Inhibitor Report for: Succinylcholine~Suxamethonium

People with genetic variants of cholinesterase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholinesterase, which occurs in homozygous form in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that none of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame shift mutation at glycine 117 which prematurely terminates protein synthesis and yields no active enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinesterase (EC 3.1.1.8). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.

A steroid, the dibutyrate analogue of pancuronium bromide (9.8 X 10(-8)M), has been used as differential inhibitor in the study of the plasma cholinesterase variants. Pancuronium dibutyrate numbers have been measured for 190 individuals, and the mean values for six of the known genotypes, E1uE1u, E1uE1f, E1uE1a, E1fE1a, E1aE1a, and E1fE1f, have been calculated. Evidence is presented that a combination of the pancuronium dibutyrate number and the fluoride number give better resolution of the six genotypes than the combination of the pancuronium dibutyrate and the dibucaine number. This new differential inhibitor has real potential for revealing the probable existence of new genotypes.

A toxic shock syndrome occurred after a femoral nail removal requiring revision surgery. After administration of suxamethonium (1 mg.kg-1), an apnoea prolonged over 45 minutes was observed. The trachea was extubated 105 minutes after suxamethonium administration. For the nail removal, two days before, the anaesthetic had been given by the same anaesthesiologist, with a similar protocol. Apnoea extended over 20 minutes. The day of the revision surgery, plasma cholinesterase activity was 410 UI.L-1 and reached 910 UI.L-1, 9 months later. Dibucaine number was 20 and fluorure number 17. The apnoea was in relation with a genetic plasma cholinesterase deficiency increased by the toxic shock syndrome. Shock and hepatic insufficiency were suspected to contribute to the decrease in plasma cholinesterase. Suxamethonium should be avoided in case of toxic shock syndrome.

OBJECTIVE The depolarizing muscle relaxant succinylcholine (SCh) may cause several side effects including muscle fasciculations and postoperative myalgia. These can be attenuated or even prevented by prior administration of a non-depolarizing muscle relaxant. A study was conducted to detect any difference between clinically established approaches concerning the successful prevention of muscular side effects and the influence on the time profile of SCh action. METHODS: The study included 64 patients (ASA status I or II) who underwent elective surgery under general anesthesia. The patients were divided into four groups; the demographic data did not differ significantly between the groups (see table 1). Before the injection of SCh (1 mg/kg) for intubation, the control group received saline (K), the other groups 5 mg Atracurium (A), 1 mg Vecuronium (V), or 1 mg Pancuronium (P), respectively. Neuromuscular block was quantified after train-of-four (TOF) stimulation of the tibial nerve by accelerometry at the toe. The first response was used to determine the onset time, duration of effect, and recovery index. It was noted whether SCh led to muscular activity. Postoperatively, patients were asked whether they experienced any muscular sequelae. Statistical significance was assessed at the 5% probability level by the Mann-Whitney-U test and the CHi2 test (Fisher's exact test, if appropriate). RESULTS: SCh caused a complete neuromuscular block in all patients. Most patients in the control group exhibited muscular contractions than in the other groups (see table 2), but only two patients reported light myalgia. There was no statistically significant difference between the four groups in the onset time and the recovery index of SCh. The duration of the effect was significantly reduced by atracurium (7.5 min) or vecuronium (8.2 min) as compared to the placebo (11.8 min) and pancuronium (13.5 min) (see figure). CONCLUSION: The prolonged duration of the SCh effect after pancuronium is probably due to the known inhibition of cholinesterase by pancuronium. The short duration of action after Atracurium and Vecuronium can be explained by the competitive antagonism at the receptor causing an increased amount of unbound SCh. The duration of the SCh effect may be influenced according to clinical needs by the choice of the non-depolarizing muscle relaxant. The significantly reduced duration of complete neuromuscular block after Atracurium or Vecuronium as precurarizing agents may be advantageous in cases where a fast recovery of spontaneous breathing is essential. If a reduction of the SCh blockade has to be avoided, Pancuronium should be selected for prior administration.

The reported effects of edrophonium on a subsequent dose of suxamethonium are variable and the effects of pyridostigmine have not been evaluated extensively. We have studied this interaction in patients anaesthetized with propofol and sufentanil. After recovery from an initial bolus (1 mg kg-1) of suxamethonium, vecuronium was infused to produce 75% block. After 30 min, the infusion was discontinued and saline 5 ml, edrophonium 0.75 mg kg-1, pyridostigmine 0.24 mg kg-1 or neostigmine 0.05 mg kg-1 was given. Fifteen minutes later the mean durations of a second bolus of suxamethonium were: 10.5 (SD 3.9) min (saline), 10.9 (3.7) min (edrophonium), 18.7 (5.4) min (pyridostigmine) and 23.8 (7.4) min (neostigmine). Corresponding plasma cholinesterase activities (percentage of baseline) were: 91 (18), 87 (9), 21 (10) and 52 (26). When both treatment groups and individual patients were compared, the changes in duration of action did not correlate with changes in cholinesterase activity. These data suggest that other mechanisms in addition to cholinesterase inhibition may contribute to this drug interaction.

Neostigmine antagonism after suxamethonium followed by mivacurium chloride bolus and infusion was studied. Thirty ASA group I or II patients were given mivacurium 0.15 mg/kg followed by infusion during nitrous oxide-enflurane-pethidine anaesthesia. Train of four (TOF) stimuli were applied to the ulnar nerve at the wrist and TOF twitch height and ratio measured by TOF-GUARD nerve stimulator. Mivacurium infusion was titrated to give a 90% block of first twitch height. Patients were randomized into two groups. Group I patients recovered from the mivacurium block spontaneously while Group II patients were given neostigmine 0.05 mg/kg and atropine 0.02 mg/kg. Time to reach train of four ratio (TOFR) of 25%, 50% and 70% were measured. This study demonstrated a mean infusion rate of 5.1 +/- 1.8 micrograms/kg/min to maintain a 90% neuromuscular block. In the spontaneous recovery group, time to reach TOFR of 25%, 50% and 70% were 9.3 +/- 2.7 min, 13.5 +/- 3.0 min and 16.7 +/- 3.0 min respectively while the corresponding times in the neostigmine group were 5.2 +/- 1.7 min, 10.9 +/- 2.2 min and 16.1 +/- 7.4 min respectively. There were significant differences in the time taken to TOFR of 25% (P < 0.0001) and 50% (P < 0.05) but no difference in the time taken for TOFR to return to 70%. We concluded that mivacurium is suitable for use in caesarean section despite a decrease in plasma cholinesterase activity. Neostigmine antagonism is not required as a routine.

For more than 20 years, the Danish Cholinesterase Research Unit (DCRU) has collected information about patients showing an abnormal response to succinylcholine. The purpose of this study was to evaluate our clinical findings in patients referred because of prolonged response following succinylcholine. Also, we wanted to evaluate the results of our prospective controlled studies of the effect of succinylcholine in patients with normal and abnormal plasma cholinesterase genotypes. An explanation for the apparent abnormal response to succinylcholine was only found in roughly 60% of the 1247 patients referred to the Unit. In the remaining nearly 40% of the patients the reason for the abnormal response remained obscure, though our results indicate that the anaesthetic technique, including hyperventilation or central respiratory depression, was most likely to be the reason. The significance of the different genotypes, including two newly discovered genotypes (AK, AH), for the reaction to succinylcholine was evaluated and found to be comparable to previous findings. Our results indicate that it is a problem for many anaesthetists to correctly diagnose a prolonged response to succinylcholine. We therefore urge the anaesthetist to use a peripheral nerve stimulator when faced with a case of apparent abnormal response to succinylcholine.

Butyrylcholinesterase [BCHE (acylcholine acyl hydrolase); EC 3.1.1.8] limits the access of drugs, including tacrine, to other proteins. The "atypical" BCHE variant, in which Asp70 at the rim of the active site gorge is substituted by glycine, displayed a more drastically weakened interaction with tacrine than with cocaine, dibucaine, succinylcholine, BW284c51 [1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide], or alpha-solanine. To delineate the protein domains that are responsible for this phenomenon, we mutated residues within the rim of the active site gorge, the region parallel to the peripheral site in the homologous enzyme acetylcholinesterase [AChE (acetylcholine acetyl hydrolase); EC 3.1.1.7], the oxyanion hole, and the choline-binding site. When expressed in microinjected Xenopus laevis oocytes, all mutant DNAs yielded comparable amounts of immunoreactive protein products. Most mutants retained catalytic activity close to that of wild-type BCHE and were capable of binding ligands. However, certain modifications in and around the oxyanion hole caused a dramatic loss in activity. The affinities for tacrine were reduced more dramatically than for all other ligands, including cocaine, in both oxyanion hole and choline-binding site mutants. Modified ligand affinities further demonstrated a peripheral site in residues homologous with those of AChE. BCHE mutations that prevented tacrine interactions also hampered its ability to bind other drugs and inhibitors, which suggests a partial overlap of the binding sites. This predicts that in addition to their genetic predisposition to adverse responses to tacrine, homozygous carriers of "atypical" BCHE will be overly sensitive to additional anticholinesterases and especially so when exposed to several anticholinesterases in combination.

A survey was conducted among British, French and German anaesthetists to evaluate possible national differences in the peri-operative use of muscle relaxants and their reversal agents. The same non-depolarizing relaxants are used in all three countries, with the exception of d-tubocurarine, which is only available in Great Britain, and alcuronium which is mainly used in Germany. The French anaesthetists seem to use significantly less succinylcholine than their peers in Great Britain or Germany for both elective and emergency intubation. Monitoring of neuromuscular blockade still relies mainly on "clinical judgement'. Reversal of non-depolarizing muscle relaxants is performed routinely in Great Britain, while a substantial number of French anaesthetists avoid the use of a reversal. Dose regimes for neostigmine vary largely, with German anaesthetists administering the lowest, and British anaesthetists administering the highest doses. Side effects of reversal agents are reported by colleagues from all three countries in too high a percentage to justify uncritical administration of these drugs. In Germany there seems to be a noteworthy lack of recovery facilities.

The relation between the level or the quality of serum cholinesterase and susceptibility to succinylcholine-induced apnea is significant because the abnormality resides in a low affinity variant rather than in a quantitative deficiency. A population study was undertaken in Trinidad to determine the pattern of the cholinesterase phenotype, using quantitative biochemical tests and the dibucaine number. Of 1290 subjects, 567 were African, 418 were Indian, 237 were of mixed lineage, and 68 belonged to the minority races. The dibucaine number did not differ between races or sexes. Of the population, 98.5% had normal enzyme characteristics. Indians had the highest values for the dibucaine number and the enzyme activity. Cholinesterase was significantly higher in African and mixed males. The homozygous atypical gene was not detected, but the frequency of the heterozygous "atypical" variant was highest in the minority races and lowest in Africans. Two sisters of Indian descent demonstrated the presence of the silent gene.

BACKGROUND: The metabolic hydrolysis of mivacurium (and succinylcholine) is markedly impaired in the presence of hereditary or acquired defects of pseudocholinesterase. Clinical reports are conflicting as to the utility of anticholinesterases, in the reversal of mivacurium paralysis. In the current study, the role of exogenous cholinesterases and/or of anticholinesterase, neostigmine, in the reversal of deep mivacurium-induced paralysis, was studied. The rat phrenic-diaphragm preparation, in a fixed volume of Krebs solution, was chosen to eliminate the confounding effects on the dissipation of neuromuscular effects caused by hydrolysis, elimination, and redistribution of the drug. METHODS: In the phrenic-diaphragm preparation, mivacurium was administered to obtain >90% single twitch inhibition. Single twitch responses (0.1 Hz) were monitored for 60 min, after which the response to train-of-four stimulation was tested. The reversal of mivacurium by 0.5, 1.0, or 2.0 units/ml of (true) acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase and by neostigmine, 0.1, 1.0, or 10.0 micrograms/ml tested. The efficacy of human plasma cholinesterase, 1 unit/ml in combination with each of the above neostigmine concentrations, also was examined. The reversal of succinylcholine-induced paralysis by the acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase (1 unit/ml) alone and in the presence of neostigmine (10.0 micrograms/ml) was additionally tested as a positive control. A train-of-four ratio > 0.75 was considered adequate reversal. RESULTS: Acetylcholinesterase was a poor hydrolyzer of mivacurium, as bioassayed by reversal of paralysis. Bovine pseudocholinesterase in concentrations of 0.5 and 1.0 units/ml did not effectively reverse single twitch and train-of-four responses by 60 min, but bovine pseudocholinesterase (2 units/ml) and all concentrations of human plasma cholinesterase did. Neostigmine alone, tested at all concentrations, was an incomplete reversal drug. Clinical or therapeutic concentrations (0.1 and 1.0 micrograms/ml) of neostigmine did not, but pharmacologic concentrations (10 micrograms/ml) interfere with the efficacy of human plasma cholinesterase (1 unit/ml). Bovine pseudocholinesterase and human plasma cholinesterase equally reversed the effects of succinylcholine but acetylcholinesterase did not, whereas the addition of 10 micrograms/ml neostigmine to the enzymes inhibited the reversal of succinylcholine. CONCLUSIONS: Human plasma cholinesterase will reverse mivacurium more effectively than bovine pseudocholinesterase, but both will effectively reverse succinylcholine. Acetylcholinesterase has no effects on either relaxant. The anticholinesterase neostigmine was an incomplete reversal drug. Pharmacologic concentrations of anticholinesterases do, while clinical or therapeutic concentrations do not, completely inhibit the metabolic activity of pseudocholinesterases.

We compared both the time course of neuromuscular blockade and the cardiovascular side-effects of suxamethonium and mivacurium during halothane and nitrous oxide anaesthesia in infants 2-12 months and children 1-12 years of age. Equipotent doses of mivacurium and suxamethonium were studied; 2.2 x ED95 was used in four groups of infants and children, while 3.4 x ED95 was used in two groups of children. Onset of neuromuscular block in infants was not significantly faster with suxamethonium than with mivacurium (P = 0.2). In all infants given suxamethonium, intubating conditions were excellent, while, in 6/10 infants given mivacurium, intubating conditions were excellent. Onset of complete neuromuscular block in children was significantly faster with suxamethonium, 0.9 min compared with mivacurium, 1.4 min (P < or = 0.05). Increasing the dose of suxamethonium or mivacurium in children to 3.4 x ED95 did not change the onset of neuromuscular block. Recovery of neuromuscular transmission to 25% of initial twitch height (T25) in infants and children was significantly faster after suxamethonium than after mivacurium, at 2.5 and 6 min, respectively (P < or = 0.05). In children given 3.4 x ED95 of suxamethonium or mivacurium, recovery from neuromuscular block was almost identical with the dose of 2.2 x ED95, with spontaneous recovery to T25 prolonged by only 0.5 min. No infant or child had hypotension after the mivacurium bolus dose.

Mivacurium is a new nondepolarizing muscle relaxant of the benzylisoquinoline type. Its short duration of action is due to rapid breakdown by plasma cholinesterase. The dose of mivacurium which produces 95% inhibition of twitch response (ED95) is between 60 and 80 micrograms/kg. Thus, mivacurium is 0.8 times and four times as potent as vecuronium and atracurium, respectively. With 2-3 x ED95, tracheal intubation can be accomplished within 2.5 min of intravenous injection. The ensuing DUR25% (time from injection to 25% recovery of control twitch tension) is twice as long as with suxamethonium and about half as long as with equipotent doses of atracurium or vecuronium. For muscle relaxation during long surgical procedures, mivacurium has been used as a continuous infusion. The average 6-min recovery index after infusion of mivacurium is particularly favourable for flexible control of muscle paralysis, whereas the recovery indices after infusion of atracurium or vecuronium are 15-30 min. In conclusion, mivacurium will close the pharmacodynamic gap between suxamethonium and the nondepolarizing muscle relaxants of intermediate duration of action. It will probably also be a suitable alternative to suxamethonium in elective cases.

We investigated the interaction between mivacurium and succinylcholine when mivacurium was administered during the early recovery from succinylcholine block. We studied 40 adult patients during propofol-alfentanil-N2O-O2 anesthesia. Neuromuscular function was monitored using an electromyographic method (Relaxograph, Datex, Helsinki, Finland). Patients randomly received either 1.0 mg/kg of succinyl-choline followed by 0.15 mg/kg of mivacurium when the first twitch (T1) during succinylcholine block recovered to 5%, or 0.15 mg/kg of mivacurium without succinylcholine. Serum cholinesterase activity was lower than normal range in two patients and higher than normal range in four patients, but the dibucaine number value was normal in every patient. The mean onset time (3.8 +/- 0.9 min) (mean +/- SD) or maximal neuromuscular block (96.6% +/- 7.2%) of mivacurium did not differ between the groups. The T1 recovery times of mivacurium were slightly shorter (P < 0.05) after succinylcholine administration than without it. During recovery of mivacurium block, the fade was significantly greater, i.e., the train-of-four (TOF) ratio was lower, after succinylcholine administration than without it. Recovery index (T1 25%-75%, mean 4.7 +/- 1.3 min) and the time from the administration of mivacurium to the recovery of TOF ratio 0.7 (mean 20.4 +/- 5.1 min) were not different between the groups. In conclusion, in healthy patients succinylcholine has negligible effects on a subsequent mivacurium-induced neuromuscular block.

Mivacurium is a relatively new short-acting nondepolarizing neuromuscular blocker. A recommended dose of 0.15-0.2 mg kg-1 provides tracheal intubating conditions within 2.5 min and duration of action of 15-30 min, making it a possible alternative to suxamethonium for short procedures requiring tracheal intubation. However, in common with suxamethonium its metabolism depends primarily on plasma cholinesterase and its duration of action is prolonged in patients with reduced plasma cholinesterase activity. We present a case of unexpected prolonged neuromuscular block in a child with previously undiagnosed plasma cholinesterase deficiency.

For more than 20 years, the Danish Cholinesterase Research Unit (DCRU) has collected information about patients showing an abnormal response to succinylcholine. The purpose of this study was, on the basis of the 20 years' experiences with the Unit, to evaluate our clinical findings in patients referred because of prolonged response following succinylcholine. Also, we wanted to evaluate the results of our prospective controlled studies of the effect of succinylcholine in patients with normal and abnormal plasma cholinesterase genotypes. An explanation for the apparent abnormal response to succinylcholine was found in 61.1% of the 1,247 patients referred to the Unit. Of the 1,247 patients, 28.5% were genotypically normal and 46.5% had an abnormal genotype. In the remaining 24.9% of the patients, the genotype could not be established. The time to sufficient recovery of neuromuscular function following succinylcholine 1.0-1.5 mg kg-1 was 15-30 min in patients heterozygous for one abnormal gene, 35-45 min in patients heterozygous for two abnormal genes and 90-180 min in patients homozygous for the atypical gene. Patients with two newly discovered genotypes (AK (5 patients) and AH (1 patient) showed slightly prolonged (20 min) and markedly prolonged (90 min) duration of action of succinylcholine, respectively. Our results indicate that it is a problem for many anaesthetists to correctly diagnose a prolonged response to succinylcholine. We therefore urge the anaesthetist always to use a peripheral nerve stimulator when faced with a case of apparent abnormal response to succinylcholine.

In 1973, a Cholinesterase Research Unit was established in Denmark (DCRU). The primary aim was to provide a central service for determining genotypes and activity of plasma cholinesterase (BChE) in patients showing abnormal response after succinylcholine. The purpose of the present study was, on the basis of 20 years experience with this Unit, to establish accurate reference intervals for BChE activity and inhibition values for the different genotypes of BChE. Also we wanted to evaluate the influence of age and sex on the BChE activity in genotypically normal patients. Plasma cholinesterase activity was measured using benzoylcholine as substrate. The genetic variations of the enzyme were identified using differential inhibitors, i.e.: Dibucaine, Sodium Fluoride, Succinylcholine, Urea and Ro-2-0683. We investigated 6,688 patients. The reference values for the 13 genotypes represented agree with previous findings. In genotypically normal patients, no age or sex differences were found in BChE activity in children below the age of 10 years. From the age of 10 years the activity decreased significantly in both males and females, the activity in females being significantly lower than in males. In females the activity was lowest in the age group 30-40 years, returning to prepuberty level at about 60 years of age. In males the activity decreased slightly up to 50-60 years of age. Hereafter the activity was stable or tended to increase slightly. Most genotypes could be recognized using the results of the different inhibition studies. We found the inhibitors Dibucaine, Sodium fluoride, Urea and Ro-2-0683 most helpful, whereas succinylcholine was of less value.

Rapid sequence induction of anaesthesia necessitating the use of suxamethonium may occasionally be needed soon after antagonism of neuromuscular block with anticholinesterase agents. The onset and duration of action of 1 mg kg-1 of suxamethonium was recorded in groups of 10 patients each, 5 or 10 min after the administration of edrophonium 1 mg kg-1 or neostigmine 40 micrograms kg-1 given for the antagonism of atracurium-induced neuromuscular block. Plasma cholinesterase activity was measured before, and 5 and 10 min after the administration of the anticholinesterases. A further 10 patients received suxamethonium 1 mg kg-1 without prior atracurium or anticholinesterase administration to serve as controls. The onset of action of suxamethonium was significantly prolonged when administered 5 min after both anticholinesterases, compared to the control group (P < 0.01). Recovery of suxamethonium block was delayed significantly after neostigmine, compared to both the edrophonium and the control groups (P < 0.05-0.001). Plasma cholinesterase activity was significantly reduced with the use of neostigmine but not with edrophonium (P < 0.001).

Mivacurium is a benzylisoquinolinium diester. The drug is a nondepolarizing relaxant which is hydrolysed by plasma cholinesterase at 70-88% of the rate of suxamethonium. Enzymatic hydrolysis gives the drug its short duration of action. The length of paralysis is about 2-2.5 times that of suxamethonium and one-half to one-third that of the intermediate-acting nondepolarizers. The development of mivacurium represents a collaboration between industrial pharmacologists and chemists at Burroughs Wellcome Co. (USA) and investigators at the Massachusetts General Hospital, Boston, MA, USA.

We report a case of prolonged neuromuscular block after administration of mivacurium 0.2 mg kg-1 to a 16-yr-old patient where the duration of block was 2.5 h. The interesting points in this case were that the patient had homozygous atypical plasma cholinesterase deficiency (both parents had a normal phenotype) following liver transplantation. Investigations showed low plasma cholinesterase activity (343 iu litre-1; normal 600-1400) and dibucaine number was 25 (normal 76-83). Despite possessing atypical enzyme normally associated with markedly prolonged duration of suxamethonium, on two occasions the patient received suxamethonium and responded normally. This had not previously been reported. The patient demonstrated prolonged block with mivacurium as a result of atypical enzyme (despite normal metabolism of suxamethonium).

The authors describe a case of prolonged neuromuscular blockade following suxamethonlum in a patient with a normal cholinesterase activity and dibucaine number > or = 75%. In this case a peripheral nerve stimulator and capnography allowed neuromuscular blockade evaluation and fresh frozen plasma infusion led to a normal recovery from suxamethonium neuromuscular blockade. This report suggests a case of abnormal cholinesterase activity described as "silent variant".

An 81-year-old patient had prolonged competitive neuromuscular blockade with train-of-four ratios of 0.1 and 0.5, respectively, after two successive anaesthesia procedures (enflurane-N2O/O2; vecuronium-succinylcholine-sequence) for transurethral prostate resection. Although antagonism with neostigmine was promptly successful after the first, 65-min period of anaesthesia (1.5 mg vecuronium for precurarization, 100 mg succinylcholine for intubation, 3 mg vecuronium), repetitive and chronologically staggered administration of neostigmine after the second, 30-min period of anaesthesia (1 mg vecuronium for precurarization, 100 mg succinylcholine for intubation) had hardly any effect, so that the patient had to be ventilated mechanically for a total of 4.5 h. Laboratory analysis revealed homozygous, atypical, plasma cholinesterase (790 U/l; dibucaine number 23; genotype E1aE1a). This retrospectively confirmed a succinylcholine-induced phase II block in both instances, as had already been suspected following the second anaesthetic procedure. The degree of block transformation, and thus the available time, are decisive in explaining the diverse effects of antagonism here. It must be assumed that a complete phase II block developed after the first succinylcholine exposure owing to the longer duration of anaesthesia; the purely competitive component (train-of-four ratio 0.1) was easily antagonized by neostigmine. At the time of the attempted antagonism after the second, shorter period of anaesthesia, however, block transformation was still incomplete (train-of-four ratio 0.5). The administration of neostigmine therefore rather intensified the depolarization segment of the mixed block, so that repeated attempts at antagonism then inhibited any further block transformation.

Plasma cholinesterase is a glycoprotein synthesized in the liver and is found in plasma, liver, intestinal mucosa and other tissues. Six percent to 7% of patients in most surgical populations have an abnormal plasma cholinesterase activity and about 65% of all cases of prolonged neuromuscular blockade following succinylcholine are due to genetic factors. This review focuses on the causes and clinical significance of plasma cholinesterase for the hydrolyses of succinylcholine. Diagnosis and treatment of prolonged response to succinylcholine in phenotypically normal patients, heterozygous abnormal patients and patients homozygous for the atypical gene is mentioned. Also presented is the relationship between plasma cholinesterase and the new relaxant mivacurium, and bambuterol, a prodrug to terbutaline. Additionally, the recent developments in the identification of the plasma cholinesterase genotypes are presented.

Children with cerebral palsy may be resistant to paralysis induced by nondepolarizing neuromuscular blocking drugs. Potency of a bolus of succinylcholine in children with cerebral palsy has not been studied previously. Therefore, we measured the response of the adductor pollicis to succinylcholine in children with cerebral palsy anesthetized with propofol and nitrous oxide. Forty children between the ages of 2 and 10.2 yr with spastic quadriplegic cerebral palsy were randomly assigned to receive 100, 175, 250, or 375 micrograms/kg of succinylcholine during anesthesia with propofol and nitrous oxide. The ulnar nerve was stimulated with a train-of-four supramaximal stimulus every 10 s and the compound electromyogram of the adductor pollicis recorded by a Datex NMT monitor. Plasma cholinesterase activity was measured in all patients with three different substrates (propionylthiocholine, benzoylcholine, and succinylcholine). Dibucaine number was also determined using inhibition of benzoylcholine degradation. ED50 of succinylcholine was 146.8 micrograms/kg with 95% confidence intervals of 111.4-193.7 micrograms/kg. ED95 of succinylcholine was 360.5 micrograms with 95% confidence intervals of 273.3-475.5 micrograms/kg. We conclude that children with cerebral palsy are slightly sensitive to succinylcholine, but probably not sufficiently to be clinically important.

We have investigated the possibility of using the pre-operative measurement of cholinesterase activity to predict the postoperative development of myalgia following the administration of suxamethonium. Seventy-seven patients presenting for elective extraction of wisdom teeth were entered in the study. All patients received a standard anaesthetic regimen, including suxamethonium to facilitate tracheal intubation, and standardised postoperative analgesia. Myalgia was assessed postoperatively and no correlation between muscle pains and cholinesterase activity was found.

Mivacurium is a potent nondepolarising neuromuscular blocking agent which is structurally related to the benzylisoquinolinium compound, atracurium. Mivacurium has a short duration of action due to its rapid elimination by plasma cholinesterase. When administered to essentially healthy adult patients receiving nitrous oxide-narcotic anaesthesia, the recommended intubating dose (2 x ED95) usually provides clinically effective neuromuscular block for approximately 15 to 20 minutes and spontaneous recovery is 95% complete within about 25 to 30 minutes. When administered to paediatric patients aged 2 to 12 years, the recommended intubating dose of mivacurium produces approximately 10 minutes of clinically effective neuromuscular block. The clinical duration of action of mivacurium is shorter than that of the other nondepolarising blockers atracurium and vecuronium, although it is still longer than that of the depolarising blocker suxamthonium (succinylcholine). The recommended intubating dose usually produces good or excellent conditions for tracheal intubation within 2 to 2.5 minutes in adult patients, although intubation times are longer than those for a standard intubating dose of suxamethonium. Thus far, mivacurium has not demonstrated a cumulative neuromuscular blockade when administered to patients with normal plasma cholinesterase activity. Furthermore, due to the intrinsically faster rate of recovery, pharmacological reversal with anticholinesterases is less likely to be indicated with mivacurium than for other, longer-acting, nondepolarising blockers. Benzylisoquinolinium compounds such as mivacurium have the potential to release histamine and cause cardiovascular instability. Interpatient variability in the susceptibility to histamine release is to be expected, although the recommended intubating dose has produced minimal haemodynamic effects in clinical trials to date. Prolonged neuromuscular block is likely in patients with markedly reduced plasma cholinesterase activity. In particular, patients homozygous for the atypical plasma cholinesterase gene are extremely sensitive to the neuromuscular blocking effects of mivacurium and should not receive the drug. In summary, a single bolus dose of mivacurium can be recommended for use in adult and paediatric patients undergoing nonemergency tracheal intubation and/or during short surgical procedures. For maintenance of neuromuscular block, mivacurium can be administered as multiple bolus doses or as a continuous infusion. In particular, the lack of a significant cumulative effect renders the drug suitable for the maintenance of neuromuscular blockade during extended surgical procedures of unpredictable length.

A 35-year-old woman undergoing laparoscopic sterilisation developed prolonged apnoea after suxamethonium. Fresh frozen plasma was given to replenish plasma cholinesterase, but recovery of neuromuscular transmission was not accelerated. Routine use of quantitative neuromuscular monitoring simplified her postoperative management.

Human tissues have two distinct cholinesterase activities: acetylcholinesterase and butyrylcholinesterase. Acetylcholinesterase functions in the transmission of nerve impulses, whereas the physiological function of butyryl-cholinesterase remains unknown. An atypical form of butyrylcholinesterase or the absence of its activity leads to prolonged apnea following administration of the muscle relaxant suxamethonium. Inheritance of these butyrylcholinesterase variants is consistent with the enzyme activity being encoded in a single autosomal locus, BCHE (formerly CHE1 and E1), which has been assigned to chromosome 3. Previous in situ hybridization of a BCHE cDNA probe gave evidence of homologous sequences at 3q26 and 16q11-q23, raising the possibility of more than one locus coding for butyrylcholinesterase [H. Soreq, R. Zamir, D. Zevin-Sonkin, and H. Zakut (1987) Hum. Genet. 77: 325-328]. Using a different cDNA probe hybridized in situ to 46,XX,inv(3)(p25q21) metaphase chromosomes, we report here the localization of BCHE to a single autosomal location: 3q26.

The object of this study was to investigate whether pretreatment with pancuronium before i.v. injection of suxamethonium could cause prolonged neuromuscular blockade in patients heterozygous for the usual and the atypical plasma cholinesterase gene (E1uE1a). Forty-three patients, 23 with genotype E1uE1a and 20 with normal genotype (E1uE1u), were pretreated with pancuronium 0.01 mg.kg-1 followed by suxamethonium 1.5 mg.kg-1, and received either neurolept anaesthesia or halothane anaesthesia. Seven patients (E1uE1a) were given suxamethonium 1.5 mg.kg-1 without pretreatment. The duration and type of neuromuscular block were evaluated using train-of-four (TOF) nerve stimulation. Type of anaesthesia did not significantly influence the results. The duration of block following pretreatment was significantly longer in heterozygous patients than in normal patients. Time to 90% twitch height recovery was 10.7 +/- 1.2 min (mean +/- s.d.) in genotypically normal patients, and 18.0 +/- 4.2 min in patients with genotype E1uE1a. Pretreatment with pancuronium caused a significantly slower recovery of the TOF ratio (phase II block). Thus, a TOF ratio of 0.7 was always reached within 13 min in genotypically normal patients. In genotypically abnormal patients, the same TOF ratio was reached within 20 min in all but three patients. In these three patients time to 90% twitch height recovery was prolonged (18-31 min), and TOF ratio did not return to normal, but stabilized at about 0.35, 0.50, and 0.65, respectively. Injection of edrophonium restored normal neuromuscular function in 10 min. It is concluded that in patients heterozygous for the usual and the atypical gene, pretreatment with pancuronium in combination with an increased dose of suxamethonium may cause a phase II block and thus a prolonged neuromuscular block.

Bambuterol (the bisdimethylcarbamate prodrug of terbutaline) is a new bronchodilator with a prolonged duration of action due to its inhibition of plasma cholinesterase during metabolism. The effect of bambuterol on suxamethonium-induced neuromuscular blockade was studied in 10 patients undergoing elective laparotomy. Thirty mg of bambuterol was given 2 h before anaesthesia, which was performed with thiopentone, fentanyl, halothane and nitrous oxide in oxygen. Neuromuscular function was monitored using supramaximal train-of-four stimulation of the ulnar nerve and a force displacement transducer. Suxamethonium 1 mg.kg-1 was given i.v. for endotracheal intubation. Plasma cholinesterase activity was measured before and after intake of bambuterol and during anaesthesia. The results from the 10 patients were compared with those of 41 patients not given bambuterol but otherwise studied during the same conditions. Following bambuterol, all patients had a significant decrease of plasma cholinesterase activity (P less than 0.001) and the suxamethonium-induced blockade was 3-4 times prolonged compared to patients not given bambuterol (P less than 0.001). Five patients with very low plasma cholinesterase activity developed a long-lasting phase II block.

Bambuterol is a new bronchodilator which is also a reversible inhibitor of plasma cholinesterase. In patients with normal plasma cholinesterase genotype, bambuterol prolongs suxamethonium-induced neuromuscular blockade. In the present study, we investigated the interaction of bambuterol and suxamethonium in nine patients heterozygous for abnormal plasma cholinesterase during anaesthesia with fentanyl, thiopentone, halothane and nitrous oxide in oxygen. The patients (seven E1uE1a and two E1uE1s) were given 20 mg of bambuterol orally 2 h before anaesthesia. Suxamethonium 1 mg.kg-1 was given for tracheal intubation. The neuromuscular function was monitored using train-of-four (TOF) stimulation of the ulnar nerve and a force displacement transducer. Plasma cholinesterase activity decreased in all patients following bambuterol (P less than 0.001). In patients with genotype E1uE1a, median time to 90% recovery of twitch height and TOF ratio greater than or equal to 0.7 (37.5 min) was prolonged compared to 28 E1uE1a patients not treated with bambuterol (14.0 min) (P less than 0.001). Four of these patients developed a phase II block apparently not correlated to plasma cholinesterase activity. In the E1uE1s; patients, full recovery was seen after 22.0 and 31.4 min, respectively. It is concluded that in patients heterozygous for abnormal plasma cholinesterase, bambuterol 20 mg taken 2 h before anaesthesia causes a 2-3 times prolongation of the neuromuscular blockade following suxamethonium 1 mg.kg-1 and in some patients a phase II block.

People with genetic variants of cholinesterase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholinesterase, which occurs in homozygous form in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that none of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame shift mutation at glycine 117 which prematurely terminates protein synthesis and yields no active enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinesterase (EC 3.1.1.8). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.

The "atypical" allelic variant of human butyrylcholinesterase (BCHE) can be characterized by its failure to bind the local anesthetic dibucaine, the muscle relaxant succinylcholine, and the naturally occurring steroidal alkaloid solanidine, all assumed to bind to the charged anionic site component within the normal BCHE enzyme. A single nucleotide substitution conferring a change of aspartate-70 into glycine was recently reported in the CHE gene encoding BCHE from several individuals having the "atypical" BCHE phenotype, whereas in two other DNA samples, this mutation appeared together with a second alteration conferring a change of serine-425 into proline. To separately assess the contribution of each of these mutations toward anionic site interactions in BCHE, three transcription constructs were engineered with each of these substitutions alone or both of them together. Xenopus oocyte microinjection of normal or mutated synthetic BCHEmRNA transcripts was employed in conjunction with biochemical analyzes of the resultant recombinant BCHE variants. The presence of the Gly-70 mutation alone was found to render the enzyme resistant to 100 microM solanidine and 5 mM succinylcholine; concentrations sufficient to inhibit the "normal," Asp-70 containing BCHE by over 50%. Furthermore, when completely inhibited by the organophosphorous poison diisopropylfluorophosphate (DFP), Gly-70 BCHE failed to be reactivated by 10 mM of the cholinesterase-specific oxime pyridine 2-aldoxime methiodide (2-PAM); a concentration restoring about 50% of activity in the "normal" Asp-70 recombinant enzyme. The Pro-425 mutation alone had no apparent influence on BCHE interactions with any of these ligands. However, it conferred synergistic effects on some of the anionic site changes induced by the Gly-70 mutation.

We report two patients with the Churg-Strauss syndrome who were found to have decreased cholinesterase activity despite normal phenotypes. Suspicion of abnormal sensitivity to suxamethonium in the first case was raised after prolonged paralysis under anaesthesia. The findings in the second were incidental during the course of intensive care treatment. Both patients received immunosuppressive therapy. Differentiation between the effects of this and the disease process itself cannot be established.

A family is reported in which the propositus was found to be sensitive to suxamethonium. Both parents were heterozygote each having genotype Ea1Ek1. The sibling of the propositus had the most common phenotype as defined by dibucaine, fluoride and RO2 numbers. Genetic analysis, however, indicated that this sibling must be an Ek1Ek1 homozygote.

An hypothesis advanced in 1970 concerning family inheritance of low enzymic activities of plasma cholinesterase has been substantiated. The recognition of three E1kE1s genotypes is reported in this family after investigation of a new generation. A second family with similar genetic characteristics is described.

An account of plasma cholinesterase activity in samples of maternal and cord blood is presented. It is confirmed that plasma exchange markedly reduces the level of activity in maternal blood, and that the level is further reduced during the first 3-4 postnatal days. A particularly marked decrease was found in those cases in which spontaneous mid-trimester abortion occurred. The level of activity in maternal blood (excluding mothers subjected to plasma exchange) at the time of delivery, was higher than that in cord blood in 61% of cases. In 23% of cases the level of activity was appreciably (0.05 units) higher in cord blood, and two-thirds of these cord samples contained the E2+ electrophoretic variant of plasma cholinesterase. The mean levels of activity in maternal and cord blood of Rhesus negative patients were significantly lower than those among Rhesus positive patients but there was no such distinction between Rhesus positive and Rhesus negative males and nonpregnant females. We encountered an incidence of 1:228 abnormal phenotypes in a series of 1593 mothers who underwent Caesarean section under a technique of general anaesthesia which included a suxamethonium infusion. However, probably only two of the seven patients would definitely be sensitive when not pregnant.

Six individuals in three families with a history of suxamethonium sensitivity have been found to have genotype E1kE1s. The biochemical data for the recognition of this genotype have been analysed and the mean values compared with similar parameters for the usual phenotype. Individuals with genotype E1kE1s will be sensitive to suxamethonium.

The first identification of the cholinesterase variants E1kE1k and E1kE1s is reported from a family study. The evidence is based on the biochemical parameters of enzymic activity, and dibucaine, fluoride and RO2 numbers. Two individuals appear to be homozygotes E1kE1k and two are heterozygotes E1kE1s with family evidence supportive of these genotypes. The heterozygotes E1kE1s will be sensitive to suxamethonium.

The identity of a peptidase activity with human serum pseudocholinesterase (PsChE) purified to apparent homogeneity was demonstrated by co-elution of both peptidase and PsChE activities from procainamide-Sepharose and concanavalin-A--Sepharose affinity chromatographic columns; comigration on polyacrylamide gel electrophoresis; co-elution on Sephadex G-200 gel filtration and coprecipitation at different dilutions of an antibody raised against purified PsChE. The purified enzyme showed a single protein band on gel electrophoresis under non-denaturing conditions. SDS gel electrophoresis under reducing conditions, followed by silver staining, also gave a single protein band (Mr approximately equal to 90,000). Peptidase activity using different peptides showed the release of C-terminal amino acids. Blocking the carboxy terminal by an amide or ester group did not prevent the hydrolysis of peptides. There was no evidence for release of N-terminal amino acids. Potent anionic or esterase site inhibitors of PsChE, such as eserine sulphate, neostigmine, procainamide, ethopropazine, imipramine, diisopropylfluorophosphate, tetra-isopropylpyrophosphoramide and phenyl boronic acid, did not inhibit the peptidase activity. An anionic site inhibitor (neostigmine or eserine) in combination with an esterase site inhibitor (diisopropylfluorophosphate) also did not inhibit the peptidase. However, the choline esters (acetylcholine, butyrylcholine, propionylcholine, benzoylcholine and succinylcholine) markedly inhibited the peptidase activity in parallel to PsChE. Choline alone or in combination with acetate, butyrate, propionate, benzoate or succinate did not significantly inhibit the peptidase activity. It appeared that inhibitor compounds which bind to both the anionic and esteratic sites simultaneously (like the substrate analogues choline esters) could inhibit the peptidase activity possibly through conformational changes affecting a peptidase domain.

Unusual inhibition characteristics in two unrelated suxamethonium-sensitive individuals were indicative of a new allele, E1h, segregating with the E1a gene. Family studies substantiate this hypothesis and three new genotypes are recognised.

The first identification of the cholinesterase variant E1kE1f is reported from a family study. The evidence is based on the determination of enzymic activity, dibucaine, fluoride and RO2 numbers. Three individuals appear to have this genotype, and family evidence is not at variance with our conclusions. All three individuals will be sensitive to suxamethonium.

Four hundred and thirty blood samples from suxamethonium-sensitive individuals have been phenotyped by the Cholinesterase Research Unit following its transfer from Exeter to the Hammersmith Hospital. The distribution of genotypes has been shown to be similar to that found in Exeter. Screening for the Elk and Elj genes has not yielded any major differences in the gene frequencies of sensitive individuals, even during pregnancy. The uneven sex distribution of the patients, as well as other unusual points that have arisen, are discussed. A new gene for the biosynthesis of cholinesterase has probably been identified.

The cholinesterase genotypes in the majority (25/35) of patients with suxamethonium sensitivity following termination of pregnancy are heterozygotes with an E1a gene. Twelve of these patients have the genotype E1uE1a. The reported duration of apnoea is minimal in the heterozygotes lacking the E1a gene (about 5-10 min) and maximal in the homozygotes E1aE1a (about 35 min). With few exceptions, the heterozygotes having an E1a gene are apnoeic for 10-15 min. The apparent low frequency of suxamethonium in these patients is discussed.

Changes in plasma cholinesterase activity during the puerperium were studied in 16 women who received epidural analgesia for labour followed by vaginal delivery and in five women who underwent elective Caesarean section under epidural analgesia A consistent fall in cholinesterase activity was demonstrated during the first 2 to 3 days post partum followed by a rise to approximately normal nonpregnant values by the end of the puerperium An additional patient who manifested prolonged paralysis following an emergency Caesarean section under general anaesthesia including a suxamethonium infusion was also studied Possible mechanisms by which the transient decrease in cholinesterase activity is produced and its clinical significance are discussed

A patient, with a history of cretinism, who developed suxamethonium apnoea as a consequence of a reduction in plasma cholinesterase activity secondary to the concurrence of pregnancy and liver dysfunction associated with pre-eclampsia is reported. The patient had a normal phenotype for plasma cholinesterase.

An account is presented of a patient who developed ileus, of greater or lesser severity, after each of seven operations (including two extra-abdominal and three Caesarean sections). During her most recent pregnancy, reviewed here, her plasma cholinesterase activity was found to be decreased and it remained low until at least the 6th day post-partum. However, as the normal activity had been gained by 6 weeks after delivery, the phenomenon had evidently been pregnancy-related. Despite receiving suxamethonium by infusion to completion of her Caesarean section, she did not show an abnormally prolonged response, although she did suffer considerable suxamethonium "after-pains". The question is posed of a possible relationship between the postoperative ileus, muscle pains and the decrease in cholinesterase activity.

The relationship between plasma cholinesterase genotype and duration and type of succinylcholine neuromuscular blockade was studied in 43 anesthetized patients heterozygous for abnormal plasma cholinesterase using train-of-four nerve stimulation. Twenty-eight patients were heterozygous for the usual and the atypical gene (E1uE1a), eight were heterozygous for the usual and the silent gene (E1uE1s), three were heterozygous for the usual and the fluoride-resistant gene (E1uE1f), three were heterozygous for the fluoride-resistant and the atypical gene (E1fE1a), and one was heterozygous for the fluoride-resistant and the silent gene (E1fE1s). Mean time to 90 per cent recovery of twitch height in patients with genotypes E1uE1a, E1uE1s, and E1uE1f (14.6, 12.4, and 12.0 min, respectively) was significantly prolonged compared to patients with normal cholinesterase genotype (9.3 min). No significant difference was found between the three groups of patients with one abnormal gene (E1uE1a, E1uE1s, and E1uE1f). In 13 (46 per cent) of the 28 patients with genotype E1uE1a the twitch height did not return to control for more than 15 min after the administration of succinylcholine and in three patients (10.7 per cent) for more than 20 min after succinylcholine. The four patients with abnormal genes on both chromosomes (E1fE1a and E1fE1s) all showed significantly prolonged paralysis following the administration of succinylcholine (mean time to 90 per cent twitch recovery was 30 min). Patients heterozygous for the usual and one of the abnormal genes (E1uE1a, E1uE1s, and E1uE1f) had typically depolarizing blocks following the administration of succinylcholine, 1 mg/kg. Patients with abnormal genes on both chromosomes (E1fE1a and E1fE1s), however, all showed desensitization type of neuromuscular blockade (phase II block).

A steroid, the dibutyrate analogue of pancuronium bromide (9.8 X 10(-8)M), has been used as differential inhibitor in the study of the plasma cholinesterase variants. Pancuronium dibutyrate numbers have been measured for 190 individuals, and the mean values for six of the known genotypes, E1uE1u, E1uE1f, E1uE1a, E1fE1a, E1aE1a, and E1fE1f, have been calculated. Evidence is presented that a combination of the pancuronium dibutyrate number and the fluoride number give better resolution of the six genotypes than the combination of the pancuronium dibutyrate and the dibucaine number. This new differential inhibitor has real potential for revealing the probable existence of new genotypes.

An 11-year-old boy was given halothane, nitrous oxide and oxygen, pancuronium 0.4 mg and suxamethonium 100 mg for induction of anaesthesia. In response to this a marked jaw stiffness occurred which lasted for two minutes and the anaesthesia were terminated. Four hours of apnoea ensued and he suffered generalized severe myalgia lasting for one week. He was found to have atypical plasma cholinesterase with a dibucaine number of 12, indicating homozygocity. This was verified by study of the family. The case shows that prolonged jaw rigidity and myalgia may occur after suxamethonium in patients with atypical cholinesterase despite pretreatment with pancuronium.

Biochemical properties of plasma cholinesterase of significance to the anaesthetist are reviewed. The role of the genetic variants of the enzyme in suxamethonium sensitivity and hyperthermia are discussed with emphasis on the pregnant patient. Altered gene frequencies of the enzyme variants in some mental disorders is commented upon.

Human plasma cholinesterase (E.C.3.1.1.8) from 1,594 blood donors was phenotyped on the basis of dibucane, fluoride, chloride and succinylcholine differential inhibitions according to the criteria of Brown et coll. The observed gene frequencies are: E1u = 0.970,8, E1a = 0.188,0, E1f = 0.103,0.

During the last 4 years, 225 patients have been referred to the Danish Cholinesterase Research Unit following an episode of prolonged apnoea after suxamethonium. Fourteen patients (6.2%) were found to have a low serum cholinesterase activity due to an acquired deficiency (for instance, liver disease, chronic debilitating disease or carcinoma). One hundred and forty-eight patients (65.8%) had an inherited abnormal serum cholinesterase, and 105 of these patients (46.7%) were homozygous for the atypical enzyme (E1 Ea1). The mean period of apnoea in this latter group was 92 min (range: 25--240). Seventeen patients (7.6%) were heterozygous for the normal and the atypical enzyme (Eu1 Ea1), with a mean apnoea period of 25 min (range: 7--60 min). Twelve patients were found to be heterozygous for the atypical and the silent gene (E(a)1 E(s)1). The mean period of apnoea was 126 min (range: 45--210 min). Fourteen patients had other rare genotypes. The longest mean period of apnoea (170 min, range: 70--330) was found in patients homozygous for the silent gene (Es1 Es1). The silent gene and the fluoride-resistant gene were found in 8.9% and 2.7% of the patients, respectively. In 63 patients (28.1%) both the type and quantity of serum cholinesterase were normal. In 34 of these patients (15.2%), the prolonged apnoea was due to other causes; for example, suxamethonium overdose, hyperventilation and central as well as peripheral respiratory depression. However, in the other 29 patients (12.9%), the reason for the prolonged apnoea could not be established. The possibility therefore exists that these cases represent unknown genotypes.

Plasma cholinesterase variants have been examined in blood samples obtained from 23 patients who, after an intravenous injection of suxamethonium 30 mg before e.c.t., had prolonged apnoea. Attempts have been made to screen the relatives of all patients shown to have an unusual plasma cholinesterase. The present study indicates an increased frequency of the fluoride-resistant variants in those psychiatric patients sensitive to suxamethonium.

Pancuronium causes a powerful and highly selective inhibition of human serum cholinesterase in vitro. The inhibition was studied in serum from 14 individuals of both sexes (5-60 years of age) with normal reactions to suxamethonium. Pancuronium, in a concentration of 2.3 x 10(-7) M, caused a 50% inhibition of the enzymatic hydrolysis of acetylcholine, when this substrate was present in a concentration of 10 x 10(-3) M. The same I50 value was also found for a commercial preparation of human serum cholinesterase. The inhibition was reversible and competitive in type. Pancuronium inhibition of the acetylcholinesterase in human red blood cells and from the electric eel was more than one thousand times weaker. Thus pancuronium is one of the most selective inhibitors of serum cholinesterase described so far. The in vivo activity of the serum cholinesterase in four patients receiving pancuronium 0.1 mg/kg decreased, during the first 3 min, by 60-80%, from the pre-induction value. After this a slow recovery occurred with 40% depression remaining at 45 min after the injection. The tachycardia produced by pancuronium may be related to this selective inhibition of serum cholinesterase. It is suggested that relaxants which selectively inhibit serum cholinesterase also selectively block the cardiac muscarinic receptors.

The importance of serum cholinesterase activity in burned patients was evaluated in relation to anaesthesia. Anaesthesia included a repeated administration of suxamethonium. Thirty-two patients with an estimated area of burn between 3 and 72% were studied during 39 anaesthetic procedures. A statistically significant inverse correlation was found between serum cholinesterase activity and the apnoea period following intravenous suxamethonium. In patients with very low enzyme activity, apnoea periods of 10 to 25 min were observed. No correlation was found between the changes in serum potassium following suxamethonium and either the serum cholinesterase activity or the changes in Pco2 and pH. The most reliable parameters in predicting a dangerous increase in serum potassium following intravenous suxamethonium were shown to be 1) the time elapsed from burn injury to anesthesia and 2) the degree of burn injury. However, abnormal reactions to suxamethonium were seen as early as 9 days following injury, and rises in serum potassium to over 6 mmol/l were observed even in patients with a total burn surface of around 8%, i.e., less than the surface of one arm.