Hereditary pseudocholinesterase deficiency discovery after electroconvulsive therapy

Abstract

Inherited pseudocholinesterase deficiency refers to an uncommon defect in the butyrylcholinesterase enzyme which can result in prolonged muscle paralysis due to delayed breakdown of choline ester paralytic anaesthetic agents. We describe a 25-year-old woman receiving electroconvulsive therapy (ECT) for treatment of depression in whom motor function did not recover adequately after administration of succinylcholine. Investigated post-ECT, she was found to have severe pseudocholinesterase deficiency. Implications of pseudocholinesterase deficiency for ECT treatment and anaesthetic strategies are discussed.

Background

Pseudocholinesterase is a plasma enzyme produced in the liver that is responsible for the hydrolysis of choline esters, such as succinylcholine, mivacurium, procaine, chloroprocaine, tetracaine and cocaine.^1–3 Individuals with normal pseudocholinesterase enzyme activity can metabolise the muscle relaxants succinylcholine and mivacurium rapidly, leading to their short duration of action. Pseudocholinesterase deficiency leads to delayed breakdown of choline esters resulting in prolonged muscle paralysis and delayed recovery after administration of paralytic anaesthetic agents such as succinylcholine.³

The aim of this report was to describe an unusual presentation of pseudocholinesterase deficiency and to review the clinical considerations pertaining to the specific situation, in which it was encountered. Written informed consent was obtained for publication of this case report as well as written authorisation for use of Health Insurance Portability and Accountability Act protected information. Per our Institutional Review Board’s policies, case reports or case series with less than five patients are not considered research.

Case presentation

A 25-year-old woman reported to our short procedures unit for electroconvulsive therapy (ECT) regarding a severely symptomatic and suicidal episode of treatment resistant major depressive disorder, without psychotic features. Her depression had made her discontinue college, remain house bound and resulted in two hospitalisations due to suicidality in the 6 months prior to being scheduled for ECT. Her medical history was significant for intractable epilepsy despite being adherent to a combination of multiple anticonvulsants and a vagal nerve stimulator implanted for treatment of epilepsy. In addition, she had obesity (weight of 95 kg, height of 1.55 m, body mass index 36.07 kg/m²). Her pre-ECT Hamilton Depression Rating Scale (HAM-D₁₇) score was 33, indicating that her depression was in the very severe range despite taking multiple psychotropic medications (levetiracetam, lacosamide, eslicarbazepine, fluoxetine, buspirone and aripiprazole) for at least 2 years in adequate dosage.

Before the ECT procedure, the patient did not report complications, either personal or family, associated with anaesthesia in the past. The anesthesiology evaluation was relevant for reported snoring and a Mallampati IV airway. She was seen by neurology for interrogation of the vagal nerve stimulator, which was found to be operating correctly, and the device was turned off prior to the ECT.

A left ankle cuff was applied to allow for motor seizure monitoring. Anaesthesia was induced with 12 mg of etomidate after which 100 mg of succinylcholine was administered for muscle relaxation. Controlled mask ventilation was established, and the first ECT stimulation was administered (bi-temporally) using 18 J of energy which resulted in only 3 s of focal motor seizures in the foot that lasted only 8 s in her electroencephalogram (EEG) traces, indicating a subtherapeutic event. A second stimulation was administered (bitemporally) using 22 J (pulse width 0.37 ms, frequency 65 Hz, stimulation time 3.25 s) which resulted in therapeutic generalised seizures that lasted for 15 s motorically and 25 s as recorded in her EEG.

Six minutes after induction, the patient was not breathing spontaneously. At this point, we became concerned that the neuromuscular blockade was prolonged as a result of a potential pseudocholinesterase deficiency.

Treatment

To protect the airway, intubation of the trachea was then achieved with video assisted laryngoscopy, and 5 mg midazolam sedation was given. The patient was transferred to the postanaesthesia care unit for observation and ventilatory support using assist-controlled ventilation. Three hours after the ECT, she first demonstrated spontaneous breathing. Considering she was known to have a difficult airway, the critical care team decided to maintain her intubated in the intensive care unit overnight with light sedation to avoid extubation failure at all cost. She was successfully extubated the next morning. Discussion with the patient revealed no recollection of the event the prior day.

Investigations

On further conversation with the patient’s parents, they disclosed that the patient’s sister experienced a similar event requiring prolonged intubation and mechanical ventilation after an otorhinolaryngology procedure. The patient and her family were offered testing for pseudocholinesterase deficiency, which revealed very low serum cholinesterase concentrations in the patient (541 IU/L) and her father (598 IU/L), considering the reference range of 3334–7031 IU/L.

Differential diagnosis

Certain drugs cause quantitative decreases in pseudocholinesterase and their use should be considered in the differential diagnosis of prolonged block from succinylcholine.⁴ Those include: echothiophate (can be used in the treatment of glaucoma), neostigmine or pyridostigmine, hexafluorenium (a non-depolarising muscle relaxant), phenelzine, trimethaphan and the antineoplastic agents cyclophosphamide and mechlorethamine. Some drugs can potentiate depolarising neuromuscular blockade; these include certain antibiotics (polymyxin, tetracycline, clindamycin, bacitracin, streptomycins), antidysrhythmics (quinidine, procainamide, calcium-channel blockers, lidocaine), cholinesterase inhibitors, furosemide, local anaesthetics, magnesium sulfate, inhalational anaesthetics and lithium. Finally, myasthenic syndrome or autoimmune disorders such as systemic lupus erythematosus, polymyositis and dermatomyositis can lead to hypersensitivity to depolarizing neuromuscular blockade.

If a non-depolarising muscle relaxant has been used, the following should be ruled out as causes of prolonged block:

• Administration of wrong drug and dosage.

• Insufficient time or dosage of reversal agent (if a non-depolarising muscle relaxant has been used).

• Inappropriately intense neuromuscular blockade such that reversal is not possible.

• Presence of potentiating agents, for example, magnesium or high-dose corticosteroid therapy.

• Abnormal renal and hepatic function.

• Hypothermia and acidosis (especially with agents that are metabolised via Hoffman elimination such as atracurium or cisatracurium).

• Electrolyte disorders.

• Malfunctioning train-of-four (TOF) monitor or inappropriately applied TOF monitor electrodes.

• Chronic debilitated state or critical illness.

• Pregnancy or the postpartum state.

TOF monitoring should be used with recovery documented prior to extubation.⁵

Follow-up

We offered the patient continued treatment with ECT by using the muscle relaxant rocuronium and sugammadex reversal to achieve short-lasting muscle relaxation that would not be affected by her pseudocholinesterase deficiency. In addition to antidepressant and antisuicidal effects, ECT in repeated administrations has antiepileptic effects since it increases the seizure threshold in the brain.⁶ The patient’s severe depressive symptoms with comorbid refractory epilepsy made ECT a particularly well-suited treatment. Unfortunately, the patient was not able to continue with ECT treatments at our facility because of her relocation to a neighbouring state, which precluded her ongoing participation in our outpatient ECT and medication management programme. In her new care team, she is currently maintained on pharmacotherapy for her depression, but not undergoing ECT because her medical insurance did not cover the procedural costs completely and the modified anaesthesia regimen was projected to lead to a significant increase in her out-of-pocket cost that she could not afford.

Discussion

Pseudocholinesterase deficiency is often diagnosed during surgical procedures when a patient has an unexpected prolonged response to succinylcholine. The aim of this report was to describe an unusual presentation of pseudocholinesterase deficiency in the context of ECT and to discuss clinical implications.

Pseudocholinesterase deficiency can be inherited or acquired. The inherited form of the deficiency transfers in an autosomal recessive manner. Affected patients inherit from each parent the atypical alleles of the butyrylcholinesterase (BChE) gene located on chromosome 3. Approximately, 1 in 4000 individuals are homozygous; the condition is less common in African Americans or Asians compared with Caucasians.^{2 7 8} Heterozygous patients (~4% of the population⁷) may have modestly prolonged paralytic responses to choline esters, especially when there is additional acquired deficiency of the pseudocholinesterase enzyme.¹

As discussed in the ‘Differential Diagnosis’ section, acquired pseudocholinesterase deficiency can occur in several disease states or with the use of certain drugs. Malnutrition, pregnancy, the postpartum period, burns, liver disease, kidney disease, haemodialysis, myocardial infarction, congestive heart failure, malignant diseases, chronic infections and drugs such as steroids and cytotoxic agents can decrease the production of the pseudocholinesterase enzyme.³ Other medications and chemicals, such as organophosphate insecticides, monoamine oxidase inhibitors inhibitors, and anticholinesterase drugs can inhibit the activity of the enzyme.³ There were no such risk factors present in the current case that could have contributed to additional acquired pseudocholinesterase deficiency.

The classical method to detect pseudocholinesterase deficiency is by determining the dibucaine number. This number is determined by applying the local anaesthetic dibucaine to serum and measuring the reduction in pseudocholinesterase hydrolysis of the choline ester benzylcholine.² However, in some cases patients have a normal dibucaine number and yet have decreased pseudocholinesterase activity.³ Quantitative testing using colorimetry can be performed to determine the actual amount of pseudocholinesterase present in the sample, as was done in the present case. The absolute pseudocholinesterase concentrations in the patient and her father are consistent with homozygous atypical alleles of the BChE gene.⁹ The patient’s mother did not undergo laboratory testing, but considering that her daughter had laboratory values consistent with homozygous atypical alleles, she at least has to be a heterozygous carrier of an atypical allele. The patient and her father’s pseudocholinesterase deficiency were documented in our electronic medical record as an ‘allergy’. We advised them to obtain and wear wrist bands to make caregivers aware of their status in case they would receive anaesthesia in an emergency situation.

On literature review, we encountered some previous cases of pseudocholinesterase deficiency presenting in the context of ECT.^9–17 Yildizhan et al¹⁷ reported that in their psychiatric hospital serum cholinesterase levels are obtained in all patients scheduled for ECT to modify the anaesthesia strategy when necessary. They argued that although genetic pseudocholinesterase deficiency is uncommon, it is helpful to screen because acquired deficiency may be more common in the population undergoing ECT because these patients tend to have multiple risk factors such as malnutrition, polypharmacy with or without associated hepatic and/or renal impairments, and cardiovascular events as well.¹⁷ Acquired deficiency combined with a heterozygous atypical BChE gene may result in substantial deficiency. Others have argued that preprocedural laboratory testing cannot be justified, considering clinically relevant deficiency is rare, the testing itself is costly, and because prolonged paralysis can be managed well with continued anaesthesia and mechanical ventilation.^{9 15} In our opinion, preprocedural serum testing is only indicated in patients with a (family) history of prolonged emergence from anaesthesia. In patients with known pseudocholinesterase deficiency rocuronium with sugammadex reversal can be used to achieve short-term muscle relaxation for ECT.¹¹ As illustrated by this case, using rocuronium and sugammadex for all ECT patients prophylactically is challenging from a monetary standpoint, because sugammadex currently costs around US$200 per single dose vial in the USA.¹⁸ Many institutions have implemented guidelines to only use sugammadex in selected cases.¹⁹

It is important to recognise and treat prolonged paralysis to avoid awake paralysis. Obtaining an anaesthesia history, including a family history, may alert clinicians to the possibility of pseudocholinesterase deficiency before the procedure.

Learning points.

• A thorough family history can alert anesthesiology and psychiatry providers involved in electroconvulsive therapy (ECT) to the possibility of pseudocholinesterase deficiency.

• Timely recognition of prolonged paralysis after succinylcholine should prompt supportive ventilation and the prevention of awake paralysis.

• Potential continuation of ECT can be facilitated using rocuronium with sugammadex reversal instead of succinylcholine.