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*Department of Anesthesiology, University of Maryland, Baltimore; Department of Psychiatry and Division of Cardiology, University of Maryland Medical System, Baltimore; and Sheppard and Enoch Pratt Hospital, Towson, Maryland
Address correspondence and reprint requests to Catherine Marcucci, MD, Department of Anesthesiology, University of Maryland, 1210 Maple Leaf Ct., Cockeysville, MD 21030. Address e-mail to sandson.marcucci{at}comcast.net.
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Case Report |
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The preoperative electrocardiogram was unremarkable except for first-degree atrioventricular block (PR interval = 280 ms). Stress thallium testing and cardiac catheterization were negative for coronary artery disease. An echocardiogram demonstrated moderate left ventricular hypertrophy. A preoperative medical consultation recommended only increasing the dose of metoprolol.
An uneventful axillary brachial plexus block using 1.5% mepivacaine (45 mL)/1% tetracaine (5 mL) with epinephrine (3 µg/mL) was performed and surgery proceeded. There were no signs of intravascular injection. The patient was hemodynamically stable for a period of 10 min but slowly developed moderate hypotension (arterial blood pressure [BP], 85/55 mm Hg) and bradycardia (heart rate [HR], 60 bpm). He received ephedrine 50 mg and phenylephrine 400 µg in divided doses without an increase in BP or HR. At 70 min after the administration of the block, the patient had sudden asystole. He received atropine 3 mg and initial pacing by precordial thump, followed by transcutaneous cardiac pacing. An epinephrine infusion (4 µg/min) was started, which was increased incrementally to 16 µg/min during the next 30 min. Dopamine (15 µg · kg–1 · min–1) and norepinephrine (8 µg/min) infusions were also required to maintain the BP at approximately 80/40 mm Hg. A transvenous pacemaker was placed by the cardiology service before leaving the room. For several hours, the patient had no underlying cardiac rhythm; later that evening, he demonstrated third-degree heart block. The decision was made not to place a permanent pacemaker. Over the next 24 h, the patient slowly regained a stable cardiac rhythm, was weaned from all infusions, and was tracheally extubated. He was ultimately discharged in stable condition.
In the months that followed, we performed several tests to better understand the preceding events. After receiving appropriate consent, a cheek swab was obtained and an analysis of the patient's Cytochrome P450 genotype was performed (Signature Genetics, Montreal, Canada). The patient's genotypes for P450 enzymes 1A2 (*1A/*1F) and 2C9 (*1/*1) corresponded to standard levels of activity for those enzymes. The patient was also found to have a polymorphism of the gene that codes for the P450 2C19 enzyme (*1/*2) that is expressed as a phenotype of mildly to moderately diminished activity of that enzyme. Also, the analysis revealed a very unusual genotype for the P450 2D6 enzyme in which there were extra allelic copies of a polymorphism associated with mildly to moderately decreased activity (*41/*41xN). The phenotype that corresponds to the genotype for that enzyme has not been well elucidated. Trough tricyclic blood levels were also obtained. The nortriptyline level was 86 ng/mL (therapeutic range, 50–140 ng/mL), and the amitriptyline level was 415 ng/mL (therapeutic range, 70–110 ng/mL) for a total tricyclic level of 501 ng/mL (therapeutic range, 120–250 ng/mL).
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Moderate-to-potent inhibition of the 1A2 enzyme occurs with the administration of caffeine, grapefruit juice, and sertraline (3–5). This is significant because 1A2 is thought to be the enzyme primarily responsible for the metabolism of mepivacaine (6,7). Additionally, P450 1A2 is both the principal enzyme that metabolizes cyclobenzaprine and a contributor to the metabolism of amitriptyline (8–10). These structurally related compounds exert quinidine-like inhibitory effects on cardiac conduction, especially in the presence of other cardioselective drugs (11). Additive inhibition at the 1A2 enzyme would result in decreased metabolism of mepivacaine, possibly causing unexpectedly high blood levels or prolonged duration of mepivacaine. We suggest this may have accentuated the effect of the decreased metabolism and high blood levels of the other proarrhythmic drugs. Curiously, had the patient been a habitual smoker, he may have had a less pronounced alteration of his 1A2 enzymatic activity. Smoking is a potent inducer of 1A2 (12,13), which might have significantly mitigated the 1A2 inhibitory effects of caffeine, sertraline, and grapefruit juice on the metabolism of both cyclobenzaprine and mepivacaine.
DDIs at the 2D6 enzyme, whereas not as critical to this case as those at the 1A2 enzyme, impair the metabolism of metoprolol through both direct and indirect mechanisms (14). First, sertraline inhibited the metabolism of amitriptyline + nortriptyline at 2D6 and other P450 enzymes (15–17). Amitriptyline and nortriptyline also inhibited the 2D6 enzyme to decrease the metabolism of metoprolol (18). The long duration of the asystole is consistent with the extended half-life of metoprolol in the presence of impaired 2D6 functioning (19), in this case caused by the coadministration of 2D6 inhibitors.
The patient's P450 genotyping results also suggested that his enzyme phenotype for P450 2C19 contributed to his difficulties. His diminished level of activity at the 2C19 enzyme would yield a higher blood level of amitriptyline than expected for any given dose, further exacerbating the amitriptyline blood level increases described above and the DDIs that arose from this factor. Although the clinical expression of his gene variant for P450 2D6 has not been completely elucidated, it was believed that the offsetting factors of multiple copies of a less active allele yielded a normal level of P450 2D6 enzymatic activity. Given the dose of amitriptyline (100 mg of qHS) and the presence of multiple drugs that inhibited the metabolism of amitriptyline plus nortriptyline, his toxic total tricyclic level (501 ng/mL) was not surprising and it was consistent with a normal extensive metabolizer phenotype. Thus, the polymorphism for P450 2C19 was probably the only genotypic abnormality that meaningfully contributed to the patient's cardiac complications.
Although a definitive cause could not be determined, there is much circumstantial evidence for multiple-drug toxicities leading to sinoatrial node failure and asystole. This explanation is supported by many well described DDIs involving the patient's medications, the particular P450 genotype, and the temporal association with mepivacaine administration in the absence of other apparent precipitants of cardiac arrest.
To the review panel, it was striking that neither the preoperative medical consultation team, the anesthesia team, nor the surgical team recognized any of the potential DDIs. In fact, the recommendation by the medical consulting team for increased ß-blockade before surgery likely contributed toward destabilizing the patient. It is incumbent on anesthesia providers to educate themselves about the serious DDIs mediated by the P450 system and the additive effects that result from our anesthetic choices. Although mastering the P450 metabolic profiles and inhibitory and inductive capabilities of all drugs encountered in anesthetic practice is a daunting task, a straightforward and concise approach can be found in the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, and P-Glycoproteins, second edition (Cozza et al., American Psychiatric Publishing, Inc., 2003). Also, Dr. David Flockhart's comprehensive tables of P450 substrates, inhibitors, and inducers can be found at http://medicine.iupui.edu/flockhart/table.htm. This case provides an example of how a focused analysis of a patient's medications for possible DDIs may be accomplished on an enzyme-by-enzyme basis.
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Accepted for publication December 21, 2005.
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  G. Weinberg and T. VadeBoncouer Drug Interaction or Drug Overdose? Supercaine Revisited Anesth. Analg., August 1, 2007; 105(2): 544 - 545. [Full Text] [PDF]
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D. E. Feierman and S. K. Mahboobi Mepivacaine Overdosage Is More Likely a Cause of Intraoperative Cardiac Arrest than Drug-Drug Interaction Anesth. Analg., May 1, 2007; 104(5): 1294 - 1294. [Full Text] [PDF]
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