Improving neuromuscular monitoring and reducing residual neuromuscular blockade via e-learning: A multicentre interrupted time-series study (INVERT study).

BACKGROUND: Neuromuscular monitoring should be applied routinely to avoid residual neuromuscular block. However, anaesthetists often refrain from applying it, even when the equipment is available. We aimed to increase neuromuscular monitoring in six Danish anaesthesia departments via e-learning. METHODS: Interrupted time series study, with baseline data from a previous study and prospective data collection after implementation of the module, which was available for 2 weeks from 21 November 2016. We included all patients receiving general anaesthesia with muscle relaxants until 30 April 2017. Main outcome was application of acceleromyography, grouped as succinylcholine only and non-depolarising relaxants. Secondary outcomes were last recorded train-of-four ratio (non-depolarising) relaxants and score on a ten-question pre- and post-course multiple-choice test. RESULTS: The post-intervention data consisted of 6525 cases (3099 (48%) succinylcholine only, 3426 (52%) non-depolarising relaxants). Analysing all departments, we found a positive pre-intervention trend in application of acceleromyography for both groups, of estimated 7.5% and 4.8% per year, respectively (p < .001). The monitoring rate increased significantly for succinylcholine in two departments post-intervention (p = .045 and .010), and for non-depolarising relaxants in one department (p = .041), but followed by a negative trend of -37.0% per year (p = .041). The rate was already close to 90% at the time of the intervention and the mean last recorded train-of-four ratio was 0.97 (SD 0.21), also without a significant change. The median score on the post-course test increased from 7 (IQR 5-8) to 9 (IQR 8-10) (p < .001, Wilcoxon Signed-Ranks Test). CONCLUSION: We found no overall effect of the e-learning module on application of neuromuscular monitoring, although the post-course test indicated an effect on anaesthetists' knowledge in this field. TRIAL REGISTRATION: Trial registration: Clinicaltrials.gov identifier: NCT02925143. https://clinicaltrials.gov/ct2/show/NCT02925143.

Barriers and aids to routine neuromuscular monitoring and consistent reversal practice-A qualitative study.

BACKGROUND: Neuromuscular monitoring is recommended whenever a neuromuscular blocking agent is administered, but surveys have demonstrated inconsistent monitoring practices. Using qualitative methods, we aimed to explore barriers and aids to routine neuromuscular monitoring and consistent reversal practice. METHODS: Focus group interviews were conducted to obtain insights into the thoughts and attitudes of individual anaesthetists, as well as the influence of colleagues and department culture. Interviews were conducted at five Danish and one US hospital. Data were analysed using template analysis. RESULTS: Danish anaesthetists used objective neuromuscular monitoring when administering a non-depolarizing relaxant, but had challenges with calibrating the monitor and sometimes interpreting measurements. Residents from the US institution used subjective neuromuscular monitoring, objective neuromuscular monitoring was generally not available and most had not used it. Danish anaesthetists used neuromuscular monitoring to assess readiness for extubation, whereas US residents used subjective neuromuscular monitoring, clinical tests like 5-second head lift and ventilatory parameters. The residents described a lack of consensus between senior anaesthesiologists in reversal practice and monitoring use. Barriers to consistent and correct neuromuscular monitoring identified included unreliable equipment, time pressure, need for training, misconceptions about pharmacokinetics of neuromuscular blocking agents and residual block, lack of standards and guidelines and departmental culture. CONCLUSION: Using qualitative methods, we found that though Danish anaesthetists generally apply objective neuromuscular monitoring routinely and residents at the US institution often apply subjective neuromuscular monitoring, barriers to consistent and correct use still exist.

Resistance towards nondepolarising muscle relaxants: prolonged onset time: A systematic review.

BACKGROUND: Nondepolarising muscle relaxants (NDMRs) provide optimal conditions for tracheal intubation and improve surgical conditions. Several clinical conditions, diseases and pharmacological interactions have been suggested to cause resistance towards NDMRs that may translate into difficult intubation or inadequate operating conditions during surgery. OBJECTIVE: The aim of this study was to evaluate the current evidence of patient groups with resistance towards NDMRs. A prolonged onset time was defined as a difference that exceeded 25% compared with controls. DESIGN: A systematic review of randomised controlled trials and cohort studies. DATA SOURCES: A comprehensive search was performed in 2016 in PubMed and EMBASE. ELIGIBILITY CRITERIA: Patients with conditions or diseases, or patients taking medication, which lead to resistance towards current NDMRs (rocuronium, vecuronium, cisatracurium, atracurium, mivacurium and pancuronium). Included outcomes were onset time defined as the time between administration of NDMR to maximal (90, 95 or 100%) depression of baseline twitch height of the first twitch in a train-of-four. RESULTS: Twenty-five studies were included. Strong evidence supports a prolonged onset time of rocuronium in patients with thermal injury and Duchenne muscular dystrophy. Moderate evidence supports a prolonged onset time of NDMRs during hypothermia and in patients with infection, oculopharyngeal muscular dystrophy, liver cirrhosis treated with ulinastatin, when remifentanil is administered prior to administration of an NDMR, in fasting patients being rehydrated intravenously prior to administration of NDMR, in children with end-stage renal failure and in patients with atrial or ventricular septal defects. CONCLUSION: A prolonged onset time should be suspected in patients with thermal injury and Duchenne's muscular dystrophy. Further, evidence supports a prolonged onset time in patients with infection, oculopharyngeal muscular dystrophy, congenital heart defects, kidney failure, liver cirrhosis treated with ulinastatin along with remifentanil or intravenous fluids administered prior to NDMR.

Deep neuromuscular blockade and surgical conditions during laparoscopic ventral hernia repair: A randomised, blinded study.

BACKGROUND: Laparoscopic ventral hernia repair is a common surgical procedure. However, muscle contractions and general muscle tension may impair the surgical view and cause difficulties suturing the hernial defect. Deep neuromuscular blockade (NMB) paralyses the abdominal wall muscles and may help to create better surgical conditions. OBJECTIVES: The current study investigated if deep compared with no NMB improved the surgical view during laparoscopic ventral hernia repair. DESIGN: Crossover study. SETTING: The study was carried out at Herlev and Gentofte Hospital, University of Copenhagen, Denmark and conducted from May 2015 until February 2017. PARTICIPANTS: A total of 34 patients were randomised in an investigator-initiated, assessor-blinded crossover design of deep vs. no NMB during laparoscopic ventral hernia repair. INCLUSION CRITERIA: Adults scheduled for elective laparoscopic ventral hernia repair. EXCLUSION CRITERIA: Known allergy to any study medication, known homozygous variants in the butyrylcholinesterase gene, severe renal disease, neuromuscular disease, lactating or pregnant women, any indication for rapid sequence induction. INTERVENTIONS: Deep NMB was established with rocuronium and reversed with sugammadex. Anaesthesia was conducted with propofol and remifentanil. MAIN OUTCOME MEASURES: The primary outcome was evaluation of surgical view assessed on a five-point rating scale. Other outcomes included the surgical conditions during laparoscopic suturing of the hernia defect. RESULTS: We found no difference in ratings for the surgical view when comparing deep with no NMB: mean -0.1 (95% confidence interval -0.4 to 0.2) (P = 0.521, paired t test). However, deep compared with no NMB improved the rating score for surgical conditions while suturing the hernia defect (P = 0.012, Mann-Whitney U test). No differences were found in either total length of surgery (P = 0.76) or hernia suturing time (P = 0.81). CONCLUSION: Deep compared with no NMB did not change the rating score of the surgical view immediately after introduction of trocars during laparoscopic ventral hernia repair, but the surgical condition were improved during suturing of the hernia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02247466.

Patients with prolonged effect of succinylcholine or mivacurium had novel mutations in the butyrylcholinesterase gene.

INTRODUCTION: Mutations in the butyrylcholinesterase enzyme (BChE) can result in prolonged duration of action of the neuromuscular blocking agents, succinylcholine and mivacurium, as BChE hydrolyses these drugs. Hereditary low BChE activity can cause extensively prolonged apnoea during general anaesthesia when these drugs are used. The aim of this study was to describe novel mutations in the butyrylcholinesterase gene (BCHE) in patients who have experienced prolonged duration of action of mivacurium or succinylcholine. METHODS: The Danish Cholinesterase Research Unit registers patients with prolonged duration of action to succinylcholine and mivacurium. Patients were studied if they had equivocal phenotypes on the basis of BChE activity, biochemical inhibitor reactions and with pedigree if possible. Complete nucleotide sequencing was performed to describe the genotype and pedigree was used to separate the alleles. Multiple sequence alignment of BChE was performed for comparison with other species. RESULTS: Genotyping indicated seven novel mutations in the BCHE (I373T, G467S, W518R, L184S, V421A, M462I and R577H). CONCLUSION: We have found seven new variants of the BCHE, which seem to reduce the activity of BChE in patients undergoing anaesthesia involving succinylcholine or mivacurium.

Postoperative shoulder pain after laparoscopic hysterectomy with deep neuromuscular blockade and low-pressure pneumoperitoneum: A randomised controlled trial.

BACKGROUND: Postoperative shoulder pain remains a significant problem after laparoscopy. Pneumoperitoneum with insufflation of carbon dioxide (CO2) is thought to be the most important cause. Reduction of pneumoperitoneum pressure may, however, compromise surgical visualisation. Recent studies indicate that the use of deep neuromuscular blockade (NMB) improves surgical conditions during a low-pressure pneumoperitoneum (8 mmHg). OBJECTIVE: The aim of this study was to investigate whether low-pressure pneumoperitoneum (8 mmHg) and deep NMB (posttetanic count 0 to 1) compared with standard-pressure pneumoperitoneum (12 mmHg) and moderate NMB (single bolus of rocuronium 0.3 mg kg with spontaneous recovery) would reduce the incidence of shoulder pain and improve recovery after laparoscopic hysterectomy. DESIGN: A randomised, controlled, double-blinded study. SETTING: Private hospital in Denmark. PARTICIPANTS: Ninety-nine patients. INTERVENTIONS: Randomisation to either deep NMB and 8 mmHg pneumoperitoneum (Group 8-Deep) or moderate NMB and 12 mmHg pneumoperitoneum (Group 12-Mod). Pain was assessed on a visual analogue scale (VAS) for 14 postoperative days. MAIN OUTCOME MEASURES: The primary endpoint was the incidence of shoulder pain during 14 postoperative days. Secondary endpoints included area under curve VAS scores for shoulder, abdominal, incisional and overall pain during 4 and 14 postoperative days; opioid consumption; incidence of nausea and vomiting; antiemetic consumption; time to recovery of activities of daily living; length of hospital stay; and duration of surgery. RESULTS: Shoulder pain occurred in 14 of 49 patients (28.6%) in Group 8-Deep compared with 30 of 50 (60%) patients in Group 12-Mod. Absolute risk reduction was 0.31 (95% confidence interval 0.12 to 0.48; P = 0.002). There were no differences in any secondary endpoints including area under the curve for VAS scores. CONCLUSION: Deep NMB and low-pressure pneumoperitoneum (8 mmHg) reduced the incidence of shoulder pain after laparoscopic hysterectomy in comparison to moderate NMB and standard-pressure pneumoperitoneum (12 mmHg). TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01722097.

Neuromuscular blockade during laparoscopic ventral herniotomy: protocol for a randomised controlled trial.

INTRODUCTION: Laparoscopic herniotomy is the preferred technique for some ventral hernias. Several factors may influence the surgical conditions, one being the depth of neuromuscular blockade (NMB) applied. We hypothesised that deep neuromuscular blockade defined as a post-tetanic count below eight would provide a better surgical workspace. METHODS: This was an investigator-initiated, assessor- and patient-blinded randomised cross-over study. A total of 34 patients with planned laparoscopic umbilical, incisional and linea alba herniotomy were studied. Patients would be randomised to receive deep NMB followed by no NMB, or no NMB followed by deep NMB. Our primary outcome was improvement of the surgical workspace (rated on a five-point scale) estimated as the difference between the workspace during deep NMB and the workspace without NMB. Secondary outcomes included, among others, surgeon's rating of surgical conditions during suturing, duration of surgery and duration of the suturing of the hernia. CONCLUSION: This randomised cross-over study investigated a potential effect on the surgical workspace in laparoscopic ventral herniotomy using deep NMB compared with no NMB. The study may provide knowledge relevant to other laparoscopic techniques. FUNDING: The study is funded by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. TRIAL REGISTRATION: NCT02247466.

Surgical space conditions during low-pressure laparoscopic cholecystectomy with deep versus moderate neuromuscular blockade: a randomized clinical study.

BACKGROUND: Laparoscopic cholecystectomy performed during low intraabdominal pressure (<12 mm Hg) is associated with significantly less postoperative pain than standard pressure (≥12 mm Hg). The impact on surgical space conditions and safety of operating at lower pressures has not been adequately described, but deep neuromuscular blockade may be beneficial. We investigated if deep muscle relaxation would be associated with a higher proportion of procedures with "optimal" surgical space conditions compared with moderate relaxation during low-pressure (8 mm Hg) laparoscopic cholecystectomy. METHODS: In this assessor-blinded study, 48 patients undergoing elective laparoscopic cholecystectomy were administered rocuronium for neuromuscular blockade and randomized to either deep neuromuscular blockade (rocuronium bolus plus infusion maintaining a posttetanic count 0-1) or moderate neuromuscular blockade (rocuronium repeat bolus only for inadequate surgical conditions with spontaneous recovery of neuromuscular function). Patients received anesthesia with propofol, remifentanil, and rocuronium. The primary outcome was the proportion of procedures with optimal surgical space conditions (assessed by the surgeon as 1 on a 4-point scale). Secondary outcomes included the proportion of procedures completed at pneumoperitoneum 8 mm Hg and surgical space conditions on dissection of the gallbladder (numeric rating scale 0-100; 0 = optimal surgical space conditions; 100 = unacceptable surgical space conditions). RESULTS: Optimal surgical space conditions during the entire procedure were observed in 7 of 25 patients allocated to deep neuromuscular blockade and in 1 of 23 patients allocated to moderate blockade (P = 0.05) with an absolute difference of 24% between the groups (95% confidence interval, 4%-43%). Laparoscopic cholecystectomy was completed at pneumoperitoneum 8 mm Hg in 15 of 25 and 8 of 23 patients in the deep and moderate group, respectively (95% confidence interval, -2% to 53%; P = 0.08). Surgical space conditions during dissection of the gallbladder assessed by use of the numeric rating scale were 20 (10-50) (median [25%-75% range]) in the deep neuromuscular blockade group and 30 (10-50) in the moderate group (P = 0.58; Wilcoxon-Mann-Whitney odds, 1.2; 95% confidence interval, 0.6-2.5). No operations were converted to laparotomy. CONCLUSIONS: Deep neuromuscular blockade was associated with surgical space conditions that were marginally better than with moderate muscle relaxation during low-pressure laparoscopic cholecystectomy.

Monitoring of intense neuromuscular blockade in a pig model.

Intense neuromuscular blockade (NMB) measured by post tetanic count (PTC) was monitored, reversed and verified in this pig model. In a cross-over assessor blinded design six pigs were randomized to either no NMB followed by intense NMB, or intense NMB followed by no NMB. Neuromuscular measurements were performed with acceleromyography [train-of-four (TOF) Watch SX]. In all pigs, the response to TOF nerve stimulation was stable and intense NMB (PTC 0-1) was established with rocuronium 3 mg/kg. For reversal, the pigs received sugammadex 20-35 mg/kg and returned to TOF-ratio above 0.90 within 2.15 min after injection. We established a pig model for monitoring intense NMB with surface stimulation electrodes and acceleromyography. We verified total relaxation of the diaphragm and the abdominal muscles at the PTC 0-1 by suction test and with surface electromyography. This pig model is suitable for studies with experimental abdominal surgery with monitoring of intense NMB, and where relaxation of the diaphragm and the abdominal muscles are required.

Tracheal intubation with a flexible fibreoptic scope or the McGrath videolaryngoscope in simulated difficult airway scenarios: a randomised controlled manikin study.

BACKGROUND: Flexible fibreoptic endoscopic (FFE) intubation is considered the 'gold-standard' when difficult airway management is anticipated. Several videolaryngoscopes have been developed to facilitate intubation by laryngoscopy. OBJECTIVE: The aim of the study was to compare the performance of the McGrath series 5 videolaryngoscope (McGrath videolaryngoscope) and the FFE for tracheal intubation in manikins with a simulated difficult airway, hypothesizing that the McGrath videolaryngoscope intubation would prove faster than FFE intubation. DESIGN: A randomised controlled study. SETTING: The Danish Institute for medical simulation between December 2009 and June 2010. PARTICIPANTS: Twenty-eight anaesthesia residents participating in the Danish mandatory 3-day airway management course. INTERVENTIONS: All participants received instructions and training in the use of the McGrath videolaryngoscope and FFE. The participants then performed tracheal intubation on a SimMan manikin once with the McGrath videolaryngoscope and once with the FFE in three difficult airway scenarios: (1) pharyngeal obstruction; (2) pharyngeal obstruction and cervical rigidity; (3) tongue oedema. MAIN OUTCOME MEASURES: We measured successful intubations, defined as intubation within 120  s, and time to tracheal intubation. RESULTS: The trachea was intubated within 120  s with the McGrath videolaryngoscope in 25 out of 27 (93%), 25 out of 28 (89%) and 18 out of 28 (64%) occasions compared with 11 out of 28 (40%), 11 out of 28 (40%) and 16 out of 28 (57%) with the FFE in scenarios (1), (2) and (3), respectively. Time to tracheal intubation was shorter with the McGrath videolaryngoscope in scenarios (1) and (2) than with the FFE (Wilcoxon signed rank sum test, P < 0.0001). CONCLUSION: The McGrath videolaryngoscope is a valuable device with higher success rate and a quicker performance in simulated difficult airways. In patients, videolaryngoscopy may have a role in difficult airway algorithms, but the optimal device has yet to be found.

Optimized surgical space during low-pressure laparoscopy with deep neuromuscular blockade.

INTRODUCTION: Laparoscopic cholecystectomy (LC) can be performed using low intra-abdominal pressure (< 12 mmHg), but surgical conditions may not be optimal. The present study aimed at comparing surgical space conditions using either deep, continuous muscle relaxation or moderate blockade during low-pressure (8 mmHg) LC. We hypothesized that a deep neuromuscular block would be associated with a higher proportion of optimal surgical space conditions. MATERIAL AND METHODS: This was an investigator-initiated, patient- and assessor-blinded study. Up to 72 patients scheduled for elective LC were randomised to either deep neuromuscular blockade (post-tetanic count 0-1) or moderate neuromuscular blockade, where at least one response to train-of-four nerve stimulation was present. The primary outcome was surgical space conditions at the time during surgery when conditions were worst. The secondary outcomes included the proportion of procedures completed at pneumoperitoneum 8 mmHg, post-operative pain, and incidence of nausea and vomiting. RESULTS: This study was the first randomised study to assess the association between depth of neuromuscular blockade and surgical space conditions during low-pressure LC. The study findings may be applicable to a general surgical population undergoing LC. FUNDING: The University of Copenhagen, Denmark and Sophus Johansens Foundation of 1981, Denmark funded this study, which was also financed by a research grant from the Investigator Initiated Studies Program of Merck Sharp and Dohme Corp. TRIAL REGISTRATION: NCT 01523886.

Awake fiberoptic or awake video laryngoscopic tracheal intubation in patients with anticipated difficult airway management: a randomized clinical trial.

BACKGROUND: Awake flexible fiberoptic intubation (FFI) is the gold standard for management of anticipated difficult tracheal intubation. The purpose of this study was to compare awake FFI to awake McGrath® video laryngoscope, (MVL), (Aircraft Medical, Edinburgh, Scotland, United Kingdom) intubation in patients with an anticipated difficult intubation. The authors examined the hypothesis that MVL intubation would be faster than FFI. METHODS: Ninety-three adult patients with anticipated difficult intubation were randomly allocated to awake FFI or awake MVL, patients were given glycopyrrolate, nasal oxygen, topical lidocaine orally, and a transtracheal injection of 100 mg lidocaine. Remifentanil infusion was administered intravenously to a Ramsay sedation score of 2-4. Time to tracheal intubation was recorded by independent assessors. The authors also recorded intubation success on the first attempt, investigators' evaluation of ease of the technique, and patients reported intubation-discomfort evaluated on a visual analog scale. RESULTS: Eighty-four patients were eligible for analysis. Time to tracheal intubation was median [interquartile range, IQR] 80 s [IQR 58-117] with FFI and 62 s [IQR 55-109] with MVL (P = 0.17). Intubation success on the first attempt was 79% versus 71% for FFI and MVL, respectively. The median visual analog scale score for ease of intubation was 2 (IQR 1-4) versus 1 (IQR 1-6) for FFI and MVL, respectively. The median visual analog scale score for patients' assessment of discomfort for both techniques was 2, FFI (IQR 0-3), MVL (IQR 0-4). CONCLUSIONS: The authors found no difference in time to tracheal intubation between awake FFI and awake MVL intubation performed by experienced anesthesiologists in patients with anticipated difficult airway.

Two novel mutations in the BCHE gene in patients with prolonged duration of action of mivacurium or succinylcholine during anaesthesia.

BACKGROUND: Butyrylcholinesterase (BChE) hydrolyses the neuromuscular blocking agents, succinylcholine and mivacurium used during general anaesthesia. Hereditary low BChE activity may result in an extensively prolonged duration of action of these drugs, especially in patients who are homozygous for the atypical or silent variants. We present three novel mutations in the butyrylcholinesterase gene (BCHE) identified in three families in which a member had experienced severely prolonged duration of action of succinylcholine. METHODS: As the phenotypes of the three probands could not be established with certainty using conventional biochemical tests, DNA samples were collected from two of the probands and four relatives. Genotypes were determined using complete nucleotide sequencing. RESULTS: Three novel mutations were identified: BCHE*FS126, BCHE*I3E4-14C and BCHE*328D. The proband in family 1 was genotyped as BCHE*115D*I3E4-14C/BCHE*FS126, whereas the proband in family 3 was compound heterozygous for BCHE*328D and BCHE*142M. In both patients, BChE activity was below detection limit, and they experienced an extensively prolonged duration of action of succinylcholine. The proband in family 2 was not sequenced, but a relative was heterozygous for BCHE*FS126. BCHE*I3E4-14C was in linkage with a known silent variant. CONCLUSIONS: Two novel variants of BCHE are silencing the enzyme function. BCHE*FS126 results in a truncated protein lacking the active site and is therefore inactive. The second variant is BCHE*328D, also resulting in an inactive protein, as this change in amino acid is radical and furthermore situated in the gorge harbouring the active site. These variants result in extensively prolonged duration of action of succinylcholine.

Pharmacokinetics and pharmacodynamics of mivacurium in patients phenotypically homozygous for the atypical plasma cholinesterase variant: effect of injection of human cholinesterase.

BACKGROUND: In patients homozygous for atypical plasma cholinesterase, mivacurium causes a long-lasting neuromuscular block, but injection of human cholinesterase has been proven effective in antagonizing the block. The purpose of this study was to evaluate the pharmacodynamics and pharmacokinetics of mivacurium in such patients, as well as the effect of cholinesterase injected early or late after mivacurium. METHODS: Eleven patients phenotypically homozygous for the atypical variant received 0.075 mg/kg (1 patient) or 0.15 mg/kg (10 patients) mivacurium. The neuromuscular block was monitored using train-of-four nerve stimulation and mechanomyography. Cholinesterase, 2.8-10.0 mg/kg, was administered approximately 30 or 120 min after mivacurium. The times to different levels of neuromuscular recovery and the venous concentrations of the isomers of mivacurium were measured. RESULTS: Injection of cholinesterase increased plasma cholinesterase activity to normal and the clearances of the active isomers and the elimination rate constants by a factor of 10-15. The first response was seen in 13.5 min (3.7-44.2 min). Time to a train-of-four ratio of 0.8 ranged from 30 to 60 min (n = 6). Neostigmine injected after cholinesterase shortened recovery further, and a train-of-four ratio of 0.8 was reached in 10-30 min. CONCLUSION: As expected, the duration of action of mivacurium is markedly prolonged in homozygous atypical patients. Injection of cholinesterase significantly increases the metabolism of mivacurium, leading to a shorter duration of action. Injection of neostigmine after the administration of cholinesterase speeds up recovery.

Response to mivacurium in patients carrying the k variant in the butyrylcholinesterase gene.

BACKGROUND: Mivacurium is hydrolyzed by the butyrylcholinesterase enzyme, and patients with hereditary changes of the enzyme often have prolonged duration of action of mivacurium. In this study, the authors investigated the significance of the most commonly occurring variant, the Kalow (K) variant, established using DNA analysis, for the response to mivacurium. METHODS: A total of 58 patients carrying either the wild-type butyrylcholinesterase or different combinations of the atypical (A) variant and the K variant were included. Patients who were homozygous for the A variant were given 0.03 mg/kg mivacurium. All other patients received 0.2 mg/kg mivacurium. The neuromuscular block was measured using train-of-four nerve stimulation and mechanomyography. Genotyping was performed with complete nucleotide sequencing. RESULTS: Heterozygosity of the K variant prolonged the time to train-of-four 0.70 from 26.6 to 34.5 min (30%; not significant) as compared with the wild type. Heterozygosity of the K variant linked to the A variant prolonged the corresponding time from 32 to 42.7 min (33%; P = 0.03) as compared with patients who were heterozygous for solely an A allele. For eight patients who were homozygous for both the A and K variants, the time to 25% recovery was 78-89 min as compared with 44-57 min in patients who were homozygous for the A variant or had only one linked K variant. CONCLUSION: The K variant prolongs the duration of action of mivacurium. The current results indicate that the effect is modest when the K variant occurs heterozygously with the wild type or the A variant but is marked in patients who are homozygous for both the A and K variants.