusion pressure (CPP) due to the effect of hypotensive agents on systemic vascular resistance [It has to be mentioned that the reported POCD in our study may be attributed to the use of general anesthetic drugs. There is strong evidence suggesting the implication of general anesthetics in developing POCD. General anesthetics such as propofol and isoflurane were reported to cause neurodegeneration, neuroapoptosis, caspase activation, and B- amyloid protein accumulation, leading to POCD [Previous studies claimed that nitroglycerin causes an increase in ICP [Whereas nitroglycerin is used broadly in multiple clinical practices in neurological and stroke intensive care units, our study implores limiting its use in anesthesia in neurologically affected patients, especially old age patients with cerebrovascular insufficiency giving chances to other hypotensive drugs in those patients.Lastly, it should be noted that the relatively small sample size and cognitive follow-up for a relatively short period are the most critical limitations of the current study. Further studies with larger sample sizes and more extended follow-up periods are warranted. | PMC10155363 |
Acknowledgements | Not applicable. | PMC10155363 | ||
Authors’ Contributions | MH, RS | WF participated in study design, collection and interpretation of data and helped to draft the manuscript. MH participated in study design, analysis and interpretation of data and helped to draft the manuscript. RM participated in study design, analysis and interpretation of data and helped to draft the manuscript. HS participated in study design, neurophysiological assessment and helped to draft the manuscript. HE participated in study design, collection and interpretation of data and helped to draft the manuscript. AM participated in neurophysiological assessment and helped to draft the manuscript. RS participated in neurophysiological assessment and helped to draft the manuscript. ME participated in neurophysiological assessment and helped to draft the manuscript. MF participated in study design, collection and interpretation of data and helped to draft the manuscript. DK participated in study design, collection and interpretation of data and helped to draft the manuscript. All authors read and approved the final manuscript. | PMC10155363 | |
Funding | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10155363 | ||
Data Availability | Authors report that the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10155363 | ||
Declarations | Authors report that the content has not been published or submitted for publication elsewhere. | PMC10155363 | ||
Competing interests | Authors have no competing interest. | PMC10155363 | ||
Ethics approval and consent to participate | Written informed written consent was signed from all participants. The study was performed in agreement with the Declaration of Helsinki. Ethical approval for this study was obtained from the Research ethical committee of Beni-Suef University. The ethical committee approval number is FMBSUREC/31032019/HUSSEIN. | PMC10155363 | ||
Consent for publication | Not applicable. | PMC10155363 | ||
References | PMC10155363 |
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