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Anesth Analg 2002;94:461-466
© 2002 International Anesthesia Research Society

GENERAL ARTICLES

Screening Patients with Prolonged Neuromuscular Blockade After Succinylcholine and Mivacurium

Charles Cerf, MD*, Martine Mesguish, PharmD{dagger}, Inanna Gabriel, MD*, Serge Amselem, MD, PhD{dagger}, and Philippe Duvaldestin, MD, PhD*

*Department of Anesthesia and Intensive Care Unit and {dagger}Department of Genetics and Biochemistry, Henri Mondor Hospital, AP-HP, Créteil, France

Address correspondence and reprint requests to Philippe Duvaldestin, MD, PhD, Department of Anaesthesia and Intensive Care Unit, Henri Mondor Hospital, 51 Avenue du Maréchal Delattre de Tassigny 94010, Créteil, France. Address e-mail to philippe.duvaldestin{at}hmn.ap-hop-paris.fr


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Patients with pseudocholinesterase (BChE) variants may exhibit markedly prolonged paralysis after the administration of succinylcholine or mivacurium. We sought to evaluate to what extent molecular biology may contribute to the biological assessment of such patients. We conducted a prospective cohort study in patients referred to our center between 1995 and 1999 for prolonged neuromuscular blockade after mivacurium or succinylcholine. For each patient, phenotyping was performed with a conventional biochemical technique and molecular biology for the detection of the atypical mutation (A variant). Among the 36 patients referred, 31 had low BChE activity, 26 had received mivacurium (BChE activity, 2.1 U/mL; 0.3–4.3 U/mL), and 5 had received succinylcholine (BChE activity, 1.9 U/mL; 1.1–3.2 U/mL) (mean; extreme values). The mean clinical duration of paralysis was 90 min (40–140 min) after succinylcholine and 301 min (120–720 min) after mivacurium. Thirty-two patients had a BChE deficiency of genetic origin: 20 were homozygous (AA), 10 were heterozygous (UA) for the A variant, and 2 did not have the A mutation (UU). One heterozygous UA patient had normal BChE activity. Nine among the heterozygous UA and the two homozygous UU patients probably carried a not-screened variant. In most cases, biochemical diagnosis was sufficient to confirm the existence of constitutional deficiency; molecular biology improved the accuracy of diagnosis in 11 patients (30%) but had few or no clinical implications for the patient him- or herself.

IMPLICATIONS: Systematic screening for the pseudocholinesterase atypical variant by biochemical and DNA analysis after a prolonged neuromuscular blocking effect of succinylcholine or mivacurium shows that molecular biology could improve the diagnosis in approximately one third of patients, but with few clinical implications, compared with biochemical testing.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Patients with pseudocholinesterase (BChE) variants may exhibit markedly prolonged paralysis after the administration of succinylcholine or mivacurium. An abnormal response to mivacurium or succinylcholine requires postoperative biochemical investigations to identify the mutation in the patient and his or her family. Identification of the human BChE variant can be performed by biochemical analysis. These tests, which have been used for 35 yr, consist of the measurement of plasma cholinesterase activity with different substrates and of testing the degree of inhibition of this activity with a well known inhibitor, such as dibucaine, fluoride, or R02-0683. However, these tests are not entirely satisfactory in differentiating the many variants of the enzyme (1). Among 1247 patients and 5441 of their relatives tested in Denmark after an abnormal response to succinylcholine or mivacurium, a response to biochemical testing was equivocal in 1092 of 6688 subjects (2). Some individuals who experienced a prolonged response to succinylcholine were classified as homozygous for the normal plasma cholinesterase gene by traditional tests (3). From conventional testing, a patient may appear as heterozygous for the atypical variant (A variant) despite markedly prolonged paralysis after mivacurium (4). By conventional testing, homozygous atypical (AA) and atypical-silent heterozygous genotypes cannot be differentiated (5). La Du (6) evoked the interest of molecular biology in the diagnosis of inherited BChE deficiency. Molecular biology techniques have indeed entered into current practice for the diagnosis of several metabolic genetic diseases (7). Nevertheless, no study that uses those techniques in a cohort of patients exhibiting prolonged neuromuscular blockade has been performed. We describe a series of patients referred to our center in whom the A variant was screened by using molecular biology and biochemical methods.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After ethical committee approval and informed consent, 36 patients from different institutions in France exhibiting a prolonged response to mivacurium or succinylcholine were studied from January 1995 to June 1999. A prolonged response to mivacurium was suspected by the absence of spontaneous ventilation 20 min after a tracheal intubating dose (0.15–0.20 mg/kg) or at least 35 min after a continuous infusion was stopped or after the last dose after repeated administration. Prolonged paralysis after succinylcholine was defined as the absence of return of spontaneous ventilation at least 10 min after its administration or by the absence of response from clinical monitoring of the thumb twitch more than 15 min after succinylcholine administration. Duration of paralysis was considered by the time of return of spontaneous ventilation or by the time of reappearance of two thumb responses after train-of-four stimulation of the ulnar nerve at the wrist.

Venous blood (10 mL) was collected (EDTA tubes) from patients, kept at +4°C, and sent to our laboratory within 48 h. BChE activity was assayed on the plasma by using an automated colorimetric method with benzoylthiocholine as a specific substrate (Ektachem; Eastman Kodak, Bagnolet, France). The range of linearity of the technique is 2 to 12.5 U/mL. Normal values are 5.9–12.2 U/mL in men and 4.7–10.4 U/mL in women. The percentage of inhibition by dibucaine (DN) was obtained by testing plasma in the presence of 15 mM dibucaine (8). In our laboratory, DN was >85% for the normal genotype (UU), 70%–83% for A variant heterozygous (UA), and <63% for AA. These values were previously calculated from testing of 80 samples from patients exhibiting prolonged paralysis, combined with their pedigree analysis.

The A variant was characterized from DNA samples obtained from leukocytes. The specific aspartic acid -> glycine 70 (GAT -> GGT) atypical mutation (5) associated with MboI restriction site deletion (position 434) was tested with polymerase chain reaction amplification of a 280-base pair (bp) fragment (350–631) of Exon 2. Polymerase chain reaction products were subjected to electrophoresis in nondenaturing gels. The migration pattern allowed us to determine the subject haplotype as follows:

Homozygous UU: three fragments, 171, 84, and 25 bp.
Homozygous AA: two fragments, 171 and 109 bp.
Heterozygous UA: four fragments, 171 and 109 bp (usual allele) and 84 and 25 bp (atypical allele).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Over the study period, 36 patients were referred because of prolonged neuromuscular blockade after the administration of succinylcholine (5 patients) or mivacurium (31 patients). The duration of neuromuscular blockade and characteristics of patients are presented in Table 1. The median age was 25 yr (0.3 to 71 yr); 16 (44%) were male, and 20 (56%) were female. The mean (range) duration of clinical neuromuscular blockade was 90 (40–140) min in patients treated with succinylcholine and 301 (120–720) min for those treated with mivacurium. In 28 of 36 patients, monitoring of neuromuscular junction at the wrist was performed. Neostigmine was administered in 14 patients (Table 1). In all but one patient (Patient 34) the biochemical analysis was performed; genetic diagnosis was performed in all cases. Blood samples were withdrawn within 72 h after the event except in Patient 34, in whom a blood sample was obtained 5 days after anesthesia.


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  		Table 1. Characteristics of the 36 Patients Referred for Prolonged Neuromuscular Blockade
 
In 31 (86%) of 36 patients, BChE was decreased <5.9 U/mL in male and <4.7 U/mL in female patients; 26 had received mivacurium (mean activity, 2.1 U/mL; 0.3–4.3 U/mL), and 5 had received succinylcholine (mean activity, 1.9 U/mL; 1.1–3.2 U/mL). Among these 31 patients, DN was normal in one patient (Patient 32), <63% in 27 patients, and 79% in one patient (Patient 22); it was unmeasurable (BChE was too low) in two patients (Patients 29 and 34) (Fig. 1).



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  		Figure 1. Results of the biochemical analysis of 36 patients referred for prolonged neuromuscular blocking effect of mivacurium and succinylcholine. BChE = butyrylcholinesterase activity; DN = dibucaine number; # = patient number; nl = normal.

 
Among the 29 patients with DN <63% or unmeasurable, 20 were homozygous (AA) and 8 were heterozygous (UA) for the A variant; one patient with a very low BChE (0.3 U/mL) did not carry the A variant. In the eight heterozygous patients, because of the low BChE activity (mean activity, 1.7 U/mL; 0.7–2.9 U/mL), we concluded that they were probably compound heterozygous for another variant as the silent one. In the remaining patient (Patient 34), the very low BChE (0.3 U/mL) activity in the absence of the A variant suggested that this patient was homozygous for the silent variant. The patient (Patient 22) with a DN of 79%, who was heterozygous for the A variant, had a BChE activity of 2.9 U/mL—a result also suggesting the presence of another variant. In the patient (Patient 32) with a normal DN of 87%, the A variant was not present; however, the low enzymatic activity (2.7 U/mL) favored the presence of another variant.

Five patients had normal BChE activity at the time of the study. One female patient (Patient 24) had an activity of 5.6 U/mL and a DN of 76% and was heterozygous for the A variant; she exhibited a duration of paralysis of 240 min after 0.2 mg/kg of mivacurium. One patient (Patient 31) received a total dose of 0.65 mg/kg of mivacurium and remained paralyzed for 120 min. When clinical monitoring assessed the appearance of recovery from neuromuscular blockade, neostigmine was administered, permitting rapid complete reversal. The three remaining patients (Patients 33, 35, and 36), with normal BChE activity and a normal genotype (UU), received a single dose of mivacurium (0.13–0.20 mg/kg). In the first case (Patient 33), the duration of clinical neuromuscular blockade was 120 min, and BChE assessed in the immediate postoperative course by the local laboratory was diminished (3 times below the lower normal value). The second patient (Patient 35) experienced a 165-min neuromuscular blockade after a single bolus of 0.20 mg/kg. At the time of the biochemical assay, BChE activity was 9.9 U/mL. Medical history indicated that the patient was polymedicated for chronic depression and, among the drugs taken by this patient, metoclopramide was identified as an inhibitor of BChE. The third case (Patient 36) had renal transplantation and had received propranolol and ciclosporin just before the induction of anesthesia; BChE measured immediately after recovery of prolonged neuromuscular blockade (300 min) was found to be 20% below the lower limit, versus 9 U/mL 5 days later in our laboratory.

In summary, in 11 patients, biochemical analysis and the molecular biology technique showed different results. In six cases (Patients 21, 23, 25, 26, 28, and 30), the biochemical analyses were consistent with an AA genotype, whereas our molecular test showed a heterozygous UA genotype. In five other cases, biochemistry found low BChE activity but remained inconclusive. In Patients 22, 27, and 32, the very low BChE activity was discordant with a normal or near normal DN; DNA analysis identified two heterozygous UA (Patients 22 and 27) genotypes and one homozygous UU (Patient 32) genotype. In Patients 29 and 34, in whom DN was not available because the BChE activity was too low, molecular biology identified one heterozygous UA (Patient 29) and one homozygous UU (Patient 34) genotype.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our study shows that prolonged paralysis after succinylcholine and mivacurium is associated with a permanent inherited BChE variant in 32 of 36 patients. We found that molecular biology improved the accuracy of the diagnosis compared with conventional testing in 11 patients.

Patients exhibiting prolonged neuromuscular blockade after succinylcholine or mivacurium should be checked for plasma BChE deficiency (9,10). Because phenotyping plasma cholinesterase with conventional techniques may misidentify genotypes (11,12), molecular biology techniques may be useful in improving the characterization (13). From these results, identification of the A variant by molecular biology improved the testing in 11 of 36 cases. In patients with low BChE and low DN, a compound heterozygous genotype (AX) cannot always be discriminated from AA, even after a pedigree analysis. La Du (6) reported that probably 20%–25% of patients characterized as homozygous AA were in fact compound heterozygous. These authors speculated that molecular biology could be very helpful in such cases. In our study, molecular biology established the diagnosis in 9 (Patients 21, 23, 25–30, and 34) of the 29 patients with low BChE and low or unmeasurable DN. Patients homozygous for the A variant were correctly characterized by the conventional technique, because all of them were recognized by biochemical tests. Nevertheless, some patients who appeared biochemically homozygous for the A variant were actually heterozygous by molecular biology testing. Among 29 patients with low BChE and low DN (<63%) or unmeasurable DN, 20 were homozygous (Patients 1–20), 8 were heterozygous for the A variant (Patients 21–30), and, in one case, the A variant was not present (Patient 34). Comparison between conventional biology and molecular biology suggests that these nine patients (Patients 21, 23, 25–30, and 34) carry another mutation, probably the silent variant.

Molecular biology can improve the accuracy of diagnosis when BChE is low, with DN >63%, or when BChE was too low to determine DN. One patient (Patient 22) with low BChE activity (2.9 U/mL) and a DN of 79% was found to be heterozygous UA. Because enzymatic activity was very low, the presence of another variant could be evoked. Six patients (Patients 31–36) were homozygous for the usual sequence at Codon 70. Among them, one patient (Patient 34), who had very low BChE, was probably homozygous for the silent allele, and another patient (Patient 32), who had low BChE activity with normal DN, could carry the silent allele in the heterozygous state. In these last two cases, molecular biology excluded the presence of an A variant and enabled us to suspect another variant.

There was no clear explanation for the abnormal response in five patients (Patients 24, 31, 33, 35, and 36). In these patients, the clinical picture of prolonged response to mivacurium was fully documented, because prolonged duration of neuromuscular blockade was ascertained by clinical monitoring. In four of them (Patients 31, 33, 35, and 36), no evidence of BChE deficiency of genetic origin was found. In one phenotypically normal subject (Patient 31), the duration of the blocking effect (120 minutes) was compatible with the cumulated dose of 0.65 mg/kg of mivacurium administered. In four patients—one heterozygous UA (Patient 24) and three phenotypically normal UU (Patients 33, 35, and 36)—other factors may have prolonged the effect of mivacurium. One UU patient (Patient 35) was polymedicated and received metoclopramide chronically. This drug inhibits BChE by as much as 70% of the normal value (14,15). The finding that immediately after anesthesia two UU patients (Patients 33 and 36) had a decreased BChE activity, whereas this activity was within normal limits at the time of the screening by our institution, suggests that a transient, acquired BChE deficit may be the cause of the prolonged effect of mivacurium documented in those patients. In one patient (Patient 24) with near normal enzymatic activity (5.6 U/mL) and a DN of 76%, molecular biology confirmed that he was heterozygous for the A variant. This patient exhibited a markedly prolonged neuromuscular blockade of 240 minutes; this was finally reversed by neostigmine. The UA genotype is reported in 2% to 10% of cases of prolonged response to succinylcholine (16–21) and is responsible for an increased duration of action of mivacurium, with a return of T4/T1 ratio to 25% after 48 minutes (22). Although the correlation between BChE activity and the duration of action of mivacurium is very weak (23–25), the 240-minute prolongation of action of mivacurium in Patient 24 can hardly be explained by the UA genotype only.

In our study, conventional biology assessed BChE and DN by using butyrylthiocholine as a substrate (8). This spectrophotometric technique in the visible region has been validated and led to similar values to that of the reference method of Kalow and Genest (26). Moreover, the limits of BChE values for each genotype (UU, UA, and AA) had previously been adjusted in our laboratory in 80 subjects (deficient patients and their relatives) by using pedigree analysis and the Kalow technique as reference. The advantage of this technique, compared with the 240-nm benzoylcholine method of Kalow and Genest (26), is that it allows the measurement of low activities (27).

In our study, the biological testing was limited to the A variant by means of two methods: one was based on DN determination, and the second relied on the identification of the aspartic acid -> glycine mutation corresponding to the A variant. The reasons we made this choice were the following. First, the A variant is most frequently involved in prolonged neuromuscular blockade. Incidences ranging from 62% to 93% are reported in cases of prolonged apnea associated with inherited BChE deficit (16–18,21,28), and in up to 76% of these cases, patients are considered homozygous for the atypical allele. Several case reports of prolonged neuromuscular blocks to mivacurium have been described (4,29–37). In most cases (9 of 10), abnormal responses were related to the homozygous AA genotype. Second, compared with other variants (F, J, H, S, and K), biochemical diagnosis of the A variant is the easiest and the most routinely established. Moreover, except for the rare J variant, in which one mutation is known to create an RsaI restriction site, other variants either are encoded by various genotypes (fluoride-1 and -2 and silent) or do not alter a known restriction site and therefore require DNA sequencing to firmly diagnose them. The K variant was not screened, but this mutation is in linkage disequilibrium with the A variant in approximately 90% of individuals with the A variant (13). Therefore, patients found to have the A variant could also carry the K mutation. However, it seems unlikely that a subject with the K variant carries the normal sequence at Codon 70.

We found in our study that more than 80% of patients experiencing prolonged neuromuscular blockade after succinylcholine or mivacurium, confirmed by monitoring, had a BChE deficiency of genetic origin. In most cases, patients were homozygous for the A variant and could be identified by conventional biochemical testing. Nevertheless, in one third of patients with low DN and BChE, molecular biology improved the accuracy of diagnosis, particularly in distinguishing homozygous and compound heterozygous genotypes, or focused diagnosis when BChE activity was too low for conventional inhibition tests.

In conclusion, in this cohort of patients having exhibited prolonged response to mivacurium or succinylcholine, we showed that 1) from a practical clinical point of view, routine evaluation by biochemical analysis with a measure of BChE activity and DN number is most often sufficient to confirm the presence of a BChE deficiency of genetic origin and that 2) screening of the BChE gene for the A mutation is easily feasible and could improve biological diagnosis in approximately one third of patients, but with little or no clinical implication for the patient. The interest of molecular biology for family investigation and counseling has to be evaluated. Future development of routine biomolecular tests for the other variants could further improve the diagnosis of this metabolic inherited disorder and progressively replace traditional biochemical inhibitor effect-based techniques.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 13, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press