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Study protocol | brachial plexus block | STERILE, PERIOSTEUM | The surgical procedure was as follows: after the patient was brought to the anaesthesia preparation room, the venous channel was opened, and electrocardiogram, oxygen saturation values and blood pressure were monitored. All operations were performed under ultrasound guidance. Patients were grouped by anaesthesiologist: medical staff randomly allocated the patients into group I (SCPB and CPB) or group II (SCPB and ISBP) and placed the details of this group allocation in an envelope. Neither the patient nor the later researchers were aware of the group information. A nurse anaesthetist opened the envelope after obtaining the patient’s consent and then prepared regional anaesthesia drugs. All regional anaesthesia procedures were performed by the same anaesthesiologist.
Superficial cervical plexus block (SCPB): The patient was placed in a supine position with the head turned to the contralateral side for adequate exposure of the neck and the upper chest. The skin of the neck was disinfected by antiseptic solution. A linear high-frequency ultrasound probe (6–13 MHz, Sonosite) was placed at the lateral side of the neck over the midpoint of the sterno-cleido-mastoid muscle at the level of cricoid cartilage, which corresponds with the C6 transverse apophysis and its characteristic anterior tubercle. Once the muscle was identified, the probe was then moved posteriorly until the posterior tapering edge of the muscle was identified where the interscalene groove between the anterior and middle scaleni muscles was identified. Then, the superficial cervical plexus (SCP) was visualized just superficial to the prevertebral fascia overlying the interscalene groove. A five-cm block needle was then introduced from lateral to medial using the posterior-in-plane technique until its tip was placed near the SCP above the prevertebral fascia. After careful negative aspiration to exclude intravascular placement, 7 mL of 0.5% ropivacaine was deposited.Clavipectoral fascial plane block (CPB): The patient was placed in a supine position with the head turned to the contralateral side, and the shoulder was padded with a small pillow. Under sterile aseptic conditions, a 6- to 13-MHz linear array probe was used for regional anaesthesia. A local anaesthetic solution of 20 mL 0.5% ropivacaine was used for regional anaesthesia. During CPB, an ultrasound probe was placed on both the inner and outer one-third of the anterior surface of the clavicle. Using the in-plane technique, a 22-gauge needle was inserted and advanced into the space between the periosteum of the clavicle and clavipectoral fascia in a caudal to cephalad direction, and a total of 20 mL of 0.5% ropivacaine was equally injected medially and laterally. The ultrasound landmarks and the in-plane needle path are shown in Fig. Ultrasound image of clavipectoral fascial plane block
A 20-G needle was inserted using the in-plane technique from the caudal to cephalic direction.Ropivacaine was injected between the periosteum of the clavicle and the surrounding fascia.The spread of the local anaesthetic.
Interscalene brachial plexus block (ISBP): The patient was placed in a supine position with the head turned to the contralateral side, and the shoulder was padded with a small pillow. Under sterile aseptic conditions, a 6- to 13-MHz linear array probe was used for regional anaesthesia. To perform ISBP, the high-frequency probe was positioned at the level of cricoid cartilage to visualize the brachial plexus between the anterior and middle scalene muscles. ISBP was performed with a 21-gauge short bevel needle using an in-plane technique. A total of 20 mL of 0.5% ropivacaine was injected into every 5-mL aliquot after negative aspiration, and the needle was adjusted to achieve its spread between the C5 and C6 nerve roots.A nurse anaesthetist (blinded to the patient allocation group) was responsible for evaluating the scale, recording research data and postoperative follow-up. The effect of the block was measured at 30 min in three areas: the sternoclavicular joint, midclavicle and acromioclavicular joint. If the effect was poor, the patient was changed to general anaesthesia and withdrawn from the study. At the beginning of the surgery, all patients were administered 0.05 mg/kg of midazolam. | PMC10371927 |
Outcomes measurement | postoperative pain | PARTIAL PARALYSIS, SECONDARY, DIAPHRAGM | The primary observation outcome was the time of first use of analgesics. Whenever postoperative pain scores were above 4, 50 mg parecoxib sodium was administered intravenously.As a secondary outcome, the effect of the block was measured at 30 min in three areas: sternoclavicular joint, midclavicular and acromioclavicular joint. Four levels were established: zero indicated no decreased sensation, one indicated decreased sensitivity to puncture, two indicated no sensitivity to puncture, and three indicated no tactile sensitivity. Values two and three were assessed as correct blocks. Modified Bromage scale (MBS) scores [Real-time M-mode ultrasonography of the hemidiaphragmDiaphragmatic movement was evaluated by real-time M-mode ultrasonography of the hemidiaphragm (sigh test), and diaphragm movement was reduced by 71%, suggesting partial paralysis of the diaphragm.
Diaphragm movement is 6.63 cm from baseline measured by M-mode ultrasound before the block.Diaphragm movement is 1.92 cm from baseline measured by M-mode ultrasound 30 min after the block. | PMC10371927 |
Statistical analysis | The primary outcome of this study was the time of the first postoperative analgesia. After reviewing the relevant literature [We used SPSS version 26.0 for the data analysis. Normally distributed data are expressed as the mean ± standard deviation, with two independent sample t tests. Count data are expressed as the rate (%). Grade data were analysed using the Mann–Whitney U test and are expressed as the median (M) and interquartile range (IQR). A | PMC10371927 | ||
Results | PMC10371927 | |||
The VAS pain scores | pain | The VAS pain scores at 6 and 12 h were not different between the two groups; however, the VAS pain score at 24 h in group I was lower than that in group II (P < 0.01) (Table | PMC10371927 | |
Hemidiaphragmatic excursion during the sign test | paresis, hemidiaphragmatic paresis | PARESIS | Diaphragmatic movement was evaluated by real-time M-mode ultrasonography of the ipsilateral hemidiaphragm. Patients were examined in an upright seated position. The range of diaphragmatic movement from the resting expiratory position to deep inspiration (sigh test) was recorded before and 30 min after the block. The baseline preblock diaphragm movement was 5.9 ± 1.2 cm and 6.2 ± 1.1 cm in group I and group II, respectively, and the diaphragm movement was 5.6 ± 1.2 cm and 2.3 ± 0.9 cm in group I and group II, respectively, after 30 min of block. The reduction in diaphragmatic movement in group II was significantly less than that in group I (P < 0.01). The incidence of hemidiaphragmatic paresis in group II was 92%, but no paresis was observed in group I (Table
Hemidiaphragmatic excursion during the sigh testData are expressed as the mean ± standard deviation
| PMC10371927 |
Adverse reaction | haemothorax, nerve injury, Horner syndrome | HAEMOTHORAX, HORNER SYNDROME, LOCAL ANAESTHETIC SYSTEMIC TOXICITY, PNEUMOTHORAX | There were no reports of local anaesthetic systemic toxicity, nerve injury, pneumothorax, haemothorax, high epidural block, or total spinal anaesthesia. However, 3 patients in group II developed Horner syndrome (Table | PMC10371927 |
Discussion | critically ill, hemidiaphragmatic, Pain, fracture, pain, fractures | ADVERSE REACTIONS, CRITICALLY ILL | In 2017, Valdés first proposed the regional anaesthesia technique CPB at the 36th European Society of Regional Anesthesia & Pain Therapy (ESRA) Symposium. Under the guidance of ultrasound, 10–15 mL of local anaesthesia was injected between the clavipectoral fascia and the superior aspect of the clavicle. Several case studies have confirmed that CPB can be used for anaesthesia and postoperative analgesia in clavicular surgery [In this study, the primary observation outcome was the time of first use of analgesics. The results of our study show that the first analgesic use in group I was 20 ± 5.8 h, which was significantly longer than that in group II, indicating that SCPB combined with CPB has longer analgesia. Leurcharusmee [There was no significant difference in the effect scores in the sternoclavicular joint, midclavicle and acromioclavicular joint between the two groups 30 min after the block. The results show that the effects of the two kinds of regional anaesthesia are very good, and our results were consistent with the results of Ince [Although SCPB combined with ISBP can provide sufficient analgesia in clavicle surgery, it can lead to serious adverse reactions, such as hemidiaphragmatic paresis[This study has several limitations. First, clavicle fractures are divided into proximal, middle and distal fractures according to the fracture site and are nondisplaced, displaced and comminuted. In this study, the effects of different fracture sites and fracture types were ignored. Second, since clavicle fractures are often common in young and middle adults, most of the cases included were nonelderly patients with good physical function. Therefore, its clinical application in elderly or critically ill patients is worthy of further exploration. Third, this study found that most patients prefer not to stay awake during surgery. They believed that even if they did not feel pain during the operation, they still felt anxious and afraid. Therefore, we suggest that some sedative drugs, such as dexmedetomidine, should be introduced into clinical practice to increase the comfort of patients. | PMC10371927 |
Acknowledgements | Assistance with the study: We would like to thank Dr. Bing Cai, Senior Consultant Anaesthesiologist, for his assistance with the study and Dr. Peng Su for statistical assistance. | PMC10371927 | ||
Author contributions | All authors contributed to the study conception, design, material preparation, data collection and analysis. The first draft of the manuscript was written by GX. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work study. | PMC10371927 | ||
Funding | We received research support from The Sichuan Academy of Medical Sciences Sichuan Provincial People’s Hospital 2021 Clinical Application New Technology Project (Grant No: 202168), Medico-Engineering Cooperation Funds from University of Electronic Science and Technology of China (ZYGX2021YGLH221) and Sichuan Provincial People’s Hospital Young Talent Fund (Grant No: 2022QN07). | PMC10371927 | ||
Data Availability | The data that support the findings of this study can be obtained from the corresponding author upon reasonable request. | PMC10371927 | ||
Declarations | PMC10371927 | |||
Conflict of interest | The authors have no relevant financial or nonfinancial interests to disclose. | PMC10371927 | ||
Ethical approval | This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Institutional Review Board of Sichuan Provincial People’s Hospital on 27 Nov 2020. | PMC10371927 | ||
Consent to participate | Written informed consent was obtained from all individual participants included in the study. | PMC10371927 | ||
Consent to publish | Not applicable. | PMC10371927 | ||
References | PMC10371927 | |||
Methods | Pain, knee osteoarthritis, KOA | KNEE OSTEOARTHRITIS | Edited by: Yun Shen, Pennington Biomedical Research Center, United StatesReviewed by: Xin Zhang, Tongji University, ChinaYang Sun, Fudan University, ChinaTo compare the reliability and effectiveness of blood blow restriction resistance training (BFR) versus traditional weight-bearing training (WB) in knee osteoarthritis (KOA) patients with metabolic dysfunction-associated steatotic liver disease (MASLD).This multicenter randomized controlled trial was conducted from January 2021 to June 2022 at Shanghai Jiao Tong University affiliated Sixth People’s Hospital and The People’s Hospital of Mengla County. A total of 120 outpatients were recruited and randomized to perform WB (n=60) or BFR (n=60) resistance training protocols in accordance with standard recommended protocols for 12 weeks. Demographic data and Kellgren and Lawrence grading system scores were collected. Pain, range of motion (ROM), scaled maximal isotonic strength (10RM), self-reported function (KOOS), and 30-s chair sit-to-stand test results were assessed at weeks 1, 4, and 12. | PMC10753484 |
Results | pain | 112 patients (57 in the WB group, 55 in the BFR group) completed the training programs and assessments. No significant intergroup demographic differences were noted. ROM and scaled 10RM significantly increased at the 4- and 12-week assessments and differed significantly between groups. The pain, ability of daily living and quality of life subscale in KOOS increased significantly at the 12-week assessment and differed significantly between groups, adjusted for baseline value. Significant and comparable increases in 30-s chair sit-to-stand test results were observed within and between study groups. | PMC10753484 | |
Conclusion | KOA, pain | BFR training enhanced muscle strength, reduced pain, and improved daily living and sports activities in patients with KOA, compared to WB training alone. BFR should be recommended for rehabilitation in KOA individuals with MASLD. | PMC10753484 | |
Clinical trial registration number | ChiCTR2100042872. | PMC10753484 | ||
Introduction | MASLD, Knee osteoarthritis, pain, KOA | BLOOD, DISEASE, KNEE OSTEOARTHRITIS | Knee osteoarthritis (KOA), especially those cases involving the medial compartment of the tibiofemoral joint, has become a major public health problem worldwide (Exercise therapy can reduce the pain symptoms of KOA at different disease stages (Blood flow restriction (BFR) training is a new strength training method that stimulates muscle growth and improves muscle function under proximal limb blood flow restriction or short-term intermittent blocking of venous blood flow during strength exercises performed with a small external load intensity (However, the effectiveness of BFR training (versus traditional WB training) for stimulating muscle strength in KOA patients with MASLD is unknown. Moreover, the effect of BFR on other aspects important in KOA rehabilitation, such as physical function and pain, has not been explored. Therefore, this study aimed to compare the reliability and effectiveness of BFR with traditional WB training in KOA patients with MASLD. | PMC10753484 |
Methods | PMC10753484 | |||
Participants | knee fracture, knee pain, trauma | DISEASES, DEGENERATION, AUTOIMMUNE | This multicenter randomized controlled trial was conducted from January 2021 to June 2022 in two trauma centers (Shanghai Jiao Tong University affiliated Sixth People’s Hospital and The People’s Hospital of Mengla County). A total of 120 eligible outpatients were recruited for this two-arm single-assessor blinded randomized control trial.Inclusion criteria included:a) Age ≥ 50 years.b) Chief complaint of persistent or recurrent knee pain in the past few months.c) A history of knee pain ≥ 3 months.d) X-ray showing bony joint degeneration of the tibial joint.e) Meet the diagnostic criteria of MASLD.f) Ability and willingness to communicate daily using WeChat (Tencent Tech, Shenzhen, China).Exclusion criteria included:a) Record or plan of knee surgery/intra-articular injection within the past or next 6 months.b) Steroid use within the previous 4 weeks.c) Autoimmune arthritis.d) History of knee fracture or lower-limb deformity.e) History of knee/hip replacement or osteotomy.f) Diseases associated with other imaged lower limb functions.g) Inability to walk normally.h) Inability to communicate normally or poor medical compliance.MASLD was confirmed based on the diagnostic criteria (All patients provided written informed consent in compliance with the declaration of Helsinki before joining the study. All study protocols were approved by the Research Ethics Committee of Shanghai Jiao Tong University affiliated Sixth People’s Hospital (REC reference no.: 2016-110). This clinical trial was registered at chichr.org.cn (ID: ChiCTR2100042872). | PMC10753484 |
Sample size | Osteoarthritis, Knee Injury, pain | OSTEOARTHRITIS | The primary outcome measure of pain (Knee Injury and Osteoarthritis Outcome Score [KOOS] pain) was used to calculate the required sample size using G*power version 3.1 (Heinrich-Heine-Universität Düsseldorf Universitätsstr, Germany) ( | PMC10753484 |
Experimental design | trauma | Two trauma centers joined this two-arm, single-assessor blinded randomized controlled trial. All recruited patients were block randomized to the WB (n=60) or BFR (n=60) group by an independent research team member. The blinding procedure was performed using opaque envelopes (n=60 for each group). Each participant was asked by an independent research team member to choose one of the 120 envelopes. The groups were coded by an independent member of the research team, while the principal assessor of the results and data analysis was blinded to the group allocations. | PMC10753484 | |
Experimental procedure | diabetes | DIABETES | The patients’ demographic data, including age, sex, BMI, smoking, diabetes, and Kellgren and Lawrence system grade, were recorded, as were their baseline data, including ROM, muscle strength (scaled maximal isotonic strength [10RM]), KOOS subscales, and 30-s chair sit-to-stand test results. All participants were then instructed to complete 12 weeks of training and undergo assessments at 4 and 12 weeks (Trial Profile of WB vs BFR in participants. | PMC10753484 |
WB training | knee extension | Each WB training intervention session included three parts: stretching exercise, ROM exercise, and strength exercise. The stretching exercises included triceps stretching in the standing position, hamstring stretching in the supine position, and quadriceps stretching in the prone position. The ROM exercises included knee extension at the end of the long sitting position, knee flexion at the end of the long sitting position, and stationary bike or trainer use. The strength exercise included quadriceps activation in the knee extension position and advanced closed-chain training of the lower limb. All training sessions were supervised by a physical therapist from the research team. Both groups were designed according to standard recommended protocols for each exercise type (Rehabilitation training program. | PMC10753484 | |
BFR training | arterial occlusion | ARTERIAL OCCLUSION | An automatically personalized tourniquet (PT) system (Delfi Medical, Vancouver, BC, Canada) was used in the BFR group. The system, set to automatically calculate occlusion pressure of the lower limb (LOP) defined as the minimum pressure required for full arterial occlusion ( | PMC10753484 |
Pain | pain | The pain was evaluated using the pain subscale of the KOOS (9-question, with a score of 0 indicating extreme pain to 36 indicating no pain). | PMC10753484 | |
Range of motion | Knee flexion was measured using a goniometer with each patient positioned supine and moving the heel as close as possible to the buttocks. Knee extension was measured with the patient maximally extending the knee joint and recorded as the difference from 0° of extension. The ROM of the knee was calculated as maximum flexion degree – maximum extension degree. | PMC10753484 | ||
Muscle strength | Scaled 10RM strength was assessed using a MED leg press (Technogym, Bracknell, UK) following a warm-up of 10 min light cycling. Beginning at 80% estimated 10RM the maximum load that could be lifted ten times through complete, the full ROM performed using the correct form was recorded as the concentric 10RM. All 10RM values were achieved within five attempts at 5-kg increments in external load at each attempt and a 3-min rest between attempts to allow full muscle recovery. The 10RM load for each patient was established at a level where they were capable of completing the 10th repetition but unable to perform an 11th repetition. Leg press exercise techniques followed the recommendation of the National Strength and Conditioning Association ( | PMC10753484 | ||
Physical function | pain | The KOOS is a self-reported tool used to assess patients’ opinions of their knee function and associated problems. The KOOS has five subscales: pain, symptoms, function in daily living, function in sport and recreation, and knee-related quality of life. Each subscale includes questions with standardized answer options across five Likert boxes scored 0–4. Each subscale was scored independently, with 0 indicating maximum symptoms.The 30-s chair sit-to-stand test (30s-CST) test is the American College of Sports Medicine (ACSM) recommended function and strength measurement test for elderly individuals. Participants were asked to stand from the chair and sit down as many times as possible in 30 s. The MDC value of the 30s-CST is 1.13 s ( | PMC10753484 | |
Data storage and analysis | pain | DISEASE | All patients’ data were coded and stored on the electronic data capture system for a specific disease. The system was operated within the hospital’s local servers. All statistical analyses were performed using SPSS Statistics version 24.0 (IBM Corp, Chicago, IL, USA). Data are presented as mean ± SD with 95% confidence intervals unless stated otherwise. Intergroup differences in patients’ baseline characteristics were assessed using independent-sample t-tests for continuous dependent variables and Fisher’s exact test for categorical data. The Shapiro-Wilks test (p>0.05) was used to examine normally distributed data, while Levene’s test of homogeneity was used to examine the homogeneity of the variances. The analysis of variance test was used to assess pain, 10RM strength, self-reported function, and 30s-CST with group allocations as the inter-subject independent factor and time as the intra-subject dependent factor. | PMC10753484 |
Results | PMC10753484 | |||
Participants and rehabilitation program | Eight participants (5 in the BFR group, 3 in the WB group) failed to complete the study due to unplanned surgery and injury (n=5) and unrelated reasons (n=3). The remaining 112 participants (93%) completed the study and the follow-up survey. There were no significant intergroup differences in baseline demographic data (Baseline characteristics of the participants.Continuous data were presented as mean ± SD. Other data were reported as percentage (n). | PMC10753484 | ||
Pain | pain | Statistically significant improvement in KOOS pain scores were detected at the 4- and 12-week follow-up assessments, with significant intergroup differences at 12 weeks (Results of pain, ROM, and physical function at baseline, week 4 and 12.Data were presented as mean ± SD. Kg/kg as a unit presented the ratio of the weight lifted to the body weight.Change of pain, ROM, and physical function in baseline, week 4 and 12.Data were presented as mean ± SD. Kg/kg as a unit presented the ratio of the weight lifted to the body weight. | PMC10753484 | |
Range of motion | A statistically significant increase in knee ROM was noted at 4 and 12 weeks, with a significant intergroup difference ( | PMC10753484 | ||
Scaled 10RM muscle strength | Scaled 10RM strength increased significantly from baseline to 12-week follow-up with significant intergroup differences ( | PMC10753484 | ||
Physical function | Statistically significant difference was noted for all KOOS subscale scores. The scores of subscales of symptoms, ability in daily living, function in sports and recreation, and knee-related quality of life showed significant intergroup differences at the 12-week follow-up (The mean 30s-CST increased significantly from baseline to 12-week follow-up with significant intergroup differences ( | PMC10753484 | ||
Discussion | KOA, pain | OBESE | This study was the first to assess the effects of a 12-week BFR training program on pain, muscle strength, and physical function among individuals with KOA complicated with MASLD. This study targeted middle-aged and elderly obese patients with a higher incidence of knee OA than other populations and aimed to evaluate the effectiveness of BFR in knee OA rehabilitation. The main findings of this study include: 1) WB training with or without BFR increases knee ROM and muscle strength in patients with KOA comorbid with MASLD; 2) pain reduction afforded by WB with BFR was greater than that of WB training in the short- (4 weeks) but not long-term (12 weeks); 3) WB with BFR improved function in daily living and knee-related quality of life better than WB training alone; 4) and WB and BFR are safe and reliable interventions for individuals with KOA comorbid with MASLD. | PMC10753484 |
Pain | KOA, OA, pain | OBESE | Different studies have evaluated the effects of training programs on pain, symptoms, physical function, and quality of life among patients with OA (The subjects of this study were obese individuals with KOA who experience greater joint stress involving a cycle of pain and loss of strength and knee function due to damaged cartilage and altered joint mechanics. Heavy load training can be risky for such patients due to further cartilage degeneration. Brky et al. reported that patients experienced significantly less joint pain during BFR than heavy load training ( | PMC10753484 |
Muscle strength | effusion, pain | EFFUSION | Muscle strength and volume increases have been reported after all exercise protocols regardless of duration (4–12 weeks). Recent studies reported that 8–13% of knee extensor muscle strength could be recovered with the aid of BFR (Arthrogenic inhibition is associated with joint cartilage impairments, effusion, and pain ( | PMC10753484 |
Physical function | hypoalgesia, knee pain | The significant and clinically important improvements in all patient’s self-reported function measures and 30s-CST performance results observed in both groups are in line with those of recent studies of knee OA patients (Recent research also suggested that BFR may have a hypoalgesia effect, as knee pain was significantly reduced during, immediately after, and 24 h after BFR versus heavy load resistance training ( | PMC10753484 | |
Implications for clinical knee OA rehabilitation | Pain, pain | The application of BFR passively or in combination with aerobic exercise during early anterior cruciate ligament rehabilitation was discussed previously (Pain extent is a major factor affecting knee OA rehabilitation results, as the pain has a detrimental effect on motor control and muscle function that results in modified movement patterns ( | PMC10753484 | |
Study strengths and limitations | KOA | STILL | During knee OA rehabilitation, applying progressively heavier loads is important to preventing muscular adaptations to the exercise (Muscle morphology is another parameter used to evaluate functional outcomes of training. Still, it was not used in our study due to the 4.2–13.0 MHz wide-band linear array scanning transducer head and the image analysis software available to our study group.BFR resistance exercise is employed by individuals with limited or incapacity of performing high-intensity resistance exercise, such as elderly (This study included a specific subgroup of KOA patients, which limits the generalization of our findings to other patient populations. Moreover, it focused on a specific degree of KOA (Kellgren and Lawrence grade II–III), which may also limit the generalizability of our results. | PMC10753484 |
Conclusion | KOA, pain | The present study demonstrated that BFR training could improve knee strength better than WB training alone, affording a greater reduction in pain and leading to greater overall improvements in functional outcomes of daily living and sport and leisure for KOA patients with MASLD. | PMC10753484 | |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Requests to access these datasets should be directed to | PMC10753484 | ||
Ethics statement | The studies involving humans were approved by the Research Ethics Committee of Shanghai Jiao Tong University affiliated Sixth People’s Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. | PMC10753484 | ||
Author contributions | Conception and design: CH, CL. Acquisition, analysis, or interpretation of data: BZ, YW, FY, JZ, WZ, SL. Drafting: CH, SL. Revising: CL. All authors contributed to the article and approved the submitted version. | PMC10753484 | ||
Conflict of interest | The 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. | PMC10753484 | ||
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. | PMC10753484 | ||
References | PMC10753484 | |||
Abstract | toxicities, DLTs, multiple mieloma, MM | ONCOLOGY, RELAPSED/REFRACTORY MULTIPLE MYELOMA, REFRACTORY MULTIPLE MYELOMA | Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed/refractory multiple myeloma (r/r MM), and in vitro synergism with bortezomib (BTZ) or DXM against MM cells. This phase I trial evaluated plitidepsin (3‐h intravenous infusion Day 1 and 15), BTZ (subcutaneous bolus Day 1, 4, 8, and 11), and DXM (orally Day 1, 8, 15, and 22), every 4 weeks in 36 r/r MM patients. Twenty‐two patients were treated using a standard dose escalation design (10 at the recommended dose [RD] cohort), and 14 additional patients were treated to expand the RD cohort. No dose‐limiting toxicities (DLTs) occurred during dose escalation. The highest dose level evaluated (plitidepsin 5.0 mg/mThis phase I trial evaluated antitumor activity for plitidepsin plus bortezomib (BTZ) and dexamethasone (DXM) in relapsed/refractory multiple mieloma patients (r/r MM). This triple combination of plitidepsin, BTZ, and DXM showed an acceptable safety profile and had moderate activity in adult patients with r/r MM that have failed to standard common therapeutic options, including BTZ and lenalidomide.
Preliminary results were presented at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting. “Ocio EM, Mateos M‐V, Prosper F, Martin J, Rocafiguera AO, Jarque I, et al. Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Journal of Clinical Oncology. 2016;34(15_suppl): Abstract #8006.” | PMC9972151 |
INTRODUCTION | Multiple myeloma, malignancy, hematological malignant diseases, MM | MULTIPLE MYELOMA | Multiple myeloma (MM) is a B‐cell malignancy accounting for 10% of hematological malignant diseases worldwide, with about 120,000 new cases every yearThe feasibility of re‐treating MM patients with single‐agent bortezomib (BTZ) was first confirmed in the phase III VISTA trial,Plitidepsin is a cyclic depsipeptide originally extracted from the tunicate In vitro, synergistic activity was found for the combination of plitidepsin with BTZ or DXM in MM cell lines and primary MM cells.The objective of this phase I clinical trial was to determine the recommended dose (RD) for phase II studies, the activity and safety profile, and the pharmacokinetics (PK) of plitidepsin in combination with BTZ and DXM in patients with r/r MM. | PMC9972151 |
METHODS | This study was conducted at six centers in Spain and one in France according with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulations for clinical trials. The study protocol was approved by the Independent Local Ethics Committee of each center. Signed written informed consent was obtained for each patient prior to any procedure. | PMC9972151 | ||
Patient population | toxicities, alopecia, MM | ONCOLOGY, ALOPECIA | Inclusion criteria were age ≥ 18 years; r/r MM diagnosed according to Durie‐Salmon criteria; ≥1 previous treatment lines; recovery from previous toxicities to grade ≤ 1 (excluding alopecia); Eastern Cooperative Oncology Group performance status score ≤ 2; normal left ventricular ejection fraction (LVEF); platelet count ≥50 × 10 | PMC9972151 |
Study treatment | DISEASE | Treatment consisted of escalating doses of plitidepsin 3‐h intravenous (i.v.) infusion Day 1 and 15, and BTZ subcutaneous bolus injection Day 1, 4, 8, and 11, with fixed DXM dose 40.0 mg orally Day 1, 8, 15, and 22, all every 4 weeks (q4wk), for a maximum of 8 cycles. If response or disease stabilization was observed, treatment after Cycle 8 could continue with plitidepsin and DXM at the same doses. Antiemetic prophylaxis was given to all patients, consisting of ondansetron 8 mg i.v. or equivalent, diphenhydramine hydrochloride 25 mg i.v. or equivalent, and ranitidine 50 mg i.v. or equivalent administered 30 min before each plitidepsin infusion. If necessary, 10 mg of metoclopramide every 8 h could be administered after the end of plitidepsin infusion or the duration of treatment with serotonin antagonists could be extended. | PMC9972151 | |
Dose escalation | Dose escalation followed a standard 3 + 3 design. The starting plitidepsin dose (4.0 mg/m | PMC9972151 | ||
Study assessments | Cancer | ADVERSE EVENT, ADVERSE EVENT, MYELOMA, CANCER | Hematology and biochemistry tests were done at baseline, before each plitidepsin or BTZ administration during Cycle 1, and before each plitidepsin administration during subsequent cycles.Adverse events (AEs) and laboratory abnormalities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE) v.4. Antitumor activity was evaluated according to the International Myeloma Working Group (IMWG) criteria. | PMC9972151 |
Pharmacokinetic analyses | Sixteen samples were collected from each patient to quantify plitidepsin whole blood and BTZ plasma concentrations at baseline and at different times 1 week after the first infusion. In patients treated at the RD, 15 additional samples were taken 1 week after the second plitidepsin infusion. | PMC9972151 | ||
Statistical analyses | Continuous variables were presented with summary statistics and categorical variables in frequency tables. Time‐to‐event variables were calculated using Kaplan–Meier approach. Binomial exact distribution was used to calculate 95% confidence intervals (95%CIs) for categorical variables. Individual PK parameters were tabulated. Statistical analyses were performed using SAS v.9.2, (SAS Institute Inc), and PK non‐compartmental analysis (NCA) was performed using Phoenix WinNonlin v.6.3. | PMC9972151 | ||
RESULTS | PMC9972151 | |||
Patient characteristics and treatment | MM, Relapsed, stage IA.Includes stage IIA, PD, MR | MULTIPLE MYELOMA, MINOR, DISEASE, ONCOLOGY, MYELOMA | A total of 39 patients were enrolled between June 2014 and August 2018. Of these, 36 patients were treated at three dose levels: eight at DL1 (plitidepsin 4.0 mg/mOf the 39 enrolled patients at all dose levels, with median age 66 years (range, 51–80 years), 19 (49%) had previously received hematopoietic stem cell transplantation (HSCT) (12 patients, 44%, at the RD) (Table Baseline characteristics of included patientsAbbreviations: BTZ, bortezomib; CR, complete response; ECOG, Eastern Cooperative Oncology Group; HSCT, hematopoietic stem cell transplantation; Ig, immunoglobulin; IMiDs, immunomodulatory; ISS, International Staging System; MM, multiple myeloma; MR, minor response; PD, progressive disease; PR, partial response; RD, recommended dose; SD, stable disease; UK, unknown; VGPR, very good partial response.All stage IA.Includes stage IIA (Includes stage IIIA (Relapsed MM: previously treated myeloma that progressed and required salvage therapy but did not meet the criteria for either “refractory” or “relapsed and refractory” myeloma. Total refractory MM includes both, “refractory MM” and “relapsed and refractory MM”. A total of 227 cycles were administered at all dose levels (median of 3 cycles per patient, range, 1–29 cycles); 111 of these cycles were given at the RD cohort, with a median of 2 cycles per patient (range, 1–29 cycles). Median relative dose intensity at the RD was 73% for both plitidepsin and BTZ, and 68% for DXM. | PMC9972151 |
Dose‐limiting toxicities and recommended dose | nausea, pneumonia, DLTs, diarrhea, toxicities, nausea and vomiting, vomiting, PD | PNEUMONIA | Twelve of the 22 patients treated at the escalation stage were evaluable for dose‐limiting toxicities (DLTs).The other10 patients were non‐evaluable for RD. Six of these patients did not receive a complete Cycle 1 (two patients discontinued before ending Cycle 1 due to pneumonia unrelated to treatment, one due to early PD, one due to plitidepsin hypersensitivity reaction, one patient had treatment omission due to treatment‐related grade 1 nausea and vomiting, and one patient due to missed oral DXM dose). Of the other four patients, two received incorrect BTZ or DXM doses at Cycle 1, one received treatment on Days 4 and 11 despite not fulfilling treatment criteria, and one had no laboratory tests done in Cycle 1.No DLTs occurred during dose escalation. Dose escalation beyond DL3 was not allowed by the study protocol; hence, DL3 (plitidepsin 5.0, BTZ 1.3 mg/mAt the RD cohort, 12 of the 24 treated patients were evaluable for DLTs. Two patients (17%) had DLTs during Cycle 1; these DLTs consisted of grade 3 diarrhea, and a combination of grade 3 nausea and grade 3 vomiting refractory to antiemetic therapy, in one patient each. | PMC9972151 |
Toxicity profile | discontinuations, nausea, Thrombocytopenia, hematological abnormalities, diarrhea, fatigue, febrile neutropenia, neutropenia, toxicity, paresthesia, vomiting, anemia, hematological abnormality, abnormal blood cell counts (grade ≥ 2), Neutropenia, peripheral neuropathy, Cancer | ADVERSE EVENT, THROMBOCYTOPENIA, NEUTROPENIA, FEBRILE NEUTROPENIA, ADVERSE EVENTS, THROMBOCYTOPENIA, PARESTHESIA, ANEMIA, NEUTROPENIA, PERIPHERAL NEUROPATHY, CANCER | The most common treatment‐related AEs found among the 36 patients treated at all dose levels were nausea (36% of patients), fatigue (28%), diarrhea (25%), and peripheral neuropathy and vomiting (19% each). Most of these AEs were grade 1/2. Grade ≥ 3 treatment‐related AEs at all dose levels comprised fatigue (Among the 24 patients treated at the RD cohort, the most frequent treatment‐related AEs were nausea (33% of patients), diarrhea (25%), fatigue (21%), and vomiting (17%). Most of these AEs were grade 1/2 (Table Treatment‐related adverse events (>10% of patients) and laboratory abnormalities at the RD cohort
Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BTZ, bortezomib; CPK, creatine phosphokinase; NCI‐CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; RD, recommended dose.The most common hematological abnormality (regardless of relationship to treatment) at all dose levels was anemia (all patients). Most cases were grade 1/2. Grade ≥ 3 anemia was found in 11 of 36 treated patients (31%). Thrombocytopenia was observed in 86% of patients reaching grade ≥ 3 in 17 patients. Neutropenia was found in 47% of patients with grade ≥ 3 in five patients. No episodes of febrile neutropenia were reported.At the RD cohort, grade ≥ 3 anemia was present in eight of 24 treated patients (33%; grade 4 in one). Thrombocytopenia was found in 83% of patients with grade ≥ 3 in 11 patients (46%; grade 4 in six). Neutropenia was found in 54% of patients, with grade 3 in four patients (Table Most patients with grade ≥ 3 hematological abnormalities at the RD already had abnormal blood cell counts (grade ≥ 2) at baseline, including six of 11 with grade 3/4 thrombocytopenia, three of four with grade 3 neutropenia, and seven of eight with grade 3/4 anemia. No treatment discontinuations, cycle delays, or dose reductions occurred at the RD due to hematological toxicity, which was managed with dose omissions.The most frequent biochemical abnormality regardless of relationship was alanine aminotransferase (ALT) increase (94%) at all dose levels, followed by aspartate aminotransferase (AST) increase (80%), creatine increase (71%), and creatine phosphokinase (CPK) increase (35%). Most transaminase increases at all dose levels were grade 1/2, and none reached grade 4. Grade 1/2 ALT increases and AST increases were reported in 26 patients each (46% of patients had grade 1 ALT increase and 57% had grade 1 AST increase). Grade 3 ALT increases were reported in seven patients (20%) and grade 3 AST increase occurred in two patients (6%).Among the 24 patients treated at the RD cohort, the most frequent biochemical abnormality regardless of relationship was ALT increase (91%), followed by AST increase (83%), creatine increase (68%), and CPK increase (36%). Most of these abnormalities at the RD cohort were grade 1/2 and none reached grade 4; grade 3 were ALT increase in six patients, and grade 3 AST increase, creatinine increase and CPK increase in one patient each (Table At the RD cohort, three treatment discontinuations occurred due to non‐hematological toxicity (grade 3 diarrhea in Cycle 2, grade 3 nausea and vomiting refractory to antiemetic therapy [DLTs] in Cycle 1, and grade 3 ALT/AST increase in Cycle 2). Six patients had dose reductions in 7 cycles. Of these, five dose reductions occurred due to toxicity, with four of them involving plitidepsin (two episodes of grade 3 ALT increase, and one episode each of grade 3 fatigue, and grade 2 CPK increase) and only one involving BTZ (grade 1 paresthesia). Two dose reductions were due to reasons unrelated to treatment. Ten patients required packed red blood cell transfusions and six were given platelet transfusions. | PMC9972151 |
Efficacy | Twenty‐eight, PD | DISEASE, MINOR, MYELOMA, RELAPSED/REFRACTORY MULTIPLE MYELOMA | Twenty‐eight patients treated at all dose levels (18 at the RD cohort) were evaluable for efficacy as per IMWG criteria. Eight patients were not evaluable because they did not receive at least one complete cycle. Overall, 10 patients showed PR or better, including two sCRs, one CR, three VGPRs, and four PRs (ORR = 35.7%; 95%CI, 18.6–55.9%). The clinical benefit rate was 82.1% (95%CI, 63.1%–93.9%) (Table Antitumor activity according to IMWG criteria in relapsed/refractory multiple myeloma patients
Abbreviations: BTZ, bortezomib; CR, complete response; DXM, dexamethasone; IMWG, International Myeloma Working Group; MR, minor response; ORR, overall response rate; PD, progressive disease; PR, partial response; RD, recommended dose; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.ORR includes sCR, CR, VGPR, and PR.Clinical benefit rate includes sCR, CR, VGPR, PR, MR, or SD.At the RD, one sCR, one VGPR, and two PRs occurred (ORR = 22.2%; 95%CI, 6.4%–47.6%). Both PRs were observed in refractory patients (one patient was refractory to lenalidomide and the other one to BTZ, lenalidomide, and pomalidomide). The clinical benefit rate was 77.8% (95%CI, 52.4–93.6%) (Table At all dose levels, the median DoR was 14.4 months (95%CI, 1.8 months‐23.9 months) and the median PFS was 4.1 months (95%CI, 2.1–10.4 months). At the RD cohort, the median DoR was 12.3 months (95%CI, 1.8–23.9 months) and the median PFS was 2.8 months (95%CI, 1.2–4.8 months). | PMC9972151 |
Pharmacokinetics | All patients were sampled for PK analysis, but only 17 and 18 of them were suitable for NCA of plitidepsin and BTZ, respectively. Mean total body clearance (CL) and volume of distribution (Non‐compartmental pharmacokinetic parameters
Abbreviations: AUC, area under the concentration–time curve from time zero to infinity; BTZ, bortezomib; CL, total clearance; CL/F, total clearance of drug after extravascular administration, corrected for absolute bioavailability; | PMC9972151 | ||
DISCUSSION | myalgia, MM, diarrhea, fatigue, thrombocytopenia, hematological toxicity, muscular toxicity, vomiting, anemia, hematological abnormality, muscular weakness, nausea, | DISEASE, THROMBOCYTOPENIA, RELAPSED/REFRACTORY MULTIPLE MYELOMA, ANEMIA, EVENTS | The RD for phase II studies for this triple combination was plitidepsin 5.0 mg/mThe most common hematological abnormality (all grades) was anemia, which occurred in all patients (grade ≥ 3 in 33% at the RD). Most cases were grade 1/2, and at the RD the majority of patients with grade ≥ 3 anemia while on treatment already had grade 2 anemia at baseline. The most common severe hematological toxicity at the RD was thrombocytopenia, which was grade ≥ 3 in half of patients with most of them (6 of 11) already having grade ≥ 2 thrombocytopenia at baseline. Lower rates of severe thrombocytopenia (21%–22%) have been previously observed in patients with r/r MM treated with the double combination of plitidepsin 5.0 mg/mThe most common biochemical abnormality was transaminase increases. Grade 3 ALT increase was most frequent at the RD (26% of patients), but it was transient and manageable with dose delays, omissions, or reductions.Treatment‐related AEs at the RD for this triple combination were mostly mild/moderate; grade 3 diarrhea, nausea, vomiting, or fatigue were observed in less than 10% of patients. Severe muscular toxicity was not observed with the triple combination in this study. In contrast, incidences of 5.4% and 3.6% were reported for severe myalgia and muscular weakness, respectively, in MM patients treated with plitidepsin plus DXM.At the RD cohort, only three patients discontinued treatment due to treatment‐related events, thereby suggesting an acceptable safety profile for plitidepsin combined with BTZ and DXM in this heavily pretreated r/r MM population (pretreated with a median of five prior lines, HSCT in 44% and refractory disease in 59%).This triple combination showed modest antitumor activity (ORR of 35.7% at all dose levels; 22.2% at the RD) in this population of heavily pretreated r/r MM patients, most of them having received BTZ and with disease refractory to the last prior therapy. Comparing the efficacy of the 18 evaluable patients during the escalation stage with an ORR of 55.6% (data presented at the ASCO 2016 Annual Meeting),The antitumor activity found in patients treated with the combination of plitidepsin, BTZ, and DXM (ORR of 35.7% at all dose levels, and 22.2% at the RD) was higher than that observed in the ADMYRE trial evaluating plitidepsin plus DXM (ORR: 13.8%),Results of the VISTA trial were further supported by those of phase II trials: RETRIEVE (ORR: 40%) and SUMMIT (ORR: 35%, including minimal response while on BTZ treatment), and of the phase III APEX trial (crossover from DXM to BTZ), in which the overall and complete response rates with BTZ were 43% and 9%, respectively.Of note, the median DoR (14.4 months at all dose levels; 12.3 months at the RD) was longer than that observed with most other BTZ and DXM‐containing combinations, including panobinostat (6.0 months),The similarity of PK parameters found in the present study compared to reference values, and the lack of overlapping metabolic routes of plitidepsin and BTZ, suggest that no major PK interaction between these two drugs is expected. Compared to the values reported herein, patients with MM treated with plitidepsin in other trials had a similar median CL (4.4 L/h) and a somewhat larger median peripheral volume (513 L) (unpublished data). The plitidepsin concentrations found in this study fitted within the 90% prediction interval simulated for patients with MM, although most were above the 50th percentile for the typical values expected during the first 48 hours after dosing (Figure Typical plitidepsin exposure in patients with in relapsed/refractory multiple myeloma patients and observed plitidepsin concentrations. Dots represent observations from the current study, lines represent the 5th, 50th, and 95th percentile of the simulated concentrations, and the shaded area represents the 90% prediction interval of plitidepsin whole blood concentrationsIn summary, the triple combination of plitidepsin 5.0 mg/m | PMC9972151 |
AUTHOR CONTRIBUTIONS | ALBERT | María Victoria Mateos: Conceptualization, Investigation, Resources, Writing—original draft, Writing—review & editing. Felipe Prosper: Investigation, Resources, Writing—review & editing. Jesús Martin Sánchez: Investigation, Resources, Writing—review & editing. Enrique M. Ocio: Methodology, Investigation, Resources, Writing—review & editing. Albert Oriol: Investigation, Resources, Writing—review & editing. Cristina Motlló: Investigation, Resources, Writing—review & editing. Jean‐Marie Michot: Investigation, Resources, Writing—review & editing. Isidro Jarque: Investigation, Resources, Writing—review & editing. Rebeca Iglesias: Investigation, Resources, Writing—review & editing. María Solé: Investigation, Resources, Writing—review & editing. Sara Martínez: Conceptualization, Methodology, Writing—original draft, Writing—review & editing, Supervision. Carmen Kahatt: Conceptualization, Methodology, Writing—review & editing, Supervision. Salvador Fudio: Conceptualization, Methodology, Formal analysis, Writing—original draft, Writing—review & editing, Supervision. Gema Corral: Methodology, Formal analysis, Writing—review & editing. Ali Zeaiter: Methodology, Writing—review & editing, Supervision. Lola Montilla: Methodology, Writing—original draft, Writing—review & editing. Vincent Ribrag: Investigation, Resources, Writing—review & editing. | PMC9972151 | |
FUNDING INFORMATION | The study was funded by Pharma Mar, S.A. | PMC9972151 | ||
CONFLICT OF INTEREST | ONCOLOGY | María Victoria Mateos has received honoraria for lectures and participation in advisory boards from Janssen, Celgene, Takeda, Amgen, GSK, AbbVie, Pharma Mar, Pfizer, Regeneron, Roche, Sanofi, Oncopeptides, and Seagen. Enrique M. Ocio has received honoraria or consultation fees from Janssen, BMS/Celgene, Sanofi, GSK, Oncopeptides, Takeda, Amgen, Pfizer, Karyopharm, and Pharma Mar. Jean‐Marie Michot has declared Principal/sub‐Investigator role of clinical trials from AbbVie, Agios, Amgen, Argen‐x, Astex, AstraZeneca, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Seattle Genetics, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor. He has also received personal fees such as honoraria, royalties or fees for consulting, lectures, speakers bureau, expert testimony, employment, advisory boards, among others from Roche, AstraZeneca, and Amgen. In addition, he has also received non‐financial support such as, equipment supplied by the entity, travel paid by the entity, writing support, administrative support, among other from Celgene, Bristol‐Myers Squibb, and GSK. Isidro Jarque has declared speakers bureau and consultancy role by AbbVie, Amgen, AstraZeneca, Bristol‐Myers Squibb, Gilead, Janssen, Novartis, Pfizer, Roche and Takeda. Carmen Kahatt, Salvador Fudio, Gema Corral and Ali Zeaiter report personal fees for salary as full time employee and stock ownership from Pharma Mar, outside the submitted work. Sara Martínez and Lola Montilla report personal fees for salary as full time employee from Pharma Mar, outside the submitted work. No disclosures were reported by the other authors. | PMC9972151 | |
Supporting information | APPENDIX |
Appendix S1
Click here for additional data file. | PMC9972151 | |
ACKNOWLEDGMENTS | The authors thank the patients, their families, and investigators teams for their participation in this phase I clinical trial. | PMC9972151 | ||
DATA AVAILABILITY STATEMENT | Individual participant data are not publicly available since this requirement was not anticipated in the study protocol considering that this trial started patient enrolment in 2014. Clinical trial summary results were placed in the European Clinical Trials Database (EudraCT; study 2013–003835‐31) and Clinical | PMC9972151 | ||
REFERENCES | PMC9972151 | |||
2. Materials and Methods | PMC10222609 | |||
2.1. Design | neurological diseases, infectious | PULMONARY EMBOLISM, NEUROLOGICAL DISEASE, COAGULATION DISORDERS, DEEP VEIN THROMBOSIS, CORONARY DISEASES | We conducted a randomized controlled trial of patients following a primary total knee replacement between October 2020 and August 2021 in our center. We excluded from our study patients with revisions and cases requiring a greater constraint than a posterior stabilized TKA (constrained or hinged knee). We also excluded patients with coronary diseases, neurological diseases, infectious conditions, coagulation disorders or a history of deep vein thrombosis or pulmonary embolism. Inclusion criteria consisted of patients aged between 50–80 years and with BMI < 45 kg/m | PMC10222609 |
2.2. Surgical Technique | knee arthroplasty, Arthritis, femoral nerve block, TKA | ARTHRITIS, COMPLICATIONS, DEEP VEIN THROMBOSIS | All TKA procedures were performed by a single, highly experienced orthopedic surgeon in our institution, who specializes in total knee arthroplasty, according to a standard protocol. The implant of choice was the Zimmer Biomet NexGen implant system. Preoperatively, 1 g of tranexamic acid was administered in all cases, with an additional 1 g administered after the procedure. All cases received spinal anesthetic with a femoral nerve block. For the T group cases, a tourniquet was installed after three minutes of elevating the lower limb, which was inflated up to 350 mm Hg prior to the incision and deflated after the implantation, in order to perform hemostasis. We used a parapatellar approach, an intramedullary femoral guide with posterior referencing, an extramedullary tibial guide and a measured resection technique. For all cases, we routinely resurfaced the patella. All cases received a deep drain, and the wound closure was performed in a layered fashion. The drain was clamped for 3 h and then released and removed 24 h after surgery. Patients began physical therapy the following day and received chemoprophylaxis for deep vein thrombosis. Physical therapy was continued either at home or in a specialized clinic.We recorded preoperative data, which included age, sex, knee range of motion and Western Ontario and McMaster Universities Arthritis Index scores (WOMAC Score). Intraoperatively we measured the amount of blood aspiration by taking into account the amount of physiological serum used for lavage and the surgical room time. After the surgical procedure, we measured the amount of blood aspirated through the drains and the hemoglobin. For the functional evaluation, we measured flexion, extension, Visual Analogue Scale (VAS) scores and WOMAC scores after 6 weeks and 6 months. All complications were recorded throughout the whole study. | PMC10222609 |
2.3. Outcome Measures | pain | OSTEOARTHRITIS | The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was the primary outcome measure of this paper; this is a questionnaire consisting of 3 subsections (pain, stiffness and function) and comprises 24 items [The Visual Analogue Scale is a measure of pain to determine the patient’s perspective of pain level. It may be dependent on the patient’s mental status, but it is very frequently used to evaluate and correlate knee function [Both measures were translated and provided for patients to answer in the hospital and during follow-up visits. | PMC10222609 |
2.4. Statistical Analysis | Continuous variables were normally distributed and were presented as means and standard deviations. A statistical analysis was performed by using an independent t-test. Categorical data were analyzed using the Chi-square test. All of the statistical analysis was performed by an independent statistician using SPSS version 26.0 (IBM Corp., Armonk, NY, USA), and we established a level of | PMC10222609 | ||
3. Results | blood loss, ±, pain | DEEP VEIN THROMBOSIS, BLOOD LOSS, COMPLICATION, ARTHROFIBROSIS, COMPLICATIONS | We included 96 patients in the T group and 94 in the NT group, respectively, who remained part of this study until the last follow-up. All 10 cases that dropped out have been excluded. Regarding patient age and gender, we did not identify any significant differences. (Regarding blood loss, the NT group demonstrated significantly lower levels: 245 ± 97.8 mL intraoperative and 324.8 ± 151.65 mL postoperative, compared to the T group, where we recorded 276 ± 109.2 mL during the surgical procedures and 353.44 ± 101.55 mL after the surgery, (At the first follow-up, we recorded significantly lower WOMAC pain scores for the NT group (7.3 ± 1.8 compared to 8.2 ± 3.1, Regarding complications, two patients from the T group and three from the NT group experienced arthrofibrosis, which required mobilization under anesthesia. In addition, two patients from the NT group and five from the T group experienced deep vein thrombosis that required therapeutic anticoagulation. Only one patient from the tourniquet group presented a wound complication, who required readmission after 15 days for a detailed assessment and who underwent antibiotic treatment for two weeks. No other complications or readmissions within 30 days were reported in our study. | PMC10222609 |
4. Discussion | blood loss, TKAs, pain | BLOOD LOSS, BLIND, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS | Tourniquet usage for TKAs has been under debate for a long time. However, the evidence regarding this topic from our country is lacking. Thus, we decided to develop this detailed study. The evidence from the literature is conflicting regarding blood loss, function and complications. Therefore, we opted for a prospective randomized trial for a more precise estimation of the postoperative outcome. The main finding of this paper was that both groups presented improvements regarding the WOMAC scores. We did not find statistically significant differences between the groups, except after 6 weeks, where we found better WOMAC pain scores for the NT group (Another parameter that we measured was the Visual Analogue Scale. Even though both groups demonstrated an improvement regarding pain, we did not find any significant differences between the groups. Despite our findings, Chen et al. reported that tourniquet usage for the entire TKA procedure was linked with significantly higher thigh pain [We recorded a significantly higher amount of blood loss during the surgery (Another essential parameter for hospital costs is the operative time. We found significantly shorter operative room times for the NT group (The usage of tourniquets is also highly debated regarding postoperative complications. Tie et al. reported an increased rate of wound complications after prolonged tourniquet usage [Our study presents some limitations. Since the hospital stay is relatively short, we could not assess the hidden blood loss in both groups. We also admit that a one-year follow-up could have added additional data, despite the relevant information that we recorded. We also were not able to blind the surgeon to the allocation of the patient. Another limitation of this paper is that we used a high-pressure tourniquet, which is correlated with higher early surgical site pain levels compared to lower pressures [ | PMC10222609 |
Author Contributions | S.D. planned the clinical study, and contributed to the conception and design of this study, as well as the acquisition and data analysis. C.D. contributed to the conception and design of this study. M.E.G. contributed to the analysis and data interpretation. M.P. planned the clinical study, and contributed to the conception and design of this study. D.C.C. contributed to the translation and critical revision of important intellectual content. All authors have read and agreed to the published version of the manuscript. | PMC10222609 | ||
Institutional Review Board Statement | All procedures performed in this paper were in accordance with the 1964 Helsinki Declaration and its later amendments, or comparable ethical standards, and according to the national ethical standards. This study received approval from the “Foisor” Orthopaedics Clinical Hospital Ethics Committee of Bucharest, Romania, approval number 2020/2316 (date of approval 10 July 2020). Informed consent was obtained from all individual participants included in this study. | PMC10222609 | ||
Informed Consent Statement | Informed consent was obtained from all participants. The procedures were conducted in accordance with national ethical standards and the 1964 Helsinki Declaration. We declare that this paper does not contain any individual personal details. | PMC10222609 | ||
Data Availability Statement | All data generated or analyzed are included in this published article. | PMC10222609 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10222609 | ||
Abbreviations | List of abbreviations.
| PMC10222609 | ||
References | Baseline characteristics.Intraoperative and postoperative parameters. * statistically significant.Postoperative results during follow-ups. * statistically significant. | PMC10222609 | ||
Background and aim | coronary artery bypass, acute pain, pain | COLD | Chest tube removal (CTR) can cause severe acute pain which is usually described by patients as a painful experience. This study compared the effects of cold compress, transcutaneous electrical nerve stimulation (TENS), and combined cold compress-TENS on CTR-associated pain among patients with coronary artery bypass grafting (CABG).
| PMC10214554 |
Methods | pain | COLD | This randomized controlled trial was conducted in 2018–2019 using a double-blind four-group design. Participants were 120 patients with CABG selected from Shafa hospital, Kerman, Iran, and randomly allocated to a cold compress, a TENS, a combined cold compress-TENS, and a placebo group (compress with room temperature) and TENS with an off TENS device. Each participant received the intervention for 15 min immediately before CTR. CTR-associated pain was assessed before, during, immediately after, and 15 min after CTR. Data were analyzed using the SPSS program (v. 22.0) at a significance level of less than 0.05. | PMC10214554 |
Results | pain | COLD | The data of 29 participants in the placebo group, 26 in the TENS group, 30 in the cold compress group, and 26 in the combined cold compress-TENS group was gathered. Baseline demographic and clinical characteristics and pain intensity scores of participants had no statistically significant differences among all four groups ( | PMC10214554 |
Conclusion | pain | COLD | Combined cold compress-TENS is more effective than separate cold compress and TENS in reducing CTR-associated pain among patients with CABG. Therefore, non-pharmacological methods such as combined cold compress-TENS are recommended for managing CTR-associated pain. | PMC10214554 |
Keywords | PMC10214554 | |||
Introduction | nausea, dyspnea, Cardiovascular disease, pain, postoperative death | RESPIRATORY INFECTIONS, CARDIOVASCULAR DISEASE, CARDIOVASCULAR DISEASE, GASTROINTESTINAL BLEEDING, COLD, RESPIRATORY COMPLICATIONS, COLD, COMPLICATIONS | Cardiovascular disease is one of the major health challenges [Cardiac surgery is a common treatment for cardiovascular disease [Ineffective pain management among patients with cardiac surgery can increase the risk of postoperative respiratory complications such as reduced respiratory muscle strength, reduced lung volume and capacity, reduced effectiveness of coughing, and increased risk of respiratory infections. These complications negatively affect postoperative recovery and are among the major causes of postoperative death [There are many different pharmacological and non-pharmacological pain management methods. Pharmacological methods (such as opioids and non-steroidal anti-inflammatory drugs) are usually associated with different side effects such as dyspnea, nausea, and gastrointestinal bleeding. Therefore, non-pharmacological methods are usually preferred for pain management [Cold compress is a common non-pharmacological method for managing CTR-associated pain. It is among the oldest, easiest, and safest pain management methods [TENS is another non-pharmacological method for pain management [Several studies reported the effectiveness of cold compress in reducing CTR-associated pain [ | PMC10214554 |
Methods | cardiac dysrhythmia, Raynaud’s disease, pain, sensory disorders, audiovisual impairments, vasovagal | CARDIAC DYSRHYTHMIA, DISORDERS, SENSORY DISORDERS, BLIND, COLD | This randomized controlled trial was conducted in 2018–2019 using a double-blind four-group design. Participants were 120 hospitalized adult patients with CABG recruited from the cardiac surgery intensive care unit of Shafa hospital, Kerman, Iran. They were selected based on the following selection criteria: an age of 18–75 years, Iranian nationality, full consciousness, hemodynamic stability, sensitivity to cold, no use of tranquilizers or analgesics 1 h before CTR, no cigarette smoking or drug abuse, and no self-report history of Raynaud’s disease, sensory disorders (such as audiovisual impairments), and mental disorders, no previous experience of using TENS before the study. Exclusion criteria were the need for analgesics during the intervention or the development of cardiac dysrhythmia or vasovagal response during CTR. All patients were selected in the morning shift and underwent CABG with an identical surgical procedure performed by an identical surgeon. The size of chest tube for all of them was 14–16 French. All participants and the person who performed pain assessment were blind to the group allocation, but we explained the purpose of the study to the participants and after finishing the procedure they were given an educational pamphlet about TENS and cold therapy.Sample size was calculated to be thirty using the results of a former study [ | PMC10214554 |
Instruments | chest pain, pain | CHRONIC DISEASE | Data collection instruments were a demographic questionnaire, a clinical data sheet, and a visual analogue scale. The items of the demographic questionnaire were related to age, gender, educational level, body mass index, occupation, pain tolerance, history of chronic disease, history of cigarette smoking, and family history of coronary artery bypass graft surgery. The clinical data sheet included items on chest tube characteristics, namely chest tube size, duration of chest tube use, and chest pain. The visual analogue scale for pain assessment was scored from zero (“No pain”) to 10 (“Highest possible pain”). This scale has been used in previous studies for pain assessment among patients with cardiac surgery [ | PMC10214554 |
Intervention | STERILE, COLD | Study intervention for all participants in all groups was implemented 15 min before CTR. In the cold compress group, the skin surrounding the chest tube insertion site was cleansed using alcohol and then, a cold compress with a temperature of – 5 °C was applied to the site for 15 min so that it covered an area of 10-cm diameter around the chest tube insertion site. A sterile gauze was placed between the skin and the cold compress in order to prevent the direct contact of the compress with the skin. In the TENS group, a TENS device named stimulator 615 k (made by Novin company, Isfahan, Iran) with two pads sized four by 6 cm was used. TENS electrodes were placed on the skin next to the chest tube insertion site and TENS was started at a frequency of 80–100 Hz, the mode of the device was on normal mode and the intensity of the device was set to 6 mA [ | PMC10214554 |
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