Efficacy and safety of adamgammadex for reversing rocuronium-induced deep neuromuscular blockade: A multicenter, randomized, phase IIb study.

The rapid reversal of deep neuromuscular blockade (NMB) is important but remains challenging. This study aimed to evaluate the efficacy and safety of adamgammadex versus sugammadex in reversing deep rocuronium-induced NMB. This multicenter, randomized, phase IIb study included 80 patients aged 18-64 years, American Society of Anesthesiologists (ASA) grade 1-2, undergoing elective surgery under general anesthesia with rocuronium. Patients were randomized to the adamgammadex 7, 8, and 9 mg/kg group or the sugammadex 4 mg/kg group. The primary efficacy variable was the time to recovery of train-of-four ratio (TOFr) to 0.9. The secondary efficacy variables were the time to recovery of TOFr to 0.7, antagonistic success rate of the recovery of TOFr to 0.9 within 5 min, and incidence rate of recurarization within 30 min after drug administration. The explorative efficacy variable was the time to recovery of the corrected TOFr to 0.9 (actual/baseline TOF ratio). Adamgammadex 7, 8, and 9 mg/kg and sugammadex 4 mg/kg groups did not significantly differ in all efficacy variables. Importantly, adamgammadex 9 mg/kg permitted reversal within a geometric mean of 2.9 min. According to the safety profile, adamgammadex achieved good tolerance and low incidence of drug-related adverse events compared with the 4 mg/kg sugammadex. Adamgammadex 7, 8, and 9 mg/kg facilitated rapid reversal of deep rocuronium-induced NMB and had good tolerance and low incidence of drug-related adverse events. Therefore, adamgammadex is a potential and promising alternative to sugammadex.

Awareness with paralysis and symptoms of post-traumatic stress disorder among mechanically ventilated emergency department survivors (ED-AWARENESS-2 Trial): study protocol for a pragmatic, multicenter, stepped wedge cluster randomized trial.

BACKGROUND: Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials have been conducted to prevent AWP in the operating room, where prevalence is 0.1-0.2%. By contrast, AWP in mechanically ventilated emergency department (ED) patients is common, with estimated prevalence of 3.3-7.4% among survivors given NMB. Longer-acting NMB use is a critical risk for AWP, and we have shown an association between ED rocuronium use and increased AWP prevalence. As NMB are given to more than 90% of ED patients during tracheal intubation, this trial provides a platform to test an intervention aimed at reducing AWP. The overall objective is to test the hypothesis that limiting ED rocuronium exposure will significantly reduce the proportion of patients experiencing AWP. METHODS: This is a pragmatic, stepped wedge cluster randomized trial conducted in five academic EDs, and will enroll 3090 patients. Per the design, all sites begin in a control phase, under observational conditions. At 6-month intervals, sites sequentially enter a 2-month transition phase, during which we will implement the multifaceted intervention, which will rely on use of nudges and defaults to change clinician decisions regarding ED NMB use. During the intervention phase, succinylcholine will be the default NMB over rocuronium. The primary outcome is AWP, assessed with the modified Brice questionnaire, adjudicated by three independent, blinded experts. The secondary outcome is the proportion of patients developing clinically significant symptoms of post-traumatic stress disorder at 30 and 180 days after hospital discharge. We will also assess for symptoms of depression and anxiety, and health-related quality of life. A generalized linear model, adjusted for time and cluster interactions, will be used to compare AWP in control versus intervention phases, analyzed by intention-to-treat. DISCUSSION: The ED-AWARENESS-2 Trial will be the first ED-based trial aimed at preventing AWP, a critical threat to patient safety. Results could shape clinical use of NMB in the ED and prevent more than 10,000 annual cases of AWP related to ED care. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05534243 . Registered 06, September 2022.

Transcutaneous electric acupoint stimulation reduces rocuronium injection-related pain: a prospective randomized controlled study.

OBJECTIVE: Various approaches have been suggested to reduce the pain and discomfort associated with rocuronium injection. This randomized controlled trial aimed at exploring the effectiveness of transcutaneous electrical acupoint stimulation (TEAS), a non-invasive modality to reduce the pain associated with rocuronium injection. PATIENTS AND METHODS: 60 patients undergoing elective general anesthesia were recruited and randomly allocated to the TEAS or placebo TEAS (no electrical output) groups. TEAS consisted of 30 min of stimulation at a frequency of 2/100 Hz and an intensity of 6-9 mA on Hegu (LI4) and Neiguan (PC6) before anesthesia induction. A blinded observer evaluated the pain using a 4-point pain scale. RESULTS: The overall incidence of rocuronium injection-related pain was significantly lower in the TEAS group than that in the placebo TEAS group (40% and 86.7%, respectively). The incidence of no or mild pain was significantly higher in the TEAS group (100%, p<0,001) group than that in the placebo TEAS group (50%). CONCLUSIONS: Pretreatment with TEAS effectively reduced the frequency and severity of pain associated with rocuronium injection.

Residual neuromuscular blockade in the ICU: a prospective observational study and national survey.

Residual neuromuscular blockade is associated with significant morbidity. It has been widely studied in anaesthesia; however, the incidence of residual neuromuscular blockade in patients managed in the ICU is unknown. We conducted a prospective observational study in a tertiary ICU to determine the incidence of residual neuromuscular blockade using quantitative accelerographic monitoring. We tested for residual neuromuscular blockade (defined as a train-of-four ratio < 0.9) before cessation of sedation in anticipation of tracheal extubation. We also surveyed 16 other ICUs in New Zealand to determine their use of neuromuscular monitoring. A total of 191 patients were included in the final analysis. The incidence (95%CI) of residual neuromuscular blockade was 43% (36-50%), with a similar incidence observed in non-postoperative and postoperative patients. There was a lower risk of residual neuromuscular blockade with atracurium than rocuronium (risk ratio (95%CI) of 0.39 (0.12-0.78)) and a higher risk with pancuronium than rocuronium (1.59 (1.06-2.49)). Our survey shows that, in New Zealand ICUs, monitoring of neuromuscular function is rarely carried out before tracheal extubation. When neuromuscular monitoring is undertaken, it is based on individual clinician suspicion and performed using qualitative measurements. No ICU reported using a quantitative monitor or a clinical guideline. The results demonstrate a high incidence of residual neuromuscular blockade in our ICU patients and identify the type of neuromuscular blocking drug as a possible risk factor. Monitoring neuromuscular function before tracheal extubation is not currently the standard of care in New Zealand ICUs. These data suggest that residual neuromuscular blockade may be an under-recognised problem in ICU practice.

Time interval between alfentanil and rocuronium administration necessary to prevent rocuronium-induced withdrawal movement.

BACKGROUND: We aimed to determine the time interval between alfentanil and rocuronium administration, at a 50% probability of preventing pain-induced withdrawal movement from rocuronium injection (TimeAR50). METHODS: A total of 64 patients scheduled for general anesthesia were enrolled in this study (33 men and 31 women). Anesthesia was induced with target-controlled infusion of propofol, at an effect-site target concentration of 3 µg/mL. Then, alfentanil 15 µg/kg was injected for 30 s. After 60 s, rocuronium 0.6 mg/kg was administered to the first patient. The Dixon's up-and-down method was used to determine the time interval for each subsequent patient (interval of 5 s). Mean arterial pressure (MAP) and heart rate (HR) were recorded at three time points: T0, pre-induction; T1, before rocuronium injection; and T2, 1 min after rocuronium injection. RESULTS: The TimeAR50 ± standard deviation (SD) was 5.6 ± 3.7 s and 21.9 ± 5.6 s in the male and female patients, respectively. Based on the probit regression, the TimeAR50 was 4.7 s (95% confidence interval [CI], 1.2-7.6 s) and 20.3 s (95% CI, 7.7-26.1 s) in the male and female patients, respectively. The TimeAR95 was 10.6 s (95% CI, 7.7-25.3 s) and 35.0 s (95% CI, 28.1-95.5 s) in the male and female patients, respectively, with significantly higher values in females than in males (P < 0.001). Compared with the T0, MAP and HR decreased significantly at T1 and T2 in both groups. CONCLUSION: The TimeAR50 required for preventing rocuronium-induced withdrawal movement were 4.7 s and 20.3 s in male and female patients, respectively. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trials Registry on April 7, 2021 (URL: http://www.chictr.org.cn . Registry number: ChiCTR2100045137 ) .

What do we know about perioperative hypersensitivity reactions and what can we do to improve perioperative safety?

Hypersensitivity reactions are an important aspect of perioperative care and are a crucial interdisciplinary issue in anaesthesiological practice, as well as allergological and laboratory diagnostics. This phenomenon was observed as early as the 1980s and 1990s in Western European countries, and knowledge on this subject has grown significantly over time. Although hypersensitivity reactions are not frequent events (the incidence of perioperative hypersensitivity reactions ranges from 1:386 to 1:13 000 procedures, with higher frequency - 1 per 6500 general anaesthesias with neuromuscular blocking agents administrations), their courses are unfortunately serious and life-threatening. It should also be noted that there is no information regarding the occurrence of perioperative hypersensitivity reactions in many countries. Hence, global assessment of the problem is underestimated. The primary source of actual knowledge comes from epidemiological studies, which indicate an increasing frequency of hypersensitivity reaction occurrence and changes in aetiological factors. The first report from France (1984 to 1989) described two main causes - neuromuscular blocking agents and hypnotic agents. The following years confirmed an increase in perioperative hypersensitivity reactions associated with latex and antibiotics. The most recent data from the National Audit Project 6 indicated increased participation of antibiotics, chlorhexidine, and contrast agents. The results of epidemiological analyses are the basis of medical management guidelines and practice modification. Thanks to the activity of many organisations monitoring the intensity and nature of perioperative hypersensitivity reactions, guidelines for diagnostics and management have been developed. This article presents the results of numerous studies, including the first and the most recent, from various geographical regions. The clinical significance, pathogenesis mechanisms are also discussed. This publication also presents important directions for further scientific and epidemiological research on perioperative hypersensitivity reactions.Key messagesThe incidence of perioperative hypersensitivity reactions ranges from 1:386 to 1:13 000 procedures, with higher frequency - 1 per 6500 general anaesthesias with neuromuscular blocking agents administrations.Reactions may occur during the first episode of anaesthesia, most frequently in the induction of general anaesthesia, and much less frequently during postoperative follow-up.The first reports of perioperative hypersensitivity reaction come from the 1990s, and knowledge on this subject has grown significantly over time.In many countries, multidisciplinary teams and organisations have been established to identify, monitor the occurrence of this phenomenon, and have set the directions of medical activities and have changed the rules and recommendations.There is no information about the occurrence of perioperative hypersensitivity reactions in many countries, and global assessment of the problem is underestimated. Additionally, there is a great need to develop a system to monitor their occurrence in other countries.The long-term epidemiologic studies have demonstrated variability in pharmacologic triggers. However, the main pharmacological substances (antibiotics, muscle relaxants, disinfectans, contrast agents) are related to aspects of patient safety during anaesthesia.

A randomized trial evaluating the safety profile of sugammadex in high surgical risk ASA physical class 3 or 4 participants.

BACKGROUND: The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest. METHODS: Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias. RESULTS: Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m2, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study. CONCLUSIONS: Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03346057 .

MRGPRX2 and Adverse Drug Reactions.

Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.

Does Sugammadex Suppress Allergic Inflammation Due to Rocuronium in Animal Model of Rat?

INTRODUCTION AND OBJECTIVES: There are a few reports in the literature about the successful use of sugammadex in the treatment of hypersensitivity reactions caused by rocuronium; however, the pathophysiological mechanism is still unknown. This study aims to investigate the changes caused by rocuronium in the lung and the effect of sugammadex on these changes with biochemical, light microscopic and immunohistochemical parameters on a rat model. MATERIALS AND METHODS: For the study, 28-male Sprague-Dawley rats were randomly divided, seven of each, into four groups. Group C (control) received only 0. 9 % NaCl without any drug. Group R received rocuronium alone 1mg/kg. Group S received sugammadex alone 96 mg/kg. Group RS received rocuronium 1mg/kg and sugammadex 96 mg/kg. After 24 h later, the animals were sacrificed and their tissues were removed. Biochemical (IgE/CRP), light microscopic and immunohistochemical findings were recorded. RESULTS: Immunoglobulin E and CRP levels, peribronchial, alveolar septal lymphocytic infiltration, thickening of the alveolar membranes and bleeding sites in Group R were significantly higher than all the other groups. In Group RS, while these parameters were significantly lower than that of Group R and Group S, it was significantly higher than that of Group C. Total mast cells and tryptase-positive mast cells counts were significantly higher in Group R than in all other groups. In Group RS, these parameters were statistically lower than that of Group R and Group S, but higher than that of Group C. CONCLUSIONS: This study shows that allergic inflammatory changes due to rocuronium in the lungs of rats are reduced with sugammadex. These results support cases of anaphylaxis due to rocuronium which improved with sugammadex.

Residual paralysis caused by 50 mg rocuronium after reversal with 4 mg/kg sugammadex: a case report.

BACKGROUND: Rocuronium-induced neuromuscular blockade can be quickly and completely reversed by administration of an optimal dose of sugammadex. Sugammadex antagonizes rocuronium-induced neuromuscular blockade by encapsulating rocuronium. Herein, we report a case of residual neuromuscular paralysis in which the recommended dose of sugammadex (4 mg·kg- 1) failed to antagonize a rocuronium-induced blockade. CASE PRESENTATION: A 71-year-old man (body mass index: 26.7 kg·m- 2) underwent endoscopic submucosal dissection of early-stage gastric cancer. He had no known factors that may have affected the effects of rocuronium and sugammadex. He received rocuronium (50 mg; 0.7 mg·kg- 1) for anesthesia induction. No additional rocuronium was administered during the 71-min procedure. Ninety-four minutes after rocuronium administration, neuromuscular monitoring showed 20 twitches in response to post-tetanic count stimulation. The train-of-four (TOF) ratio was not measurable despite sugammadex (280 mg; 4 mg/kg) administration, although four weak twitches in response to TOF stimulation appeared in 3 min. The TOF ratio became detectable following administration of an additional dose of sugammadex (120 mg; 1.7 mg·kg- 1), and it recovered to 107% 8 min after the second dose. The patient opened his eyes; moved his neck, arms, and limbs; and regained consciousness. The trachea was extubated and the patient was transferred to the ward. CONCLUSIONS: Neuromuscular monitoring should be used if a neuromuscular blockage agent is administered, even if the recommended dose of sugammadex is administered.

Does Sugammadex Suppress Allergic Inflammation Due to Rocuronium in Animal Model of Rat?

Introduction and Objectives: There are a few reports in the literature about the successful use of sugammadex in the treatment of hypersensitivity reactions caused by rocuronium; however, the pathophysiological mechanism is still unknown. This study aims to investigate the changes caused by rocuronium in the lung and the effect of sugammadex on these changes with biochemical, light microscopic and immunohistochemical parameters on a rat model. Materials and Methods: For the study, 28-male Sprague-Dawley rats were randomly divided, seven of each, into four groups. Group C (control) received only 0. 9 % NaCl without any drug. Group R received rocuronium alone 1mg/kg. Group S received sugammadex alone 96 mg/kg. Group RS received rocuronium 1mg/kg and sugammadex 96 mg/kg. After 24 h later, the animals were sacrificed and their tissues were removed. Biochemical (IgE/CRP), light microscopic and immunohistochemical findings were recorded. Results: Immunoglobulin E and CRP levels, peribronchial, alveolar septal lymphocytic infiltration, thickening of the alveolar membranes and bleeding sites in Group R were significantly higher than all the other groups. In Group RS, while these parameters were significantly lower than that of Group R and Group S, it was significantly higher than that of Group C. Total mast cells and tryptase-positive mast cells counts were significantly higher in Group R than in all other groups. In Group RS, these parameters were statistically lower than that of Group R and Group S, but higher than that of Group C. Conclusions: This study shows that allergic inflammatory changes due to rocuronium in the lungs of rats are reduced with sugammadex. These results support cases of anaphylaxis due to rocuronium which improved with sugammadex (AU)

Comparison of Rocuronium with Succinylcholine for Rapid Sequence Induction Intubation in the Emergency Department: A Retrospective Study at a Single Center in China.

BACKGROUND This retrospective study was conducted at a single center in China and aimed to compare rocuronium with succinylcholine for rapid sequence induction intubation in the Emergency Department of a hospital. MATERIAL AND METHODS An orotracheal intubation procedure was performed in a total of 267 patients by direct laryngoscopy using an intravenous bolus injection of 1 mg/kg of succinylcholine (n=141; SY group) or 1.2 mg/kg of rocuronium (n=126; RM group) for a rapid sequence induction in the emergency department. The success of orotracheal intubation was evaluated by a capnography curve. The modified Cormack-Lehane score was used to grade the direct laryngoscopy. RESULTS There was no statistically significant difference in numbers of patients with successful first-attempt orotracheal intubation between the groups (112 vs. 87, P=0.067). Fewer intubation failures under direct laryngoscopy were reported in the SY group than in the RM group (23 [16%] vs. 34 [27%], P=0.037). The number of intubation attempts was higher in the RM group than in the SY group (1.52±0.87 per patient vs. 1.27±0.60 per patient, P=0.032). CONCLUSIONS The findings from this study support results from previous studies, showing that even in the Emergency Department setting, rocuronium was equivalent to succinylcholine in achieving rapid sequence induction intubation, when the dose was appropriate. However, as current clinical guidelines highlight, succinylcholine has more contraindications and adverse effects, including hyperkalemia, which should be monitored, and rocuronium has a longer duration of action.

Relationship of perioperative anaphylaxis to neuromuscular blocking agents, obesity, and pholcodine consumption: a case-control study.

BACKGROUND: The observation that patients presenting for bariatric surgery had a high incidence of neuromuscular blocking agent (NMBA) anaphylaxis prompted this restricted case-control study to test the hypothesis that obesity is a risk factor for NMBA anaphylaxis, independent of differences in pholcodine consumption. METHODS: We compared 145 patients diagnosed with intraoperative NMBA anaphylaxis in Western Australia between 2012 and 2020 with 61 patients with cefazolin anaphylaxis with respect to BMI grade, history of pholcodine consumption, sex, age, comorbid disease, and NMBA type and dose. Confounding was assessed by stratification and binomial logistic regression. RESULTS: Obesity (odds ratio [OR]=2.96, χ2=11.7, P=0.001), 'definite' pholcodine consumption (OR=14.0, χ2=2.6, P<0.001), and female sex (OR=2.70, χ2=9.61, P=0.002) were statistically significant risk factors for NMBA anaphylaxis on univariate analysis. The risk of NMBA anaphylaxis increased with BMI grade. Confounding analysis indicated that both obesity and pholcodine consumption remained important risk factors after correction for confounding, but that sex did not. The relative rate of rocuronium anaphylaxis was estimated to be 3.0 times that of vecuronium using controls as an estimate of market share, and the risk of NMBA anaphylaxis in patients presenting for bariatric surgery was 8.8 times the expected rate (74.9 vs 8.5 per 100 000 anaesthetic procedures). CONCLUSIONS: Obesity is a risk factor for NMBA anaphylaxis, the risk increasing with BMI grade. Pholcodine consumption is also a risk factor, and this is consistent with the pholcodine hypothesis. Rocuronium use is associated with an increased risk of anaphylaxis compared with vecuronium in this population.

Safety and efficacy of unilateral topical application of rocuronium bromide in healthy scops owls (Otus scops).

OBJECTIVE: To evaluate the safety and efficacy of unilateral topical application of rocuronium bromide in scops owls. ANIMALS STUDIED: Ten healthy adult scops owls. PROCEDURES: Birds weighting between 82-111 g were enrolled. Complete physical and ophthalmic examinations were performed. Each animal received a single dose of 0.15 mg of rocuronium bromide (30 µL) in a randomly selected eye. Static pupillometric evaluations were performed before and after drug instillation at 0, 30, 60, 90, and 120 minutes, in a room with fixed light intensity. Physical and ophthalmic examinations were carried out to evaluate possible adverse effects. RESULTS: Median pupil (95% CI) size at t0 was 7.10 mm (5.51-7.41) for placebo eyes and 7.22 mm (6.93-7.48) for treated eyes, showing no statistical differences (P > .05). When compared to the placebo eye, significant mydriasis was achieved at t30 [8.18 mm (7.22-9.00)] (P = .014) and lasting until t90 [7.35 mm (6.20-9.52)] (P = .004). Maximal mydriasis was obtained at t60 [8.63 mm (7.72-9.81)] (P = .001). During this period, the treated eye no longer responded to direct light stimulation. Complete mydriasis was observed in 5/10 birds (mean weight 97.4 g). Pupil size at t90 and t120 did not differ from baseline (P > .05) in treated eyes. No adverse effects were seen during the study period. CONCLUSION: Single-dose topical rocuronium bromide (0.15 mg) is a safe and effective medium duration mydriatic agent in scops owls. Further studies are needed to evaluate bilateral topical application and standardize the mydriatic protocol.

Incidence of Anaphylaxis to Sugammadex in a Single-Center Cohort of 19,821 Patients.

BACKGROUND: Sugammadex is a modified cyclodextrin that is being increasingly used in anesthetic practice worldwide for the reversal of the aminosteroid neuromuscular blockers rocuronium and vecuronium. Its safety profile, however, is incompletely understood. One such aspect is the incidence of anaphylactic reactions that occur after its administration. While several case reports exist in the literature, there is a paucity of information on the actual incidence of anaphylactic reactions. METHODS: A single-center retrospective chart review identified patients who experienced anaphylaxis to sugammadex in the institutional electronic medical record system. These charts were then reviewed to determine whether the etiology of anaphylaxis was sugammadex administration. RESULTS: Two patients experienced anaphylaxis to sugammadex, which occurred in a single institution cohort of 19,821 patients who received 23,446 total doses. This rate is markedly lower than the 1/300 that the manufacturer's package insert states and also lower than the 1/2500 that the only other large cohort study performed has reported. CONCLUSIONS: The incidence of anaphylaxis to sugammadex in this cohort of patients was 2 of 19,821 patients, who received a total of 23,446 doses.

MRGPRX2 activation in mast cells by neuromuscular blocking agents and other agonists: Modulation by sugammadex.

BACKGROUND: Neuromuscular-blocking agents (NMBAs) can cause both IgE-dependent and IgE-independent anaphylactic reactions, with activation of the mast cell receptor MRGPRX2 being important to the latter. Sugammadex, a reversal agent for certain aminosteroid NMBAs, has been proposed as an antidote for these anaphylactic events with conflicting outcomes. OBJECTIVE: We further characterize the involvement of MRGPRX2 in NMBA-induced mast cell activation and determine how this is influenced by sugammadex. We then apply these in vitro results to infer the possible utility of sugammadex in the acute management of non-IgE-dependent anaphylaxis. METHODS: The LAD2 human mast cell line and a MRGPRX2 knock-down derivative were used to validate the involvement of MRGPRX2 and to test the effect of sugammadex on mast cell activation by NMBAs and other MRGPRX2 agonists. RESULTS: All MRGPRX2 agonists tested were shown to induce MRGPRX2-dependent LAD2 mast cell calcium mobilization and cytokine release and all, apart from rocuronium, induced degranulation. Co-treatment of mast cells with sugammadex and some MRGPRX2 agonists significantly reduced cell activation, but if sugammadex was administered a few minutes following stimulation, degranulation was not attenuated. However, addition of sugammadex up to 180 min following LAD2 MRGPRX2 stimulation, significantly reduced CCL2 mRNA and protein induction. CONCLUSIONS AND CLINICAL RELEVANCE: We show that sugammadex, known to reverse muscle blockade by certain NMBAs, is also able to reduce MRGPRX2 activation by NMBAs and other, but not all, MRGPRX2 agonists. As sugammadex was ineffective in attenuating mast cell degranulation when added rapidly post MRGPRX2 activation, this suggests against the agent having efficacy in controlling acute symptoms of anaphylaxis to NMBAs caused by MRGPRX2 activation. Interestingly, however, sugammadex did impair MRGPRX2-induced CCL2 release, suggesting that it may have some benefit in perhaps dampening less well-defined adverse effects of MRGPRX2-dependent anaphylaxis associated with the more slowly elaborated mast cell mediators.