Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults.

BACKGROUND: Acetylcholinesterase inhibitors, such as neostigmine, have traditionally been used for reversal of non-depolarizing neuromuscular blocking agents. However, these drugs have significant limitations, such as indirect mechanisms of reversal, limited and unpredictable efficacy, and undesirable autonomic responses. Sugammadex is a selective relaxant-binding agent specifically developed for rapid reversal of non-depolarizing neuromuscular blockade induced by rocuronium. Its potential clinical benefits include fast and predictable reversal of any degree of block, increased patient safety, reduced incidence of residual block on recovery, and more efficient use of healthcare resources. OBJECTIVES: The main objective of this review was to compare the efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade caused by non-depolarizing neuromuscular agents in adults. SEARCH METHODS: We searched the following databases on 2 May 2016: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (WebSPIRS Ovid SP), Embase (WebSPIRS Ovid SP), and the clinical trials registries www.controlled-trials.com, clinicaltrials.gov, and www.centerwatch.com. We re-ran the search on 10 May 2017. SELECTION CRITERIA: We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published, or language. We included adults, classified as American Society of Anesthesiologists (ASA) I to IV, who received non-depolarizing neuromuscular blocking agents for an elective in-patient or day-case surgical procedure. We included all trials comparing sugammadex versus neostigmine that reported recovery times or adverse events. We included any dose of sugammadex and neostigmine and any time point of study drug administration. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts to identify trials for eligibility, examined articles for eligibility, abstracted data, assessed the articles, and excluded obviously irrelevant reports. We resolved disagreements by discussion between review authors and further disagreements through consultation with the last review author. We assessed risk of bias in 10 methodological domains using the Cochrane risk of bias tool and examined risk of random error through trial sequential analysis. We used the principles of the GRADE approach to prepare an overall assessment of the quality of evidence. For our primary outcomes (recovery times to train-of-four ratio (TOFR) > 0.9), we presented data as mean differences (MDs) with 95 % confidence intervals (CIs), and for our secondary outcomes (risk of adverse events and risk of serious adverse events), we calculated risk ratios (RRs) with CIs. MAIN RESULTS: We included 41 studies (4206 participants) in this updated review, 38 of which were new studies. Twelve trials were eligible for meta-analysis of primary outcomes (n = 949), 28 trials were eligible for meta-analysis of secondary outcomes (n = 2298), and 10 trials (n = 1647) were ineligible for meta-analysis.We compared sugammadex 2 mg/kg and neostigmine 0.05 mg/kg for reversal of rocuronium-induced moderate neuromuscular blockade (NMB). Sugammadex 2 mg/kg was 10.22 minutes (6.6 times) faster then neostigmine 0.05 mg/kg (1.96 vs 12.87 minutes) in reversing NMB from the second twitch (T2) to TOFR > 0.9 (MD 10.22 minutes, 95% CI 8.48 to 11.96; I2 = 84%; 10 studies, n = 835; GRADE: moderate quality).We compared sugammadex 4 mg/kg and neostigmine 0.07 mg/kg for reversal of rocuronium-induced deep NMB. Sugammadex 4 mg/kg was 45.78 minutes (16.8 times) faster then neostigmine 0.07 mg/kg (2.9 vs 48.8 minutes) in reversing NMB from post-tetanic count (PTC) 1 to 5 to TOFR > 0.9 (MD 45.78 minutes, 95% CI 39.41 to 52.15; I2 = 0%; two studies, n = 114; GRADE: low quality).For our secondary outcomes, we compared sugammadex, any dose, and neostigmine, any dose, looking at risk of adverse and serious adverse events. We found significantly fewer composite adverse events in the sugammadex group compared with the neostigmine group (RR 0.60, 95% CI 0.49 to 0.74; I2 = 40%; 28 studies, n = 2298; GRADE: moderate quality). Risk of adverse events was 28% in the neostigmine group and 16% in the sugammadex group, resulting in a number needed to treat for an additional beneficial outcome (NNTB) of 8. When looking at specific adverse events, we noted significantly less risk of bradycardia (RR 0.16, 95% CI 0.07 to 0.34; I2= 0%; 11 studies, n = 1218; NNTB 14; GRADE: moderate quality), postoperative nausea and vomiting (PONV) (RR 0.52, 95% CI 0.28 to 0.97; I2 = 0%; six studies, n = 389; NNTB 16; GRADE: low quality) and overall signs of postoperative residual paralysis (RR 0.40, 95% CI 0.28 to 0.57; I2 = 0%; 15 studies, n = 1474; NNTB 13; GRADE: moderate quality) in the sugammadex group when compared with the neostigmine group. Finally, we found no significant differences between sugammadex and neostigmine regarding risk of serious adverse events (RR 0.54, 95% CI 0.13 to 2.25; I2= 0%; 10 studies, n = 959; GRADE: low quality).Application of trial sequential analysis (TSA) indicates superiority of sugammadex for outcomes such as recovery time from T2 to TOFR > 0.9, adverse events, and overall signs of postoperative residual paralysis. AUTHORS' CONCLUSIONS: Review results suggest that in comparison with neostigmine, sugammadex can more rapidly reverse rocuronium-induced neuromuscular block regardless of the depth of the block. Sugammadex 2 mg/kg is 10.22 minutes (˜ 6.6 times) faster in reversing moderate neuromuscular blockade (T2) than neostigmine 0.05 mg/kg (GRADE: moderate quality), and sugammadex 4 mg/kg is 45.78 minutes (˜ 16.8 times) faster in reversing deep neuromuscular blockade (PTC 1 to 5) than neostigmine 0.07 mg/kg (GRADE: low quality). With an NNTB of 8 to avoid an adverse event, sugammadex appears to have a better safety profile than neostigmine. Patients receiving sugammadex had 40% fewer adverse events compared with those given neostigmine. Specifically, risks of bradycardia (RR 0.16, NNTB 14; GRADE: moderate quality), PONV (RR 0.52, NNTB 16; GRADE: low quality), and overall signs of postoperative residual paralysis (RR 0.40, NNTB 13; GRADE: moderate quality) were reduced. Both sugammadex and neostigmine were associated with serious adverse events in less than 1% of patients, and data showed no differences in risk of serious adverse events between groups (RR 0.54; GRADE: low quality).

Chemotherapy alters cisatracurium induced neuromuscular blockade characteristics: A prospective cohort study.

STUDY OBJECTIVE: To compare the characteristics of NMDR induced muscle paralysis in breast cancer patients with and without a history of recent chemotherapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) regimen. DESIGN: This is a non-randomized prospective cohort study. SETTING: Operating room of a university-affiliated teaching hospital. PATIENTS: Out of a total of 50 patients who had undergone mastectomy, 22 patients were allocated to the "Chemo group" and 28 patients to the "Non-Chemo group", based on a valid history of recent chemotherapy. INTERVENTION: After induction of anesthesia with thiopental and cisatracurium, neuromuscular monitoring was started for all patients. MEASUREMENTS: Initially the time to 100% single-twitch (ST) suppression was measured. Then, the time for the appearance of the first response to post-tetanic count (PTC) stimulation, Train-of-Four (TOF) stimulation, and TOF50% were measured consequently. MAIN RESULTS: Time to get STzero was significantly longer in the Chemo group than in the Non-chemo group. Time for the appearance of the first response of PTC and TOF and TOF50% was significantly shorter in the Chemo group than the other group. The mean duration of intense block was 27.66 minutes in the Chemo group versus 42.47 minutes in the Non-chemo group. CONCLUSION: This research demonstrated that in patients having undergone chemotherapy, the effect of NDMRs starts with a longer lag time and finishes earlier too. Thus, these patients are ready for intubation after a longer time. Moreover, we have to repeat cisatracurium injections after shorter intervals to maintain the desired level of blockade.

Optimum dose of neostigmine to reverse shallow neuromuscular blockade with rocuronium and cisatracurium.

We examined the use of neostigmine for reversing shallow (defined as train-of-four ratio of 0.5), cisatracurium- and rocuronium-induced neuromuscular block in 112 patients, by use of 0 µg.kg(-1) , 10 µg.kg(-1) , 20 µg.kg(-1) or 40 µg.kg(-1) dose of neostigmine for reversal. The times from neostigmine administration to train-of-four ratios of 0.7, 0.9 and 1.0 were evaluated. Analysis of variance showed that the duration of action was significantly longer after cisatracurium compared with rocuronium. The time to reach a train-of-four ratio of 1.0 was significantly shorter with neostigmine 40 µg.kg(-1) compared with lower neostigmine doses, and at this dose the time did not differ between cisatracurium and rocuronium. The recovery time from a train-of-four ratio of 0.5-1.0 did not differ between cisatracurium and rocuronium, and was significantly shortened by the administration of neostigmine. We conclude that a neostigmine dose of 40 µg.kg(-1) was the most effective at reducing recovery time after neuromuscular blockade.

Neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of autosomal-recessive centronuclear myopathy.

BACKGROUND: Centronuclear myopathy (CNM) is a rare congenital condition associated with skeletal muscle weakness. Patients with CNM may have decreased acetylcholine receptor expression and a reduced number of releasable quanta. Such perturbations could affect the time-course of neuromuscular blocking agents (NMBAs) and their antagonism with cholinesterase inhibitors. As a result of the rarity of CNM, prospective data regarding NMBA use in this subpopulation is scarce. We evaluated the neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of CNM. METHODS: Six dogs with congenital autosomal-recessive CNM and six controls received cisatracurium 0.15 mg kg(-1) i.v. under general anaesthesia and intermittent positive pressure ventilation. Neuromuscular function was monitored with acceleromyography.When the second response (T2) to train-of-four (TOF) stimulation returned, neostigmine 0.04 mg kg(-1) (with glycopyrrolate) were administered i.v. The onset time, time to spontaneous return of T2, and the time to reach a TOF ratio ≥0.9 after neostigmine administration were recorded. RESULTS: Onset time was no different between groups. Median (interquartile range) time to return of T2 was 27 (24-31) min for control dogs and 26 (22-31) min for CNM dogs (P=0.93).After neostigmine administration, a TOF ratio ≥0.9 was reached in 12 (10-15) min and 17 (16-19) min in control and CNM, respectively (P=0.005). CONCLUSIONS: The spontaneous return of T2 was not different between groups. However, neostigmine-facilitated recovery was significantly slower in dogs with CNM. Canine autosomal-recessive CNM does not preclude the use of cisatracurium or its antagonism with neostigmine.

Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents.

BACKGROUND: The authors evaluated the comparative effectiveness of calabadion 2 to reverse non-depolarizing neuromuscular-blocking agents (NMBAs) by binding and inactivation. METHODS: The dose-response relationship of drugs to reverse vecuronium-, rocuronium-, and cisatracurium-induced neuromuscular block (NMB) was evaluated in vitro (competition binding assays and urine analysis), ex vivo (n = 34; phrenic nerve hemidiaphragm preparation), and in vivo (n = 108; quadriceps femoris muscle of the rat). Cumulative dose-response curves of calabadions, neostigmine, or sugammadex were created ex vivo at a steady-state deep NMB. In living rats, the authors studied the dose-response relationship of the test drugs to reverse deep block under physiologic conditions, and they measured the amount of calabadion 2 excreted in the urine. RESULTS: In vitro experiments showed that calabadion 2 binds rocuronium with 89 times the affinity of sugammadex (Ka = 3.4 × 10 M and Ka = 3.8 × 10 M-). The results of urine analysis (proton nuclear magnetic resonance), competition binding assays, and ex vivo study obtained in the absence of metabolic deactivation are in accordance with an 1:1 binding ratio of sugammadex and calabadion 2 toward rocuronium. In living rats, calabadion 2 dose-dependently and rapidly reversed all NMBAs tested. The molar potency of calabadion 2 to reverse vecuronium and rocuronium was higher compared with that of sugammadex. Calabadion 2 was eliminated renally and did not affect blood pressure or heart rate. CONCLUSIONS: Calabadion 2 reverses NMB induced by benzylisoquinolines and steroidal NMBAs in rats more effectively, i.e., faster than sugammadex. Calabadion 2 is eliminated in the urine and well tolerated in rats.

The effect of routine reversal of neuromuscular blockade on adequacy of recurrent laryngeal nerve stimulation during thyroid surgery.

Testing of the integrity of the recurrent laryngeal nerve during thyroid surgery has become routine practice for many surgeons to aid dissection and minimise the chance of inadvertent nerve injury. We hypothesised that routine reversal of an intermediate-acting, non-depolarising neuromuscular blocking agent would improve conditions for stimulation of the recurrent laryngeal nerve. We conducted a single-centre, randomised, double-blind placebo-controlled trial of patients undergoing thyroid surgery by the same surgeon. After randomisation, the participants received either neostigmine 2.5 mg with glycopyrrolate 0.4 mg or placebo, at 30 minutes after induction of anaesthesia and administration of 0.4 mg/kg of atracurium. The primary outcome was the subjective assessment by the surgeon as to whether the neuromuscular function was adequate for stimulation of the recurrent laryngeal nerve using a neuromuscular integrity monitor (NIM). Time to NIM stimulation was 44.6 minutes in the placebo group and 41.4 minutes in the intervention group (P=0.268). Of the 21 patients who received the neuromuscular blockade reversal, 20 (95.2%) had adequate surgical conditions for NIM stimulation, compared to 9 out of 18 patients (50%) in the placebo group (P=0.002). Three of the ten patients (30%) with inadequate reversal showed no evidence of residual blockade assessed peripherally. The routine reversal of neuromuscular blockade at 30 minutes post induction appears to result in adequate surgical conditions for safe stimulation of the recurrent laryngeal nerve. Return of neuromuscular function at a peripheral site does not guarantee adequate laryngeal muscle function for use of the NIM.

[Impact of sugammadex on neuromuscular blocking agents use: a multicentric, pharmaco-epidemiologic study in French university hospitals and military hospitals]. / Impact du sugammadex sur les consommations de curares : étude pharmaco-épidémiologique multicentrique dans les centres hospitalo-universitaires et hôpitaux d'instructions des armées français.

INTRODUCTION: Seven Neuromuscular Blocking Agents (NMBA) are commercialized in France. Four of them have an intermediate duration of action. Sugammadex required the use of NMBA slightly employed in clinical practice in France. Its introduction in routine practice could have an impact on NMBA use in clinical practice. This study was then conducted to assess and compare NMBA use before and after the commercialization of sugammadex. MATERIALS AND METHODS: A longitudinal, retrospective, observational study was conducted between 2008 and 2011 in French university hospitals and military hospitals. The consumption data for sugammadex and NMBA were collected using a collection grid which was filled by pharmacists or anesthesiologists. Drug use was measured by the number of vials used divided by the annual number of hospitalizations in surgery and obstetrics (HSO). An overall analysis of the annual frequency of NMBA use was firstly performed, then individual data of each hospital were analyzed. Descriptive statistical analysis including mean, standard deviation, median, minimum and maximum was achieved. RESULTS: Thirty-four out of 39 hospitals participated in the study (87%) and analysis was performed on 26 of them (7%). The data of eight institutions were excluded due to missing values or because of the non-admission of sugammadex in their formulary. The NMBA mostly used were non-steroidal NMBA (75% of market share) with an increased use between 2008 and 2011 concerning atracurium (from 41 to 51 vials of 50mg atracurium used per 100 HSO). The overall analysis revealed an increase of the occurrence of rocuronium (between 2008 and 2011: from 1 to 4.8 vials of 50mg rocuronium used per 100 HSO). Individual analyses on each hospital showed a possible effect of sugammadex introduction on NMBA use in nine hospitals. DISCUSSION AND CONCLUSIONS: The commercialization of sugammadex seems to have induced a discrete increase of steroidal NMBA but non-steroidal NMBA remain the leading agent in France. A long-term follow-up is deserved.

Calabadion: A new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents.

INTRODUCTION: To evaluate whether calabadion 1, an acyclic member of the Cucurbit[n]uril family of molecular containers, reverses benzylisoquinoline and steroidal neuromuscular-blocking agent effects. METHODS: A total of 60 rats were anesthetized, tracheotomized, and instrumented with IV and arterial catheters. Rocuronium (3.5 mg/kg) or cisatracurium (0.6 mg/kg) was administered and neuromuscular transmission quantified by acceleromyography. Calabadion 1 at 30, 60, and 90 mg/kg (for rocuronium) or 90, 120, and 150 mg/kg (for cisatracurium), or neostigmine/glycopyrrolate at 0.06/0.012 mg/kg were administered at maximum twitch depression, and renal calabadion 1 elimination was determined by using a H NMR assay. The authors also measured heart rate, arterial blood gas parameters, and arterial blood pressure. RESULTS: After the administration of rocuronium, resumption of spontaneous breathing and recovery of train-of-four ratio to 0.9 were accelerated from 12.3 ± 1.1 and 16.2 ± 3.3 min with placebo to 4.6 ± 1.8 min with neostigmine/glycopyrrolate to 15 ± 8 and 84 ± 33 s with calabadion 1 (90 mg/kg), respectively. After the administration of cisatracurium, recovery of breathing and train-of-four ratio of 0.9 were accelerated from 8.7 ± 2.8 and 9.9 ± 1.7 min with placebo to 2.8 ± 0.8 and 7.6 ± 2.1 min with neostigmine/glycopyrrolate to 47 ± 13 and 87 ± 16 s with calabadion 1 (150 mg/kg), respectively. Calabadion 1 did not affect heart rate, mean arterial blood pressure, pH, carbon dioxide pressure, and oxygen tension. More than 90% of the IV administered calabadion 1 appeared in the urine within 1 h. CONCLUSION: Calabadion 1 is a new drug for rapid and complete reversal of the effects of steroidal and benzylisoquinoline neuromuscular-blocking agents.

What rules of thumb do clinicians use to decide whether to antagonize nondepolarizing neuromuscular blocking drugs?

BACKGROUND: In anesthesia practice, inadequate antagonism of neuromuscular blocking drugs (NMBD) may lead to frequent prevalence of residual neuromuscular block that is associated with morbidity and death. In this study we analyzed the clinical decision on antagonizing NMBD to generate hypotheses about barriers to the introduction of experts' recommendations into clinical practice. METHODS: Sequential surveys were conducted among 108 clinical anesthesiologists to elicit the rules of thumb (heuristics) that support their decisions and provide a measurement of the confidence the clinicians have in their own decisions in comparison with their peers' decisions. RESULTS: The 2 most frequently used heuristics for administering reversal were "the interval since the last NMBD dose was short" and "the breathing pattern is inadequate," chosen by 73% and 71% of the clinicians, respectively. Clinicians considered that the prevalence of clinically significant residual block is higher in their colleagues' practices than in their own practice (60% vs 16%, odds ratio=7.8, 95% confidence interval, 3.8 to 16.2, P=0.0001). The clinicians were less likely to use antagonists if >60 minutes had elapsed after a single dose of atracurium (0.5 mg/kg) (31%) in comparison with after rocuronium 0.6 mg/kg (53%) (P=0.0035). CONCLUSIONS: In our institution, the clinical decision to antagonize NMBD is mainly based on the pharmacological forecast and a qualitative judgment of the adequacy of the breathing pattern. Clinicians judge themselves as better skilled at avoiding residual block than they do their colleagues, making them overconfident in their capacity to estimate the duration of action of intermediate-acting NMBD. Awareness of these systematic errors related to clinical intuition may facilitate the adoption of experts' recommendations into clinical practice.

Rapid chemical antagonism of neuromuscular blockade by L-cysteine adduction to and inactivation of the olefinic (double-bonded) isoquinolinium diester compounds gantacurium (AV430A), CW 002, and CW 011.

BACKGROUND: The ultra-short-acting neuromuscular blocker gantacurium is chemically degraded in vitro by rapid adduction of L-cysteine to its central olefinic double bond. Preliminary data have suggested that exogenous (intravenous) L-cysteine abolishes gantacurium blockade. Two new analogues of gantacurium (CW 002 and CW 011) have been synthesized to undergo slower L-cysteine adduction, yielding intermediate duration. L-cysteine adduction to and antagonism of these novel agents is further defined herein. METHODS: Comparative reaction half-time for L-cysteine adduction in vitro of the three compounds was determined by high-performance liquid chromatography. ED95 for twitch inhibition in monkeys under isoflurane was calculated, and duration at approximately 4-5x ED95 was correlated with reaction half-time for adduction. Speed of L-cysteine antagonism was contrasted with anticholinesterase reversal. Potencies of CW 002 and its adduction product were compared to provide a basis for L-cysteine antagonism. RESULTS: Rate of L-cysteine adduction in vitro (reaction half-time) was 11.4 and 13.7 min for CW 002 and CW 011 versus 0.2 min for gantacurium, and was inversely related to duration of block (P < 0.0001). CW 002 and CW 011 were 3x longer acting than gantacurium (28.1 and 33.3 min vs. 10.4 min), but only half the duration of cisatracurium. The adduct of CW 002 was approximately 70x less potent than CW 002. L-cysteine (10-50 mg/kg intravenously) given 1 min after approximately 4-5x ED95 doses of all the three compounds abolished block within 2-3 min. CONCLUSIONS: L-cysteine adduction occurs at different rates by design in olefinic isoquinolinium diester neuromuscular blockers, yielding corresponding durations of action. Antagonism by exogenous L-cysteine is superior to anticholinesterases, inducing inactivation of the active molecules to restore function rapidly at any time.

Hemodynamic effects of atracurium and cisatracurium and the use of diphenhydramine and cimetidine.

BACKGROUND AND OBJECTIVES: Since atracurium can cause hypotension in humans, the hemodynamic effects of atracurium and cisatracurium as well as the hemodynamic protection of diphenhydramine and cimetidine were investigated in rats. METHODS: 1) Wistar rats were anesthetized with sodium pentobarbital and prepared according to Brown et al. to evaluate different doses of atracurium and cisatracurium in the reduction of T4/T1 equal or greater than 95%. 2) Assessment of the hemodynamic changes caused by the intravenous administration of atracurium and cisatracurium by monitoring the blood pressure in the carotid artery and the electrocardiogram of rats. 3) Observation of the hemodynamic protection of prior treatment with the intravenous administration of diphenhydramine (2 mg.kg(-1)) and/or cimetidine (4 mg.kg(-1)). STATISTICAL ANALYSIS: Student t test and ANOVA. RESULTS: Doses of 1 mg.kg(-1) and 0.25 mg.kg(-1) of atracurium and cisatracurium respectively did not change the mean arterial pressure (MAP). Doses of 4 mg.kg(-1) of atracurium and cisatracurium decreased MAP to 62.8 +/- 4.5% and 82.5 +/- 2.3% respectively when compared to control levels. When the rats were pre-treated with diphenhydramine and cimetidine, diastolic pressure was reduced to 95.4% +/- 2.5%. With cimetidine, diastolic pressure was reduced to 82.7 +/- 8.4% when compared to the control group. The effects on systolic and diastolic blood pressure were reflected in the levels of MAP. CONCLUSIONS: The isolated administration of diphenhydramine and cimetidine did not prevent the reduction in mean arterial pressure induced by atracurium. However, the association of both drugs was able to prevent the hemodynamic effects of atracurium. The doses of cisatracurium used in this study did not cause a reduction in blood pressure significant enough to justify the use of the preventive measures used in the atracurium groups.

Antagonism of low degrees of atracurium-induced neuromuscular blockade: dose-effect relationship for neostigmine.

BACKGROUND: Low degrees of residual paralysis (i.e., a train-of-four [TOF] ratio > 0.4) are relatively frequent, difficult to detect, and still potentially harmful. Unfortunately, the appropriate dose of anticholinesterase for this situation has not been determined. This may be of clinical interest because a high dose of neostigmine given at a shallow level of neuromuscular block may produce neuromuscular weakness. The purpose of this study was to investigate the dose-effect relationship of neostigmine to antagonize residual paralysis corresponding to a TOF ratio of 0.4 and 0.6. METHODS: Recovery after 10, 20, 30 microg/kg neostigmine or placebo given at either 0.4 or 0.6 TOF ratio was assessed by acceleromyography in 120 patients undergoing intravenous anesthesia. Time to a 0.9 and 1.0 TOF ratio was measured, and the probability of successful reversal within 10 min after the respective neostigmine doses was calculated. In addition, the dose of neostigmine needed to achieve the recovery targets in 5 or 10 min was also determined. RESULTS: When given at a TOF ratio of either 0.4 or 0.6, time to 0.9 and 1.0 TOF ratio was significantly shorter with any dose of neostigmine than without. The probability of successful reversal after 20 microg/kg neostigmine was 100% when a TOF ratio of 0.9 was the target; for a TOF ratio of 1.0, the probability was 93% and 67%, dependent on whether the dose of neostigmine was given at TOF ratio of 0.6 or 0.4, respectively. With a dose of 30 microg/kg, a TOF ratio of 1.0 is expected to be reached within approximately 5 min. Low doses of neostigmine are required to reach a TOF ratio of 0.9 or to accept an interval of 10 min. CONCLUSION: Reduced doses (10-30 microg/kg) of neostigmine are effective in antagonizing shallow atracurium block. For successful reversal within 10 min, as little as 20 microg/kg neostigmine may be sufficient. These dose recommendations are specific for atracurium and an intravenous anesthetic background.

[Reversal from non-depolarising neuromuscular blockade in the postoperative period]. / Ocena przewodnictwa nerwowo-miesniowego po operacjach wykonywanych w znieczuleniu ogólnym z zastosowaniem niedepolaryzujacych srodków zwiotczajacych.

BACKGROUND: Postoperative residual curarisation (PORC) is a serious and underestimated problem and may occur even after relaxation with medium-acting non-depolarising agents. METHODS: One hundred adult patients, scheduled for elective surgical procedures, were enrolled in the study. Atracurium or cis-atracurium was used for relaxation. Neostigmine was administered for reversal at the end of surgery, at the discretion of the attending anaesthesiologist. Neuromuscular transmission was not monitored in the operating room. In the recovery room, the presence of residual block was assessed by a blinded investigator using accelerometry (TOF-Guard, Organon, Holland) immediately after arrival (T-A) and after 45 min (T-B). Those who received neostigmine were allocated to group I (49 patients), and those who did not were allocated to group II (51 patients). RESULTS: The mean duration of anaesthesia was 92 min in group I and 103 min in group II. The respective doses of atracurium were 78.2 and 72.0 mg; and of cis-atracurium--17.6 mg and 18.0 mg. Immediately after arrival, a TOF below 0.7 was detected in 26% of patients, and below 0.9 in 48% of patients. After forty-five minutes the TOF was still below 0.7 in one patient and below 0.9 in seven. The number of patients with residual block (TOF<0.9) did not differ statistically between those who received neostigmine and those who did not (3.92% and 10.2%, respectively). CONCLUSION: The clinical assessment of neuromuscular blockade reversal did not allow for detection of PORC. Neostigmine was not fully effective in reversal.

Reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostigmine.

BACKGROUND: Reversal of the residual effect of rocuronium or cisatracurium by neostigmine may be slow and associated with side-effects. This randomized, safety-assessor-blinded study compared the efficacy of sugammadex, a selective relaxant binding agent for reversal of rocuronium-induced neuromuscular block, with that of neostigmine for reversal of cisatracurium-induced neuromuscular block. The safety of sugammadex and neostigmine was also evaluated. METHODS: Adult surgical patients (ASA class I-III) were randomized to sugammadex 2.0 mg kg(-1) for reversal of block induced by rocuronium 0.6 mg kg(-1), or neostigmine 50 microg kg(-1) for reversal of block induced by cisatracurium 0.15 mg kg(-1). Anaesthesia was induced and maintained using i.v. propofol and remifentanil, fentanyl, or sufentanil. Neuromuscular function was monitored using acceleromyography (TOF-Watch SX). Sugammadex or neostigmine was administered at reappearance of T(2). The primary efficacy variable was time for recovery of the train-of-four (TOF) ratio to 0.9. RESULTS: Eighty-four patients were randomized, 73 of whom received sugammadex (n=34) or neostigmine (n=39). Time from start of administration of reversal agent to recovery of the TOF ratio to 0.9 was 4.7 times faster with sugammadex than with neostigmine (geometric mean=1.9 vs 9.0 min, P<0.0001). Reversal of block was sustained in all patients. There were no serious adverse effects from either reversal agent and no significant changes in any measure of safety, except for similar elevations in urinary N-acetyl glucosaminidase in both groups. CONCLUSIONS: Sugammadex 2.0 mg kg(-1) administered at reappearance of T(2) was significantly faster in reversing rocuronium-induced blockade than neostigmine was in reversing cisatracurium-induced block.

Influence of a continuous prednisolone medication on the time course of neuromuscular block of atracurium in patients with chronic inflammatory bowel disease.

BACKGROUND: Corticosteroids interact with neuromuscular blocking agents. However, experimental data are contradictory: enhancement and attenuation of the neuromuscular block has been observed. This study tested the influence of long-term medication with prednisolone on atracurium-induced neuromuscular block. METHODS: Sixty patients with chronic inflammatory bowel disease undergoing elective abdominal surgery were investigated. Thirty patients received a long-term medication with prednisolone (Group A) and 30 were without corticoid medication (Group B). Additionally, another 30 patients without inflammatory bowel disease and without corticoid medication served as control (Group C). The following parameters of an atracurium-induced neuromuscular block (0.25 mg kg(-1)) were measured: onset time, maximum block, recovery to 25% first twitch height, recovery index (time from 25% until 75% recovery of first twitch), duration to recovery to a train-of-four (TOF) rate of 0.7 and 0.9. RESULTS: The groups did not differ with regard to onset time, maximum block, and recovery index. The duration to 25% twitch height was significantly lower in Group A [18.1 (0-30.7) min] compared with Group B [23.5 (0-36.7) min; P<0.05]. Duration to a TOF rate of 0.7 and 0.9, respectively, were significantly reduced in Group A [36.1 (7.9) and 40.9 (9.0 min)] compared with Group B [47.9 (7.6) and 53.4 (9.2) min; P<0.001]. CONCLUSIONS: Long-term medication with prednisolone resulted in a shorter duration of an atracurium-induced neuromuscular block in patients with Crohn's disease or ulcerative colitis. The presence of the inflammatory bowel disease did not influence the time course of the neuromuscular block.

Cardiovascular and autonomic nervous effects of edrophonium and atropine combinations during neuromuscular blockade antagonism in sheep.

OBJECTIVE: To study heart rate (HR), arterial blood pressure (BP) and autonomic nervous (AN) effects of edrophonium-atropine combinations during neuromuscular blockade (NMB) antagonism in sheep. EXPERIMENTAL DESIGN: Randomized, prospective and experimental study. ANIMALS: Seventy-eight Scottish blackface ewes; mean age: 4.5 years; mean body mass: 54 kg. METHODS: After induction with IV etomidate (0.5 mg kg(-1)) and midazolam (0.5 mg kg(-1)), anaesthesia was maintained with halothane and NMB produced with atracurium or mivacurium. In the first study (n = 53), the electrocardiographic (ECG), HR, BP and AN effects of low (40 microg kg(-1)) and high (80 microg kg(-1)) atropine doses combined with either of two edrophonium doses (0.5 or 1.0 mg kg(-1)) were investigated. These variables were also measured in a second study when edrophonium (1.0 mg kg(-1)) was administered 5 minutes before atropine (80 microg kg(-1)) and vice versa. Data were analysed using one-way within-subjects and repeated measures anova. RESULTS: In the first study, all combinations reversed NMB but significantly (p < 0.001) increased HR and BP within 2 minutes without arrhythmias. In the second study, edrophonium (1.0 mg kg(-1)) significantly increased HR and BP, saliva flow (n = 1) and lung sounds (n = 3) and caused ECG changes (n = 1). Cardiovascular changes were partially reversed by atropine (80 microg kg(-1)) administered 5 minutes later. Administered first, atropine (80 microg kg(-1)) significantly decreased HR and BP effects which were fully (HR) and partially (BP) reversed by edrophonium (1 mg kg(-1)) administered 5 minutes later. CONCLUSION AND CLINICAL RELEVANCE: The cardiovascular effects of edrophonium and atropine were opposite to those reported in humans and dogs. Edrophonium (0.5 mg kg(-1)) and atropine (80 microg kg(-1)) caused the mildest HR changes without ECG and noncardiac AN disturbances, and is recommended for the antagonism of NMB in sheep.

[Influence of neostigmine on the course of neuromuscular blockade with rocuronium or cisatracurium: a randomized, double-blind trial]. / Influencia de la neostigmina en la evolución clínica del bloqueo neuromuscular de rocuronio y cisatracurio. Estudio aleatorizado doble ciego.

OBJECTIVES: To compare the time-course of neuromuscular blockade with rocuronium or cisatracurium during intravenous anesthesia, in terms of both the time to spontaneous recovery or time to reversal after administration of neostigmine. MATERIAL AND METHODS: Patients classified as ASA 1-2 were randomized to receive blinded administration of a single injection of twice the 95% effective dose of rocuronium or cisatracurium for general anesthesia, and then neostigmine plus atropine at recovery of the first train-of-4 (TOF) twitch at 5% or 25%, or normal saline solution as placebo at recovery of the first TOF twitch at 25%. The neuromuscular blockade was monitored by acceleromyography. Intergroup comparisons were carried out by Student t test and analysis of variance. RESULTS: Sixty patients were enrolled. Mean (SD) time to onset was faster with rocuronium at (1.04 [0.32] minutes) compared with cisatracurium at (2.58 [0.81] minutes) and duration was shorter: time to the first twich at 5% was 30 (6.4) minutes with rocuronium and 38.1 (9.7) minutes with cisatracurium. The total duration of blockade (time to the 80% TOF ratio) was also shorter with rocuronium when the neuromuscular blockade was reversed, but there were no differences in the time to block reversal when neostigmine was not used: 62 (18.9) minutes to recovery from the rocuronium blockade vs 66.96 (15.9) minutes to recover from a cisatracurium blockade. A high percentage of patients had less than an 80% TOF ratio at 60 and 90 minutes of administration of the neuromuscular blockerswhen reversal was not used (patients receiving rocuronium, 60% at 60 minutes, and 20% at 90 minutes; patients receiving cisatracurium, 80% at 60 minutes, and 40% at 90 minutes). CONCLUSION: Not antagonizing a rocuronium- or cisatracurium-induced neuromuscular blockade in surgical procedures lasting less than 90 minutes can lead to a high percentaje of residual blockade (TOF ratio <80%).

Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in the anaesthetized Rhesus monkey.

BACKGROUND: Binding of the steroidal molecule of rocuronium by a cyclodextrin is a new concept for reversal of neuromuscular block. The present study evaluated the ability of Sugammadex Org 25969, a synthetic gamma-cyclodextrin derivative, to reverse constant neuromuscular block of about 90% induced by rocuronium or the non-steroidal neuromuscular blocking drugs, mivacurium or atracurium, in the anaesthetized Rhesus monkey. METHODS: After a bolus injection of rocuronium, mivacurium or atracurium, a continuous infusion of these drugs was started to maintain the first twitch contraction of the train-of-four at approximately 10% of its baseline value. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either sugammadex 0.5 or 1.0 mg kg(-1) was given in the rocuronium-induced blockade and sugammadex 1.0 mg kg(-1) was given in the mivacurium- and atracurium-induced blockade. RESULTS: Sugammadex caused a rapid and complete reversal of rocuronium-induced neuromuscular block. The recovery time to train of four ratio=0.9 after spontaneous recovery was 14.4 min (sd=3.4 min; n=14). This was reduced significantly (P<0.001) to 3.7 min (sd=3.3 min; n=4) with sugammadex 0.5 mg kg(-1) and to 1.9 min (sd=1.0 min; n=4) with sugammadex 1.0 mg kg(-1). Signs of residual blockade or re-curarization were not observed. Reversal of mivacurium- or atracurium-induced neuromuscular block (n=2 in each experiment) by sugammadex (1.0 mg kg(-1)) was not effective. In all experiments, injection of sugammadex had no effects on blood pressure or heart rate. CONCLUSIONS: Sugammadex is effective in reversing rocuronium, but not mivacurium- or atracurium-induced neuromuscular block.

[Effect of neostigmine on atracurium-induced neuromuscular blockage in patients pretreated with magnesium sulphate].

OBJECTIVE: To determine the effect of neostigmine on antagonizing atracurium-induced neuromuscular blockage with sulfate magnesium pretreatment. METHODS: Forty patients who undertook elective gynecologic laparoscopic examinations and treatments under general anesthesia were randomized into four groups (group A, B, C, and D, group A paired with group C, and group B paired with group D). Before induction of general anesthesia, patients in group A and group C received MgSO4 30 mg/kg in saline intravenously within 5 min, while patients in group B and group D received the same volume of saline. Anesthesia was induced with fentanyl and propofol; subsequently tracheal intubation was performed with 0.5 mg/kg atracurium after stabilization of the electromyography recording, and neostigmine (0.02 mg/kg) and atropine (0.01 mg/kg) were infused in group C and group D when neuromuscular recovery (T1/T(C)) reached 10%. T1/T(C) changes after neostigmine infusion as well as haemodynamic changes and other responses during induction and neostigmine and atropine infusion were recorded. RESULTS: The neuromuscular recovery speed had no significant difference between group A and group B after the neuromuscular recovery reached 10%, but it was lower in group C than in group D (P < 0.05). Significant difference existed between group AC and group BD (P < 0.05). No haemodynamic changes and other responses were found during induction and neostigmine and atropine infusion. CONCLUSION: Neostigmine-induced neuromuscular recovery can be attenuated in patients pretreated with magnesium sulfate.

Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function.

STUDY OBJECTIVE: The purpose of this study is to determine the incidence of significant (train-of-four [TOF] ratio <0.70), but clinically undetectable (TOF ratio >0.40), residual neuromuscular block after neostigmine antagonism of profound cisatracurium (CIS) or rocuronium (ROC) block. DESIGN: Prospective, randomized, open-label study. SETTING: University hospital. PATIENTS: Forty ASA physical status I and II undergoing elective surgical procedures. INTERVENTIONS: Anesthesia was induced with propofol 1.5 to 2.5 mg/kg IV plus fentanyl 2 to 4 mug/kg and maintained with N(2)O/desflurane plus narcotic supplementation. The electromyographic response of the adductor pollicis was recorded. Train-of-four stimulation was given every 20 seconds. Twitch height (T1) and TOF fade ratio were continuously recorded. In group 1 (n = 20), neuromuscular block was induced with CIS 0.10 mg/kg, and T1 was maintained at 5% of control by a constant infusion of CIS until the end of surgery. One minute after the termination of the infusion, neostigmine 0.05 mg/kg was administered. T1 and TOF values were monitored continuously for the next 20 minutes. Group 2 (n = 20) is identical to group 1 except that the initial drug was ROC 0.60 mg/kg, and paralysis was maintained with an infusion of ROC. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in the recovery patterns of CIS vs ROC. The duration (bolus to end of infusion) in both groups averaged 2.7 hours, and the mean cumulative dose of relaxant approximated 4 x the ED(95). T1 at the time of reversal was 6% (4%-10%) of control. Mean TOF ratios at 10, 15, and 20 minutes were 0.55, 0.71, and 0.0.81, respectively. Return to a TOF ratio >0.40 was always achieved in 15 minutes or less. However, at 20 minutes postreversal, 5 of 40 subjects had TOF ratios <0.70 and only 11 individuals had recovered to a TOF ratio of 0.90 or greater. CONCLUSIONS: Most clinicians cannot detect tactile fade once the TOF ratio exceeds 0.40. When reversing profound block, an objective monitor of neuromuscular function is required if the extent of residual block is to be assessed with any confidence.