Anesth Analg 1999;89:1579
© 1999 International Anesthesia Research Society
CASE REPORTS
Increased Plasma Cholinesterase Activity and Mivacurium Resistance: Report of a Family
Mohamed Naguib, MB, BCh, MSc, FFARCSI, MD*,
Mohamed Gomaa, MB, BCh, MSc, DA, CABA&IC ,
Abdulhamid H. Samarkandi, MB, BS, KSUF, FFARCSI ,
David R. Bevan, MB, BChir, FRCA, MRCP§,
A. K. Akkielah, MB, BCh, FRCS (Ed),
Catherine Watson, PhD||,
Scott Billecke, BS||, and
Bert N. La Du, Jr., MD, PhD||
Departments of Anesthesia at
*University of Iowa, Iowa City, Iowa,
Security Forces Hospital,
King Saud University, Riyadh, Saudi Arabia,
§University of British Columbia, Vancouver, Canada; and
||University of Michigan Medical Center, Ann Arbor, Michigan
Address correspondence and reprint requests to Mohamed Naguib, MD, University of Iowa College of Medicine, Department of Anesthesia, 200 Hawkins Dr., 6JCP, Iowa City, IA 52242-1009. Adress e-mail to mohamed-naguib{at}uiowa.edu
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Introduction
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Although most genetic variants of serum butyrylcholine esterase (BChE; cholinesterase: E.C. 3.1.1.8, acetylcholine acylhydrolase) are associated with decreased activity, some rare variants are associated with increased enzyme activity (2–3 times normal) (1–8). These variants have normal dibucaine and fluoride numbers, and the enhanced activity has been attributed to either an increased number of enzyme molecules (1,2) or increased activity per active site (3). Resistance to succinylcholine as a result of increased plasma cholinesterase activity was described in four reports (5–8), but neuromuscular function was not monitored.
Mivacurium chloride is a bis-benzylisoquinolinium nondepolarizing neuromuscular blocking drug that is hydrolyzed by serum butyrylcholine esterase (8). In this report, we describe the response to mivacurium in a patient with hypercholinesterasemia and the distribution of this isozymic variant in her family.
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Case Report
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A 26-yr-old, 167-cm, 53-kg, ASA physical status I woman scheduled for septorhinoplasty and bilateral partial inferior turbinectomy was selected for an institutionally approved study assessing the neuromuscular effects of mivacurium. Results of a physical examination was normal. There was no history of serious illness in her family, and neither the patient nor anyone in her immediate family had received anesthesia. Preoperative routine biochemistry (including liver function tests) and hematology investigations results were normal.
Anesthesia was induced with 150 mg propofol and 50 µg fentanyl and maintained with an infusion of propofol, 50–140 mg · kg-1 · min-1, and 70% nitrous oxide in oxygen and incremental fentanyl. The trachea was intubated after topical anesthesia with 4 mL of 4% lidocaine. The concentrations of nitrous oxide, oxygen, and carbon dioxide were measured continuously with a multiple-gas analyzer (Capnomac; Datex Instrumentarium Corporation, Helsinki, Finland). Ventilation was adjusted to maintain normocapnia (PETCO2 35–40 mm Hg). Electrocardiogram, pulse oximetry, and arterial blood pressure were monitored, and hand temperature was maintained above 32.5°C.
Neuromuscular function was monitored using train-of-four (TOF) stimulation of the ulnar nerve repeated every 20 s with a frequency of 2 Hz and an intensity of 70 mA, and the integrated compound action potential of the adductor pollicis muscle was recorded using a Datex monitor.
After a 5-min stabilization, 0.2 mg/kg mivacurium was administered. The first measurable effect (lag time) and the maximal neuromuscular block (onset time) developed in 100 and 220 s, respectively (Fig. 1). The maximal block attained was 44% inhibition of the single twitch (T1), with a TOF ratio of 0.73. Nine minutes after the first administration of mivacurium, an infusion of 15 µg · kg-1 · min-1 mivacurium was started. Resistance to mivacurium was noted, and repeated boluses of mivacurium, in addition to increasing infusion rates, were needed to maintain the twitch depression at 90%–95% (Fig. 1). The T1 response at the termination of the infusion was 11%. After discontinuation of the infusion, no antagonist was given, and spontaneous recovery to TOF ratio of 0.78 and T1 of 75% of control was noted 11 min later. Venous blood was drawn, 2 mo after surgery, from the patient, her parents, her sister, and her two brothers for determinations of total proteins, serum BChE activity, dibucaine and fluoride numbers, and for determination of the relative quantity of BChE enzyme protein by rocket immunoelectrophoresis.
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Figure 1. Neuromuscular response and time course of mivacurium-induced neuromuscular block in the patient with hypercholinesterasemia.
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Plasma cholinesterase activity was determined on three different occasions from the same samples taken from the family. At King Khalid University Hospital laboratory, in December, 1997, plasma cholinesterase activity was measured by the change in absorbance at 600 nm after the reduction of butyrylthiocholine to thiocholine, using Du Pont’s DIMENSION, Clinical Chemistry System (Wilmington, DE). Two other measurements were performed at the University of Michigan Medical Center in June, 1998, and March, 1999, where BChE activity was determined according to the method described by Kalow and Lindsay (9). Phenotypes were determined by the inhibition of BChE activity by dibucaine (10) and sodium fluoride (11) (Table 1). The proband, the patient’s mother, and one of the patient’s brothers (#2) had high levels of BChE activity, but plasma from the patient’s father showed a high level of BChE on the first and second measurements only. Total proteins were within the normal range for the proband and all family members.
The relative quantity of BChE enzyme present in the serum of the various family members was estimated by rocket immunoelectrophoresis (12) in March, 1999, at the University of Michigan Medical Center (Fig. 2 and Table 2). The relative quantity of BChE enzyme was doubled in the patient, her mother, and one of her brothers.
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Figure 2. Rocket immunoelectrophoresis of butyrylcholine esterase (BChE). The lower panel shows a representative rocket gel for BChE. Samples (3 µL) were electrophoresed through a 1% agarose gel containing rabbit anti-human cholinesterase antibody and stained for BChE activity. Standards, five serial dilutions of standard serum (1/32, 1/16, 1/8, 1/4, and 1/2, respectively). Patients, serial dilutions of the patient’s serum (1/20, 1/10, 1/5, respectively). The upper panel illustrates the family pedigree of the patients investigated, with black symbols indicating individuals with high BChE activity and protein levels. The symbol for each patient is directly above the corresponding rockets.
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Table 2. Comparison of BChE Activity Relative to Enzyme Levels Based on the Analysis Performed at UMMC (March, 1999)
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Discussion
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This report documents, for the first time, the response of a neuromuscular blocker metabolized by BChE in a patient with hypercholinesterasemia. The duration of neuromuscular block after the administration of mivacurium or succinylcholine is determined primarily by the rate of hydrolysis by plasma cholinesterase (13,14). In patients with normal plasma cholinesterase phenotype, an inverse correlation was found between plasma cholinesterase activity and the duration of action of mivacurium (13,14). Increased BChE activity may cause resistance to mivacurium (as noted in our patient) and to succinylcholine (5–8). Yao and Savarese (8) reported that hypercholinesterasemia could be an unusual cause of difficult intubation resulting from succinylcholine resistance.
The calculated 95% effective dose (ED95) for mivacurium (and 95% confidence interval) during oxygen-nitrous oxide-opioid anesthesia is 69 (66–71) µg/kg (15). Goudsouzian et al. (16) reported that, in adult patients with normal cholinesterase activity, 0.15 mg/kg mivacurium (2 x ED95) produced 98.4% ± 0.9% (mean ± SD) suppression of the twitch response. Neuromuscular transmission recovered to 5% of control response in 14.5 ± minutes (16). They also noted that the mean mivacurium infusion requirement to maintain 97% ± 1% depression of the twitch response was 6.0 ± 0.4 µg · kg-1 · min-1 (16). Goudsouzian et al. (16) also noted that it took 9.4 ± 1 minutes for T1 to recover from 5.2% ± 2.1% to 25% of control after the termination of the infusion. In contrast, in our patient the maximal block attained was 44% inhibition of T1 after mivacurium 0.2 mg/kg, and repeated boluses of mivacurium, in addition to increasing infusion rates (up to 25 µg · kg-1 · min-1), were required to maintain the twitch depression at approximately 90% (Fig. 1). The T1 response at the termination of the infusion in our patient was 11% of control, and it took only 2.3 minutes for T1 to recover spontaneously to 25% of control (Fig. 1).
As noted in Figure 1, it is not uncommon to find that the T1 of the integrated evoked electromyography may only recover to 79% of control, despite a TOF ratio of 0.99. Although the cause of this phenomenon has remained uncertain, the five-minute stabilization period may have been inadequate to prevent T1 drift with the Datex monitor (17).
The reported family has the equivalent of the Cynthiana variant (1). Other BChE variants that are associated with increased enzyme activity have been reported (2–5). All of these variants had a normal dibucaine number. It has been suggested that most these variants are inherited as autosomal dominant traits. The BChE activity reported for our patient, her mother, her father (in the first two measurements), and one of her brothers was approximately 2.5 times the normal. It seems, therefore, that the parents are heterozygous for the super allele. The children with increased BChE activities inherited at least one of the mutant (super) alleles; the other children inherited the usual allele from both parents. The rocket immunoelectrophoresis (Fig. 2 and Table 2) indicated that the high BChE activity noted with the mother and two children is caused by a proportional increase in their enzyme level. However, the serum BChE values of the father have decreased more than for the other family members. A specific mutation associated with this type of instability has been described for a variant that drops with freezing and thawing and was found to be associated with this type of instability (18).
In conclusion, the high activity variant in this family resulted in resistance to mivacurium in our patient, as has been previously shown for such variants with succinylcholine.
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References
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Accepted for publication August 30, 1999.
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Introduction
Case Report
