Skip to main content

Main menu

  • Home
  • About
    • Clinical Chemistry
    • Editorial Board
    • Most Read
    • Most Cited
    • Alerts
    • CE Credits
  • Articles
    • Current Issue
    • Early Release
    • Future Table of Contents
    • Archive
    • Browse by Subject
  • Info for
    • Authors
    • Reviewers
    • Subscribers
    • Advertisers
    • Permissions & Reprints
  • Resources
    • AACC Learning Lab
    • Clinical Chemistry Trainee Council
    • Clinical Case Studies
    • Clinical Chemistry Guide to Scientific Writing
    • Clinical Chemistry Guide to Manuscript Review
    • Journal Club
    • Podcasts
    • Q&A
    • Translated Content
  • Abstracts
  • Submit
  • Contact
  • Other Publications
    • The Journal of Applied Laboratory Medicine

User menu

  • Subscribe
  • My alerts
  • Log in

Search

  • Advanced search
Clinical Chemistry
  • Other Publications
    • The Journal of Applied Laboratory Medicine
  • Subscribe
  • My alerts
  • Log in
Clinical Chemistry

Advanced Search

  • Home
  • About
    • Clinical Chemistry
    • Editorial Board
    • Most Read
    • Most Cited
    • Alerts
    • CE Credits
  • Articles
    • Current Issue
    • Early Release
    • Future Table of Contents
    • Archive
    • Browse by Subject
  • Info for
    • Authors
    • Reviewers
    • Subscribers
    • Advertisers
    • Permissions & Reprints
  • Resources
    • AACC Learning Lab
    • Clinical Chemistry Trainee Council
    • Clinical Case Studies
    • Clinical Chemistry Guide to Scientific Writing
    • Clinical Chemistry Guide to Manuscript Review
    • Journal Club
    • Podcasts
    • Q&A
    • Translated Content
  • Abstracts
  • Submit
  • Contact
Article CommentaryClinical Case Study

A Patient with Prolonged Paralysis

JoDell E. Whittington, Hoai D. Pham, Melinda Procter, David G. Grenache, Rong Mao
DOI: 10.1373/clinchem.2011.163782 Published February 2012
JoDell E. Whittington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hoai D. Pham
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Melinda Procter
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David G. Grenache
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rong Mao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: rong.mao@aruplab.com
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

CASE

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.

QUESTIONS TO CONSIDER

  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?

DISCUSSION

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 of 0.7 min and a volume of distribution of 0.02–0.04 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)] × 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).

View this table:
  • View inline
  • View popup
Table 1. Characteristics associated with BChE phenotypes.

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).

PATIENT FOLLOW-UP

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.

Fig. 1.
  • Download figure
  • Open in new tab
Fig. 1. BCHE sequencing results identifying a unique hemizygous/homozygous mutation: 1240 C>T (p.Arg414Cys, known as Arg386Cys) in exon 2.

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 AA BCHE 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 genotype, which produced a BChE variant with very low catalytic activity.

POINTS TO REMEMBER

  • 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.

Footnotes

  • ↵4 Nonstandard abbreviations:

    BChE,
    butyrylcholinesterase;
    DN,
    dibucaine number

  • 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.

  • Received for publication February 17, 2011.
  • Accepted for publication June 13, 2011.
  • © 2012 The American Association for Clinical Chemistry

References

  1. 1.↵
    1. Darvesh S,
    2. Hopkins DA,
    3. Geula C
    . Neurobiology of butyrylcholinesterase. Nat Rev Neurosci 2003;4:131–8.
    OpenUrlCrossRefPubMed Order article via Infotrieve
  2. 2.↵
    1. Primo-Parmo SL,
    2. Bartels CF,
    3. Wiersema B,
    4. van der Spek AF,
    5. Innis JW,
    6. La Du BN
    . Characterization of 12 silent alleles of the human butyrylcholinesterase (BCHE) gene. Am J Hum Genet 1996;58:52–64.
    OpenUrlPubMed Order article via Infotrieve
  3. 3.↵
    1. Cokugras AN
    . Butyrylcholinesterase: structure and physiological importance. Turk J Biochem 2003;28:54–61.
    OpenUrl
  4. 4.↵
    1. Kalow W,
    2. 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.
    OpenUrlCrossRefPubMed Order article via Infotrieve
  5. 5.↵
    1. Kalow W,
    2. Lindsay HA
    . A comparison of optical and manometric methods for the assay of human serum cholinesterase. Can J Biochem Physiol 1955;33:568–74.
    OpenUrlCrossRefPubMed Order article via Infotrieve
  6. 6.↵
    1. Lehmann H,
    2. Ryan E
    . The familial incidence of low pseudocholinesterase level. Lancet 1956;271:124.
    OpenUrlPubMed Order article via Infotrieve
  7. 7.↵
    1. Harris H,
    2. Whittaker M
    . Differential inhibition of human serum cholinesterase with fluoride: recognition of two new phenotypes. Nature 1961;191:496–8.
    OpenUrlCrossRefPubMed Order article via Infotrieve
  8. 8.↵
    1. Hodgkin W,
    2. Giblett ER,
    3. Levine H,
    4. Bauer W,
    5. Motulsky AG
    . Complete pseudocholinesterase deficiency: genetic and immunologic characterization. J Clin Invest 1965;44:486–93.
    OpenUrlPubMed Order article via Infotrieve
  9. 9.↵
    1. Bartels CF,
    2. Jensen FS,
    3. Lockridge O,
    4. van der Spek AF,
    5. Rubinstein HM,
    6. Lubrano T,
    7. 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.
    OpenUrlPubMed Order article via Infotrieve
  10. 10.↵
    1. Yen T,
    2. Nightingale BN,
    3. Burns JC,
    4. Sullivan DR,
    5. Stewart PM
    . Butyrylcholinesterase (BCHE) genotyping for post-succinylcholine apnea in an Australian population. Clin Chem 2003;49:1297–308.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. De Jaco A,
    2. Comoletti D,
    3. Kovarik Z,
    4. Gaietta G,
    5. Radic Z,
    6. Lockridge O,
    7. 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.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Parnas ML,
    2. Procter M,
    3. Schwarz MA,
    4. Mao R,
    5. Grenache DG
    . Concordance of butyrylcholinesterase phenotype with genotype: implications for biochemical reporting. Am J Clin Pathol 2011;135:271–6.
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top

In this issue

Clinical Chemistry: 58 (3)
Vol. 58, Issue 3
March 2012
  • Table of Contents
  • Index by author
  • Table of Contents (PDF)
  • Cover (PDF)
  • Advertising (PDF)
  • Ed Board (PDF)
Print
Share
A Patient with Prolonged Paralysis
JoDell E. Whittington, Hoai D. Pham, Melinda Procter, David G. Grenache, Rong Mao
Clinical Chemistry Mar 2012, 58 (3) 496-500; DOI: 10.1373/clinchem.2011.163782
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Article Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
A Patient with Prolonged Paralysis
JoDell E. Whittington, Hoai D. Pham, Melinda Procter, David G. Grenache, Rong Mao
Clinical Chemistry Mar 2012, 58 (3) 496-500; DOI: 10.1373/clinchem.2011.163782

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • CASE
    • DISCUSSION
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Commentary
  • Persistent Jaundice and Multiple Fractures in a Newborn
  • Commentary
Show more Clinical Case Study

Similar Articles

Subjects

  • TRANSLATED CONTENT
    • Portuguese Translations
    • Spanish Translations
    • Japanese Translations
  • SUBJECT AREAS
    • Molecular Diagnostics and Genetics
  • SECTIONS
    • Clinical Case Studies

Options

  • Home
  • About
  • Articles
  • Information for Authors
  • Resources
  • Abstracts
  • Submit
  • Contact
  • RSS

Other Publications

  • The Journal of Applied Laboratory Medicine
Footer logo

© 2019 American Association for Clinical Chemistry

Powered by HighWire