Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models.

Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.

Association between reversal agents (sugammadex vs. neostigmine) for neuromuscular block and postoperative pulmonary complications: A retrospective analysis.

AIMS: Residual neuromuscular blockade has been linked to pulmonary complications in the postoperative period. This study aimed to determine whether sugammadex was associated with a lower risk of postoperative pulmonary complications (PPCs) compared with neostigmine. METHODS: This retrospective cohort study was conducted in a tertiary academic medical center. Patients ≥18 year of age undergoing noncardiac surgical procedures with general anesthesia and mechanical ventilation were enrolled between January 2019 and September 2021. We identified all patients receiving rocuronium and reversal with neostigmine or sugammadex via electronic medical record review. The primary endpoint was a composite of PPCs (including pneumonia, atelectasis, respiratory failure, pulmonary embolism, pleural effusion, or pneumothorax). The incidence of PPCs was compared using propensity score analysis. RESULTS: A total of 1786 patients were included in this study. Among these patients, 976 (54.6%) received neostigmine, and 810 (45.4%) received sugammadex. In the whole sample, PPCs occurred in 81 (4.54%) subjects (7.04% sugammadex vs. 2.46% neostigmine). Baseline covariates were well balanced between groups after overlap weighting. Patients in the sugammadex group had similar risk (overlap weighting OR: 0.75; 95% CI: 0.40 to 1.41) compared to neostigmine. The sensitivity analysis showed consistent results. In subgroup analysis, the interaction P-value for the reversal agents stratified by surgery duration was 0.011. CONCLUSION: There was no significant difference in the rate of PPCs when the neuromuscular blockade was reversed with sugammadex compared to neostigmine. Patients undergoing prolonged surgery may benefit from sugammadex, which needs to be further investigated.

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 ) .