Continuing Education Activity

Pseudocholinesterase deficiency, also known as butyrylcholinesterase deficiency, refers to a rare acquired or inherited defect in the pseudocholinesterase enzyme produced by the liver. This activity reviews the evaluation and management of pseudocholinesterase deficiency, and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the risk factors for pseudocholinesterase deficiency.
• Describe the pathophysiology of pseudocholinesterase deficiency.
• Review the management of pseudocholinesterase deficiency.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with pseudocholinesterase deficiency.

Introduction

Pseudocholinesterase deficiency, also known as butyrylcholinesterase deficiency, refers to a rare acquired or inherited defect in the pseudocholinesterase enzyme produced by the liver.[1] In clinical anesthesia practice, the muscle relaxants succinylcholine and mivacurium are drugs used to optimize intubating conditions and surgical exposure.[2] The drugs succinylcholine and mivacurium are both metabolized by the pseudocholinesterase enzyme.[3]  Patients with defective forms of pseudocholinesterase will have a reduced ability to metabolize these two muscle relaxants and will present with prolonged muscular paralysis from standard doses of succinylcholine and mivacurium.[3]

Etiology

Pseudocholinesterase deficiency can be acquired and/or be inherited.[4][[1]

The inherited form of the enzyme transfers in an autosomal recessive manner secondary to mutations in the butyrylcholinesterase gene, located on chromosome 3, 3q26.1-26.20.[5]  Patients may therefore present as heterozygotes with only one gene coding for the abnormal enzyme or as a homozygote with both genes coding for the defective pseudocholinesterase enzyme.  Heterozygotes will present with an approximate 30 percent increase in the duration of the neuromuscular blockade after standard succinylcholine dosing.[6] Homozygotes, however, can present with neuromuscular blockade for a clinically significant greater duration (2 to 3 hrs).[6]  

Acquired pseudocholinesterase deficiency can also occur in several disease states or with the use of certain drugs.  Malnutrition, pregnancy and the postpartum period, burns, liver disease, kidney disease, hemodialysis, MI, CHF, malignancy, chronic infections and drugs such as steroids and cytotoxic agents can decrease the production of the pseudocholinesterase enzyme.  Certain other medications and chemicals, such as organophosphate insecticides, MAO inhibitors, and anticholinesterase drugs can inhibit the activity of the enzyme.[5][7]

Epidemiology

The incidence of patients that present as homozygotes for abnormal pseudocholinesterase enzyme is approximately 1 per 2000 to 5000 people.[4][8]  The incidence of heterozygotes for the abnormal enzyme is approximately 1 per 500[9]. Male to female incidence for atypical pseudocholinesterase enzyme occurs in 2 to 1 ratio. Populations with the highest prevalence of pseudocholinesterase deficiency include Caucasian males of European descent, Persian people of the Jewish community, and a subset of Alaska Natives.[10]

Pathophysiology

Pseudocholinesterase is a plasma enzyme produced in the liver that is responsible for the metabolism of the common anesthesia drugs, succinylcholine, and mivacurium, as well as ester local anesthetics, including cocaine. Individuals with a normally functioning version of the enzyme can rapidly and extensively metabolize succinylcholine and mivacurium, leading to their short duration of action (less than 10 minutes for succinylcholine).[6][11]  With an inherited deficiency, the defective form of the enzyme is unable to metabolize succinylcholine and mivacurium to the same degree, leading to prolonged neuromuscular paralysis for those who inherited atypical pseudocholinesterase enzyme.[3]  Duration of neuromuscular blockade is dependant upon whether the patient is homozygous or heterozygous for the defective enzyme.[6] Heterozygotes will experience a muscular blockade of moderate duration, while homozygotes can have muscular paralysis longer than 2 hours.[6]

With an acquired deficiency, there is a decreased ability to degrade the substrate drugs solely due to decreased concentration of the enzyme in the serum.

History and Physical

Pseudocholinesterase deficiency is often only diagnosed after the patient experiences prolonged neuromuscular blockade following standard doses of succinylcholine or mivacurium.[1].  A focused history should include questions regarding previous anesthetics requiring extended mechanical ventilation due to neuromuscular blockade.[11] It is also important to inquire about any family history of relatives diagnosed with pseudocholinesterase deficiency.[5]

Patients with a history of specific disease states, including malignancy, extensive burn injuries, myocardial infarction, CHF, pregnancy, liver disease, hemodialysis, and chronic infections may present with the acquired form of pseudocholinesterase deficiency.[9][12]  These disease states can result in significantly reduced concentrations of the pseudocholinesterase enzyme, therefore predisposing the patient to prolonged neuromuscular blockade following standard doses of succinylcholine or mivacurium. As noted previously, certain medications can interfere with and decrease the activity of pseudocholinesterase, which can be additive to other acquired and/or inherited enzyme deficiencies.

There are no specific physical exam findings attributed to pseudocholinesterase deficiency. Patients will either present with normal physical exam (inherited form) or physical exam findings consistent with their disease state (acquired form).

Evaluation

Laboratory analysis for pseudocholinesterase deficiency can be performed by taking a sample of the patient’s plasma and performing a qualitative test of pseudocholinesterase enzyme activity.[13][14] Dibucaine is an amino amide local anesthetic that will inhibit the activity of the normal variant of the pseudocholinesterase enzyme by 80%.[14]  The activity of the atypical variants of the pseudocholinesterase enzyme is, however, reduced to a much smaller degree when exposed to dibucaine. Enzymatic inhibition for heterozygotes is between 50 to 60% and 20 to 30% for those that are homozygous.[13][14] The degree of enzymatic inhibition resulting from dibucaine exposure is the dibucaine number.

Quantitative testing is done to determine the actual amount of pseudocholinesterase present in the sample and is performed using colorimetry.

Treatment / Management

Individuals with pseudocholinesterase deficiency are often only diagnosed after experiencing prolonged neuromuscular paralysis following standard doses of succinylcholine and mivacurium.[3] The mainstay of treatment involves respiratory support with mechanical ventilation until the spontaneous resolution of neuromuscular blockade.[11]  Repeated evaluation for the return of motor function can be assessed through the use of nerve stimulation.[6][8] Patients should also remain sedated during this period to reduce the risk of awareness while awaiting the return of motor function.[6][8] Conservative, supportive treatment with sedation and mechanical ventilation until recovery, which is usually only several hours, is felt to involve less risk than reversal with transfusion of plasma or use of other medications, which have not been reliable previously, to try to reverse the block.

Management for those previously diagnosed with pseudocholinesterase deficiency includes the avoidance of depolarizing the neuromuscular blocker succinylcholine and the non-depolarizing muscular blocker mivacurium.  Other nondepolarizing neuromuscular blockers such as atracurium, rocuronium, and vecuronium safe for use in future anesthetics.[5]

Differential Diagnosis

The differential diagnosis for pseudocholinesterase deficiency include, but not limited to:

• Narcotic overdose
• Residual neuromuscular blockade
• Cholinergic crisis
• Myasthenia gravis
• Myasthenic syndrome
• Hypermagnesemia
• Hypophosphatemia
• Hypokalemia

Prognosis

Pseudocholinesterase deficiency is a clinical condition that is often only discovered after exposure to succinylcholine or mivacurium.[3]  Patients may be unaware that they have pseudocholinesterase deficiency if they have never had exposure to these two agents. Patients diagnosed with pseudocholinesterase deficiency after exposure to succinylcholine or mivacurium are expected to make a full recovery, following the spontaneous return of motor function.[11] Mechanical ventilation and close clinical monitoring will be required during the time to prevent hypoxic respiratory failure.

Complications

The primary complication of pseudocholinesterase deficiency is respiratory failure following the prolonged neuromuscular paralysis after administration of succinylcholine or mivacurium.  Careful monitoring with mechanical respiratory ventilation is necessary until the spontaneous return of muscle function. Individuals with pseudocholinesterase deficiency may also be at risk for sudden cardiac death from cocaine use.[14]

Deterrence and Patient Education

Individuals diagnosed with pseudocholinesterase deficiency should inform their doctor and anesthesia provider of their condition before any surgery. The patient's medical record should be updated to reflect the diagnosis of pseudocholinesterase deficiency. Future anesthetics should avoid administration of succinylcholine and mivacurium to avoid prolonged neuromuscular blockade and possibly respiratory failure.  Family members of patients with pseudocholinesterase deficiency are encouraged to undergo laboratory testing due to a strong genetic component associated with inheriting an abnormal variant of the pseudocholinesterase gene.

Enhancing Healthcare Team Outcomes

Pseudocholinesterase deficiency is an infrequently encountered genetic or acquired condition; discovery is typically only after exposure to succinylcholine or mivacurium.  Anesthesiologist, anesthesia nurses, intensivists and emergency department physicians involved in the care of patients with pseudocholinesterase deficiency should be aware of the following key points: 

• The prolonged neuromuscular blockade should receive treatment with mechanical respiratory support until the spontaneous return of muscle function.
• Patients may be unaware they have pseudocholinesterase deficiency if there is no prior exposure to succinylcholine or mivacurium.
• Future anesthetics should avoid administration of succinylcholine or mivacurium to avoid prolonged neuromuscular blockade.
• Family members of individuals diagnosed with pseudocholinesterase deficiency are encouraged to undergo testing for pseudocholinesterase deficiency.
• Patients with pseudocholinesterase deficiency may experience sudden cardiac arrest after cocaine use.
• Patients with a history of malignancy, extensive burn injuries, pregnancy, liver disease, and chronic infections are at increased risk for pseudocholinesterase deficiency.

 While a rare condition, pseudocholinesterase deficiency is best addressed via an interprofessional healthcare team approach, with physicians, specialists, specialty trained nursing staff, and pharmacists, working and communicating to achieve the best possible patient outcomes. [Level V]