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Succinylcholine and Prolonged Muscle Paralysis with Apnea: An Adverse Drug Reaction Case Report

Monday, December 17, 2018  
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Adeline Cruz, PharmD Candidate 2019, Temple University School of Pharmacy 

Stanislav Gluhov, PharmD Candidate 2019, Temple University School of Pharmacy

Patrick J. McDonnell, PharmD, FASHP,  Temple University School of Pharmacy

 

Succinylcholine is a depolarizing neuromuscular blocking agent (NMBA) which was introduced in 1951.1 Given its rapid onset of action (about 60 seconds) and short half-life (4 to 6 minutes), it is used in endotracheal intubation, during surgery, and sometimes electroconvulsive therapy. The primary mechanism of action of succinylcholine is to agonizes nicotinic acetylcholine receptors (nAChR) located on the motor end plate of the neuromuscular junction (NMJ) of the skeletal muscle membrane. This agonistic action leads to continuous muscle contraction followed by desensitization of these nAChR with muscle paralysis. Paralysis of the respiratory muscles from succinylcholine requires patients to be placed on mechanical ventilation with close monitoring for the duration of therapy. Intravenous administration of succinylcholine is rapidly hydrolyzed by butyrylcholinesterase (BChE) enzymes located in the plasma with approximately 10% of the administered dose reaching the synaptic cleft of the NMJ.1 However, BChE deficiency can generate lower metabolism rates, thus increasing the concentration of the drug reaching the NMJ and prolonging the effects of muscle paralysis from minutes to hours. The duration of the neuromuscular block is determined by the rate of drug dissociation from the NMJ and the rate of the metabolism. Since low BChE enzyme levels can be caused by a variety of factors, including genetic variations, it is not always possible to predict and prevent these outcomes and use of succinylcholine. The following case describes the occurrence of an adverse drug reaction for a man with an unknown BChE deficiency.

A 50-year-old Caucasian male presented to the emergency department with a chief complaint of vomiting and abdominal pain. He was admitted to the hospital for a laparoscopic appendectomy. No adverse reactions to anesthesia were found during the preoperative medical assessment or while reviewing his past medical and family histories. The patient’s comorbidities included hypertension, eczema, anxiety, depression, and opiate abuse. General anesthesia was administered to this patient which included midazolam 2 mg, propofol 150 mg, fentanyl 100 mcg, rocuronium 5 mg and succinylcholine 100 mg along with sevoflourane for anesthesia maintenance. After the approximately forty-minute procedure, the medical team was unable to extubate the patient due to prolonged muscle paralysis and the patient was transferred to the intensive care unit requiring supportive care. There was a suspicion regarding the prolonged paralysis and apnea as it was thought to be an effect secondary to succinylcholine with an unknown cholinesterase deficiency. This was indeed confirmed with the following laboratory findings: a plasma test revealed significantly lower plasma cholinesterase levels of 354 U/L (normal range 2504-6297 U/L) with the phenotypic test revealing low dibucaine numbers of 33.5% (normal range 81.6-88.3%) correlating with atypical homozygous or atypical silent heterozygous genes. Twelve hours after the procedure, the patient had full recovery from paralysis and was successfully extubated. A day later the patient was discharged from the hospital without any additional complication.

BChE enzyme levels and activity that are affected by genetic variations are uncommon (about 1 out of 3500 Caucasians), but can lead to either lower or no production of BChE enzymes or altering enzyme activity having similar effects as BChE deficiency.1,2 BChE is not the only enzyme known to be impacted by genetic variation. Pharmacogenetics influence many other drugs in regards to their pharmacokinetic and pharmacodynamic parameters.3 To date, there are over 60 BChE variants known that one can inherit which may result in minimal to extended muscle paralysis post succinylcholine administration.1,2 The BChE gene is located on the long arm of chromosome 3 at 3q26.1-26.2 and can be inherited as an autosomal recessive trait. Most clinically relevant genetic variants found in patients with prolonged apnea are atypical variant (A), K variant, and silent variant (S).1,2 Testing for BChE deficiency can be done prior to the administration of succinylcholine to prevent prolonged muscle paralysis and apnea, however due to the rarity of this deficiency it is not considered to be a standard of care. Biochemical assay testing is performed to determine qualitative defects present in BChE enzyme activity with normal serum cholinesterase levels of 3200 - 6600 IU/L. The phenotype of the BChE variants can be determined by the commonly used dibucaine number (DN) test.4 Dibucaine is a competitive inhibitor of the BChE enzyme and is used to help determine enzyme activity.4 The dibucaine number is a percentage of the BChE enzyme inhibition in the presence of dibucaine.1,2,5 Typical BChE enzyme is very sensitive to dibucaine inhibition, with 83% of inhibition. On the other hand, atypical (A) BChE variant is resistant to dibucaine inhibition due to an alteration of the catalytic site having a DN range of 8-28%.1 However, this testing is not routinely performed in practice unless BChE deficiency is suspected. Other molecular testing, such as polymerase chain reaction, are only performed for research purposes at this time.2

Succinylcholine is a common agent used as a part of anesthesia induction. Predicting prolonged paralysis and apnea due to BChE deficiency prior to exposure is difficult. Since pharmacogenomic testing is not a part of the current standard of practice, it is challenging to protect the BChE deficient patient from a prolonged stay at the hospital. Letting the patient recover spontaneously with mechanical ventilation support is the treatment that is used in many institutions and this method was utilized as seen in this patient case. In addition, taking precautions such as cholinesterase genetic testing can be costly, but is important to prevent future adverse drug events. Once a deficiency is found, proper documentation and patient education is vital to prevent future events[DDZ1] . As healthcare professionals, protection of our patients is our goal and integrating pharmacogenomic testing can become an integral part of pharmacy care.

 

 

References

1.     Lockridge O. Genetic Variants of Human Serum Cholinesterase Influence Metabolism of The Muscle Relaxant Succinylcholine. Pharmacol Ther. 1990; 47(1):35-60.

2.     Soliday FK, Conley YP, Henker R. Pseudocholinesterase Deficiency: A comprehensive Review of Genetic, Acquired, and Drug Influences. AANA J. 2010; 78(4):313-320.

3.     Ahmed S, Zhou Z, Zrou J, Chen SQ. Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine. Genomic Proteomics Bioinformation. 2016; 14:298-313.

4.     Alvarellos ML, McDonagh EM, Patel S, McLeod HL, Altman RB, Teri KE. PharmGKB Summary: Succinylcholine Pathway, Pharmacokinetics / Pharmacodynamics. Pharmacogenet Genomics. 2015; 25(12):622-630. doi: 10.1097/FPC.0000000000000170

5.     Parnas ML, Procter M, Schwarz MA, Mao R, Grenache DG. Concordance of Butyrylcholinesterase Phenotype with Genotype. Am J Clin Phathol. 2011; 135:271-276.


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