BACKGROUND: Mivacurium is a short-acting non-depolarizing muscle relaxant, which is hydrolyzed by butyrylcholinesterase. The neuromuscular block (NMB) can be antagonized with cholinesterase inhibitors (CHEI), but the short duration of action of mivacurium questions the need. This systematic review evaluated if the use of CHEIs (neostigmine, pyridostigmine or edrophonium) facilitates reversal of mivacurium-induced NMB. METHOD: Randomized controlled trials and crossover-studies comparing spontaneous recovery with CHEI reversal in patients with mivacurium-induced NMB, assessed with quantitative neuromuscular monitoring, were included. Mean time from injection of the CHEI or allowing of spontaneous recovery to an endpoint representing full recovery was used as outcome. First response to train-of-four nerve stimulation (T1 ) described the level of NMB for administration of the CHEI. Moderate NMB refers to T1 >/= 5% and deeper NMB refers to T1 < 5%. Systematic critical appraisal was performed using the Scottish Intercollegiate Guidelines Network guidelines. Overall quality assessment was done using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Sixteen studies with data from 546 patients were included. Low quality of evidence was found that neostigmine and edrophonium administered at moderate NMB accelerated recovery with up to approximately 5.5-6.5 and 6.5-9.0 minutes, respectively. At deeper NMB only edrophonium accelerated recovery. The effect of neostigmine was not clarified at deeper mivacurium-induced NMB. No studies with reversal by pyridostigmine were identified. CONCLUSION: Low quality of evidence supports that neostigmine and edrophonium accelerate the recovery of mivacurium-induced NMB with 5-6.5 and 6-9.0 minutes respectively, when administered at moderate NMB. At deeper NMB only edrophonium accelerated the recovery.
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.
Title: Plasma cholinesterase deficiency in Turkish patients - a reply Thomsen JL, Gatke MR Ref: Anaesthesia, 71:982, 2016 : PubMed
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.
Title: [Danish Cholinesterase Research Unit diagnoses patients with prolonged paralysis after succinylcholine and mivacurium] Eskildsen KZ, Gatke MR Ref: Ugeskr Laeger, 177:866, 2015 : PubMed
The Danish Cholinesterase Research Unit (DCRU) is a nationwide unit for patients carrying mutations in the butyrylcholinesterase enzyme (BChE). BChE hydrolyzes the neuromuscular blocking drugs succinylcholine and mivacurium. Patients with mutations in the butyrylcholinesterase gene are at risk of experiencing a prolonged effect of the drugs, such as weakness or paralysis for hours. In order to diagnose the referred patients correctly, DCRU combines results such as BChE activity, genotyping, pedigree and clinical reactions to succinylcholine or mivacurium.
Title: Awareness during emergence from anaesthesia: significance of neuromuscular monitoring in patients with butyrylcholinesterase deficiency Thomsen JL, Nielsen CV, Eskildsen KZ, Demant MN, Gatke MR Ref: British Journal of Anaesthesia, 115 Suppl 1:i78, 2015 : PubMed
BACKGROUND: Butyrylcholinesterase deficiency can result in prolonged paralysis after administration of succinylcholine or mivacurium. We conducted an interview study to assess whether patients with butyrylcholinesterase deficiency were more likely to have experienced awareness during emergence from anaesthesia if neuromuscular monitoring had not been applied. METHODS: Patients referred during 2004-2012 were included. Data on the use of neuromuscular monitoring were available from a previous study. Interviews, conducted by telephone, included questions about awareness and screening for post-traumatic stress disorder. Reports of panic, hopelessness, suffocation, or a feeling of being dead or dying resulted in the experience being classified further as distressful. Patients were categorized as aware or unaware by investigators blinded to use of neuromuscular monitoring. RESULTS: Ninety-five patients were eligible to be interviewed. Of the 70 patients interviewed, 35 (50%) were aware while paralysed during emergence. Of these, 28 (80%) were not monitored with a nerve stimulator when awakened, compared with 17 (49%) of the 35 unaware patients (P=0.012, Fisher's exact test). Thirty (86%) aware patients reported distress compared with seven (20%) unaware patients (P<0.001). The aware patients scored higher in screening for post-traumatic stress disorder (P=0.006, Mann-Whitney U-test). CONCLUSIONS: Butyrylcholinesterase deficiency is a major risk factor for distressing awareness during emergence. Lack of neuromuscular monitoring increases the risk significantly. Neuromuscular monitoring should be applied even when using short-acting neuromuscular blocking agents.
Title: Premature awakening and underuse of neuromuscular monitoring in a registry of patients with butyrylcholinesterase deficiency Thomsen JL, Nielsen CV, Palmqvist DF, Gatke MR Ref: British Journal of Anaesthesia, 115 Suppl 1:i89, 2015 : PubMed
BACKGROUND: Patients with butyrylcholinesterase (BChE) deficiency can experience prolonged paralysis after receiving suxamethonium or mivacurium. We hypothesized that patients suspected of BChE deficiency had a higher risk of being awakened while paralysed and having respiratory complications if neuromuscular monitoring was not applied before awakening. METHODS: We retrospectively included patients referred to the Danish Cholinesterase Research Unit between 2004 and 2012 on suspicion of BChE deficiency. We collected data on genotype, BChE activity, neuromuscular blocking agents administered, neuromuscular monitoring, and postoperative respiratory complications, defined as arterial oxygen desaturation <90%, assisted ventilation, reintubation of the trachea, and pulmonary aspiration. Patients were classified as prematurely awakened if anaesthesia had been terminated while the patient was still paralysed. RESULTS: We included 123 patients. Neuromuscular monitoring was applied before awakening in 48 (39%) patients. A nerve stimulator was never used or only after attempted awakening in the remaining 75 (61%) patients. Premature awakening occurred in 75 (100%) and 14 (29%) of the unmonitored and monitored patients, respectively (P<0.001, Fisher's exact test). In 11 of the monitored patients, the results of neuromuscular monitoring were interpreted as equipment failure or were disregarded. Respiratory complications occurred in 19 (25%) and five (10%) of the unmonitored and monitored patients, respectively (P=0.06). CONCLUSIONS: Patients with BChE deficiency are at higher risk of being awakened while paralysed if neuromuscular monitoring is not applied or used; neuromuscular monitoring is recommended whenever a neuromuscular blocking agent is administered.
Title: Use of neuromuscular monitoring to detect prolonged effect of succinylcholine or mivacurium: three case reports Cassel J, Staehr-Rye AK, Nielsen CV, Gatke MR Ref: Acta Anaesthesiologica Scandinavica, 58:1040, 2014 : PubMed
Mutations in the butyrylcholinesterase gene can lead to a prolonged effect of the neuromuscular blocking agents, succinylcholine and mivacurium. If the anaesthesiologist is not aware of this condition, it may result in insufficient respiration after tracheal extubation. However, this can be avoided with the use of objective neuromuscular monitoring if used adequately. Three case reports of prolonged effect of succinylcholine or mivacurium were presented to illustrate the importance of neuromuscular monitoring during anaesthesia. In the first case, continuous intraoperative neuromuscular monitoring allowed a prolonged neuromuscular blockade to be discovered prior to tracheal extubation of the patient. The patient was extubated after successful reversal of the neuromuscular blockade. On the contrary, neuromuscular monitoring was not used during anaesthesia in the second patient; hence, the prolonged effect of the neuromuscular blocking agent was not discovered until after extubation. In the third patient, the lack of response to nerve stimulation was interpreted as a technical failure and the prolonged effect of succinylcholine was discovered when general anaesthesia was terminated. Both patients had insufficient respiration. They were therefore re-sedated, transferred to the intensive care unit and the tracheas were extubated after full recovery from neuromuscular blockade. We recommend the use of monitoring every time these agents are used, even with short-acting drugs like succinylcholine and mivacurium.
Title: [Danish Cholinesterase Research Unit diagnoses patients with prolonged paralysis after succinylcholine and mivacurium.] Eskildsen KZ, Gatke MR Ref: Ugeskr Laeger, 176:, 2014 : PubMed
The Danish Cholinesterase Research Unit (DCRU) is a nationwide unit for patients carrying mutations in the butyrylcholinesterase enzyme (BChE). BChE hydrolyzes the neuromuscular blocking drugs succinylcholine and mivacurium. Patients with mutations in the butyrylcholinesterase gene are at risk of experiencing a prolonged effect of the drugs, such as weakness or paralysis for hours. In order to diagnose the referred patients correctly, DCRU combines results such as BChE activity, genotyping, pedigree and clinical reactions to succinylcholine or mivacurium.
Title: Patient information sheet for plasma cholinesterase deficiency Thomsen JL, Gatke MR Ref: Anaesthesia, 69:1287, 2014 : PubMed
BACKGROUND: Succinylcholine is usually metabolized quickly by the butyrylcholinesterase enzyme (BChE) but genetic variants of BChE may prolong the duration of action. The Kalow (K) variant is the most common mutation in the butyrylcholinesterase gene (BCHE), being present in 25% of Caucasians. The significance of the K-variant for the duration of action of succinylcholine has not been well studied. Our hypothesis was that the duration of action of succinylcholine would be prolonged in patients heterozygous for the K-variant genotype compared with the normal genotype (wild-type). METHODS: We included 70 adult surgical patients who received succinylcholine 1 mg/kg for rapid sequence induction. Neuromuscular monitoring was performed using ulnar nerve stimulation and acceleromyography. Duration of action of succinylcholine was defined as the time to 90% recovery of first twitch in train-of-four (T(1) 90%), BChE activity was determined, and the presence of BCHE K and A (atypical) variants were determined using DNA analysis. RESULTS: The wild-type BCHE was present in 38 patients, and 21 were heterozygous for the K-variant. Mean (SD) T(1) 90% in patients heterozygous for the K-variant, 11.6 (3.5) minutes, was longer than in patients with the wild-type genotype, 9.5 (2.7) minutes (P = 0.023), with a mean (95% confidence interval) difference of 2.1 (0.3-4.0) minutes. Patients heterozygous for the K-variant had a BChE activity of 5978 U/L compared with 7703 U/L in the wild-type group (P = 0.0045). CONCLUSION: We conclude that the mean duration of action of succinylcholine is prolonged for the patient heterozygous for the K-variant allele by at most 4 minutes relative to the wild-type, but this difference is small relative to the wide variability and overlap in recovery times among all patients.
BACKGROUND: patients undergoing electroconvulsive therapy (ECT) often receive succinylcholine as part of the anesthetic procedure. The duration of action may be prolonged in patients with genetic variants of the butyrylcholinesterase enzyme (BChE), the most common being the K- and the A-variants. The aim of the study was to assess the clinical significance of genetic variants in butyrylcholinesterase gene (BCHE) in patients with a suspected prolonged duration of action of succinylcholine after ECT. METHODS: a total of 13 patients were referred to the Danish Cholinesterase Research Unit after ECT during 38 months. We determined the BChE activity and the BCHE genotype using molecular genetic methods, the duration of apnea, time to sufficient spontaneous ventilation and whether neuromuscular monitoring was used. The duration of apnea was compared with published data on normal subjects. RESULTS: in 11 patients, mutations were found in the BCHE gene, the K-variant being the most frequent. The duration of apnea was 5-15 min compared with 3-5.3 min from the literature. Severe distress was noted in the recovery phase in two patients. Neuromuscular monitoring was used in two patients. CONCLUSION: eleven of 13 patients with a prolonged duration of action of succinylcholine had mutations in BCHE, indicating that this is the possible reason for a prolonged period of apnea. We recommend objective neuromuscular monitoring during the first ECT.
Title: Two novel mutations in the BCHE gene in patients with prolonged duration of action of mivacurium or succinylcholine during anaesthesia Gatke MR, Bundgaard JR, Viby-Mogensen J Ref: Pharmacogenet Genomics, 17:995, 2007 : PubMed
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.
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.
Title: Pharmacokinetics and pharmacodynamics of mivacurium in patients phenotypically homozygous for the atypical plasma cholinesterase variant: effect of injection of human cholinesterase Ostergaard D, Viby-Mogensen J, Rasmussen SN, Gatke MR, Varin F Ref: Anesthesiology, 102:1124, 2005 : PubMed
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.
Title: Pharmacokinetics and pharmacodynamics of mivacurium in patients phenotypically heterozygous for the usual and atypical plasma cholinesterase variants (UA) Ostergaard D, Viby-Mogensen J, Rasmussen SN, Gatke MR, Pedersen NA, Skovgaard LT Ref: Acta Anaesthesiologica Scandinavica, 47:1219, 2003 : PubMed
BACKGROUND: Mivacurium is hydrolyzed by plasma cholinesterase (pChe). The purpose of this study was to evaluate the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium in patients phenotypically heterozygous for the usual and the atypical pChe variant (UA). METHODS: Thirty-two patients were included in a dose-response study, in which the patients received one of four doses of mivacurium. An additional bolus dose of mivacurium, to a total of 0.1 mg kg-1, was given followed by a continuous infusion adjusted to maintain 91-99% neuromuscular block. The times to different levels of recovery following the infusion were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Twelve of the patients with an estimated duration of anaesthesia of more than 90 min were (randomly) selected for the pharmacokinetic part of the study. Venous samples were taken for determination of the three isomers of mivacurium. These results were compared with results from a previous study in phenotypically normal patients (UU). RESULTS: The estimated ED50 and ED95 were 24 and 69 microg kg-1, respectively. The median (range) infusion rate was 3.7 microg kg-1 min-1 (1.2-2.9) and the time to a TOF ratio of 0.7 was 29.8 min (16.1-44.8). The median clearances of the cis-cis, cis-trans and trans-trans isomers were 3.7, 29 and 28 ml kg-1 min-1, respectively. The elimination half-lives of the isomers were 45, 6.7 and 6.3 min, respectively. CONCLUSION: In patients heterozygous for the usual and the atypical variant (UA), the potency of mivacurium is higher, the infusion requirements lower and the rate of spontaneous recovery prolonged, compared with phenotypically normal patients. The clearances of the active isomers are significantly lower and the elimination half-lives longer in heterozygous patients than in phenotypically normal patients (UU). The pharmacokinetics of the inactive cis-cis isomer was not affected.
Title: Rapid simultaneous genotyping of the frequent butyrylcholinesterase variants Asp70Gly and Ala539Thr with fluorescent hybridization probes Gatke MR, Viby-Mogensen J, Bundgaard JR Ref: Scand J Clin Lab Invest, 62:375, 2002 : PubMed
BACKGROUND: The clinically important variants of butyrylcholinesterase (BChE) are the A- (Asp70Gly) and K-variants (Ala539Thr), which are common among Caucasians. These variants are associated with abnormal drug metabolism during anaesthesia, which leads to a prolonged neuromuscular block following administration of the neuromuscular blocking agents, mivacurium and succinylcholine. In addition, the K-variant has been proposed to be associated with Alzheimer's disease together with apolipoprotein E epsilon4. To facilitate diagnostics, we set out to establish a rapid and simple method for simultaneous genotyping of the A- and K-variants. METHODS: Using the LightCycler, a rapid-cycle duplex PCR is combined with generation of allele-specific fluorescent probe melting profiles. This allows simultaneous detection of both of the mutations in the BChE gene. The results were compared with direct sequencing and phenotyping results. RESULTS: Samples from 80 subjects were genotyped. The genotypes determined using the LightCycler were identical to those obtained by direct sequencing of conventional polymerase chain reaction products and was more accurate than phenotyping based on biochemical assays. CONCLUSIONS: A high-speed and easy to perform mutation detection assay has been established for the two most common mutations, Asp70Gly and Ala539Thr, in BChE, using the LightCycler technology and melting curves.
BACKGROUND: In children, onset time and duration of action of mivacurium are shorter than in adults. Some suggest that this is due to differences in plasma cholinesterase (pChe), whereas others indicate that there is no difference. The purpose of this study was to evaluate the pharmacodynamics and pharmacokinetics of mivacurium in phenotypically normal children aged 3-6 and 10-14 years old, respectively. METHODS: Ten children aged 3-6 years and 10 children aged 10-14 years were studied during halothane anaesthesia. Before induction of anaesthesia, a blood sample was drawn to measure the pChe activity and phenotype. The neuromuscular block was monitored at the thumb using train-of-four (TOF) nerve stimulation every 12 s and mechanomyography. The times to different levels of neuromuscular recovery following mivacurium 0.2 mg/kg were recorded. The concentrations in venous blood of the three isomers and the metabolites of mivacurium were measured. RESULTS: No statistically significant difference was found in pChe activity or in the pharmacodynamics of mivacurium. The onset time was 1.4 min (0.8-1.9) median (range) and 1.3 min (1.1-1.9) and the time to first response to TOF nerve stimulation was 9.6 min (6.5-12.6) and 10.5 min (7.0-14.0) in young and older children, respectively. The pharmacokinetic data were too sparse to allow analysis of the two age groups separately (8 and 8 patients), hence the data were pooled. The median clearances of the cis-cis, the cis-trans, and the trans-trans isomer were 5.5, 51.0 and 30.5 ml/kg/min, respectively. CONCLUSION: Our data indicate that there are no major differences in pharmacodynamics or pharmacokinetics of mivacurium between young (3-6 years) and older (10-14 years) children.
Title: Response to mivacurium in a patient compound heterozygous for a novel and a known silent mutation in the butyrylcholinesterase gene: genotyping by sequencing Gatke MR, Ostergaard D, Bundgaard JR, Varin F, Viby-Mogensen J Ref: Anesthesiology, 95:600, 2001 : PubMed
BACKGROUND Patients who are homozygous for the atypical mutation, compound heterozygous for atypical and silent mutations, or homozygous for silent mutations (SS) respond to mivacurium with extensively prolonged neuromuscular block. Although important, exact phenotyping of these patients is difficult. This article presents the pharmacodynamics and pharmacokinetics of a normal dose of mivacurium in a patient with phenotype SS, including a pedigree analysis and delineation of the molecular genetic method used to identify the genotype.
METHODS:
The neuromuscular block following administration of mivacurium, at a dose of 0.14 mg/kg, was monitored in a 30-yr-old healthy man with use of a mechanosensor and mechanomyography, and times to different levels of recovery were measured. Venous samples for determination of the mivacurium isomers were collected during the interval 134-494 min after administration of mivacurium, and the terminal half-lives were calculated. Butyrylcholinesterase activity, phenotype, and genotype were determined for both the patient and the family. Complete nucleotide sequencing was used to identify the genotype.
RESULTS:
A train-of-four ratio of 0.75 was reached 469 min after the injection of mivacurium. The terminal elimination half-lives of the mivacurium isomers, cis-trans and trans-trans, were 90 min. Complete nucleotide sequencing revealed two point mutations, the known silent variant S7 and a previously undescribed mutation of amino acid residue 170 introducing a stop codon.
CONCLUSIONS:
The patient was compound heterozygous for silent mutations in the butyrylcholinesterase gene. The response to mivacurium was an extensively prolonged duration of action. Identification of the rare silent mutations presupposes access to modern molecular genetic methods such as complete nucleotide sequencing.
