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.

Epidemiology of perioperative anaphylaxis in France in 2017-2018: the 11th GERAP survey.

BACKGROUND: Perioperative anaphylaxis is rare but is associated with significant morbidity. This complication has been well described in France by the GERAP (Groupe d'Etude des Réactions Anaphylactiques Périopératoires), a network focused on its study. The epidemiology of perioperative anaphylaxis is evolving, influenced by environmental factors and clinical practice. The aim of this study was to update the epidemiology of perioperative anaphylaxis in France. METHODS: This multicentre retrospective study was performed in 26 allergy clinics of the GERAP network in 2017-8. RESULTS: There were 765 patients with perioperative anaphylaxis included. Most cases were severe, with 428 (56%) reactions graded as 3 or 4 according to the Ring and Messmer classification. Skin test results were available for 676 patients, with a culprit agent identified in 471 cases (70%). Neuromuscular blocking agents were the main cause of perioperative anaphylaxis (n=281; 60%), followed by antibiotics (n=118; 25%) and patent blue dye (n=11; 2%). Cefazolin was the main antibiotic responsible for perioperative anaphylaxis (52% of antibiotic-related reactions). Suxamethonium and rocuronium were the main neuromuscular blocking agents responsible for perioperative anaphylaxis with 7.1 (6.1-8.4) and 5.6 (4.2-7.4) reactions per 100,000 vials sold, respectively, whereas cefazolin-related cases were estimated at 0.7 (0.5-0.9) reactions per 100,000 vials sold. CONCLUSIONS: Our results confirm that most commonly identified triggering agents remain neuromuscular blocking agents. Reactions to antibiotics, particularly cefazolin, are becoming increasingly frequent. The origin of sensitisation to cefazolin is unknown, as no cross-sensitisation has been described, and it should be the subject of further study. Perioperative anaphylaxis should be followed over the years and understood given the changing triggers. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04654923).

Residual Neuromuscular Block Remains a Safety Concern for Perioperative Healthcare Professionals: A Comprehensive Review.

Residual neuromuscular block (RNMB) remains a significant safety concern for patients throughout the perioperative period and is still widely under-recognized by perioperative healthcare professionals. Current literature suggests an association between RNMB and an increased risk of postoperative pulmonary complications, a prolonged length of stay in the post anesthesia care unit (PACU), and decreased patient satisfaction. The 2023 American Society of Anesthesiologists Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade provide guidance for the use of quantitative neuromuscular monitoring coupled with neuromuscular reversal to recognize and reduce the incidence of RNMB. Using sugammadex for the reversal of neuromuscular block as well as quantitative neuromuscular monitoring to quantify the degree of neuromuscular block may significantly reduce the risk of RNMB among patients undergoing general anesthesia. Studies are forthcoming to investigate how using neuromuscular blocking agent reversal with quantitative monitoring of the neuromuscular block may further improve perioperative patient safety.

Anaphylaxis mortality in the perioperative setting: Epidemiology, elicitors, risk factors and knowledge gaps.

Perioperative anaphylaxis (PA) is a severe condition that can be fatal, but data on PA mortality are scarce. The aim of this article is to review the epidemiology, elicitors and risk factors for PA mortality and identify knowledge gaps and areas for improvement regarding the management of severe PA. PA affects about 100 cases per million procedures. Mortality is rare, estimated at 3 to 5 cases per million procedures, but the PA mortality rate is higher than for other anaphylaxis aetiologies, at 1.4% to 4.8%. However, the data are incomplete. Published data mention neuromuscular blocking agents and antibiotics, mainly penicillin and cefazolin, as the main causes of fatal PA. Reported risk factors for fatal PA vary in different countries. Most frequently occurring comorbidities are obesity, male gender, cardiovascular diseases and ongoing treatment with beta-blockers. However, there are no clues about how these factors interact and the impact of individual risk factors. The pathophysiology of fatal PA is still not completely known. Genetic factors such as deficiency in PAF-acetyl hydrolase and hereditary alpha-tryptasemia, have been reported as modulators of severe anaphylaxis and possible targets for specific treatments. Our review underlines unmet needs in the field of fatal PA. Although we confirmed the need for timely administration of an adequate dose of adrenaline and the proper infusion of fluids, there is no evidence-based data on the proper dose of intravenous titrated adrenaline and which clinical manifestations would flag the need for fluid therapy. There are no large clinical studies supporting the administration of alternative vasopressors, such as glucagon and methylene blue. Further research on pathophysiological mechanisms of PA and its severity may address these issues and help clinicians to define new therapeutic approaches.

Evaluation of a rapid sequence induction technique in dogs with or without rocuronium.

OBJECTIVE: To determine, using a rapid sequence induction (RSI) technique, whether rocuronium improves the quality and speed of endotracheal intubation in healthy dogs. STUDY DESIGN: Randomized, crossover, experimental study. ANIMALS: Six adult intact male Beagles (12.3 ± 0.4 kg). METHODS: Dogs were premedicated with intravenous acepromazine (0.03 mg kg-1) and hydromorphone (0.1 mg kg-1). Ten minutes later, anesthesia was induced with intravenous propofol (2 mg kg-1 over 5 seconds), followed by saline (0.06 mL kg-1, CT group) or rocuronium (0.6 mg kg-1, RT group), with orotracheal intubation attempted after 45 seconds. Intubation time (IT) and conditions (IC) were assessed. PaO2, PaCO2, arterial blood pH and serum cortisol were obtained before and after RSI. After endotracheal intubation, saline (0.04 mL kg-1) or sugammadex (4 mg kg-1) were administered intravenously in CT or RT groups, respectively. Spontaneous ventilation restoration was noted. RESULTS: The IT was 54.3 ± 6.9 (mean ± SD) and 57.8 ± 5.2 seconds for CT and RT, respectively (p = 0.385). All laryngoscopies indicated good IC in both treatment groups. Heart rate was lower in CT group than in RT group (66 ± 16 versus 103 ± 39 beats minute-1, p = 0.016). PaCO2, pH, PaO2 and cortisol did not differ between treatments. Compared with baseline, PaCO2 increased from 47.7 ± 6.2 to 58.8 ± 5.8 (p < 0.001) and pH decreased from 7.35 ± 0.04 to 7.28 ± 0.04 (p = 0.003), independent of treatment. Dogs in both treatment groups returned to spontaneous ventilation within 30 seconds of RSI. CONCLUSIONS AND CLINICAL RELEVANCE: RSI resulted in respiratory acidosis without hypoxemia or increased cortisol. Rocuronium did not improve IT or IC. Spontaneous ventilation was observed immediately after administering saline or sugammadex. The co-administration of rocuronium showed no clinical benefits over propofol alone in RSI in healthy dogs.

Pholcodine and allergy to neuromuscular blocking agents: where are we and how did we get here?

Despite the purported link between pholcodine and neuromuscular blocking agent allergy, screening for prior pholcodine use offers no practical benefit to patients, and anaesthetists should continue to use a neuromuscular blocking agent where this is clinically indicated.

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.

Comparison of the passive mast cell activation test with the basophil activation test for diagnosis of perioperative rocuronium hypersensitivity.

BACKGROUND: Rocuronium is a major cause of perioperative hypersensitivity (POH). Skin tests (STs) and quantification of specific immunoglobulin E antibodies (sIgEs) can yield incongruent results. In such difficult cases, the basophil activation test (BAT) can be helpful. Here, we evaluated the passive mast cell activation test (pMAT) as a substitute of BAT as part of the diagnostic tests for rocuronium allergy. METHODS: Sera from patients with a suspected POH reaction potentially related to rocuronium were included. All patients had a complete diagnostic investigation, including STs, quantification of sIgEs to morphine and rocuronium, and BAT. For execution of pMAT, human mast cells were generated from healthy donor peripheral blood CD34+ progenitor cells and sensitised overnight with patient sera. RESULTS: In total, 90 sera were studied: 41 from ST+sIgE+ patients, 13 from ST-sIgE- patients, 20 from ST+sIgE- patients, and 16 from ST-sIgE+ patients. According to BAT results, patients were further allocated into subgroups. Of the 38 BAT+ patients, 25 (66%) showed a positive pMAT as well. Of the 44 BAT- patients, 43 (98%) also showed a negative pMAT. Mast cells that were not passively sensitised did not respond to rocuronium. CONCLUSIONS: We show that the pMAT, in many cases, can substitute for BAT in the diagnosis of rocuronium hypersensitivity and advance diagnosis in difficult cases with uncertain ST or sIgE results when BAT is not locally available.

Rocuronium-Induced Anaphylaxis in the Perioperative Period: A Clinical Review.

Rocuronium, a nondepolarizing neuromuscular blocking agent used for muscle relaxation especially during endotracheal intubation, can cause hypersensitivity reactions. This article provides an overview of anaphylactic reactions; risk factors; and the pathophysiology, presentation, diagnosis, treatment, and nursing implications associated with rocuronium-induced anaphylaxis. Life-threatening anaphylaxis can be immunoglobulin E-mediated or non-immunoglobulin E-mediated and usually occurs after the first dose. Anaphylaxis can present with hypotension and bronchospasm; cutaneal symptoms, such as erythema, may not be obvious. Diagnosis is initially presumptive and may require a transesophageal echocardiogram to rule out other causes of hypotension (eg, pulmonary embolus). Emergency treatment begins with epinephrine administration and fluid boluses; cardiac support devices may be needed. Definitive diagnosis requires early measurement of histamine and tryptase levels and skin testing after the patient recovers from the reaction. Perioperative nurses should be prepared to participate in emergency treatment of anaphylaxis and advocate for testing for a definitive diagnosis.

Post-intubation analgesia and sedation following succinylcholine vs. rocuronium in the emergency department.

BACKGROUND: Succinylcholine and rocuronium are the most commonly utilized neuromuscular blocker agents (NMBAs) for rapid sequence intubation (RSI) in the emergency department (ED). The duration of action of rocuronium is significantly longer (∼30 min) compared to succinylcholine (∼10 min) and previous studies have shown that patients receiving rocuronium are more likely to have longer time to sedation initiation following RSI. Furthermore, patients receiving rocuronium may be more likely to experience awareness with paralysis than those receiving succinylcholine. The primary goal for this study was to evaluate the association between NMBA use during RSI and post-intubation sedation and analgesia practices in the ED. METHODS: This was a retrospective, multicenter cohort study including patients 18 years and older that received succinylcholine or rocuronium during RSI in the ED between September 1, 2020 and August 31, 2021. Patients were excluded if they were intubated prior to ED arrival, experienced an out-of-hospital or in ED cardiac arrest, or received sugammadex within 60 min of rocuronium administration. Patients were screened in reverse chronological order until the targeted sample size was achieved and all data was abstracted from the electronic health record. The primary outcome was the time to initiation of analgesia or sedation. Secondary outcomes included dose of sedatives or analgesia administered at 30- and 60 min, and medications administered for post-intubation sedation or analgesia. FINDINGS: A total of 200 ED patients were included of which 100 received succinylcholine and 100 received rocuronium. There was no difference in the median time to initiation of analgesia or sedation between the succinylcholine and rocuronium groups (10 vs 8.5 min, p = 0.82) or in Kaplan-Meier cumulative probabilities (p = 0.17). At 60 min post-RSI, those receiving succinylcholine received significantly higher median doses of propofol (20 µg/kg/min vs. 10 µg/kg/min; p = 0.02) and fentanyl [100 µg vs. 84.2 µg; p = 0.02]. CONCLUSION: While no differences were observed in the time to initiation of post-intubation sedation or analgesia in ED patients receiving succinylcholine compared to rocuronium, differences in the intensity of post-intubation regimens was observed. Further investigation is needed to evaluate the adequacy of sedation following RSI in the ED.

Pharmacotherapy optimization for rapid sequence intubation in the emergency department.

PURPOSE: Rapid-sequence intubation (RSI) is the process of administering a sedative and neuromuscular blocking agent (NMBA) in rapid succession to facilitate endotracheal intubation. It is the most common and preferred method for intubation of patients presenting to the emergency department (ED). The selection and use of medications to facilitate RSI is critical for success. The purpose of this review is to describe pharmacotherapies used during the RSI process, discuss current clinical controversies in RSI medication selection, and review pharmacotherapy considerations for alternative intubation methods. SUMMARY: There are several steps to the intubation process requiring medication considerations, including pretreatment, induction, paralysis, and post-intubation sedation and analgesia. Pretreatment medications include atropine, lidocaine, and fentanyl; but use of these agents in clinical practice has fallen out of favor as there is limited evidence for their use outside of select clinical scenarios. There are several options for induction agents, though etomidate and ketamine are the most used due to their more favorable hemodynamic profiles. Currently there is retrospective evidence that etomidate may produce less hypotension than ketamine in patients presenting with shock or sepsis. Succinylcholine and rocuronium are the preferred neuromuscular blocking agents, and the literature suggests minimal differences between succinylcholine and high dose rocuronium in first-pass success rates. Selection between the two is based on patient specific factors, half-life and adverse effect profiles. Finally, medication-assisted preoxygenation and awake intubation are less common methods for intubation in the ED but require different considerations for medication use. AREAS FOR FUTURE RESEARCH: The optimal selection, dosing, and administration of RSI medications is complicated, and further research is needed in several areas. Additional prospective studies are needed to determine optimal induction agent selection and dosing in patients presenting with shock or sepsis. Controversy exists over optimal medication administration order (paralytic first vs induction first) and medication dosing in obese patients, but there is insufficient evidence to significantly alter current practices regarding medication dosing and administration. Further research examining awareness with paralysis during RSI is needed before definitive and widespread practice changes to medication use during RSI can be made.

Reversal of neuromuscular block: what are the costs?

Patients requiring neuromuscular block for anaesthesia have a higher risk of adverse postoperative outcomes. The choice of reversal drug and its corresponding dose is critical for improving clinical outcomes. Although drug costs are higher for sugammadex relative to neostigmine, additional factors need to be considered when choosing one drug over the other. New data from a recent study in the British Journal of Anaesthesia indicate cost advantages for sugammadex in low-risk and ambulatory patients, but for neostigmine in high-risk patients. These findings highlight the need to take local and temporal factors into consideration in addition to clinical effectiveness when performing cost analyses for administrative decision-making.

Evaluation of the Effects of an Extubation Protocol With Neostigmine on Duration of Mechanical Ventilation After Cardiac Surgery.

OBJECTIVES: Residual neuromuscular blockade is associated with increased postoperative pulmonary complications. This study aimed to evaluate the effect of an extubation protocol incorporating neuromuscular blockade reversal (NMBR) by train-of-four monitoring on "fast-track" cardiac surgery outcomes. DESIGN: A retrospective cohort study. SETTING: At a university hospital. PARTICIPANTS: Out of 1,843 cardiac surgery patients, from February 2, 2015, to March 31, 2017, 957 (52%) underwent cardiac surgery on or after February 29, 2016. INTERVENTIONS: An extubation protocol, comprised of weaning from mechanical ventilation and NMBR guidelines, was implemented on February 29, 2016. MEASUREMENTS AND MAIN RESULTS: The associations of baseline characteristics with the postoperative duration of mechanical ventilation (primary outcome) and respiratory and/or adverse complications (secondary outcomes) were evaluated using regression and interrupted- time series models. The implementation of an extubation protocol was associated with an 18% decrease in the duration of mechanical ventilation (incident rate ratio [IRR] 0.82, 95% CI 0.72-0.94; p < 0.01), statistically insignificant 26% increase in patients extubated ≤6 hours (odds ratio [OR] 1.26, 95% CI 0.97-1.65; p = 0.09), and 13% shorter intensive care unit length of stay (LOS) (IRR 0.87, 95% CI 0.79-0.97; p < 0.01). Patients undergoing isolated coronary artery bypass graft or isolated valve procedures, on or after February 29, 2016, had decreased extubation times (IRR 0.82, p < 0.01 and IRR 0.80, p = 0.02). The protocol did not have a statistically significant association with hospital LOS (IRR 0.98, p = 0.57) or readmission (OR 1.22, p = 0.33), and differences in the occurrence of pulmonary complications and adverse outcomes between the pre- and postprotocol groups were clinically insignificant. CONCLUSIONS: The application of an extubation protocol incorporating NMBR based on neuromuscular monitoring was associated with a decrease in postoperative duration of mechanical ventilation and facilitated more patients meeting the early extubation benchmark without an increased risk of respiratory complications or adverse outcomes.