Phase III clinical trial comparing the efficacy and safety of adamgammadex with sugammadex for reversal of rocuronium-induced neuromuscular block.

BACKGROUND: Preliminary clinical trials of adamgammadex, a new cyclodextrin-based selective reversal agent, have demonstrated its efficacy in reversing neuromuscular block by rocuronium. METHODS: This multicentre, randomised, double-blind, positive-controlled, non-inferiority phase III clinical trial compared the efficacy and safety of adamgammadex and sugammadex. We randomised 310 subjects to receive adamgammadex (4 mg kg-1) or sugammadex (2 mg kg-1) at reappearance of the second twitch of the train-of-four (TOF), and standard safety data were collected. RESULTS: For the primary outcome, the proportion of patients with TOF ratio ≥0.9 within 5 min was 98.7% in the adamgammadex group vs 100% in the sugammadex group, with a point estimate and 95% confidence interval (CI) of 1.3% (-4.6%, +1.3%); the lower limit was greater than the non-inferiority margin of -10%. For the key secondary outcome, the median (inter quartile range) time from the start of administration of adamgammadex or sugammadex to recovery of TOF ratio to 0.9 was 2.25 (1.75, 2.75) min and 1.75 (1.50, 2.00) min, respectively. The difference was 0.50 (95% CI: 0.25, 0.50); the upper limit was lower than the non-inferiority margin of 5 min. In addition, there were no inferior results observed in secondary outcomes. Adamgammadex had a lower incidence of adverse drug reactions compared with sugammadex (anaphylactic reaction, recurarisation, decreased heart rate, and laryngospasm; P=0.047). CONCLUSIONS: Adamgammadex was non-inferior to sugammadex with a possible lower incidence of adverse drug reactions compared with sugammadex. Adamgammadex may have a potential advantage in terms of its overall risk-benefit profile. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000039525. Registered October 30, 2020. https://www.chictr.org.cn/showproj.html?proj=56825.

Under-dosing and over-dosing of neuromuscular blocking drugs and reversal agents: beware of the risks.

The phenomena of residual curarisation and recurarisation after the use of long-acting non-depolarising neuromuscular blocking drugs such as tubocurarine and pancuronium were well recognised 60 years ago. But the incidence seemed to decline with the introduction of atracurium and vecuronium. However, recently there have been an increasing number of reports of residual and recurrent neuromuscular block. Some of these reports are a result of inappropriate doses of rocuronium, sugammadex or both, together with inadequate neuromuscular monitoring. We urge clinicians to review their practice to ensure the highest standards of clinical care when using neuromuscular blocking drugs and reversal agents. This includes the use of quantitative neuromuscular monitoring whenever neuromuscular blocking drugs are administered.

Reversal of rocuronium induced neuromuscular block with sugammadex in patients under 2 years of age. A series of 280 cases.

AIM: Neuromuscular muscle relaxants are still indispensable for surgical procedures requiring general anesthesia, and the use of these agents may result in postoperative residual curarization. Sugammadex may offer a distinct advantage to pediatric patients where residual neuromuscular blockade may be poorly tolerated. Sugammadex is approved for use in adults and children over two years. This is the main reason why large-scale studies could not be conducted in the group of patients younger than two years old. This study aimed to evaluate the efficacy and safety of sugammadex for reversing deep rocuronium-induced neuromuscular blockade in children under two years of age. METHODS: Pediatric patients younger than two years of age who underwent neurosurgery under sevoflurane anesthesia were included in the study. Neuromuscular block was achieved by the administration of rocuronium. It was antagonized by the administration of 5 mg/kg sugammadex and evaluated using train-of-four (TOF). Primary outcome measure was the time from sugammadex administration to return of the TOF ratio to 0,9. Postoperative adverse events were also recorded. RESULTS: Two hundred eighty patients (10 day-24 months of age; 3-18 kg) were included in this study. Reversal of deep rocuronium-induced neuromuscular block with sugammadex was rapid in all patients. No residual curarization or recurarization was observed. No adverse events or hypersensitivity reactions were observed after administration of sugammadex. CONCLUSION: Reversal of rocuronium-induced deep neuromuscular block in infants was rapid and safe. Sugammadex provided safe extubation in patients younger than two years of age who had undergone neurosurgery. Research Fund. KEY WORDS: Neuromuscular blockade, Neuromuscular monitoring, Pediatrics, Sugammadex.

Suspected Accidental Infiltration of Rocuronium During General Anesthesia Induction: A Case Report.

There are few reports on rocuronium infiltration under general anesthesia. We report a case of suspected accidental rocuronium infiltration during anesthesia induction. A 25-year-old woman with autism spectrum disorder, intellectual disability, and epilepsy was scheduled for the extraction of 4 impacted third molars under general anesthesia. After induction with sevoflurane, an intravenous (IV) line was established in the left cephalic vein. Rocuronium was administered; however, subcutaneous swelling at the IV site was observed immediately. Spontaneous ventilations were maintained until additional rocuronium was administered via a new IV line. After heat pack application, the swelling disappeared 60 minutes after infiltration, and no tissue damage was observed. A strategy was developed to continue neuromuscular monitoring until recovery occurred. Acceleromyography was used, and the train-of-4 ratios at 99, 130, and 140 minutes after infiltration were 0.79, 0.91, and 1.0, respectively. Sugammadex was administered to prevent neuromuscular blockade recurrence. The patient was extubated once adequate return of muscle function and consciousness were observed. No neuromuscular block prolongation or recurrence were observed postoperatively. When rocuronium infiltration is suspected, it is important to eliminate swelling at the infiltration site and determine a management strategy based on neuromuscular monitoring.

Recurarization with magnesium sulfate administered after two minutes sugammadex reversal: A randomized, double-blind, controlled trial.

STUDY OBJECTIVE: The current study tested the hypothesis that magnesium sulfate after reversal with sugammadex causes recurarization. DESIGN: A single-center, prospective, randomized, double-blind, controlled trial. SETTING: Terciary care hospital in Rio de Janeiro, Brazil. PATIENTS: Included 60 patients undergoing for elective otolaryngological surgery. INTERVENTIONS: All patients received total intravenous anesthesia and a single dose of rocuronium (0.6 mg/kg). In 30 patients, the neuromuscular blockade was reversed with sugammadex (4 mg/kg) at the reappearance of one or two posttetanic counts (deep-blockade series). In 30 other patients, sugammadex (2 mg/kg) was administered at the reappearance of the second twitch of the train-of-four (moderate-blockade series). After the normalized train-of-four ratio recovered to ≥0.9, the patients in each series were randomized to receive intravenous magnesium sulfate (60 mg/kg) or placebo for 10 min. Neuromuscular function was measured by acceleromyography. MEASUREMENTS: The primary outcome was the number of patients who exhibited recurarization (normalized train-of-four ratio < 0.9). The secondary outcome was rescue with an additional dose of sugammadex after 60 min. MAIN RESULTS: In the deep-blockade series, a normalized train-of-four ratio < 0.9 occurred in 9/14 (64%) patients receiving magnesium sulfate and 1/14 (7%) receiving placebo, RR 9.0 (95% CI: 62-1.30), and (p = 0.002), with four rescues with sugammadex. In the moderate-blockade series, neuromuscular blockade recurred in 11/15 (73%) patients receiving magnesium sulfate and in 0/14 (0%) receiving placebo (p < 0.001), with two rescues. The absolute differences in recurarization were 57% and 73% in the deep-blockade and moderate-blockade, respectively. CONCLUSIONS: Single-dose magnesium sulfate led to a normalized train-of-four ratio < 0.9, 2 min after recovery from rocuronium-induced deep and moderate neuromuscular blockade using sugammadex. Additional sugammadex reversed prolonged recurarization.

Findings of the neuromuscular blocking agent rocuronium in blood from deceased subjects several months after exposure: A report of two cases.

Rocuronium is a neuromuscular blocking agent mainly used in anesthetic procedures. Two patients who died 53 and 76 days, respectively, after their last rocuronium exposure had low (0.002-0.007 mg/L) levels of the drug in femoral blood, urine and vitreous humor samples obtained at autopsy. In neither case, the cause of death was related to the exposure to rocuronium. Here, these two cases are presented and the implications of the findings discussed.

Traumatic brain injury and RSI is rocuronium or succinylcholine preferred?

PURPOSE OF REVIEW: Traumatic brain injury is widespread and has significant morbidity and mortality. Patients with severe traumatic brain injury often necessitate intubation. The paralytic for rapid sequence induction and intubation for the patient with traumatic brain injury has not been standardized. RECENT FINDINGS: Rapid sequence induction is the standard of care for patients with traumatic brain injury. Historically, succinylcholine has been the agent of choice due to its fast onset and short duration of action, but it has numerous adverse effects such as increased intracranial pressure and hyperkalemia. Rocuronium, when dosed appropriately, provides neuromuscular blockade as quickly and effectively as succinylcholine but was previously avoided due to its prolonged duration of action which precluded neurologic examination. However, with the widespread availability of sugammadex, rocuronium is able to be reversed in a timely manner. SUMMARY: In patients with traumatic brain injury necessitating intubation, rocuronium appears to be safer than succinylcholine.

Peri-operative management of neuromuscular blockade: A guideline from the European Society of Anaesthesiology and Intensive Care.

Recent data indicated a high incidence of inappropriate management of neuromuscular block, with a high rate of residual paralysis and relaxant-associated postoperative complications. These data are alarming in that the available neuromuscular monitoring, as well as myorelaxants and their antagonists basically allow well tolerated management of neuromuscular blockade. In this first European Society of Anaesthesiology and Intensive Care (ESAIC) guideline on peri-operative management of neuromuscular block, we aim to present aggregated and evidence-based recommendations to assist clinicians provide best medical care and ensure patient safety. We identified three main clinical questions: Are myorelaxants necessary to facilitate tracheal intubation in adults? Does the intensity of neuromuscular blockade influence a patient's outcome in abdominal surgery? What are the strategies for the diagnosis and treatment of residual paralysis? On the basis of this, PICO (patient, intervention, comparator, outcome) questions were derived that guided a structured literature search. A stepwise approach was used to reduce the number of trials of the initial research ( n  = 24 000) to the finally relevant clinical studies ( n  = 88). GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was used for formulating the recommendations based on the findings of the included studies in conjunction with their methodological quality. A two-step Delphi process was used to determine the agreement of the panel members with the recommendations: R1 We recommend using a muscle relaxant to facilitate tracheal intubation (1A). R2 We recommend the use of muscle relaxants to reduce pharyngeal and/or laryngeal injury following endotracheal intubation (1C). R3 We recommend the use of a fast-acting muscle relaxant for rapid sequence induction intubation (RSII) such as succinylcholine 1 mg kg -1 or rocuronium 0.9 to 1.2 mg kg -1 (1B). R4 We recommend deepening neuromuscular blockade if surgical conditions need to be improved (1B). R5 There is insufficient evidence to recommend deep neuromuscular blockade in general to reduce postoperative pain or decrease the incidence of peri-operative complications. (2C). R6 We recommend the use of ulnar nerve stimulation and quantitative neuromuscular monitoring at the adductor pollicis muscle to exclude residual paralysis (1B). R7 We recommend using sugammadex to antagonise deep, moderate and shallow neuromuscular blockade induced by aminosteroidal agents (rocuronium, vecuronium) (1A). R8 We recommend advanced spontaneous recovery (i.e. TOF ratio >0.2) before starting neostigmine-based reversal and to continue quantitative monitoring of neuromuscular blockade until a TOF ratio of more than 0.9 has been attained. (1C).

Reversal of rocuronium-induced intense neuromuscular blockade by sugammadex in Korean children: A pharmacokinetic and pharmacodynamic analysis.

Sugammadex, a selective antagonist of steroidal non-depolarizing neuromuscular blocking agents, has been used in children in limited circumstances. However, neither pharmacokinetics (PKs) nor recovery profile of sugammadex for intense neuromuscular blockade reversal in children have been reported. This prospective study aimed to obtain a PK model of sugammadex and evaluate its efficacy and safety for intense neuromuscular blockade reversal in children. Forty children (age, 2-17 years) who underwent surgery that required early neuromuscular blockade reversal were enrolled. After neuromuscular blockade with 1 mg∙kg-1 of rocuronium, sugammadex (2, 4, and 8 mg∙kg-1 ) or a conventional dose of neostigmine (0.03 mg∙kg-1 ) was administered randomly after confirmation of zero post-tetanic count. The plasma concentrations of rocuronium and sugammadex were measured 2 min after rocuronium injection; immediately before, 2, 5, 15, 60, 120, 240, and 480 min after the study drug injection. Response to train-of-four stimulation was continuously recorded. Noncompartmental analysis and population PK modeling were performed. For pharmacodynamics, the recovery profile was measured. Three-compartment PK model was established for sugammadex. The median (interquartile range [IQR]) time from injection of 8 mg∙kg-1 of sugammadex to recovery of T4 /T1 greater than or equal to 0.9 at train-of-four stimulation was 1.1 (IQR: 0.88-1.8) min. No adverse events related to sugammadex were observed. We present a PK analysis of sugammadex for rocuronium-induced intense neuromuscular blockade reversal in children with its recovery profile. The time to recover T4 /T1 greater than or equal to 0.9 at train-of-four stimulation with 8 mg∙kg-1 of sugammadex was less than 3 min and comparable to that in adults.

Successful management of rocuronium-induced anaphylaxis with sugammadex: A case report.

Although anaphylaxis during anaesthesia is a rare event, neuromuscular blocking drugs are responsible for 62% of anaesthesia-related anaphylaxis. However, sugammadex, a modified gamma-cyclodextrin, can encapsulate rocuronium molecules and cause the rapid reversal of the neuromuscular blockade. A 68-year-old man who presented for a radical prostatectomy was induced with IV fentanyl/propofol/rocuronium. He had not received rocuronium previously but had received cisatracurium. Shortly after anaesthesia, the patient's heart rate abruptly increased, and systolic blood pressure (SBP) dropped to 40 mm Hg. Despite cardiopulmonary resuscitation and intensive management, his haemodynamic stability did not improve until he received IV sugammadex, 200 mg. Intradermal skin tests showed he was positive for cisatracurium, rocuronium and succinylcholine. The patient was suspected to have cross-reactivity of rocuronium with cisatracurium. This case highlights the potential benefit of sugammadex as an adjunct to conventional measures during rocuronium-induced anaphylaxis.

Adamgammadex in patients to reverse a moderate rocuronium-induced neuromuscular block.

AIMS: The aim of this study was to investigate the effectiveness, safety and pharmacokinetics of adamgammadex in surgical patients. METHODS: Forty-eight patients aged 18-64 years old were randomized to receive adamgammadex (2, 4, 6, and 8 mg.kg-1 ) or placebo at a ratio of 10:2 for reversal of 0.6 mg.kg-1 rocuronium-induced neuromuscular block. Neuromuscular function was monitored by TOF-Watch® SX. When the T2 of train-of-four (TOF) reappeared at the end of surgery, patients received an intravenous administration of adamgammadex or placebo. RESULTS: The recovery time of the TOF ratio to 0.9 decreased significantly from 39.3 [29.5, 50.2] minutes in the group that received placebo to 3.0 [2.3, 3.9] minutes, P < .0001; 2.1 [1.5, 3.0] minutes, P < .0001; 2.1 [1.8, 3.3] minutes, P < .0001; and 1.8 [1.5, 2.2] minutes, P < .0001 in the 2, 4, 6 and 8 mg.kg-1 adamgammadex groups, respectively. Then, adamgammadex also showed a shortened recovery time for the TOF ratio recovered to 0.8 and 0.7. Adamgammadex was well tolerated, and no cases of anaphylactic reactions, post-operative bleeding, recurarization, abnormal basic vital signs and prolonged QT intervals were observed. The pharmacokinetics of adamgammadex in plasma increased in dose-dependent manner. The 24-hour cumulative fraction of adamgammadex in urine was 65-83%, and that of rocuronium was increased after using adamgammadex from 15% to about 25-30%. CONCLUSION: Adamgammadex was found to be effective for reversal of rocuronium-induced neuromuscular block, and it was safe and well tolerated in patients.

Role of sugammadex in the treatment of anaphylaxis due to rocuronium in children: Extrapolation from adult and animal reports.

Allergic reactions are generalized hypersensitivity processes triggered by different antigenic stimuli, resulting in the end effect of mast cell degranulation and adverse physiologic effects. During the perioperative period, the most commonly identified agents include antibiotics, neuromuscular blocking agents (rocuronium and succinylcholine), chlorhexidine, and iodinated dyes for radiologic imaging. Sugammadex is a novel agent for the reversal of neuromuscular blockade achieved with rocuronium or vecuronium. Its unique mechanism of action, whereby it encapsulates and forms a one-to-one complex with rocuronium, has led to its anecdotal use as an adjunct in the treatment of anaphylactic and anaphylactoid reactions following rocuronium. The current manuscript discusses the potential use of sugammadex in the treatment of allergic reactions following the administration of rocuronium, reviews previous anecdotal reports of its use in these scenarios, and provides recommendations for future care.

Rocuronium-induced respiratory paralysis refractory to sugammadex in Charcot-Marie-Tooth disease.

PURPOSE: Prolonged postoperative neuromuscular respiratory paralysis after administration of a nondepolarizing neuromuscular blocking agent is a serious concern during anesthetic management of patients with Charcot-Marie-Tooth disease (CMTD). Some recent reports have described rocuronium use without respiratory paralysis in CMTD patients when sugammadex was used for its reversal. We report a case in which an induction dose of rocuronium caused a prolonged respiratory paralysis in a patient with undiagnosed type 1A CMTD (CMT1A). CLINICAL FEATURES: A 63-yr-old-male with an American Society of Anesthesiologists Physical Status score of III underwent a left hip arthroplasty under general anesthesia for osteoarthritis. Preoperative pulmonary function testing indicated a restrictive impairment. Anesthesia was induced with fentanyl, remifentanil, propofol, and 0.73 mg·kg-1 of rocuronium. The train-of-four (TOF) count was 0 for the 273-min duration of surgery. After repeated doses of sugammadex failed to recover the TOF count and spontaneous respirations, a total of 1,200 mg (17.3 mg·kg-1) of sugammadex, which was assumed to be a sufficient amount for capturing the residual rocuronium, was administered. Although the patient expressed that he was awake via eye blinking, he could not breathe. Thus, he was placed on mechanical ventilation for 18 hr after surgery. A postoperative neurology consultation revealed a delayed nerve conduction velocity of 20 m·sec-1 and a mutated duplication of the PMP22 gene; a diagnosis of CMT1A was made. CONCLUSIONS: Our case shows that rocuronium can cause a prolonged neuromuscular respiratory paralysis refractory to sugammadex in patients with CMT1A and impaired respiratory function. Our case may also indicate that restrictive pulmonary impairment and low nerve conduction velocity of 20 m·sec-1 are predictive factors that cause prolonged neuromuscular respiratory paralysis refractory to sugammadex in CMT1A.

RéSUMé: OBJECTIF: La paralysie respiratoire neuromusculaire postopératoire prolongée après l'administration d'un bloqueur neuromusculaire non dépolarisant est une préoccupation sérieuse lors de la prise en charge anesthésique des patients atteints de la maladie de Charcot-Marie-Tooth (CMT). Certains comptes rendus récents ont décrit l'utilisation de rocuronium sans paralysie respiratoire chez les patients atteints de CMT lorsque le sugammadex était utilisé pour le neutraliser. Nous rapportons un cas dans lequel une dose d'induction de rocuronium a provoqué une paralysie respiratoire prolongée chez un patient atteint de CMT de type 1A (CMT1A) non diagnostiquée. CARACTéRISTIQUES CLINIQUES: Un homme de 63 ans avec un score de statut physique III selon la classification de l'American Society of Anesthesiologists a bénéficié d'une arthroplastie de la hanche gauche sous anesthésie générale pour son ostéo-arthrite. Les tests préopératoires de la fonction pulmonaire ont indiqué un syndrome restrictif. L'anesthésie a été induite avec du fentanyl, du rémifentanil, du propofol et 0,73 mg·kg-1 de rocuronium. Le décompte du train-de-quatre (TdQ) était de 0 pour toute la durée de la chirurgie, soit 273 minutes. Après l'échec de doses répétées de sugammadex qui n'ont pas réussi à rétablir un TdQ normal ni la respiration spontanée, un total de 1200 mg (17,3 mg·kg-1) de sugammadex (une quantité qu'on a présumé suffisante pour neutraliser le rocuronium résiduel) a été administré. Bien que le patient ait exprimé qu'il était éveillé en clignant des yeux, il ne pouvait pas respirer. Il a donc été placé sous ventilation mécanique pendant 18 heures après l'opération. Une consultation postopératoire en neurologie a révélé une vitesse de conduction nerveuse retardée de 20 m·sec-1 et une duplication mutée du gène PMP22; un diagnostic de CMT1A a été posé. CONCLUSIONS: Notre cas montre que le rocuronium peut provoquer une paralysie respiratoire neuromusculaire prolongée réfractaire au sugammadex chez les patients atteints de CMT1A et d'une altération de la fonction respiratoire. Notre cas pourrait également indiquer qu'un syndrome restrictif pulmonaire et une faible vitesse de conduction nerveuse de 20 m·sec-1 constituent des facteurs prédictifs provoquant une paralysie respiratoire neuromusculaire prolongée réfractaire au sugammadex dans les cas de CMT1A.

Rocuronium-Induced Dilated Nonreactive Pupils in a Patient With Coronavirus Disease 2019: A Case Report.

We report the clinical case of a patient with coronavirus disease 2019 (COVID-19) who had recently undergone neurosurgery and presented with dilated nonreactive pupils during continuous rocuronium infusion, which was reversible with the suspension of the drug. Both the neurosurgical procedure and possible disruption of the blood-brain barrier due to COVID-19 infection may have led to the action of rocuronium in the central nervous system (CNS). Thus, clinicians must remember that neuromuscular blocking agents (NMBAs) can cause dilated nonreactive pupils in patients with COVID-19.