An Experimental Study to Optimize Neuromuscular Blockade Protocols in Cynomolgus Macaques: Monitoring, Doses, and Antagonism.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are a crucial component of anesthesia and intensive care through the relaxation of skeletal muscles. They can lead to adverse reactions such as postoperative residual neuromuscular block. Only one agent is capable of an instant block reversal in deep block situations, but is restricted to aminosteroid agents. Among animal models, non-human primates are an essential model for a great diversity of human disease models. The main objective of this study was to establish a model for NMBA monitoring with current available drugs before testing new reversal agents. METHODS: Seven healthy male cynomolgus macaques were randomly assigned to this study. Experiments using macaques were approved by the local ethical committee (CEtEA #44). All animals were anesthetized according to institutional guidelines, with ketamine and medetomidine, allowing IV line placement and tracheal intubation. Anesthesia was maintained with isoflurane. Either rocuronium bromine (with or without sugammadex reversal) or atracurium besylate was evaluated. Monitoring was performed with two devices, TOF-Watch and ToFscan, measuring the T4/T1 and the T4/Tref ratios, respectively. Nonparametric Mann-Whitney statistical analyses were done when indicated. RESULTS: NMBA monitoring required adaptation compared to humans, such as stimulus intensity and electrode placement, to be efficient and valid in cynomolgus macaques. When administered, both NMBAs induced deep and persistent neuro-muscular block at equivalent doses to clinical doses in humans. The rocuronium-induced profound neuromuscular block could be reversed using the cyclodextrin sugammadex as a reversal agent. We report no adverse effects in these models by clinical observation, blood chemistry, or complete blood count. CONCLUSION: These results support the use of non-human primate models for neuromuscular block monitoring. This represented the first step before the forthcoming testing of new NMBA-reversal agents.

Effect of sugammadex with neostigmine on postoperative bowel function and on recovery of neuromuscular functions: A randomized controlled trial.

BACKGROUND: Early recovery of neuromuscular and bowel function after abdominal surgery are important clinical indicators of postoperative recovery. This study aimed to investigate the effects of sugammadex, and neostigmine added to sugammadex, on postoperative bowel function and recovery from neuromuscular blocking agents. METHODS: Ninety gynecological surgery patients, aged 18 to 65 years, with American Society of Anesthesiologists of 1 to 2 were randomly assigned to 3 groups: sugammadex 2 mg/kg (Group S), sugammadex 1 m/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S1N), and sugammadex 1.5 mg/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S2N), for reversal at the end of surgery during moderate block (train-of-four [TOF] count 1-2). Propofol, remifentanil, rocuronium, and sevoflurane were used for general anesthesia, and neuromuscular function was assessed using kinemyography. The primary outcomes assessed the effects of sugammadex alone and in combination with neostigmine on the time to first flatus. The secondary outcomes included time to first defecation and recovery time; defined as the administration of reversal agent to TOF ratio 90%. RESULTS: Data from 90 female patients who underwent abdominal gynecological surgery were analyzed. No significant differences were found between the groups in term of the time to first flatus, defecation, or postoperative nausea and vomiting after surgery. However, significant differences were observed in the time to reach a TOF ratio 90% (P < .001) and extubation time (P = .003). CONCLUSION: The addition of neostigmine to sugammadex did not affect bowel function recovery. However, combining 20 µg/kg neostigmine with 1.5 mg/kg sugammadex or 2 mg/kg sugammadex alone antagonized moderate-depth nondepolarizing neuromuscular blockade with similar efficacy.

Evaluation of surgical condition during laparoscopic gynaecological surgery in patients with moderate vs. deep neuromuscular block in low-pressure pneumoperitoneum.

INTRODUCTION: The significant effect of deep neuromuscular block (NMB) in laparoscopic surgery is still controversial, especially in lower-pressure pneumoperitoneum. This study investigates the effect of deep neuromuscular block on intraabdominal pressure (IAP), surgical space quality, post-operative abdominal pain, and shoulder tip pain in laparoscopic gynaecological surgery. MATERIAL AND METHODS: This is a randomised, double-blinded control trial which randomised samples to moderate NMB (train-of-four count [TOF] of 1 or 2) or deep NMB (post-tetanic count [PTC] of 1 or 2). Surgery began with IAP 8 mmHg but was allowed to increase the pressure if the surgical condition was unfavourable. The surgical condition was rated on a 4-point scale. Post-operative abdominal pain and shoulder tip pain was assessed using a numerical rating scale for pain, with 0 defined as no pain and 10 severe pain at recovery area (time 0), 30 minutes, and 24 hours post-operation. RESULTS: Seventy patients completed the study. The rate of increasing IAP between the 2 groups ( P = 0.172) is not significant, but deep NMB requires less pressure - mean highest IAP of 10.31 (± 1.39) mmHg, moderate NMB 11.54 (± 1.69) mmHg. The mean surgical space condition score was significantly better in the deep NMB group at 2.4 (± 0.7) compared to moderate NMB at 3.2 (± 0.66), P < 0.005. There was a significantly lower post-operative abdominal pain score in deep NMB but no significant difference in shoulder tip pain score between the 2 groups. CONCLUSIONS: Deep NMB enables the usage of lower IAP in laparoscopic surgery without interfering with surgical space condition, and it reduces the post-operative abdominal pain score in 24 hours compared to moderate NMB.

[Neuromuscular Blockade in the Critically Ill]. / Muskelrelaxanzien in der Intensivmedizin.

The management of sedation in intensive care medicine has changed substantially in the last few years. Neuromuscular blocking agents (NMBA) are only rarely indicated in modern intensive care medicine. In this review, the mechanism of action, potential side effects, and special considerations for the application of NMBA to critically ill patients will be discussed. We further present the rationale for the use of NMBA for the remaining indications, such as endotracheal intubation, selected cases of severe acute respiratory distress syndrome, and shivering during temperature control after cardiac arrest. The review will close with a description of potential side effects of NMBA use in the intensive care setting, such as awareness, acquired skeletal muscle weakness as well as corneal injuries, and how monitoring of sedation and peripheral muscle blockade may be handled.

[Neuromuscular Blockade in Paediatric Patients]. / Muskelrelaxierung bei pädiatrischen Patient*innen.

The administration of muscle relaxants has been used in anesthesia for decades and continues to play an important role in modern anaesthesia. Special patient populations, such as infants or very young patients require adapted use. The article discusses the specifics of muscle relaxant administration in these patient groups.

[Neuromuscular Blockade in Geriatric Patients]. / Muskelrelaxierung bei geriatrischen Patient*innen.

The administration of neuromuscular blocking agents has been used in anesthesia for decades and continues to play an important role in modern anesthesia. Special patient populations, such as very young or very old patients, require adapted use. The following article discusses the specifics of neuromuscular blocking agents administration in geriatric patients.

[Update: Neuromuscular Blockade during General Anesthesia]. / Update: Muskelrelaxierung in der Anästhesie.

The correct use of muscle relaxants and neuromuscular monitoring during anesthesia has been subject of controversial discussions for decades. Particularly important in clinical practice are identification and management of residual neuromuscular blockages and avoidance of associated complications. Despite the differences in the molecular mechanisms of action between depolarizing and non-depolarizing muscle relaxants the blockade of the postsynaptic nicotinic acetylcholine receptor remains a common ending pathway. Due to its unfavorable side effect profile, succinylcholine should only be used in justified exceptional cases. The use of muscle relaxants generally reduces the complication rate in airway management. However, even the single use of muscle relaxants increases the likelihood of postoperative pulmonary complications. These complications associated with the use of muscle relaxants, such as residual neuromuscular blockade, must be anticipated. The application of guideline-based approaches, including continuous neuromuscular monitoring and the application of muscle relaxant reversal agents, may significantly reduce the rate of adverse events associated with the use of muscle relaxants.

Effects of neuromuscular block reversal with neostigmine/glycopyrrolate versus sugammadex on bowel motility recovery after laparoscopic colorectal surgery: A randomized controlled trial.

STUDY OBJECTIVE: To compare the effects of neostigmine/glycopyrrolate (a traditional agent) and sugammadex on bowel motility recovery and the occurrence of digestive system complications after colorectal surgery. DESIGN: Prospective, randomized controlled trial. SETTING: A single tertiary center. PATIENTS: 111 patients undergoing laparoscopic colorectal surgery. INTERVENTIONS: Patients were randomized into two groups based on the block reversal agent: 1) a mixture of 50 µg.kg-1 of neostigmine and 10 µg.kg-1 of glycopyrrolate (neostigmine group) and 2) 2 mg.kg-1 of sugammadex (sugammadex group). MEASUREMENTS: The primary outcome was the time from the surgery's completion to the first flatus. The time to the first postoperative defecation, incidences of postoperative nausea or vomiting, ileus, and dry mouth, as well as postoperative length of stay, were also assessed. MAIN RESULTS: The time to the first flatus was significantly shorter in the sugammadex group than in the neostigmine group (59 [42-79] h vs 69 [53-90] h, P = 0.027). The time to the first defecation and the incidences of postoperative nausea or vomiting and ileus did not differ between the groups, nor did the postoperative length of stay. However, the incidence of postoperative dry mouth was significantly lower in the sugammadex group than in the neostigmine group (7 patients [13%] vs 39 patients [71%], P < 0.001). CONCLUSIONS: The time to the first flatus was shorter using 2 mg.kg-1 sugammadex to reverse the neuromuscular block for laparoscopic colorectal surgery compared to reversal with conventional neostigmine/glycopyrrolate.

Sugammadex and neuromuscular disease: a systematic review with assessment of reporting quality and content validity.

BACKGROUND: Efficacy and safety of sugammadex for the reversal of neuromuscular blocking agents (NMBAs) in patients with neuromuscular diseases remains unclear. We summarised the available evidence and evaluated the quality of data reporting and the validity of published reports. METHODS: We searched for reports (any design) on the usage of sugammadex (any regimen) for the reversal of an NMBA in patients (any age) with any neuromuscular disease. We used a modified CARE checklist (maximum score 23) to assess the quality of data reporting and an original specific validity checklist (maximum score 41) that was developed through a Delphi process. RESULTS: We retrieved 126 observational reports (386 patients). Most dealt with myasthenia gravis patients receiving rocuronium. The train-of-four ratio returned to ≥0.9 in 258 of 265 (97.4%) patients in whom neuromonitoring was used. Adverse events occurred in 14 of 332 (4.2%) patients in whom adverse events were reported as present or absent. In 90 case reports, the median score of the 23-point CARE checklist was 13.5 (inter-quartile range [IQR] 11-16). In all 126 reports, the median score of the 41-point validity checklist was 23 (IQR 20-27). Scores were positively correlated. CONCLUSIONS: These uncontrolled observations (of mainly low to moderate quality and validity) do not allow confident assessment of the efficacy and safety of sugammadex for the reversal of NMBAs in patients with neuromuscular diseases. Reporting of observational data should follow established guidelines, include specific information to ensure validity, and emphasise what the new data add to current knowledge. SYSTEMATIC REVIEW PROTOCOL: PROSPERO 2019 (CRD42019119924).

Comparison of inflammatory markers in low-pressure pneumoperitoneum with deep neuromuscular block versus standard pressure pneumoperitoneum among patients undergoing laparoscopic cholecystectomy for gallstone disease: a randomized control trial.

BACKGROUND: Low-pressure pneumoperitoneum (LPP) is an attempt to improve laparoscopic surgery. Lower pressure causes lesser inflammation and better hemodynamics. There is a lack of literature comparing inflammatory markers in LPP with deep NMB to standard pressure pneumoperitoneum (SPP) with moderate NMB in laparoscopic cholecystectomy. METHODOLOGY: This was a single institutional prospective randomized control trial. Participants included all patients undergoing laparoscopic cholecystectomy for symptomatic gall stone disease. Participants were divided into 2 groups group A and B. Group A-Low-pressure group in which pneumoperitoneum pressure was kept low (8-10 mmHg) with deep Neuromuscular blockade (NMB) and Group B-Normal pressure group (12-14 mmHg) with moderate NMB. A convenience sample size of 80 with 40 in each group was selected. Lab investigations like CBC, LFT, RFT and serum IL-1, IL-6, IL-17, TNF alpha levels were measured at base line and 24 h after surgery and compared using appropriate statistical tests. Other parameters like length of hospital stay, post-operative pain score, conversion rate (low-pressure to standard pressure), and complications were also compared. RESULTS: Eighty participants were analysed with 40 in each group. Baseline characteristics and investigations were statistically similar. Difference (post-operative-pre-operative) of inflammatory markers were compared between both groups. Numerically there was a slightly higher rise in most of the inflammatory markers (TLC, ESR, CRP, IL-6, TNFα) in Group B compared to Group A but not statistically significant. Albumin showed significant fall (p < 0.001) in Group B compared to Group A. Post-operative pain was also significantly less (p < 0.001) in Group A compared to Group B at 6 h and 24 h. There were no differences in length of hospital stay and incidence of complications. There was no conversion from low-pressure to standard pressure. CONCLUSION: Laparoscopic cholecystectomy performed under low-pressure pneumoperitoneum with deep NMB may have lesser inflammation and lesser post-operative pain compared to standard pressure pneumoperitoneum with moderate NMB. Future studies with larger sample size need to be designed to support these findings.

Shortened time to neuromuscular recovery with lower doses of rocuronium in elderly patients.

INTRODUCTION: The effect of neuromuscular blocking agents may be reversed by administration of neostigmine, when two twitches are present using train-of-four (TOF) stimulation. However, in elderly patients, limited data are available about when to administer neostigmine. We hypothesised that time to two twitches after TOF (TOF-2) was shorter after rocuronium 0.6 mg/kg than after rocuronium 0.9 mg/kg. Also, we hypothesised that time to TOF-2 would be shorter after rocuronium 0.3 mg/kg than after rocuronium 0.6 mg/kg. METHODS: This was a secondary analysis of 50 elderly patients > 80 years; 16 patients received rocuronium 0.6 mg/kg, another 16 patients received rocuronium 0.9 mg/kg; and, finally, 18 patients received rocuronium 0.3 mg/kg. Patients received total intravenous anaesthesia, and neuromuscular block was monitored with acceleromyography. RESULTS: Time to TOF-2 was shorter after rocuronium 0.6 mg/kg than after rocuronium 0.9 mg/kg: 37 min. versus 59 min. (difference: 22 min. (95% confidence intervals (CI): 10 to 33 min.), p = 0.0007). Time to TOF-2 after rocuronium 0.3 mg/kg was shorter than after rocuronium 0.6 mg/kg: 19 min. versus 37 min. (difference: 18 min. (95% CI: 11 to 25 min.), p = 0.00006). However, only 33% of the patients receiving 0.3 mg/kg obtained full effect i.e. TOF-0. CONCLUSION: Time to TOF-2 was shorter after rocuronium 0.6 mg/kg than after 0.9 mg/kg and shorter after rocuronium 0.3 mg/kg than after 0.6 mg/kg. FUNDING: This work was supported by departmental sources. TRIAL REGISTRATION: This study was a secondary analysis of two clinical trials. CLINICALTRIALS: gov (NCT04512313), (NCT03857750).

Sugammadex use in pediatric patients with stage IV-V chronic kidney disease in a quaternary referral hospital: a case series.

BACKGROUND: Sugammadex is a pharmacologic agent that provides rapid reversal of neuromuscular blockade via encapsulation of the neuromuscular blocking agent (NMBA). The sugammadex-NMBA complex is primarily cleared through glomerular filtration from the kidney, raising the possibility that alterations in renal function could affect its elimination. In pediatric patients, the benefits of sugammadex have led to widespread utilization; however, there is limited information on its application in pediatric renal impairment. This study examined sugammadex use and postoperative outcomes in pediatric patients with severe chronic renal impairment at our quaternary pediatric referral hospital. METHODS: After IRB approval, we performed a retrospective analysis in pediatric patients with stage IV and V chronic kidney disease who received sugammadex from January 2017 to March 2022. Postoperative outcomes studied included new or increased respiratory requirement, unplanned intensive care unit (ICU) admission, postoperative pneumonia, anaphylaxis, and death within 48 h postoperatively, unplanned deferral of intraoperative extubation, and repeat administrations of NMBA reversal after leaving the operating room. RESULTS: The final cohort included 17 patients ranging from 8 months to 16 years old. One patient required new postoperative noninvasive ventilation on postoperative day 2, which was credited to hypervolemia. Another patient had bronchospasm intraoperatively resolving with medication, which could not definitively be associated sugammadex administration. There were no instances of deferred extubation, unplanned ICU or need for supplemental oxygen after tracheal extubation identified. CONCLUSION: No adverse effects directly attributable to sugammadex in pediatric patients with severe renal impairment were detected. There may be a role for utilization of sugammadex for neuromuscular reversal in this population.

Impact of neuromuscular block on myocardial injury after non-cardiac surgery (MINS) incidence in the early postoperative stage of older patients undergoing laparoscopic colorectal cancer resection: a randomized controlled study.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) is a common and serious complication in older patients. This study investigates the impact of neuromuscular block on the MINS incidence and other cardiovascular complications in the early postoperative stage of older patients undergoing laparoscopic colorectal cancer resection. METHODS: 70 older patients who underwent laparoscopic colorectal cancer resection were separated into the deep neuromuscular block group and moderate neuromuscular block group for 35 cases in each group (n = 1:1). The deep neuromuscular block group maintained train of four (TOF) = 0, post-tetanic count (PTC) 1-2, and the moderate neuromuscular block group maintained TOF = 1-2 during the operation. Sugammadex sodium was used at 2 mg/kg or 4 mg/kg for muscle relaxation antagonism at the end of surgery. The MINS incidence was the primary outcome and compared with Fisher's exact test. About the secondary outcomes, the postoperative pain was analyzed with Man-Whitney U test, the postoperative nausea and vomiting (PONV) and the incidence of cardiovascular complications were analyzed with Chi-square test, intraoperative mean artery pressure (MAP) and cardiac output (CO) ratio to baseline, length of stay and dosage of anesthetics were compared by two independent samples t-test. RESULTS: MINS was not observed in both groups. The highest incidence of postoperative cardiovascular complications was lower limbs deep vein thrombosis (14.3% in deep neuromuscular block group and 8.6% in moderate neuromuscular group). The numeric rating scale (NRS) score in the deep neuromuscular block group was lower than the moderate neuromuscular block group 72 h after surgery (0(1,2) vs 0(1,2), P = 0.018). The operation time in the deep neuromuscular block group was longer (356.7(107.6) vs 294.8 (80.0), min, P = 0.008), the dosage of propofol and remifentanil was less (3.4 (0.7) vs 3.8 (1.0), mg·kg-1·h-1, P = 0.043; 0.2 (0.06) vs 0.3 (0.07), µg·kg-1·min-1, P < 0.001), and the length of hospital stay was shorter than the moderate neuromuscular block group (18.4 (4.9) vs 22.0 (8.3), day, P = 0.028). The differences of other outcomes were not statistically significant. CONCLUSIONS: Maintaining different degrees of the neuromuscular block under TOF guidance did not change the MINS incidence within 7 days after surgery in older patients who underwent laparoscopic colorectal cancer resection. TRIAL REGISTRATION: The present study was registered in the Chinese Clinical Trial Registry (10/02/2021, ChiCTR2100043323).

Effect of tetanic stimulation prior to train-of-four monitoring on the time to muscle response stabilization with neuromuscular blockade with rocuronium in patients aged 60 to 80 years: A prospective randomized controlled trial.

PURPOSE: To determine the effect of tetanic stimulation on the time to achieve stabilization of the T1 height, by acceleromyography train-of-four (TOF) ratio monitoring, in patients aged 60 to 80 years. METHODS: Randomized, prospective, single-blind, controlled trial in patients aged 60 to 80 years undergoing elective surgery under general anesthesia in two university hospitals in Brazil between December 2019 and March 2022. This trial was performed in accordance with the principles of the Helsinki Declaration and the guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II. Participants were randomly allocated by computer-generated numbers to receive tetanic stimulation (intervention group, n = 25) or not receive tetanic stimulation (control group, n = 25) to achieve T1 height stabilization on TOF ratio monitoring. The primary endpoint was to evaluate the effect of tetanic stimulation on the time to achieve stabilization of the T1 height. We also evaluated the effect on the onset time of rocuronium and time to recover from neuromuscular blockade with a single dose of rocuronium 0.6 mg.kg-1 with spontaneous recovery. RESULTS: There was no statistically significant difference between the groups in the time to T1 height stabilization (intervention: 4.3 [2.0-8.0] min; control: 5.8 [2.0-10.5] min; p = 0.202), onset time of the neuromuscular blocking agent (intervention: 1.9 [±0.7] min; control: 2.2 [±1.0] min; p = 0.219), or neuromuscular blockade recovery times to normalized TOF values of 0.7 (intervention: 106.1 [±37.2] min; control: 91.7 [±27.5] min; p = 0.295), 0.8 (intervention: 114.3 [±40.1] min; control: 97.8 [±28.9] min; p = 0.225), 0.9 (intervention: 126.5 [±44.0] min; control: 106.9 [±30.6] min; p = 0.153), and 1.0 (intervention: 138.3 [±43.4] min; control: 123.8 [±43.5] min; p = 0.425). CONCLUSION: The results of this study suggest that the recommendation to use tetanic stimulation to shorten the time to T1 height stabilization in neuromuscular monitoring did not alter the stabilization time of the T1 twitch or the pharmacodynamics of neuromuscular blockade with rocuronium in patients aged 60 to 80 years.