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Background Malnutrition is one of the most important comorbidities in patients with heart failure with preserved ejection fraction. We recently reported the prognostic significance of serum cholinesterase level and superior predictive power of cholinesterase level to other objective nutritional indices such as the controlling nutritional status score, prognostic nutritional index, and geriatric nutritional risk index in patients with acute decompensated heart failure. The aim of this study was to clarify the prognostic role of cholinesterase in patients with heart failure with preserved ejection fraction/acute decompensated heart failure and investigate incremental cholinesterase value. Methods and Results We prospectively studied 274 consecutive patients from the PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients with Heart Failure With Preserved Ejection Fraction) study. During a follow-up period of 1.2±0.6 years, 56 patients reached the composite end points (cardiovascular death and readmission for worsening heart failure). In the multivariable Cox analysis, cholinesterase level was significantly associated with the composite end points after adjustment for major confounders. A Kaplan-Meier analysis revealed that patients with low cholinesterase levels (stratified by tertile) had significantly greater risk of reaching the composite end points than those with middle or high cholinesterase levels ( P =0.0025). Cholinesterase level showed the best C-statistics (0.703) for prediction of the composite end points among the objective nutritional indices. C-statistics of the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score for prediction of the composite end points were improved when cholinesterase level was added (C-statistics, from 0.601 to 0.705; P =0.0408). Conclusions Cholinesterase was a useful prognostic marker for prediction of adverse outcome in patients with heart failure with preserved ejection fraction/acute decompensated heart failure.

Plasma cholinesterase (PCHE) activity is an important auxiliary test in human clinical medicine. It can distinguish liver diseases from non-liver diseases and help detect organophosphorus poisoning. Animal experiments have confirmed that PCHE activity is associated with obesity and hypertension and changes with physiological changes in an animal's body. The objective of this study was to locate the genetic loci responsible for PCHE activity variation in ducks. PCHE activity of Pekin duck × mallard F2 ducks at 3 and 8 weeks of age were analyzed, and genome-wide association studies were conducted. A region of about 1.5 Mb (21.8-23.3 Mb) on duck chromosome 9 was found to be associated with PCHE activity at both 3 and 8 weeks of age. The top SNP, g.22643979C>T in the butyrylcholinesterase (BCHE) gene, was most highly associated with PCHE activity at 3 weeks (-logP = 21.45) and 8 weeks (-logP = 27.60) of age. For the top SNP, the strong associations of CC and CT genotypes with low PCHE activity and the TT genotype with high PCHE activity indicates the dominant inheritance of low PCHE activity. Problems with block inheritance or linkage exist in this region. This study supports that BCHE is a functional gene for determining PCHE levels in ducks and that the genetic variations around this gene can cause phenotypic variations of PCHE activity., (© 2019 Stichting International Foundation for Animal Genetics.)

This study examined the effects of Y-27632, a selective Rho-kinase inhibitor, on organophosphate-induced acute toxicity in rats. Rats were randomly divided into four groups as control (corn oil), dichlorvos (30 mg kg(-1) i.p.), 1 and 10 mg kg(-1) Y-27632 + dichlorvos groups. Cholinergic signs (fatigue, tremor, cyanosis, hyper-secretion, fasciculations) were observed in all the rats in the dichlorvos group and the mortality rate was 50%. No cholinergic findings and deaths were observed in the control and Y-27632 groups. Plasma cholinesterase activities were suppressed with dichlorvos and these reductions were attenuated with Y-27632 pretreatment. There was a marked increase in plasma malondialdehyde level in the dichlorvos group, but Y-27632 pretreatment abolished this elevation. Dichlorvos markedly depressed cardiac paraoxonase activity, but these changes were not markedly modified with Y-27632. Total antioxidant capacities, total oxidant status, oxidative stress index, total free sulfhydryl groups and catalase activities in plasma and cardiac tissues were not markedly different between the groups. No significant changes were observed with cardiac myeloperoxidase activities or plasma arylesterase and ceruloplasmin activities. In conclusion, our results suggest that Rho-kinase pathway is involved in organophosphate intoxication, and a decrease in cardiac paraoxonase activities may play a role in the pathogenesis of acute organophosphate poisoning in rats., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Background: The Washington State Cholinesterase Monitoring Program for pesticide handlers requires blood draws at local clinics, with samples tested at a central laboratory. At present, workers with inhibited cholinesterase activity may be re-exposed before they can be removed from work. In this study we explored the option of on-site testing at local clinics using the EQM Test-mate Kittrade mark, a portable cholinesterase test kit., Methods: Test kit cholinesterase activity measurements were performed on 50 blood samples by our research staff, and compared to measurements on the same samples by the Washington State Public Health Laboratory. Another set of samples was also analyzed with the test kit by medical staff at an eastern Washington clinic., Results: Triplicate measurements with the test kit had a 3.3% average coefficient of variation (CV) for plasma cholinesterase (PChE), and a 3.5% average CV for erythrocyte cholinesterase (AChE) measurements. The kit's PChE measurements were similar to PHL measurements (average ratio of 0.98) when performed in the laboratory, but had a tendency to underestimate activity when used in the clinic setting (average ratio of 0.87). The kit systematically overestimated AChE activity by 42-48% relative to the PHL measurements, regardless of where the samples were analyzed., Conclusions: This easy-to-use test kit appeared to be a viable method for clinic-based PChE measurements, but was less consistent for AChE measurements performed in the clinic. Absolute measurements with the kit need to be evaluated carefully relative to standardized methods., ((c) 2008 Wiley-Liss, Inc.)

Background: Pesticide handlers in Washington State are predominantly Mexican and, therefore, require a culturally appropriate process of informed consent. In addition, members of this occupational group are vulnerable to coercion because of poverty, lack of insurance, inability to read, and employment status, Methods: To create a process of culturally competent informed consent for Washington State's cholinesterase monitoring program, we used focus groups to collect data about cultural beliefs, attitudes, knowledge, language, and traditions of Mexican-American pesticide handlers. With this information, we developed a final consent form and evaluated it using a 10-item test-retest questionnaire in a sample of 103 handlers., Results: Using qualitative methods, we created English and Spanish consent forms that incorporated culturally defined risk information. Both the written and audiotape formats significantly improved comprehension; but, for subjects with less than 7 years of schooling, audiotapes in Spanish yielded significantly higher scores (mean comprehension score 7.0 vs. 6.1, t = - 2.2, P = 0.03)., Conclusions: Culturally competent informed consent for particularly vulnerable populations of non-native speakers of English is possible. It requires both knowledge of specific cultural elements and the application of appropriate technology.

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.

Background: The short duration of action of mivacurium is due to its rapid hydrolysis by plasma cholinesterase (pChe). In patients with normal phenotype, low pChe activity because of, for instance, disease or intake of drugs may prolong the duration of action of mivacurium. The purpose of this study was to evaluate the relationship between pChe activity and the duration of action of mivacurium 0.2 mg/kg in phenotypically normal patients., Material: Forty-three adult patients with normal pChe phenotype and low or normal pChe activity, undergoing a variety of surgical procedures were included in the study with their informed consent and Ethics Committee approval. The neuromuscular block was monitored using TOF stimulation every 12 s and mechanomyography. The time to reappearance of the first response to TOF stimulation was measured., Results: The patients pChe activities ranged from 45 to 1272 U/l (normal range 660-1620 U/l) and the time to first response to TOF from 8.1 to 62.7 min. An inverse relationship between enzyme activity and duration of action of mivacurium was found. The relationship was described by the equation: log10 (time) =alpha- beta log10 (pChe), where alpha (SD) is 2.547 (0.186) and beta (SD) 0.454 (0.069)., Conclusion: In patients with phenotypically normal pChe, prediction of the duration of action of mivacurium is possible from the patients actual pChe activity. In patients with pChe activities below the normal range, the time to reappearance of the first response to TOF stimulation may vary from 10 to 180 min Only patients with pChe activities <220 U/l had a significantly prolonged duration of action of mivacurium.

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.

In order to investigate the effect of metoclopramide on the duration of action of mivacurium, 45 patients were randomized into three groups. Group M10 (n = 15) and M20 (n = 15) received 10 and 20 mg of metoclopramide i.v., respectively, and group S (n = 15) received saline 2 min before induction of anesthesia with fentanyl, thiopental and mivacurium. Plasma cholinesterase activity (pCHE) was measured before induction of anesthesia and 2 min after injection of metoclopramide and saline. Neuromuscular block was monitored by a force transducer using train of four nerve stimulation. Anesthesia was maintained with isoflurane and N2O. Time to recovery of a twitch height of 90% was significantly prolonged in group M10 and M20 (44 +/- 15 and 57 +/- 10 min) as compared to group S, 32 +/- 9 min, P < 0.05). A slight but significant decrease in pCHE was observed in group M20. Because of the risk of prolonged duration of action of mivacurium, neuromuscular blockade should always be monitored whenever metoclopramide is given before injection of mivacurium.

Serum cholinesterase activity was measured at induction, and following anaesthesia in 41 children aged between 4 and 30 months. The median exposure to sevoflurane was 273%.min. The results did not demonstrate any significant difference in cholinesterase activity, when expressed by gram of serum proteins following inhalation anaesthesia using sevoflurane or intravenous anaesthesia using propofol. The values (SD) obtained were 175 (42) UI.g(-1) before anaesthesia and 177 (43) UI.g(-1) following anaesthesia. The only change in cholinesterase activity detected was related to heamodilution. We conclude that plasma fluoride concentration following sevoflurane administration [13.8 (4.2) microm x l(-1)] is too low to exert an inhibiting effect on in vivo cholinesterase activity and that the previously reported decrease in mivacurium requirements during sevoflurane anaesthesia is unlikely to be due to inhibition by fluoride ions.

Aims: To investigate dose proportionality, dosing frequency, and ethnic aspects of the pharmacokinetics of bambuterol in asthmatic children, and to discuss the relationship with previous observations in adults., Methods: Forty-eight children in four different studies completed two double-blind bambuterol treatments each (daily doses of bambuterol hydrochloride): 12 preschool (5 mg x 2 vs 10 mg) and 12 school (10 mg vs 20 mg) Caucasians, 12 preschool (2.5 mg vs 5 mg), and 12 school (10 mg vs 20 mg) Orientals. Peak plasma concentrations and dosing interval area under curve (AUC) of bambuterol and the active metabolite terbutaline were assessed at steady state. Treatment differences were analysed statistically within each study. Differences between the studies and the relation to steady-state AUC in adults were described., Results: Dose proportionality was seen for terbutaline but not for bambuterol. Twice-daily dosing (2 x AUC(0,12 h)) could not be shown to differ from once-daily dosing (AUC(0,24 h)) in the preschool Caucasians. Mean AUC of terbutaline was 128 and 242 nmol l-1 h in the preschool Caucasians (5 mg/12 h; 10 mg/24 h), 213 and 406 nmol l-1 h in the Caucasian school children (10 mg; 20 mg), 87.4 and 202 nmol l-1 h in the Oriental preschool children (2.5 mg; 5 mg), and 356 and 640 nmol l-1 h in the Oriental school children (10 mg; 20 mg). Oriental school children had higher plasma concentrations of bambuterol and terbutaline than Caucasian school children. The strict ethnic implication of the difference could not be elucidated, because demographic data were not perfectly matched. Terbutaline AUC was only moderately increased in the Caucasian school children compared with Caucasian adults. The increase was more pronounced in Oriental children and in some preschool Caucasians. The highest concentration of terbutaline, 58 nmol l-1, was seen in an Oriental school child after a 20 mg dose., Conclusions: Caucasian school children can be given bambuterol hydrochloride very much as Caucasian adults, 10 or 20 mg once daily, but Oriental preschool and school children plus preschool Caucasians should be given lower doses.

Objective: There are an increasing number of patients with severe liver dysfunction subjected to open heart surgery. This retrospective study was designed to assess operative results and clarify the degree of liver injury in patients with liver dysfunction undergoing open heart surgery. In addition, determinants influencing their prognosis were assessed., Methods: In a 9-year period from 1988 to 1996, we operated on 31 patients with posthepatitis liver dysfunction and 16 with chronic passive congestion of the liver. This group was 2.3% and 1.6% of the 1368 patients undergoing cardiac surgery in the same period. We compared several perioperative factors between survivors and nonsurvivors to determine risk factors affecting mortality., Results: In the group with posthepatitis liver dysfunction, the postoperative course of 5 patients among 31 (16.1%) was poor. Serum cholinesterase concentration was lower only in the nonsurvivor group (nonsurvivor vs survivor: 1979+/-949 vs 3515+/-1424 IU/I, p < 0.05). All patients with cholinesterase < 2000 IU/L died. The duration of CPB (212+/-53 vs 150+/-54 minutes, p < 0.03) and ACC time (151+/-38 vs 96+/-40 minutes, p < 0.02) was longer in the nonsurvivor group. In the group with chronic passive congestion, the postoperative course of 5 of 16 (31.3%) patients with valvular disease was poor. Serum cholinesterase concentration was lower only in the nonsurvivor group (nonsurvivor vs survivors: 2006+/-435 vs 3483+/-1442 IU/L, p < 0.02), and all patients with cholinesterase < 2000 IU/L died. Postoperative bleeding was greater in the nonsurvivor group (3327+/-2106 vs 1428+/-643 mL, p < 0.05). Multivariate logistic regression analysis including the described pre- and intraoperative factors identified only serum cholinesterase concentration (F = 9.18) as significant., Conclusions: A low value of preoperative serum cholinesterase (< 2,000 IU/L) is thought to be the predictor of prognosis after open heart surgery in patients with severe posthepatitis and congestive liver dysfunction. Operative factors (cardiopulmonary time in posthepatitis liver dysfunction and postoperative bleeding in the congestive liver dysfunction) also influenced the prognosis.

The use of xenogenic or genetically engineered cell types in bioartificial liver support systems requires separation methods between the patients' blood and the liver support bioreactors that guarantee the sufficient transfer of pathophysiologically relevant substances but prevent complications. The present paper describes a new membrane separation system that is nearly impermeable to proteins but enables the exchange of water soluble and protein bound toxins by a special membrane and a recycled protein containing dialysate. Because the full range of toxins in hepatic failure has still not been identified, the value of this membrane separation method was evaluated clinically. Thirteen patients suffering from life threatening hepatic failure who had not responded to state of the art therapy were treated with this device, the molecular adsorbent recycling system (MARS). The overall survival rate was 69%. All patients showed positive response to the therapy, indicating that the presented membrane separator combines therapeutic effectivity with the highest safety criteria for the patient by cutting the exchange of substances below the level of proteins.

Background: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect., Methods: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg.kg-1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg.kg-1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg.kg-1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus., Results: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min)., Conclusion: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.

Aims: It has been assumed that both plasma cholinesterase (EC 3.1.1.8) and oxidative enzymes are needed for optimum formation of the bronchodilator terbutaline from its biscarbamate prodrug bambuterol. The present study aimed at investigating the fate of bambuterol in subjects with deficient plasma cholinesterase but with normal oxidative (CYP2D6) capability., Methods: The pharmacokinetics of bambuterol and terbutaline were studied in four healthy subjects (two men and two women) being homozygous for the atypical gene for plasma cholinesterase. Their oxidative metabolism was apparently good as they were all rapid metabolizers of debrisoquine. Bambuterol hydrochloride 20 mg was given orally once daily for 10 days, and plasma and urine samples were taken for 1.5 days (plasma) and 4.5 days (urine) after administration of the last dose., Results: The pharmacokinetic parameters in the present study were grossly similar to those found in a study of bambuterol in subjects with normal plasma cholinesterase activity (N). However, subjects with atypical cholinesterase had a shorter terminal half-life of bambuterol (a measure of uptake rate), 4.8-12.6 h vs 8.3-22.3 h in N, and slightly higher plasma concentrations of bambuterol (average concentrations 1.9-3.7 nmol l(-1) vs 1.5-3.1 nmol l(-1) in N). Peak/trough terbutaline plasma concentrations ratios (2.1-3.2) were somewhat increased, but average plasma concentrations (8.3-14.5 nmol l(-1)) and terminal half-life (16.5-21.8 h) of terbutaline did not differ., Conclusions: In Caucasian populations, one subject out of 2500 is homozygous for the atypical gene for plasma cholinesterase. The atypical enzyme has a much lower affinity for bambuterol than the normal enzyme. Nevertheless, the subjects with atypical cholinesterase were able to produce terbutaline as efficiently as normal subjects. This might be explained by an altered uptake and metabolism in the absence of plasma cholinesterase, or the importance of this enzyme for the formation of terbutaline from bambuterol in vivo may have been overestimated.

Aims: To study the pharmacokinetics and bioavailability of the prodrug bambuterol and its bronchodilator moiety terbutaline in healthy subjects., Methods: Eight healthy subjects (four women) received intravenous doses of bambuterol and terbutaline. On a third occasion, they, plus another four subjects, ingested oral bambuterol as a single dose followed by repeated doses once daily for 7 days. Plasma concentrations and urinary excretion of bambuterol and terbutaline were measured., Results: After intravenous administration, renal clearances of bambuterol and terbutaline were similar (about 140 ml min(-1)), but there was a five-fold difference in total clearance (bambuterol 1.25 l min(-1), terbutaline 0.23 l min(-1)). Volume of distribution (Vss) was 1.6 l kg(-1) b.w. for both substances. A similar renal clearance of bambuterol was found during oral administration but that of terbutaline decreased (to about 120 ml min(-1)). Mean terminal half-life of bambuterol was 2.6 h after intravenous and 12 h after oral administration, implying that uptake was rate-limiting. Mean residence time of terbutaline generated from oral bambuterol was 34 h compared with 8.0 h when terbutaline as such was infused. Generated terbutaline had a bioavailability of 36% (28-46) after intravenous and 10.2% (6.1-13.2) after oral administration of the prodrug. Bambuterol was well tolerated. The mean activity of plasma cholinesterase, an enzyme catalyzing bambuterol metabolism, was inhibited between 30-60% during repeated oral dosing. It virtually regained original activity within 48 h after the last dose., Conclusions: The plasma concentration ofterbutaline fluctuated little during repeated oral administration (mean peak: trough ratio 1.9), as a result of prolonged absorption of bambuterol and slow formation of terbutaline. Thus, the pharmacokinetic properties of bambuterol make it suitable for oral once-daily dosage.

We compared the dose-response relationship and the neuromuscular blocking effects of mivacurium during infusions of esmolol in 40 anaesthetised rabbits. Train-of-four stimuli were applied every 10 s to the common peroneal nerve and the force of contraction of the tibialis anterior muscle was measured. Plasma cholinesterase activity decreased by 13% after esmolol infusion. The ED95 of mivacurium increased significantly from 29 (4.8) micrograms.kg-1 with placebo to 61 (9.8) micrograms.kg-1 during esmolol 100 micrograms.kg-1.min-1, 49 (8.2) micrograms.kg-1 during esmolol 300 micrograms.kg-1.min-1 and 54 (7.3) micrograms.kg-1 during esmolol 500 micrograms.kg-1.min-1, respectively (p < 0.001). The duration of neuromuscular block with mivacurium 0.16 mg.kg-1 was prolonged by 30% with esmolol due to diminished plasma cholinesterase activity (p < 0.05). Heart rate and mean arterial blood pressure decreased by 15% with esmolol (p < 0.05). The results of this study show that, in rabbits, esmolol decreased plasma cholinesterase activity, antagonised the neuromuscular blocking potency of mivacurium and prolonged its neuromuscular blocking effect.

Plasma cholinesterase is an enzyme which has importance to the anaesthetist primarily for its role in the metabolism of suxamethonium, although other anaesthetic related drugs that this enzyme metabolises are also increasingly important. In this article we review current thoughts on the function, profile and chemistry of plasma cholinesterase. Causes of variations in the activity of the enzyme are described and the basis of genetic variations is explained.

During thiopentone-fentanyl-nitrous oxide anaesthesia and using a cumulative design, we studied the dose-response relationship of mivacurium in 8 patients: 7 patients phenotypically homozygous for the atypical plasma cholinesterase gene and 1 patient homozygous for the silent gene. The estimated mean ED50 and ED95 were 15 and 20 micrograms.kg.bw-1 in patients homozygous for the atypical gene, and 13 and 16 micrograms.kg.bw-1 in the patient homozygous for the silent gene, respectively. The results indicate that mivacurium is 4-5 times more potent in patients homozygous for the atypical or the silent gene than in patients with normal plasma cholinesterase activity and phenotype.

The interaction between mivacurium and succinylcholine when mivacurium was administered during the early recovery from succinylcholine block was studied in 30 children 2-12 years of age anaesthetized with propofolalfentanil-N2O-O2. Neuromuscular response was monitored by adductor pollicis EMG. Fifteen patients received 200 micrograms.kg-1 of mivacurium (Group M), and another fifteen received 1500 micrograms.kg-1 of succinylcholine followed by 200 micrograms.kg-1 of mivacurium when the first EMG response recovered to 5% of calibration value (Group SchM). Plasma cholinesterase (pChE) activity was normal in each patient. The recovery times following mivacurium did not differ between the two groups. Times required for recovery of the first EMG response from 25 to 75% of full EMG recovery were 3.6 +/- 1.0 (mean +/- SD) and 4.0 +/- 0.7 min for the Groups M and SchM, respectively. The time from administration of mivacurium to the recovery of train-of-four ratio 0.70 was 13.2 +/- 3.3 min for the Group M and 13.6 +/- 3.1 min for the Group SchM (NS). Thus, in patients with normal pChE activity preceding administration of succinylcholine did not influence the recovery of neuromuscular function from subsequent mivacurium.

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).

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.

A 32-year-old man presented with symptoms of severe organophosphate poisoning and required an atropine infusion for 5 weeks. We believe the development of a paralytic ileus occurred as a rare feature of atropine toxicity when other signs were masked by the underlying condition. The onset of a paralytic ileus coincided with a spontaneous increase in red cell cholinesterase levels and may be an early sign of recovery from organophosphate poisoning.

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.

Cholinesterase activity was determined in 18 patients who had undergone either hypothermic (n = 9) or normothermic (n = 9) cardiopulmonary bypass. The anaesthetic technique was standardised to avoid agents known to affect cholinesterase. Activity was determined in blood samples taken before the induction of anaesthesia, during cardiopulmonary bypass and for at least 7 days postoperatively. In six patients cholinesterase activity was also measured at 6 weeks postoperatively. All the patients were of normal cholinesterase genotype. In both groups cholinesterase activity fell by approximately 60% coinciding with the start of cardiopulmonary bypass, from a mean of 5976 to 2636 IU.l-1 in the hypothermic group, and from 5901 to 2615 IU.l-1 in the normothermic group (p < 0.001 in both instances) (normal range 4300-10,500 IU.l-1). Cholinesterase activity remained at this reduced level for at least 7 days postoperatively. By 6 weeks, activity had returned to within 7% of pre-induction values. There were no differences in cholinesterase activity between the hypothermic and normothermic groups at any of the sampling times.

The duration of action of mivacurium was evaluated during a modified neurolept anaesthesia in 17 patients heterozygous for the usual and the atypical plasma cholinesterase (pChe) gene (E1uE1a) and in five patients homozygous for the atypical gene (E1aE1a). The response to train-of-four nerve stimulation was recorded using a Myograph 2000. Five heterozygous patients were given a small dose of mivacurium 0.03 mg kg bw-1 intravenously (Group 1). The mean (range) suppression of the first twitch in the train-of-four response (T1) was 91% (69-100%). The time to 90% T1 recovery was 23.9 min (14.0-31.3 min). Twelve other heterozygous patients (Group 2) received mivacurium 0.2 mg kg bw-1 (2.5 x ED95). In these patients the time to 100% T1 suppression was 1.4 min (1.1-2.0 min). The time to reappearance of the T1 response, to 90% T1 recovery, and the recovery index (25.3 min (14.5-34.5), 45.5 min (30.9-59.2), and 9.8 min (6.8-19.6), respectively) were significantly longer than reported in phenotypically normal patients. Five patients homozygous for the atypical gene (Group 3) were given 0.03 mg kg bw-1 mivacurium. The time to reappearance of T1 response following this low dose of mivacurium ranged from 26-128 min. In all five patients the neuromuscular block was successfully antagonized with neostigmine preceded by atropine. In conclusion, mivacurium-induced neuromuscular blockade was moderately prolonged in patients heterozygous for the usual and the atypical gene for plasma cholinesterase. Patients homozygous for the atypical plasma cholinesterase gene appear to be markedly sensitive to mivacurium.

A case of acute severe organophosphate poisoning by deliberate self administration is reported. The patient required intensive therapy for 30 days. Unusual features of the case were the avoidance of atropine, because of the high risk of ventricular fibrillation, and the ineffectiveness of pralidoxime.

We studied preoperative and postoperative plasma hydrolysis of aspirin and plasma cholinesterase activity in surgical patients. Postoperative aspirin esterase and cholinesterase activities fell sharply (119 +/- 32 micrograms ml h-1 and 3746 +/- 1068 U l-1 respectively; P < 0.01) in comparison to basal preoperative values (157 +/- 33 micrograms ml h-1 and 4620 +/- 940 U l-1 respectively, P < 0.01). We suggest that alterations in plasma esterase during the postoperative period may be related to the metabolic response to anesthesia- and surgery-induced stress.

Recently, several new alleles have been identified at plasma cholinesterase locus E1. We have had the opportunity for the first time to monitor the response to succinylcholine in two patients with the newly discovered genotype Ea1Ek1. The duration of action and type of neuromuscular block following succinylcholine 1.0 and 1.5 mg kg-1 i.v., respectively, were evaluated using train-of-four nerve stimulation and a Myograph 2000. One patient was anaesthetized with halothane, and the other was given a modified neurolept anaesthesia. Time to first response to nerve stimulation was 15 and 16 min, and time to 50% twitch height recovery was 19 and 20 min, respectively in the two patients. Both showed a depolarizing block. One of the patients received three bolus doses of succinylcholine 1 mg kg-1. This patient gradually developed a phase II block, which was easily reversed by edrophonium. The results indicate that patients with genotype Ea1Ek1 are slightly more sensitive to succinylcholine than are genotypically normal patients (Eu1Eu1) and patients heterozygous for the normal and the atypical gene (Eu1Ea1).

The significance of plasma cholinesterase (pChe) activity for the duration of action of mivacurium in phenotypically normal patients was evaluated in 35 patients during neurolept anaesthesia. The response to train-of-four nerve stimulation was recorded using a Myograph 2000. Ten patients with normal pChe (Group I) and five patients with decreased pChe activity (Group 2) were given a small test dose of mivacurium 0.03 mg kg-1. Mivacurium 0.1 mg kg-1 was administered following spontaneous recovery from the first dose. The mean suppression of the height of the first (T1) of the train-of-four responses following mivacurium 0.03 mg kg-1 patients with normal and decreased enzyme activity was 40% and 56%, respectively, and the mean T1 suppression after mivacurium 0.1 mg kg-1 was 100% in both groups. The times to different levels of twitch height recovery following the 0.1 mg kg-1 dose did not differ between the two groups of patients. Another 20 patients with normal or decreased pChe activity (Group 3) were given mivacurium 0.2 mg kg-1. In this group the time to maximum block was 1.4 min (1.0-4.0) mean (range) and the time to reappearance of the T1 response was 15.0 min (7.4-22.7) (range). An inverse relationship was found between the patients' pChe activity and the time to first response. It is concluded that mivacurium is short-acting in patients with normal pChe phenotype and normal to low-normal pChe activity. No patient with very low pChe activity was included in the study. A prolonged response to mivacurium may, however, be expected in these patients.

The neuromuscular block of suxamethonium 1.5 mg.kg-1 was investigated in three myasthenic patients (Class IIA), undergoing thymectomy. Two of the patients were receiving pre-operative pyridostigmine therapy. In the three patients, plasma cholinesterase activity was determined on the morning of surgery and was correlated with the neuromuscular response to suxamethonium as monitored by electromyography. The results suggest that the response to suxamethonium in the myasthenic patients can show wide variations according to the level of their plasma cholinesterase activity. The degree and duration of suxamethonium block is inversely related to the plasma cholinesterase activity.

The aim of the present study was to develop a method which allows determination of pseudo (PsChE) and acetyl cholinesterase (AChE) activities in single hemolyzed blood samples of workers exposed to cholinesterase-inhibiting compounds, avoiding the time-consuming and laborious separation of plasma and erythrocytes. Two methods based on Ellman's colorimetric determination of cholinesterase activity were compared, and three different substrates were tested. The best results were obtained with the substrates butyrylthiocholine and acetyl(beta-methyl)thiocholine, both showing a substrate specificity of more than 97% with respect to PsChE and AChE, respectively. The method showed sensitivity to detect low levels of inhibition of AChE and PsChE in blood. The between-day precision was less than 4% for both cholinesterase activities. It was demonstrated with this method that hemolyzed blood can be stored at -20 degrees C at least 18 months without loss of cholinesterase activity. The method has been used for 18 months in a monitoring program for laboratory employees working with various cholinesterase-inhibiting compounds. The average co-efficients of intraindividual variation amounted to 6.8% (range 2.2-9.6%; 90 percentile, 8%) and 6.6% (range 2.9-9.9%; 90 percentile, 7.9%) for PsChE and AChE, respectively. In a group of non-exposed workers the average intraindividual variations were 4.0% (range 1.5-7.7%; 90 percentile, 7.6%) and 3.6% (range 0.6-6.6%; 90 percentile, 5.3%), respectively. Using the value of 4.0%, it appears possible to detect an individual decrease in cholinesterase activity of more than 8% below a baseline based on three determinations. The method can thus be used to detect relatively low levels of cholinesterase inhibition.

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.

Serum albumin, cholinesterase, and cholesterol were measured in ten patients with aplastic anemia and eight with myelodysplastic syndrome who received the administration of recombinant human GM-CSF. Serum albumin, cholinesterase, and cholesterol were significantly lowered by the administration of GM-CSF and recovered after the cessation of GM-CSF. These data suggest that GM-CSF impairs the biosynthesis of liver cells and that cholesterol-lowering activity of GM-CSF, which is previously reported, is due to the impairment of liver biosynthesis by GM-CSF.

Staff of the California Department of Health Services investigated the death of a parathion applicator in California that was thought to be pesticide-related. A crew of eleven workers (including six sprayers, three mixer/loaders, one mixer/sprayer and one foreman) had been applying 0.125% parathion spray to almond orchards for approximately three weeks. On the day of the fatality, a sprayer rapidly developed symptoms of salivation, sweating, and convulsions after a half-day of work. Despite aggressive medical treatment, the worker died within one hour of his initial symptoms. Significant laboratory results for the decreased case included: parathion residue on the inner and outer garments worn by the worker, parathion in the post-mortem gastric contents, and elevated urinary metabolites consistent with acute parathion intoxication. Interviews with the work crew revealed that three of the 10 workers had complaints of headaches, vomiting, and/or sore throat; yet, subsequent plasma and red cell cholinesterase tests of the co-workers did not show any significant depressions in comparison with pre-season baseline values. This worker death is consistent with prior reports of parathion-related sprayer/applicator intoxications and is the first worker-related parathion death in California since 1972. Substitution of pesticides with less toxic active ingredients or the elimination of parathion is recommended.

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.

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.

Cholinesterase activities were measured on serum from 941 pregnant women distributed evenly throughout the 40 weeks of gestation. A rapid fall has been shown to occur during the first trimester to a level which did not alter significantly during the remainder of pregnancy. Even lower values were observed in 105 patients examined during the first 7 days following delivery. Enzyme activity was used to determine the probable incidence of a prolonged reaction to suxamethonium in obstetric patients. The risk was greatest in the immediate post partum period affecting 11% of the patients investigated.

A case of prolonged action of suxamethonium in a patient with gestational trophoblastic disease is reported. Postoperatively the patient was found to have markedly reduced plasma cholinesterase activity (363 IU/litre) with a normal cholinesterase phenotype. Consequently plasma cholinesterase activity and phenotype were measured in six other patients with the condition and these results compared with those of 22 patients with normal first trimester pregnancies undergoing therapeutic abortion. Plasma cholinesterase phenotype was normal in all patients studied. The activity was significantly decreased (p less than 0.05) from the normal range (620-1370 IU/litre) in all patients with trophoblastic disease. In the 22 patients with normal pregnancies, 14 had activity values in the abnormal range (less than 620 IU/litre) while the mean cholinesterase activity of the group as a whole was significantly decreased (561.8 IU/litre, p less than 0.05) below the normal range. These results confirm the presence of a decrease in plasma cholinesterase activity in early pregnancy and provide new evidence for a decrease in activity in a pseudopregnancy state.