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.

Navigating Anesthesia: Muscle Relaxants and Reversal Agents in Patients with Renal Impairment.

This comprehensive review explores the interaction between neuromuscular blocking agents, reversal agents, and renal function, focusing on various drugs commonly used in anesthesia and their effects on kidney health. Succinylcholine, commonly used for anesthesia induction, can trigger elevated potassium levels in patients with specific medical conditions, leading to serious cardiac complications. While studies suggest the use of succinylcholine in patients with renal failure is safe, cases of postoperative hyperkalemia warrant further investigation. Some agents, such as atracurium and mivacurium, are minimally affected by impaired kidney function, whereas others, such as cisatracurium and rocuronium, can have altered clearance, necessitating dose adjustments in patients with renal failure. The reversal agents neostigmine and sugammadex affect renal markers, while cystatin C levels remain relatively stable with sugammadex use, indicating its milder impact on glomerular function, compared with neostigmine. Notably, the combination of rocuronium and sugammadex in rat studies shows potential nephrotoxic effects, cautioning against the simultaneous use of these agents. In conclusion, understanding the interplay between neuromuscular blocking agents and renal function is crucial for optimizing patient care during anesthesia. While some agents can be used safely in patients with renal failure, others can require careful dosing and monitoring. Further research is needed to comprehensively assess the long-term impact of these agents on kidney health, especially in high-risk patient populations. This article aims to review the use of muscle relaxants and reversal for anesthesia in patients with impaired renal function.

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).

Occurrence of hemodynamic changes following administration of rocuronium in a dog presenting for an ophthalmic procedure.

A 10-year-old, neutered male, Golden Retriever dog presented for surgical correction of a descemetocele. Acepromazine (0.02 mg/kg) and methadone (0.5 mg/kg) were administered intramuscularly for sedation, propofol (2 mg/kg) and midazolam (0.2 mg/kg) were administered intravenously for anaesthetic induction and isoflurane in oxygen was utilised for anaesthetic maintenance. Rocuronium (0.5 mg/kg), a neuromuscular blocking agent, was administered intravenously to facilitate central positioning of the eye for surgery. Within 10 min of rocuronium administration, the dog became tachycardic and hypotensive. Hemodynamic aberrations did not resolve with initial interventions but were successfully mitigated with the administration of diphenhydramine (0.8 mg/kg) intravenously. The dog remained stable throughout the remainder of the procedure and experienced a smooth and uneventful recovery. While it is difficult to confirm that the hemodynamic changes observed in this clinical case resulted solely from administration of rocuronium, the observance of the cardiovascular changes, timing of events and response to therapy suggest that rocuronium elicited a histamine response that was successfully treated with diphenhydramine.

The Influence of Acid-Base Balance on Anesthetic Muscle Relaxants: A Comprehensive Review on Clinical Applications and Mechanisms.

Muscle relaxants have broad application in anesthesiology. They can be used for safe intubation, preparing the patient for surgery, or improving mechanical ventilation. Muscle relaxants can be classified based on their mechanism of action into depolarizing and non-depolarizing muscle relaxants and centrally acting muscle relaxants. Non-depolarizing neuromuscular blocking drugs (NMBDs) (eg, tubocurarine, atracurium, pipecuronium, mivacurium, pancuronium, rocuronium, vecuronium) act as competitive antagonists of nicotine receptors. By doing so, these drugs hinder the depolarizing effect of acetylcholine, thereby eliminating the potential stimulation of muscle fibers. Depolarizing drugs like succinylcholine and decamethonium induce an initial activation (depolarization) of the receptor followed by a sustained and steady blockade. These drugs do not act as competitive antagonists; instead, they function as more enduring agonists compared to acetylcholine itself. Many factors can influence the duration of action of these drugs. Among them, electrolyte disturbances and disruptions in acid-base balance can have an impact. Acidosis increases the potency of non-depolarizing muscle relaxants, while alkalosis induces resistance to their effects. In depolarizing drugs, acidosis and alkalosis produce opposite effects. The results of studies on the impact of acid-base balance disturbances on non-depolarizing relaxants have been conflicting. This work is based on the available literature and the authors' experience. This article aimed to review the use of anesthetic muscle relaxants in patients with acid-base disturbances.

A pharmacovigilance study of FDA adverse events for sugammadex.

BACKGROUND: Sugammadex, a selective steroidal neuromuscular blocking agent reversal agent, is increasingly employed for the rapid restoration of neuromuscular function. This study aimed to conduct a comprehensive evaluation of sugammadex's safety profile. METHODS: Adverse events (AEs) related to sugammadex reported in the FDA Adverse Event Reporting System (FAERS) database from January 2009 to September 2023 were extracted. Disproportionality analysis with four measures: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) were employed to detect significant AEs. We also inspected for unexpected AEs absent from the sugammadex FDA approval documentation and categorized AEs based on the latest version (26.1) of 'Important Medical Event Terms List (IME list)' developed by the EudraVigilance Expert Working Group. RESULTS: A total of 1452 reports were linked to sugammadex. At the preferred terms (PTs) levels, 98 sugammadex-related AEs were identified, including "anaphylactic reaction", "bradycardia", "bronchospasm" and "cardiac arrest". Among them, 37 representing unexpected events were absent from official FDA labeling, and 50 AEs were recognized as IME warranting observation. Notably, 19 PTs denoted serious AEs were absent from labeling yet needing IME surveillance, including: "Kounis syndrome", "angioedema", "pulseless electrical activity" and "laryngeal edema". CONCLUSION: The study identified unexpected and potentially life-threatening AEs associated with sugammadex, a valuable agent for rapidly reversing neuromuscular blockade. Clinicians are advised to be mindful of these potential risks, particularly in patients with allergies or existing cardiovascular or respiratory conditions.

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.

A new pharmacological approach for tracheal intubation?

Anaesthesia induced with remimazolam and a fentanyl-series opioid can be reversed with flumazenil and naloxone. Concomitant paralysis with rocuronium can facilitate tracheal intubation whilst being reversible with sugammadex. Together, this combination might offer full reversibility of a 'routine' or a 'rapid-sequence' induction anaesthesia. Whether this is useful, or even safe, requires careful evaluation.

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.

The safety and efficacy of sugammadex for reversing neuromuscular blockade in younger children and infants.

INTRODUCTION: Sugammadex, a novel selective antagonist of non-depolarizing neuromuscular blocking agents, has been shown to rapidly and effectively reverse moderate and deep paralysis in adults and pediatric patients over age 2, improving patient recovery and reducing the risk of postoperative complications. AREAS COVERED: Since the use of sugammadex in patients under age 2 is not widely studied, we aim to provide an overview on the drug's application and potential use in infants and neonates. There is a limited but growing body of evidence for the safe, efficacious use of sugammadex in children under age 2. Relevant studies were identified from the most updated data including case reports, clinical trials, systematic reviews, and meta analyses. EXPERT OPINION: The results suggest that at a dose of 2 to 4 mg/kg of sugammadex can be safely used to rapidly and effectively reverse neuromuscular blockade in neonates and infants; it is non-inferior based on incidence of adverse events compared to neostigmine. Additionally, sugammadex doses between 8 and 16 mg/kg may be used as a rescue agent for infants during 'can't intubate, can't ventilate' crisis. Overall, sugammadex offers new value in the perioperative care of patients under age 2, with further studies warranted to better understand its application and full effect in the pediatric population.

Onset time, duration of action, and intubating conditions after mivacurium in elderly and younger patients.

BACKGROUND: The neuromuscular blocking agent mivacurium can be used during anesthesia to facilitate tracheal intubation. Data on onset time, duration of action, and effect on intubating conditions in patients 80 years and older are however limited. We hypothesized that onset time and duration of action of mivacurium would be longer in elderly patients than in younger adults. METHODS: This prospective observational study included 35 elderly (≥80 years) and 35 younger (18-40 years) patients. Induction of anesthesia comprised fentanyl 1-3 µg kg-1 and propofol 1.5-2.5 mg kg-1 and propofol and remifentanil for maintenance. Acceleromyography was used for monitoring neuromuscular blockade. The primary outcome was onset time defined as time from injection of mivacurium 0.2 mg kg-1 to a train-of-four (TOF) count of zero. Other outcomes included duration of action (time to TOF ratio ≥0.9), intubating conditions using the Fuchs-Buder scale and the intubating difficulty scale (IDS), and occurrence of hoarseness and sore throat postoperatively. RESULTS: No difference was found in onset time comparing elderly with younger patients; 219 s (SD 45) versus 203 s (SD 74) (difference: 16 s (95% CI: -45 to 14), p = .30). Duration of action was significantly longer in elderly patients compared with younger patients; 52 min (SD 17) versus 30 min (SD 8) (difference: 22 min [95% CI: 15 to 28], p < .001). No difference was found in the proportion of excellent intubating conditions (Fuchs-Buder); 31/35 (89%) versus 26/35 (74%) (p = .12) or IDS score (p = .13). A larger proportion of younger patients reported sore throat 24 h postoperatively; 34% versus 0%, p = .0002. No difference was found in hoarseness. CONCLUSION: No difference in onset time of mivacurium 0.2 mg kg-1 was found comparing elderly and younger patients. However, elderly patients had significantly longer duration of action. No difference was found in intubating conditions.

The impact of sugammadex dosing and administration practices on potential cost savings for pharmacy departments.

PURPOSE: Neuromuscular blocking agents (NMBAs) are commonly used during surgery, and restoring neuromuscular function at the end of surgery is vital in preventing complications of residual paralysis. Recent guidelines from the American Society of Anesthesiology recommend using sugammadex over neostigmine; however, sugammadex is significantly more expensive than neostigmine and may increase drug expenditure for pharmacy departments. This review summarizes evidence evaluating sugammadex dose adjustments and the potential of these dose adjustments to lead to cost savings for pharmacy departments. SUMMARY: We found evidence suggesting that the manufacturer-recommended sugammadex dose may not be needed in many patients and that dosing based on an adjusted body weight or based on depth of neuromuscular blockade may lead to lower sugammadex usage. Combining sugammadex with neostigmine could also decrease the dose of sugammadex required. We have highlighted the importance of objective neuromuscular monitoring to guide sugammadex dosing and evaluation for residual neuromuscular blockade. Cost savings for pharmacy departments may be realized by these alternative dosing strategies and/or vial-splitting practices. CONCLUSION: Implementing practices related to sugammadex vial splitting and dose adjustment based on body weight and depth of neuromuscular blockade shows potential benefits in terms of sugammadex cost savings.

Comparison between conventional-dose and high-dose rocuronium use in general anesthesia for Cesarean section.

Background: There have been few studies comparing the effects of high- and low-dose rocuronium during cesarean section by directly measuring the concentration. Therefore, we conducted a study to examine the blood concentrations and clinical effects of both doses of rocuronium on mothers and fetuses. Methods: Eighteen patients were randomly assigned to two groups: C Group (0.6 mg/kg), and H Group, (1.0 mg/kg). The primary outcome was the comparison of umbilical vein rocuronium concentration between two groups. We assessed ease of intubation, time from rocuronium administration to some TOF points, post-anesthesia care unit (PACU) stay time, infused remifentanil dose, maternal rocuronium concentration, and Apgar scores. Results: No differences were observed in demographic data, ease of intubation, PACU stay time, 1 min Apgar scores, umbilical venous blood gas analysis between both groups. However, the time from rocuronium administration to T3 disappearance was shorter (p=0.009) and time to T1 and T2 reappearance were longer (p=0.003, p=0.009) in H group than that in C group. The administered remifentanil dose (p=0.042) was lower in the H group than in the C group. Rocuronium concentrations in the umbilical vein (p=0.004) and maternal vein before cord clamping (p=0.002) and at discharge (p<0.001) were also found to be higher in the H group than in the C group. Conclusions: We observed no prolongation of PACU stay, and no differences in Apgar scores in H group compared to C group. It suggests that 1.0 mg/kg of rocuronium has no negative effects on the fetus and mother in cesarean section.

A Practical Dosing Algorithm for Deep Neuromuscular Blockade during Total Intravenous Anesthesia: ROCURITHM.

BACKGROUND: The number of trials investigating the effects of deep neuromuscular blockade (NMB) on surgical conditions and patient outcomes is steadily increasing. Consensus on which surgical procedures benefit from deep NMB (a posttetanic count [PTC] of 1 to 2) and how to implement it has not been reached. The European Society of Anaesthesiology and Intensive Care does not advise routine application but recommends use of deep NMB to improve surgical conditions on indication. This study investigates the optimal dosing strategy to reach and maintain adequate deep NMB during total intravenous anesthesia. METHODS: Data from three trials investigating deep NMB during laparoscopic surgery with total intravenous anesthesia (n = 424) were pooled to analyze the required rocuronium dose, when to start continuous infusion, and how to adjust. The resulting algorithm was validated (n = 32) and compared to the success rate in ongoing studies in which the algorithm was not used (n = 180). RESULTS: The mean rocuronium dose based on actual bodyweight for PTC 1 to 2 was (mean ± SD) 1.0 ± 0.27 mg · kg-1 ·h-1 in the trials, in which mean duration of surgery was 116 min. An induction dose of 0.6 mg ·kg-1 led to a PTC of 1 to 5 in a quarter of patients after a mean of 11 min. The remaining patients were equally divided over too shallow (additional bolus and direct start of continuous infusion) or too deep; a 15-min wait after PTC of 0 for return of PTC to 1 or higher. Using the proposed algorithm, a mean 76% of all 5-min measurements throughout surgery were on target PTC 1 to 2 in the validation cohort. The algorithm performed significantly better than anesthesiology residents without the algorithm, even after a learning curve from 0 to 20 patients (42% on target, P ≤ 0.001, Cohen's d = 1.4 [95% CI, 0.9 to 1.8]) to 81 to 100 patients (61% on target, P ≤ 0.05, Cohen's d = 0.7 [95% CI, 0.1 to 1.2]). CONCLUSIONS: This study proposes a dosing algorithm for deep NMB with rocuronium in patients receiving total intravenous anesthesia.