Extravascular injection of neuromuscular blocking drugs: A systematic review of current evidence and management.

Extravascular injection of neuromuscular blocking drugs (NMBDs) can cause a neuromuscular block because of systemic absorption. Currently, there are no guidelines available on managing extravasation of NMBDs. This article reviews the available literature on extravasation of NMBDs. Medline and Embase databases were searched for studies concerning the paravenous or subcutaneous injection of NMBDs. Nine articles were included consisting of seven case reports, one case series and one clinical trial. Rocuronium was used as primary NMBD in nine cases, vecuronium in two cases and pancuronium in one case. Although there exists significant heterogeneity between the reported information in the included studies, the majority of the case reports describe a slower onset, with a median delay of 20 min and prolonged duration of the neuromuscular block. Nine patients had a residual neuromuscular block at the end of the surgery. Postoperative monitoring in the recovery room was prolonged (median time 4 h). Most studies suggest that the delay in NMBD onset and recovery is caused by the formation of a subcutaneous depot, from which the NMBD is slowly absorbed into the systemic circulation. According to the current literature, extravasation of NMBDs results in an unpredictable neuromuscular block. Strategies to prevent potentially harmful side effects, such as frequent train-of-four (TOF) monitoring, the use of NMBD reversal agents and prolonged length of stay in the postanaesthesia care unit (PACU), should be considered. This article suggests a clinical pathway that can be used after extravascular injection of NMBDs.

Sugammadex for reversal of neuromuscular blockade in pediatric patients: Results from a phase IV randomized study.

BACKGROUND: Few randomized studies have assessed recovery from rocuronium- or vecuronium-induced moderate or deep neuromuscular blockade with sugammadex in pediatric participants. AIM: To assess sugammadex for reversal of neuromuscular blockade in pediatric participants. METHODS: This was a randomized, phase IV, active comparator-controlled, double-blind study. Participants aged 2 to <17 years, under moderate or deep neuromuscular blockade, were administered sugammadex (2 or 4 mg/kg) or neostigmine (50 µg/kg; for moderate neuromuscular blockade only). Predefined adverse events of clinical interest, including clinically relevant bradycardia, hypersensitivity, and anaphylaxis, were monitored. The primary efficacy endpoint was time to recovery to a train-of-four ratio of ≥0.9 in participants receiving sugammadex 2 mg/kg versus neostigmine for reversal of moderate neuromuscular blockade, analyzed by analysis of variance adjusted for neuromuscular blocking agent and age. RESULTS: Of 288 randomized participants, 272 completed the study and 276 were included in the analyses. Clinically relevant bradycardia was experienced by 2.0%, 1.6%, and 5.9% of participants in the sugammadex 2 mg/kg, sugammadex 4 mg/kg, and neostigmine groups, respectively. No hypersensitivity or anaphylaxis events were observed. Recovery to a train-of-four ratio of ≥0.9 with sugammadex 2 mg/kg was faster than neostigmine (1.6 min, 95% CI 1.3 to 2.0 vs. 7.5 min, 95% CI 5.6 to 10.0; p < .0001) and was comparable to sugammadex 4 mg/kg (2.0 min, 95% CI 1.8 to 2.3). CONCLUSIONS: Pediatric participants recovered from rocuronium- or vecuronium-induced moderate neuromuscular blockade significantly faster with sugammadex 2 mg/kg than with neostigmine. Time to reversal of deep neuromuscular blockade with sugammadex 4 mg/kg was consistent with that of moderate neuromuscular blockade reversal. No meaningful differences in clinically relevant bradycardia, hypersensitivity, or anaphylaxis were seen with sugammadex vs neostigmine. These results support the use of sugammadex for reversal of moderate and deep rocuronium- and vecuronium-induced neuromuscular blockade in patients aged 2 to <17 years. CLINICAL TRIAL REGISTRATION: NCT03351608/EudraCT 2017-000692-92.

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 .

Quantitative Structure-Activity Relationship (QSAR) Model for the Severity Prediction of Drug-Induced Rhabdomyolysis by Using Random Forest.

Drug-induced rhabdomyolysis (DIR) is a rare and potentially life-threatening muscle injury that is characterized by low incidence and high risk. To our best knowledge, the performance of the current predictive models for the early detection of DIR is suboptimal because of the scarcity and dispersion of DIR cases. Therefore, on the basis of the curated drug information from the Drug-Induced Rhabdomyolysis Atlas (DIRA) database, we proposed a random forest (RF) model to predict the DIR severity of the marketed drugs. Compared with the state-of-art methods, our proposed model outperformed extreme gradient boosting, support vector machine, and logistic regression in distinguishing the Most-DIR concern drugs from the No-DIR concern drugs (Matthews correlation coefficient (MCC) and recall rate of our model were 0.46 and 0.81, respectively). Our model was subsequently applied to predicting the potentially serious DIR for 1402 drugs, which were reported to cause DIR by the postmarketing DIR surveillance data in the FDA Spontaneous Adverse Events Reporting System (FAERS). As a result, 62.7% (94) of drugs ranked in the top 150 drugs with the Most-DIR concerns in FAERS can be identified by our model. The top four drugs (odds ratio >30) including acepromazine, rapacuronium, oxyphenbutazone, and naringenin were correctly predicted by our model. In conclusion, the RF model can well predict the Most-DIR concern drug only based on the chemical structure information and can be a facilitated tool for early DIR detection.

The Effects of Postoperative Residual Neuromuscular Blockade on Hospital Costs and Intensive Care Unit Admission: A Population-Based Cohort Study.

BACKGROUND: Postoperative residual neuromuscular blockade continues to be a frequent occurrence with a reported incidence rate of up to 64%. However, the effect of postoperative residual neuromuscular blockade on health care utilization remains unclear. We conducted a retrospective cohort study to investigate the effects of postoperative residual neuromuscular blockade on hospital costs (primary outcome), intensive care unit admission rate, and hospital length of stay (secondary outcomes). METHODS: We performed a prespecified secondary analysis of data obtained in 2233 adult patients undergoing surgery under general anesthesia. Postoperative residual neuromuscular blockade was defined as a train-of-four ratio <0.9 in the postanesthesia care unit (PACU). Our confounder model adjusted for a variety of patient, surgical, and anesthesia-related factors. We fitted truncated negative binomial regression models for hospital cost and hospital length of stay analyses and a logistic regression model for our intensive care unit admission analysis. RESULTS: Overall, 457 (20.5%) patients in our cohort had residual neuromuscular blockade on admission to the PACU. Postoperative residual neuromuscular blockade was not independently associated with increased hospital costs (adjusted incidence rate ratio, 1.04, CI, 0.98-1.11; P = .22). There were significantly higher odds of intensive care unit admission in those with postoperative residual neuromuscular blockade compared to those without (adjusted odds ratio, 3.03, CI, 1.33-6.87; P < .01). Further, we found a trend toward increased hospital length of stay in patients with postoperative residual neuromuscular blockade (adjusted incidence rate ratio, 1.09; P = .06). Sensitivity analysis using the same model in the day of surgery admissions and ambulatory surgery confirmed our findings. CONCLUSIONS: Postoperative residual neuromuscular blockade at PACU admission was not significantly associated with increased hospital costs, but was associated with higher rates of intensive care unit admission. These findings support the view that clinicians should continue to work to reduce the rate of postoperative residual neuromuscular blockade.

Anaphylactic Bronchospasm during Induction of General Anaesthesia: A Case Report.

Bronchospasm represents the clinical manifestation of bronchial muscles contraction resulting in reduced alveolar air flow. Non-allergic mechanisms or anaphylaxis underlie the genesis of perioperative bronchospasm, a potential anaesthetic disaster. Early recognition and treatment are crucial. We report a rare incident of anaphylactic bronchospasm without hypotension during general anaesthesia. Urticaria appeared in chest and abdomen suggesting anaphylaxis. After the event resolved with bronchodilators, surgery continued uneventfully. Vecuronium was the most probable culprit but confirmation was not possible as the patient was lost to follow up. Rarely, perioperative anaphylaxis presents only with bronchospasm that requires prompt attention to avoid adverse outcome. Keywords: allergy; anaphylaxis; bronchial spasm; general anesthesia.

Comparison of Different Muscle-Relaxant Anesthetics on Growth, Migration and Invasion of Gastric Cancer Cells.

BACKGROUND/AIM: Muscle relaxants, also known as neuromuscular blocking agents, can block nerve impulses to the muscles and are always used in surgery for general anesthesia. However, the effect of muscle-relaxant anesthetics on cell activity in gastric cancer is currently unknown. The present study aimed to examine and compare the role of three different muscle-relaxant anesthetics in gastric cancer cells. MATERIALS AND METHODS: Gastric cancer cells (SGC7901 and BGC 823) were treated with a different dose of muscle-relaxant anesthetics, Rocuronium bromide (Rb), Vecuronium bromide (Vb) and Cisatracurium Besilate (CB). Using in vitro models, the effects on gastric cancer cell invasion, growth and migration of various anesthetics were subsequently investigated. RESULTS: We found that Rb increased the growth, invasion and migration of gastric cancer cells SGC7901 and BGC823. However, Vb and CB, as relatively mitigative anesthetics, did not significantly affect gastric cancer cell malignant phenotype at their regular blood concentration. CONCLUSION: Our results are important in selecting the type and dose of anesthetic used for surgery of gastric cancer patients. An understanding of the effect of muscle-relaxant anesthetics and their impact on tumor metastasis is critical, since it provides insight into the appropriate anesthetic strategy that could improve long-term survival in some patients with gastric cancer.

Efficacy and safety of sugammadex compared to neostigmine for reversal of neuromuscular blockade: a meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: Sugammadex has been introduced for reversal of rocuronium (or vecuronium)-induced neuromuscular blockade (NMB). Although its efficacy has been established, data are conflicting whether it is safer than neostigmine traditionally used for reversing NMB. DESIGN: Meta-analysis of data about effectiveness and safety of sugammadex compared to neostigmine for reversing NMB in adults was performed using the PRISMA methodology. SETTING: University medical hospital. METHODS: A comprehensive search was conducted using PubMed, Web of Science, and Cochrane Library electronic databases to identify English-language randomized controlled trials. Two reviewers independently selected the trials; extracted data on reversal times, incomplete reversals of NMB, and adverse events (AEs); and assessed the trials' methodological quality and evidence level. Only AEs that were related to study drug by a blinded safety assessor were considered for meta-analysis. PATIENTS: A total of 1384 patients from 13 articles were included in this meta-analysis. MAIN RESULTS: Compared to neostigmine, sugammadex was faster in reversing NMB (P<.0001) and more likely to be associated with higher train-of-four ratio values at extubation (mean difference, 0.18; 95% confidence interval [CI], 0.14-0.22; P<.0001) and lower risk of postoperative residual curarization after extubation (odds ratio [OR], 0.05; 95% CI, 0.01-0.43; P=.0068). Compared to neostigmine, sugammadex was associated with a significantly lower likelihood of global AEs (OR, 0.47; 95% CI, 0.34-0.66; P<.0001), respiratory AEs (OR, 0.36; 95% CI, 0.14-0.95; P=.0386), cardiovascular AEs (OR, 0.23; 95% CI, 0.08-0.61; P=.0036), and postoperative weakness (OR, 0.45; 95% CI, 0.21-0.97; P=.0409). Sugammadex and neostigmine were associated with a similar likelihood of postoperative nausea and vomiting (OR, 1.23; 95% CI, 0.70-2.15; P=.4719), pain (OR, 1.06; 95% CI, 0.15-7.36; P=.9559), neurologic AEs (OR, 1.47; 95% CI, 0.52-4.17; P=.4699), general AEs (OR, 0.75; 95% CI, 0.47-1.21; P=.2448), and changes in laboratory tests' values (OR, 0.57; 95% CI, 0.18-1.78; P=.3368). CONCLUSIONS: Results from this meta-analysis suggest that sugammadex is superior to neostigmine, as it reverses NMB faster and more reliably, with a lower risk of AEs.

Intraoperative anaphylaxis to neuromuscular blocking agents: the incidence over 9 years at two tertiary hospitals in South Korea: A retrospective observational study.

BACKGROUND: Intraoperative anaphylaxis to neuromuscular blocking agents (NMBAs) is a rare event that is unpredictable and potentially life threatening. Most of the previous reports on such intraoperative anaphylaxis used market share surveys or self-reported data to estimate the incidence. OBJECTIVE: To determine the incidences of intraoperative anaphylaxis to NMBAs using electronic medical records. DESIGN: A retrospective observational study. SETTING: Two tertiary hospitals in South Korea. PATIENTS: This study involved patients exposed to NMBAs during anaesthesia between 1 January 2005 and 31 May 2014. Nineteen episodes were deemed to be intraoperative anaphylaxis to NMBAs. MAIN OUTCOME MEASURES: We calculated the incidences of intraoperative anaphylaxis to NMBAs. Exposure to the agents was determined from intraoperative records maintained in an electronic medical recording system. An anaphylactic reaction was determined from both clinical signs and the results of skin tests. RESULTS: Over 9 years, 729 429 patients were exposed to NMBA, the most frequently used being rocuronium [425 047 (58.3%)] and vecuronium [274 801 (37.7%)]. The overall incidence of intraoperative anaphylaxis was 2.6 per 100 000 (19 cases), and was higher with rocuronium (16 cases, 3.8 per 100 000) than with vecuronium (two cases, 0.7 cases per 100 000), P = 0.014. Comparing the first 3 years with the last 6 years, the incidence of intraoperative rocuronium anaphylaxis appeared to increase 1.4-fold (P = 0.006). CONCLUSION: Among commonly used NMBAs, rocuronium appears to have the highest incidence of anaphylaxis. Our findings suggest that future prospective investigation for NMBA-induced anaphylaxis should use internationally agreed skin test protocols.

Intractable Polyuria Mimicking Diabetes Insipidus-Source Traced to Vecuronium Infusion.

Continuous infusion of vecuronium is a commonly used technique for patients requiring prolonged neuromuscular blockade for mechanical ventilation. As compared with older neuromuscular blocking agents, it confers the advantages of rapid excretion and intermediate duration of action. Prolongation of neuromuscular blockade and muscle weakness are the known complications of continuous vecuronium infusion. This report attempts to describe polyuria, as a hitherto unknown complication of vecuronium infusion, which can occur due to the mannitol present in commercially available preparation of vecuronium bromide.

Sugammadex and rocuronium-induced anaphylaxis.

Perioperative anaphylaxis is a life-threatening clinical condition that is typically the result of drugs or substances used for anesthesia or surgery. The most common cause of anaphylaxis during anesthesia is reportedly neuromuscular blocking agents. Of the many muscle relaxants that are clinically available, rocuronium is becoming popular in many countries. Recent studies have demonstrated that succinylcholine (but also rocuronium use) is associated with a relatively high rate of IgE-mediated anaphylaxis compared with other muscle relaxant agents. Sugammadex is widely used for reversal of the effects of steroidal neuromuscular blocking agents, such as rocuronium and vecuronium. Confirmed cases of allergic reactions to clinical doses of sugammadex have also been recently reported. Given these circumstances, the number of cases of hypersensitivity to either sugammadex or rocuronium is likely to increase. Thus, anesthesiologists should be familiar with the epidemiology, mechanisms, and clinical presentations of anaphylaxis induced by these drugs. In this review, we focus on the diagnosis and treatment of anaphylaxis to sugammadex and neuromuscular blocking agents. Moreover, we discuss recent studies in this field, including the diagnostic utility of flow cytometry and improvement of rocuronium-induced anaphylaxis with the use of sugammadex.

Recovery from neuromuscular block in dogs: restoration of spontaneous ventilation does not exclude residual blockade.

OBJECTIVE: To evaluate if return of spontaneous ventilation to pre-relaxation values indicates complete recovery from neuromuscular blockade. STUDY DESIGN: Prospective, with each individual acting as its own control. ANIMALS: Ten healthy adult female Beagle dogs weighing 6.2-9.4 kg. METHODS: Dogs were anesthetized with propofol, dexemedetomidine and isoflurane. Spontaneous ventilation was assessed by measuring end-tidal CO2 , expired tidal volume, peak inspiratory flow, respiratory rate and minute ventilation. Vecuronium 25 µg kg(-1) IV was administered and neuromuscular block was evaluated by measuring the train-of-four (TOF) ratio with acceleromyography in the hind limb. During spontaneous recovery from neuromuscular block, the TOF ratio when each ventilatory variable returned to baseline was recorded. RESULTS: This dose of vecuronium produced moderate neuromuscular block in all dogs, with TOF ratio values of 0-18% at maximal block. Expired tidal volume, peak inspiratory flow and minute ventilation returned to pre-relaxation values when the median TOF ratio was ≤ 20%. The median TOF ratio was 42% when the end-tidal CO2 returned to pre-relaxation values. CONCLUSIONS AND CLINICAL RELEVANCE: Significant residual neuromuscular block could be measured at the hind limb with acceleromyography when ventilation had spontaneously returned to pre-vecuronium values. Monitoring spontaneous ventilation, including end-tidal CO2 , expired tidal volume, peak inspiratory flow or minute ventilation cannot be used as a surrogate for objective neuromuscular monitoring, and this practice may increase the risk of postoperative residual paralysis.

Fracaso de extubación por bloqueo residual prolongado tras vecuronio. Tratamiento con sugammadex / Extubation failure due to prolonged residual block after vecuronium. Treatment with sugammadex

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Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011.

BACKGROUND: Neuromuscular blocking drugs (NMBDs) are the most common cause of intraoperative anaphylaxis in Western Australia. Differences in the rates of anaphylaxis between individual agents have been surmised in the past, but not proven, and are an important consideration if agents are otherwise equivalent. METHODS: We estimated a rate of anaphylaxis to NMBDs by analysing cases of NMBD anaphylaxis referred to the only specialized diagnostic centre in Western Australia over a 10 yr period. Exposure was approximated by analysing a 5 yr period of NMBD ampoule sales data. Agents were also ranked according to the prevalence of cross-reactivity in patients with previous NMBD anaphylaxis. RESULTS: Rocuronium was responsible for 56% of cases of NMBD anaphylaxis, succinylcholine 21%, and vecuronium 11%. There was no difference in the severity of reactions for different NMBDs. Rocuronium had a higher rate of IgE-mediated anaphylaxis compared with vecuronium (8.0 vs 2.8 per 100,000 exposures; P=0.0013). The prevalence of cross-reactivity after NMBD anaphylaxis suggested that succinylcholine also has a high risk of triggering anaphylaxis. Cisatracurium had the lowest prevalence of cross-reactivity in patients with known anaphylaxis to rocuronium or vecuronium. CONCLUSIONS: Rocuronium has a higher rate of IgE-mediated anaphylaxis compared with vecuronium, a result that is statistically significant and clinically important. Cisatracurium had the lowest rate of cross-reactivity in patients who had previously suffered anaphylaxis to rocuronium or vecuronium.

Recovery of train-of-four ratio to 0.70 and 0.90 is delayed in type 2 diabetes with vecuronium-induced neuromuscular block.

CONTEXT: The recovery profile of train-of-four ratio to more than 0.70 in patients with diabetes mellitus has not been well investigated. OBJECTIVE: Our primary objective was to evaluate the spontaneous recovery profile of neuromuscular block by vecuronium until train-of-four ratio more than 0.90 in patients with type 2 diabetes mellitus compared with controls, using first dorsal interosseous electromyography. DESIGN: Single-centre prospective case-control study. SETTING: The operating theatres of Fukuoka University Hospital. PATIENTS: Fourteen adults with type 2 diabetes mellitus (diabetes mellitus group) and 14 control patients (control group) were included in this study. INTERVENTION: Evoked responses to train-of-four stimuli were measured by electromyography at the first dorsal interosseous muscle. General anaesthesia was induced with propofol, fentanyl and remifentanil. Vecuronium (0.1  mg kg) was administered to all patients. Anaesthesia was maintained with propofol, fentanyl and remifentanil. The neuromuscular block was assessed until spontaneous recovery to train-of-four ratio more than 0.90. MAIN OUTCOME MEASURES: Recovery times to train-of-four ratio 0.70 and 0.90. RESULTS: Recovery times to train-of-four ratio 0.70 and 0.90 were significantly longer in the diabetes mellitus group than the control group (P = 0.041 and P = 0.027, respectively). The time from train-of-four ratio 0.25 to 0.90 was also significantly longer in the diabetes mellitus group than the control group (P = 0.029). In five of 14 patients in the diabetes mellitus group, the time from train-of-four ratio 0.25 to 0.90 was longer than 60  min, which is longer than the duration of action of neostigmine. The time from train-of-four ratio 0.25 to 0.90 was longer than 60  min in only one of 14 in the control group. CONCLUSION: Recovery times to train-of-four ratio 0.70 and 0.90 were delayed in patients with type 2 diabetes mellitus. Neuromuscular block by vecuronium should be carefully monitored in patients with type 2 diabetes mellitus until recovery of train-of-four ratio to a safe level is confirmed.

Failure to investigate anaesthetic anaphylaxis resulting in a preventable second anaphylactic reaction.

We present a case of anaphylaxis to suxamethonium and/or vecuronium in a patient who had previously suffered an anaphylactic reaction, presumably to rocuronium. The patient had not been referred for formal allergy testing after the first anaphylactic reaction. Subsequent formal allergy testing revealed sensitivities to suxamethonium, rocuronium and vecuronium. Her next anaesthetic, using cisatracurium, was uneventful. It is recommended that all patients with suspected perioperative anaphylaxis are referred for testing. This is the responsibility of the anaesthetist. Particular caution should be used with suspected neuromuscular blocking drug allergy as cross-reactivity is common and not predictable by drug structure.