Mivacurium is a potent benzylisoquinoline, nondepolarizing neuromuscular blocking drug. A recommended intravenous dose of 0.15 to 0.2 mg/kg provides tracheal intubating conditions within 2 to 2.5 minutes, with a predicted duration of action of 15 to 25 minutes, making it an ideal drug for short procedures requiring tracheal intubation [8
]. İt is a structural relative of atracurium, but it does not undergo Hofmann elimination and is rapidly hydrolysed by PChE. Its duration of action is affected by the activity of this enzyme.
PChE is a tetrameric glycoprotein enzyme produced by the liver that hydrolyzes choline esters, such as those found in succinylcholine, mivacurium, procaine, chloroprocaine, tetracaine, cocaine and heroine [9
]. In patients with a normal genotype for PChE, mivacurium's duration of action is inversely related to PChE activity and duration of action is slightly prolonged if activity is low [10
]. Reduced PChE activity may occur as a result of inherited causes related to mutations at a single autosomal location on the long arm of chromosome 3 [11
When there is a deficiency of this enzyme due to the presence of one or more atypical alleles, the mivacurium is not properly metabolized and thus, muscle paralysis can last for several hours. There are two forms of inherited atypical pseudocholinesterase deficiency. The heterozygous atypical form affects anywhere from 1 in 25, to 1 in 480 individuals (depending on the severity of the condition) [9
]. Patients heterozygous for an abnormal enzyme may show up to 50% prolongation of block [12
]. The homozygous atypical form affecting approximately 1 in 3200 to 5000 individuals [9
]. In patients homozygous for an abnormal enzyme duration may be significantly prolonged, and even a small dose, (eg.0.03 mg/kg) can result in complete paralysis for up to 128 minutes [13
]. Patient 4 did not have an operation previously as well, he also did not have a negative medical family history and he did not accept our spinal anaesthesia offer. Block time was prolonged by 30-35 minutes which did not require a post-operative care unit. Enzyme level was found to be slightly low (961 UI/L). And the case was considered as heterozygote atypic enzyme defected.
PChE activity may be affected by different disease states and/or by drug administrations. Physiologic reductions may occur with extremes of age and during pregnancy [14
]. The low enzyme value (1017 IU/L) of Patient 1 which was measured during her cesarean section operation was found to be within the normal ranges in the laboratory assessment carried out during the control after two months (3124 IU/L) which proved us right in thinking that the PChE deficiency was due to pregnancy.
Other acquired causes of decreased activity include renal and liver disease, malignancy, burns, chronic debilitation/malnutrition, myocardial infarction/cardiac failure, collagen diseases, myxedema, and organophosphate poisoning [14
]. Patient 3 previously had three operations under general anaesthesia by using succinylcholine. Renal function was normal in this patient. Liver function tests exposed a reduced albumin level (2.1 g/dL = 21 g/L), consistent with the diagnosis of malnutrition that was evident from patient's general cachectic appearance (weighing only 43 kg), and history of reduced caloric intake and recent weight loss. However, presence of a prolonged apnea and low enzyme activity (598 IU/L) in this operation although the case had not had any problems during the previous operations led us to think that this was a malnutrition-associated PChE deficiency. Actually, plasma cholinesterase levels in human subjects with protein energy malnutrition has been investigated [15
]. PChE deficiency secondary to malnutrition has also been reported in patients with active Crohn's disease [16
], and anorexia nervosa [17
In addition, drugs which inhibit the enzyme's activity include acetylcholinesterase inhibitors (neostigmine, pyridostigmine, physostigmine, and edrophonium) anticholinesterases (especially echothlophate), cytotoxic agents (such as cyclophosphamide), steroids, ester-type local anaesthetics, hexafluorenium, pancuronium and oral contraceptives [18
Sertraline is a serotonin reuptake inhibitor (SSRI) that is indicated for the treatment of depression. With therapeutic doses, side effects are minimal. Sertraline has a wide therapeutic index and appears to be safer than the tricyclic antidepressants in overdose [19
]. On the other hand, the usual clinical antidepressants (fluoxetine, sertraline, and amitriptyline) are inhibitors of the cholinesterases on human serum and erythrocyte membrane. The order of inhibitory potency was sertraline> amitriptyline>>fluoxetine [20
]. Our Patient 2 patient had been using sertraline (100 mg/day) for 3 years due to depression. He previously had three operations under general anaesthesia by using succinylcholine. However, presence of a prolonged apnea and low enzyme activity (788 IU/L) in this operation, although the case had not had any problems during the previous operations led us to think that this was a sertaline-associated acquired PChE deficiency. Besides, the re-tested (3 months after the operation) PChE value (2762 IU/L) was seen to have turned back to normal after the patient gave up using sertraline under psychiatrist control. We did not discover a case that implies an interaction between sertraline and pseudocholinesterase in our literature review. We believe this is the first case presentation in that sense.
Mivacurium should probably not be used for any patient who gives a history of prolonged block after succinylcholine. Any patient who experiences prolonged block after mivacurium should be advised on the need to have their own and their immediate family's plasma cholinesterase status checked. It was detected from the blood-samples received from the first-degree relatives of Patient 4 that PChE activities of them were also lower than 900 IU/L, and however that incidentally none of them had operation histories.
The clinician should be aware that if they have administered neostigmine to a patient with prolonged mivacurium-induced block, then the patient's plasma cholinesterase activity will be inhibited. Therefore, blood should not be drawn for cholinesterase activity until the effect of neostigmine has dissipated. As for four of our cases, by the time PChE defect suspicions alongwith PNS findings arose, we send blood samples to laboratory for enzyme values. We supported the cases for degradation of mivacurium with present enzyme activities solely with sedation, mechanical ventilation and PNS monitorization and without neostigmine application.