Prolonged paralysis following emergent cesarean section with succinylcholine despite normal dibucaine number.
This case report describes a patient who developed prolonged paralysis following administration of succinylcholine for emergent surgery. The patient was unable to be extubated following surgery and required ventilatory support for several hours. This case report highlights a potential risk of the neuromuscular blocker succinylcholine which is frequently utilized in the operating room and the emergency department. Patients with atypical variants of pseudocholinesterase with deficient enzymatic activity may require mechanical ventilation and close monitoring following administration of this muscle relaxant. The diagnosis must be quickly recognized because these patients require prolonged ventilatory support and sedation. (1)
A healthy 28-year-old, 91 kilogram gravida 1, para 0 female was admitted to the hospital at 39 weeks gestation with ruptured membranes and in active labor. After approximately two hours her labor was complicated by fetal distress, and she was taken to the operating room for an emergent cesarean section. The patient underwent general anesthesia with a rapid sequence induction utilizing 170 mg propofol and 200 mg succinylcholine followed by tracheal intubation. Anesthesia was maintained with sevoflurane and nitrous oxide throughout the case. The patient was given 15 mg intravenous morphine for postoperative pain control after successful delivery of the infant. The surgery was uneventful and at the end of the procedure, the volatile anesthetic was discontinued in preparation for emergence and extubation. However, the patient remained unresponsive and became progressively more tachycardic and hypertensive. Peripheral nerve stimulation revealed no twitches on train-of-four stimulation, consistent with intense neuromuscular blockade. A diagnosis of atypical pseudocholinesterase or pseudocholinesterase deficiency was suspected at this time. The patient was immediately anesthetized with propofol and sevoflurane to prevent awareness. The patient was transferred to the ICU for observation and mechanical ventilation where she was sedated with a propofol infusion. Lab values obtained in the ICU were similar to preoperative levels with the exception of hemoglobin, which had dropped appropriately post-surgery. In order to assess the patient's pseudocholinesterase enzyme quantity and function, blood was sent for laboratory analysis of enzyme level and dibucaine number. Neuromuscular blockade was monitored closely utilizing a peripheral nerve stimulator. Five and a half hours after the administration of succinylcholine, the patient had fully regained her strength and was successfully extubated. Surprisingly, while the pseudocholinesterase level was low at 772 Units/Liter (normal 18006600 U/L), the dibucaine number, a measure of enzyme function, was normal at 81 (normal 70-90%).
Succinylcholine is a depolarizing neuromuscular blocker that is primarily used to facilitate tracheal intubation through paralysis. In adults, the recommended dose of succinylcholine is 1-2 mg/kg to produce satisfactory intubating conditions. (2) The primary indication for the drug is for a "rapid sequence induction (RSI)," which is performed when tracheal intubation is required in a patient considered to be at significant risk for aspiration. During RSI, positive pressure ventilation is avoided until after tracheal intubation to decrease the risk of aspiration. Because succinylcholine produces rapid, intense neuromuscular blockade, many physicians still believe that it is the drug of choice for RSI. In most patients, Succinylcholine is rapidly degraded by pseudocholinesterase leading to a short duration of action (9-13 minutes). (2,3)
The plasma enzyme pseudocholinesterase is produced in the liver and functions to metabolize ester linkages of compounds in the plasma including succinylcholine, ester local anesthetics, and other medications. (1,4) There are multiple different genetic variants of the pseudocholinesterase enzyme, some of which have decreased enzymatic activity which results in a prolonged response to succinylcholine. The presence of the atypical (A) variant was originally demonstrated by Kalow and colleagues using the local anesthetic dibucaine as an inhibitor. (1,4) The dibucaine number is currently used to characterize patients as normal (70-90%), intermediate (60%), and atypical (20%) pseudocholinesterase variants. (1) Patients who are heterozygous for the (A) variant have a prevalence of 1 in 25, a normal or minimally prolonged response to succinylcholine, and a dibucaine number of 60.5 Patients homozygous for the (A) variant have a dibucaine number of approximately 20. These patients have a prevalence of 1 in 3000 and exhibit a significantly prolonged response (>2 hours paralysis) to succinylcholine. (1,5) As the use of succinylcholine increased, a subset of patients with normal dibucaine numbers and a prolonged apneic response to succinylcholine were encountered. In an attempt to classify these patients, sodium fluoride was used as an inhibitor. However, the results correlated with the dibucaine numbers. Some patients with normal dibucaine numbers (70-90) were found to have unexpectedly low fluoride numbers (60) and a slight increase in the duration of paralysis. Other patients assumed to be heterozygotes based on their dibucaine number (60) were found to have extremely low fluoride numbers (20's) and a moderate increase in the duration of paralysis (1-2 hours), with a prevalence of 1 in 150,000. (1,5)
A third variant, known as the silent (S) type, leads to almost no pseudocholinesterase activity. S type homozygotes are extremely rare (1 in 10,000) and would have significant paralysis from a single dose of succinylcholine that may last more than four hours. (1) Another variant (K) discussed here is also one of the most common variants (13%) and is frequently associated with other types. In over 80% of the cases where an atypical (A) variant was present, the K variant was also present. (1) Although only a few have been discussed here, over twenty mutations in the cholinesterase gene have been discovered and most are clinically insignificant. (2) If any of these milder variants are combined with an acquired quantitative pseudocholinesterase deficiency such as has been shown in pregnancy, an additive effect resulting in a significantly prolonged response to succinylcholine would be expected. The standard methods to detect abnormal pseudocholinesterase, such as the dibucaine or fluoride inhibition tests, fail to detect some enzyme variants. It is now possible to use molecular genetic techniques to identify alterations in the cholinesterase gene. (6)
Multiple studies have confirmed that pseudocholinesterase (ChE) activity decreases during pregnancy, starting at about the tenth week. (5,7,8) This decrease in ChE activity slowly progresses during pregnancy and peaks at approximately the 3rd post-partum day. (7,8) Compared with non-pregnant patients, the ChE activity decreases by approximately 20% by the third trimester, by 25% on the 1st post-partum day, and by 33% three days post-partum. (7,8) In patients with qualitatively normal pseudocholinesterase, the absolute level must decrease by at least 70% before a clinically significant prolongation of succinylcholine-induced paralysis can occur. (1) The decreased levels associated with pregnancy by itself are unlikely to cause prolonged muscle weakness after a single dose of succinylcholine. In fact, if a patient experiences prolonged apnea following surgery, one must first identify the cause. If residual paralysis is suspected, a decreased twitch response to a peripheral nerve stimulator must be demonstrated. Once the diagnosis of prolonged neuromuscular blockade has been established, ventilator support and sedation should be provided until the return of muscle strength occurs. Other treatment modalities, such as administration of whole blood, fresh frozen plasma, and human serum cholinesterase, have been attempted to hasten the recovery. (1,4) These modalities are rarely employed because of the risks of transfusion therapy. Neuromuscular function typically returns to normal within a few hours without treatment. Therefore' it is unwise to subject the patient to additional transfusion-related risks. (1)
Other causes of prolonged paralysis following the administration of succinylcholine include a quantitative deficiency of the pseudocholinesterase enzyme' overdose of succinylcholine' liver disease' prior use of magnesium sulfate or anticholinesterase drugs' and the presence of significant metabolic or electrolyte abnormalities. (9) In this case, the patient received one 200 mg dose of succinylcholine (2.2 mg/kg) with no further muscle relaxants given throughout the case. This dose was unlikely to be large enough to cause prolonged paralysis. The patient had not received magnesium and was not previously taking or exposed to any anticholinesterases. Her liver function tests were within normal limits, and she had no significant metabolic or electrolyte abnormalities.
The dibucaine number, which is a measure of the enzymatic activity of pseudocholinesterase, was 81 (Normal values are > 70). In addition, the patient's pseudocholinesterase level was 772 U/L, which is approximately 43% of the lower limit of the normal range at our institution. This level alone is unlikely to be solely responsible for the patient's greater than five hours prolonged response to succinylcholine. These laboratory tests were not obtained until the first postoperative day due to the necessity of sending to an outside laboratory and also to confirm that the cost of the testing would not be charged to the patient's account. These tests are expensive to perform and may not be covered by all insurance carriers.
The serum pseudocholinesterase level and serum dibucaine inhibition tests were performed at the Mayo Clinic Laboratory. The test for the cholinesterase level is based on the ability of the enzyme to hydrolyze the substrate acetylthiocholine into thiocholine which is then measured utilizing colorimetric analysis. (10,11) Listed reference values from the laboratory include males > 18 years 3,100-6,500 U/L, females 18-49 years 1,800-6,660 U/L, and females > 50 years 2,550-6,800 U/L. (12) The dibucaine inhibition is obtained by a similar method with the addition of the inhibitor dibucaine to the sample. (11) Reference values for this test include normal range 70-90%, and congenital deficiency 18-20%.13 There are several potential pitfalls to be considered when comparing cholinesterase enzyme activity. The units of measurement may be different when the test is performed using different techniques and are not easily converted because of non-similar kinetics. (10) In addition, the reference ranges for the test are often extremely wide. (11) It is possible for someone to lose over half of their enzyme activity and still fall within the acceptable range. (11) Normal physiologic variation may account for changes in pseudocholinesterase activity of up to 20% when multiple samples are obtained. (11)
Our patient experienced prolonged paralysis after undergoing a rapid sequence induction utilizing succinylcholine for an emergent cesarean section. After approximately five hours, the patient spontaneously recovered motor strength and was extubated. Postoperative laboratory evaluation revealed an abnormally low pseudocholinesterase level (greater than the typical 20-30% reduction expected during pregnancy). Even at this reduced level, it was unlikely to have been the sole cause of the prolonged paralysis. It is possible that the patient had a pseudocholinesterase enzyme variant, such as the fluoride -resistant or K type, which is unlikely to be detected utilizing a standard dibucaine inhibition test. A reasonable explanation of this patient's prolonged paralysis is the combination of the decreased level of enzyme coupled with an atypical pseudocholinesterase variant.
(1.) Davis L, Britten JJ, Morgan M. Cholinesterase Its Significance in Anaesthetic Practice. Anaesthesia. 1997;52:244-260.
(2.) Barash PG. Clinical Anesthesia. 7th ed. Barash PG, editor. Philadelphia: Lippincott Williams & Wilkins;2013. 530-533.
(3.) Viby-Mogensen J. Correlation of succinylcholine duration of action with plasma cholinesterase activity in subjects with the genotypically normal enzyme. Anesthesiology. 1980;53:517-520.
(4.) Soliday, FK, Conley YP, Henker R. Pseudocholinesterase Deficiency: A Comprehensive Review of Genetic, Acquired, and Drug Influences. AANA J. 2010;78(4):313320.
(5.) Robertson GS. Serum Cholinesterase Deficiency II: Pregnancy. Brit J Anaesth. 1966;38:361-369.
(6.) Pantuck EJ. Plasma Cholinesterase: Gene and Variations. Anesthesia and Analgesia. 1993;77:380-386.
(7.) Shnider SM. Serum Cholinesterase Activity During Pregnancy, Labor and the Puerperium. Anesthesiology. 1965;26(3):335-339.
(8.) Whittaker M. Plasma cholinesterase variants and the anaesthetist. Anaesthesia. 1980;35:174-197.
(9.) Ravindran RS, Cummins DF, Pantazis KL, Strausburg BJ, Baenziger JC. Unusual Aspects of Low Levels of Pseudocholinesterase in a Pregnant Patient. Anesth Analg. 1982;61(11):953-955.
(10.) Trundle D, Marcial G. Detection of cholinesterase inhibition. The significance of cholinesterase measurements. Ann Clin Lab Sci. 1988; 18(5):345-352.
(11.) McQueen MJ. Clinical and analytical considerations in the utilization of cholinesterase measurements. Clin Chim Acta. 1995; 237(1-2):91-105.
Matthew Ellison, MD
Brian Grose, MD
Stephen Howell, MD
Colin Wilson, MD
Jackson Lenz, MD
Richard Driver, MD
Department of Anesthesiology, West Virginia University
Corresponding Author: Matthew Ellison, MD, WVUSOM, Dept. of Anesthesiology, 1 Medical Center Drive, Morgantown, WV 26506-9134. Email: firstname.lastname@example.org
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|Title Annotation:||Case Report|
|Author:||Ellison, Matthew; Grose, Brian; Howell, Stephen; Wilson, Colin; Lenz, Jackson; Driver, Richard|
|Publication:||West Virginia Medical Journal|
|Article Type:||Case study|
|Date:||Mar 1, 2016|
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