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A patient with prolonged paralysis.


A 19-year-old Asian male with no notable medical history presented to the emergency department with a 12-h history of acute abdominal pain. The patient's condition was diagnosed as acute appendicitis, and he underwent an emergent laparoscopic appendectomy. A 1-mg dose of vecuronium followed by 120 mg of succinylcholine was administered to induce paralysis and facilitate endotracheal intubation.

The progression of the patient's muscle relaxation was monitored intraoperatively with a train-of-four twitch monitor and was marked by fewer stimuli making it across the neuromuscular junction. In general surgeries, a neuromuscular block down to 2 twitches is adequate for rapid sequence induction. Normally, a dose of 0.5-2 mg succinylcholine per kilogram body weight completely abolishes the muscle response to nerve stimulation. Within 2 to 2.5 min, the neuromuscular junction starts to show signs of recovery, or twitches. In this case, the patient was administered 1.7 mg/kg succinylcholine. After the appendectomy was completed, however, the patient uncharacteristically remained paralyzed for 1.75 h. He showed no muscle twitches, no spontaneous inspiratory efforts, and no protective airway reflexes. He subsequently required sedation and assisted ventilatory support.


Cholinesterases are enzymes that catalyze the hydrolysis of choline esters. Acetylcholinesterase is distributed in the gray matter of the central nervous system, where it terminates synaptic transmission by specifically hydrolyzing the neurotransmitter acetylcholine (1,2). Butyrylcholinesterase (BChE),4 also known as pseudocholinesterase, is distributed in the white matter of the central nervous system and in the blood. Although it has no known physiological function, BChE is of pharmacologic and toxicologic importance (1). Unlike acetylcholinesterase, BChE is capable of hydrolyzing exogenous carboxylic or phosphoric acid esters found in succinylcholine, aspirin, mivacurium, ester-type local anesthetics, amitriptyline, cocaine, heroin, and several anticonvulsant drugs (3).

Succinylcholine, a neuromuscular blocking agent commonly used in surgical procedures to aid in endotracheal intubation, acts as a depolarizing neuromuscular blocker by mimicking the action of acetylcholine, thus generating an action potential at the motor end-plate. Succinylcholine has a half-life of0.7 min and a volume of distribution of0.02-0.04 L/kg. The action of succinylcholine is terminated by its diffusion away from the motor end-plate into the blood, where it is hydrolyzed by BChE (3). Normally, muscle function is restored approximately 10 min after discontinuation of the drug. Extended blockade with succinylcholine occurs in a subset of individuals who have BChE variants that either lack sufficient quantity of the enzyme or demonstrate a decreased affinity for substrate, thereby causing prolonged paralysis.

BChE is the product of the BCHE (butyrylcholinesterase) gene on chromosome 3 region 3q26. The gene consists of 73 kilobases in 4 exons separated by 3 introns (3). Mutations in the BCHE gene encode BChE protein products with varying reductions in activity that produce extended blockade and apnea in patients after exposure to succinylcholine. These genetically determined enzyme variants are characterized by decreased BChE production (quantitative variants) or by the production of dysfunctional BChE molecules having decreased to no activity (qualitative variants) (2). BChE deficiency is often recognized only after an individual experiences unexpected periods of prolonged paralysis after succinylcholine administration.

A biochemical test from the 1950s for the phenotypic identification of BChE variants helped determine that the pharmacogenetic effect of BChE variants was familial (4-6). The test quantifies BChE enzyme activity in the serum in the presence and absence of the competitive inhibitor dibucaine, allowing the calculation of a "dibucaine number" (DN) that corresponds to the percentage of enzymatic inhibition: DN = [1--(Inhibited BChE activity)/(Total BChE activity)] X 100, where BChE activity is in units per liter. Together, the BChE activity and the DN can be used to determine an individual's biochemical phenotype (Table 1).

With a prevalence of 96%, the most common phenotype is the usual (U) phenotype, which is characterized by a DN >80%. Individuals with this phenotype respond normally to succinylcholine administration with neuromuscular junction recovery achieved in approximately 10 min after exposure. In contrast, individuals with the atypical (A) phenotype have a DN <32% and experience prolonged paralysis after exposure to succinylcholine. A single allele at a frequency of 1 in 3000 is known to produce the A phenotype (4). Approximately 3% of individuals have the heterozygous UA phenotype and demonstrate clinical and biochemical properties between the U and A phenotypes. The fluoride-resistant (F) phenotype shows increased resistance to inhibition by fluoride and reduces an individual's ability to hydrolyze succinylcholine. There are 2 known fluoride-resistant mutations, but their frequency is very rare (1 in 150 000 individuals) (7). Individuals with the rare silent (S) phenotype completely lack or have only minimal BChE activity (8).

Three quantitative BChE variants have been described: James (J), Kalow (K), and Hammersmith (H). All have normal substrate binding activity but show decreased concentrations in the plasma (2). The slight decreases in BChE activity due to the quantitative variants do not usually cause a clinically important prolonged response to succinylcholine. These variants are more likely to affect the duration of response when present with other factors that influence BChE activity, such as a qualitative BChE variant, pregnancy, and anticholinesterase drugs (9).


A blood sample was obtained for BChE activity and DN testing. The BChE activity was 57 U/L (reference interval, 3300-10 300 U/L) and the DN was <5% (reference interval, 83%-88%).

After a period of 4 h beyond the expected duration of succinylcholine action, the patient recovered his strength and met the criteria for extubation. He was discharged from the hospital 27.5 h after surgery. Because succinylcholine binds to the BChE active site, its presence in plasma will produce falsely decreased BChE activity and DN results. In the reported case, the initial BChE test was performed on a sample collected when succinylcholine was likely to be circulating in the patient's blood. A repeat blood sample was obtained 8 days later for a repeat evaluation of the BChE activity and the DN; the results were 89 U/L and <5%, respectively. This BChE finding in conjunction with the low DN (<5%) suggested the patient had the S phenotype (Table 1). Knowledge of the phenotype is important because it will guide decisions regarding any future use of succinylcholine.


To better understand the genetic cause of the patient's reduced BChE activity, we performed BCHE sequencing. PCR amplification of the 3 coding regions and intron/exon boundaries of the BCHE gene was performed with M13-tailed primers. Unincorporated primers and deoxynucleoside triphosphates were inactivated by incubating with ExoSAP (USB Corporation). Bidirectional DNA sequencing was performed with BigDye Terminator chemistry (Applied Biosystems) and M13 primers, and the product was analyzed on the ABI 3100 Genetic Analyzer (Applied Biosystems). Data were analyzed with Mutation Surveyor software (SoftGenetics) by comparing the generated sequence to a reference BCHE sequence (Genbank NC_000003.11).

BCHE sequencing identified a homozygous mutation: c.1240 C>T (p.Arg414Cys, known as Arg386Cys in the mature protein) in exon 2 (Fig. 1). This rare mutation has previously been reported only as a heterozygote and with an unknown clinical importance (10, 11). The case we have presented establishes that the BCHE Arg414Cys variant in the homozygous state produces prolonged paralysis upon exposure to succinylcholine, in agreement with an S phenotype.

Arg414Cys is most likely a missense mutation causing inactivation of the BChE active site.

Although the anesthesia community is aware that some individuals will have BChE variants with reduced catalytic activity, BChE and DN testing is infrequently performed, most likely because of the relatively low incidence of BChE variants within the general population. Testing is frequently prompted when an individual experiences prolonged paralysis after exposure to succinylcholine, as occurred in this case. In this scenario, however, the timing of sample collection is important, and samples should be obtained only after all succinylcholine has completely cleared. Failure to do so can produce misleading results or uninterpretable biochemical data that could lead to an error, for example, in which the phenotype obtained implies no or only a slight risk of prolonged paralysis in an individual who is actually at high risk. In one study (12), 3 patients were assigned a BChE phenotype of UF (slight risk), but 1 of the patients was determined to have an AABCHE genotype (high risk) (12).

Because the half-life of succinylcholine is prolonged beyond the expected 0.7 min in patients with qualitative BChE variants due to impaired catalytic activity, we recommend waiting a minimum of 48 h after succinylcholine exposure before collecting a sample for BChE phenotyping.

For our patient, similar BChE and DN results were obtained with 2 different samples, one of which was collected when succinylcholine was likely still present in the patient's blood. The effect of succinylcholine on the BChE and DN results was less apparent because the patient had a rare SS BCHE geno type, which produced a BChE variant with very low catalytic activity.


1. What are the pharmacodynamic properties of succinylcholine?

2. What is the role of butyrylcholinesterase in the pharmacokinetics of succinylcholine?

3. What conditions can cause delayed recovery from succinylcholine administration?

4. What additional testing should be used to further evaluate this patient?


* Succinylcholine is a paralytic drug used to induce muscle relaxation and short-term paralysis.

* BChE has no known physiological function but is capable of hydrolyzing exogenous choline esters found in certain drugs of abuse, aspirin, antidepressants, anticonvulsants, and paralytics.

* Extended paralysis by succinylcholine occurs in individuals with reduced BChE activity due to genetically determined enzyme variants.

* Dibucaine is a competitive inhibitor of BChE and is used to determine an individual's DN, which is the percentage of BChE inhibited by dibucaine.

* The BChE activity and DN can be used to infer an individual's biochemical BChE phenotype.

Acknowledgments: We are grateful to Dr. Christopher Reif at the Community University Health Care Center, University of Minnesota, Minneapolis, Minnesota, and his help in obtaining patient samples and clinical information.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.


(1.) Darvesh S, Hopkins DA, Geula C. Neurobiology of butyrylcholinesterase. Nat Rev Neurosci 2003;4:131-8.

(2.) Primo-Parmo SL, Bartels CF, Wiersema B, van der Spek AF, Innis JW, La Du BN. Characterization of 12 silent alleles of the human butyrylcholinesterase (BCHE) gene. Am J Hum Genet 1996;58:52-64.

(3.) Cokugras AN. Butyrylcholinesterase: structure and physiological importance. Turk J Biochem 2003;28:54-61.

(4.) Kalow W, Genest K. A method for the detection of atypical forms of human serum cholinesterase; determination of dibucaine numbers. Can J Biochem Physiol 1957;35:339-46.

(5.) Kalow W, Lindsay HA. A comparison of optical and manometric methods for the assay of human serum cholinesterase. Can J Biochem Physiol 1955;33: 568-74.

(6.) Lehmann H, Ryan E. The familial incidence of low pseudocholinesterase level. Lancet 1956;271:124.

(7.) Harris H, Whittaker M. Differential inhibition of human serum cholinesterase with fluoride: recognition of two new phenotypes. Nature 1961; 191:496-8.

(8.) Hodgkin W, Giblett ER, Levine H, Bauer W, MotulskyAG. Complete pseudocholinesterase deficiency: genetic and immunologic characterization. J Clin Invest 1965;44:486-93.

(9.) Bartels CF, Jensen FS, Lockridge O, van der Spek AF, Rubinstein HM, Lubrano T, La Du BN. DNA mutation associated with the human butyrylcholinesterase K-variant and its linkage to the atypical variant mutation and other polymorphic sites. Am J Hum Genet 1992;50: 1086-103.

(10.) Yen T, Nightingale BN, Burns JC, Sullivan DR, Stewart PM. Butyrylcholines terase (BCHE) genotyping for post-succinylcholine apnea in an Australian population. Clin Chem 2003;49:1297-308.

(11.) De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, et al. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha, beta-hydrolase fold protein family. J Biol Chem 2006;281:9667-76.

(12.) Parnas ML, Procter M, Schwarz MA, Mao R, Grenache DG. Concordance of butyrylcholinesterase phenotype with genotype: implications for biochemical reporting. Am J Clin Pathol 2011;135:271-6.

JoDell E. Whittington, [1] Hoai D. Pham, [2] Melinda Procter, [3] David G. Grenache, [1,3] and Rong Mao [1,3] *

[1] Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT; [2] Department of Anesthesiology, University of Minnesota, Minneapolis, MN; [3] ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT.

* Address correspondence to this author at: ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108-1221. E-mail

Received February 17, 2011; accepted June 13, 2011.

Previously published online at DOI: 10.1373/clinchem.2011.163782

[4] Nonstandard abbreviations: BChE, butyrylcholinesterase; DN, dibucaine number. QUESTIONS TO CONSIDER
Table 1. Characteristics associated with BChE phenotypes.

   BChE               BChE          DN, %
phenotype (a)     activity, U/L

    U               3300-10 300     83-88
    A               1600-4100       24-31
    F               1600-4101       79-81
    S                 0-650          Any
    UA              1930-7300       72-79
    UF              1260-5800       80-83
    US              1300-5100       83-87
    AS               540-1800       24-31
    AF               800-3100       60-71
    FS              1000-3800       78-84

   BChE           Susceptibility (b)     Frequency (c)
phenotype (a)

    U                None                96%
    A                Very                1 in 3000
    F                Somewhat            1 in 150 000
    S                Very                1 in 40 000
    UA               Slightly            3%
    UF               Slightly            Rare
    US               Slightly            1 in 150
    AS               Very                1 in 8000
    AF               Somewhat            Rare
    FS               Somewhat            Rare

(a) U, usual phenotype; A, atypical phenotype; F,
fluoride-resistant phenotype; S, silent phenotype. Other phenotypes
are heterozygous combinations of the U, A, F, and S phenotypes.

(b) Susceptibility to paralysis induced by neuromuscular blocking
agents that require metabolism via BChE activity.

(c) Frequency of BChE phenotypes within the general population.


George Despotis *

In this Clinical Case Study by J.E. Whittington et al., the authors summarize the literature regarding butyrylcholinesterase (BChE) deficiency and provide a comprehensive summary of the various phenotypes in Table 1, which illustrates the relatively low frequencies of the atypical phenotypes of BChE. Nevertheless, there are substantial clinical implications of reduced BChE activity. Patients who have a low-activity BChE phenotype may experience serious complications if this genetic predisposition is not managed appropriately. Although the authors' case illustrates the potentially serious implications of this disorder from a ventilatory perspective, the relative importance of reduced BChE activity on the pharmacokinetic and biologic activity of various other pharmacologic agents is also highlighted.

One issue not addressed in this Clinical Case Study is related to iatrogenic inhibition of this enzyme in the setting of either perioperative reversal of nondepolarizing muscle relaxant agents (e.g., neostigmine) or with the chronic management of myasthenia gravis (e.g., pyridostigmine). Although the prolonged duration of action of succinylcholine after the administration of agents like neostigmine has been extensively described, there are also a few reports of resistance to muscle relaxation with succinylcholine. One can speculate that patients with a hereditary reduction in BChE activity may display more-profound effects when these acetylcholinesterase inhibitors are administered. The clinical utility of recombinant (transgenic) BChE in these variant patients may also be of some benefit.

A better understanding of the issues outlined in this case should help clinicians confirm the diagnosis and help with the management of patients with reduced BChE when they are encountered in their clinical practice.

Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.

* Address correspondence to the author at: Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, 669 S Euclid Ave., Box 8118, St. Louis, MO 63110. Fax 314-362-1461; e-mail

Received August 22, 2011; accepted August 29, 2011.

DOI: 10.1373/clinchem.2011.170530


Roberta Goodall *

Prolonged paralysis due to low butyrylcholinesterase (BChE) activity after suxamethonium administration arises from either an inherited or an acquired deficiency, but the risk of prolonged paralysis is dependent on both enzyme activity and genotype. BCHE is a highly polymorphic gene, and the prevalences of the different mutations show large geographic and ethnic variation. The terminology can be challenging (1). Biochemical phenotypes are defined by the pattern of values obtained after differential enzyme inhibition to determine "inhibitor numbers," e.g., the dibucaine number (DN). The most accurate identification of phenotype uses 3 inhibitors, typically dibucaine plus fluoride and the carbamate Ro 02-0683 (2), which allow identification of such phenotypes as AK and AF, as well as the original Atypical (A) and UA phenotypes, and improves the extrapolation of phenotype to genotype.

Low DN values normally indicate the A phenotype (DN typically 20-30), which is demonstrated only by homozygotes for the defining Asp70Gly mutation (A/A genotype) or by its compound heterozygotes with a silent variant mutation (A/S genotype)--the silent variant gene product contributing little to the total. At very low enzyme activity, little significance can be placed on the DN; imprecision at these levels prevents its accurate determination. A very low DN should be thought of as pointing neither to a "silent" phenotype nor to an A phenotype, a conclusion supported in this case by the fact that the genotype results do not show the Asp70Gly mutation. In cases in which inhibitor numbers can be determined accurately, the presence of a silent variant in heterozygotes is masked by the phenotype of the other allele. That has been demonstrated in regard to a heterozygote for the Arg386Cys mutation described here, which demonstrated a "Usual" phenotype, as well as for other U/S and compound heterozygotes.

This case shows the value of genotyping in a case of low BChE activity, because identifying a genetic cause may have repercussions for other family members.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.


(1.) La Du BN, Bartels C, Noqueira CP, Arpagaus M, Lockridge O. Proposed nomenclature for human butyrylcholinesterase genetic variants identified by DNA sequencing. Cell Mol Neurobiol 1991;11:79-89.

(2.) Goodall R. Cholinesterase: phenotyping and genotyping. Ann Clin Biochem 2004;41:98-110.

Department of Clinical Biochemistry, North Bristol NHS Trust, Southmead Hospital, Bristol, UK.

* Address correspondence to the author at: Department of Clinical Biochemistry, North Bristol NHS Trust, Southmead Hospital, Bristol, UK BS10 5NB. Fax +44-117-3238377; e-mail

Received July 12, 2011; accepted July 14, 2011.

DOI: 10.1373/clinchem.2011.170548
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Title Annotation:Clinical Case Study
Author:Whittington, JoDell E.; Pham, Hoai D.; Procter, Melinda; Grenache, David G.; Mao, Rong
Publication:Clinical Chemistry
Date:Mar 1, 2012
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