CASE REPORT
Isolated Tramadol Overdose Associated with Brugada ECG Pattern JON B. COLE, M.D.,*,† SRINIVASAN SATTIRAJU, M.D.,‡ ELISABETH F. BILDEN, M.D.,* RICHARD W. ASINGER, M.D.,† and STEFAN C. BERTOG, M.D.§ From the *Hennepin Regional Poison Center, Minneapolis, Minnesota; †Hennepin County Medical Center, Minneapolis, Minnesota; ‡University of Minnesota, Minneapolis, Minnesota; and §Veterans Affairs Medical Center, Minneapolis, Minnesota
Tramadol is a commonly prescribed synthetic opioid analgesic. In humans, electrocardiogram (ECG) changes consistent with sodium-channel blockade have not been described in overdoses with tramadol. We report a case of isolated tramadol overdose associated with a Brugada ECG pattern. A review of the literature reveals no previous human cases of tramadol overdose causing ECG changes consistent with sodium-channel blockade. However, in vitro blockade of sodium-channels has been demonstrated with high concentrations of tramadol. Tramadol overdose should be recognized as a cause for the manifestation of a Brugada ECG pattern in the setting of suicidal intoxication. (PACE 2010; 1–3) brugada, tramadol, ECG pattern, sodium channel blockers Introduction Tramadol is a commonly prescribed opioid analgesic. It has weak µ-receptor agonist activity in the central nervous system (CNS) causing blockade of pain pathways. In addition, via serotonin and norepinephrine reuptake inhibition, it increases the pain threshold. Toxicity of tramadol can cause seizures along with the typical manifestations of opioid overdose. Electrocardiogram (ECG) changes in opioid overdose are well described with propoxyphene.1 These changes include QRS and QT interval widening and tachyarrhythmias resembling tricyclic antidepressant poisoning. However, a specific ECG pattern, the Brugada pattern, previously reported with tricyclic antidepressant overdose2 and attributed to sodium-channel blockade, has not been described with isolated tramadol overdose. This ECG pattern consists of a characteristic pseudoright bundle branch block (RBBB) morphology with J-point elevation and coved down-sloping ST segments in V1 and V2. In some clinical contexts it has been associated with ventricular dysrhythmias, including ventricular fibrillation. Several medications and conditions have been implicated in the manifestation of the Brugada ECG pattern.3 Here, we report a case of a Brugada
None of the authors has any disclosures relevant to this topic. Address for reprints: Stefan C. Bertog, M.D., 111 C Department of Cardiology, One Veterans Drive, Minneapolis, MN 55417. Fax: 612 727 5668; e-mail:
[email protected] Received June 1, 2010; revised July 21, 2010; accepted August 5, 2010. doi: 10.1111/j.1540-8159.2010.02924.x
type 1 ECG pattern with an isolated tramadol overdose. Case Report A 47-year-old man with a history of depression was found, by his roommate, unresponsive with an empty bottle of tramadol. The bottle previously contained 60 50-mg tablets. Four milligrams of IV naloxone were administered by the paramedics after which the patient regained consciousness and reported the intentional ingestion of all tablets contained in the bottle. Subsequently, due to the deterioration of his mental status along with hypoventilation, he was intubated. On hospital arrival, vital signs were: temperature 37.3◦ C, pulse 80/min, blood pressure 163/87 mmHg, respirations 18/min. The initial ECG in the emergency room showed sinus tachycardia, a pseudo-RBBB pattern with ST elevation in leads V1–V3 with a coved type downsloping ST segment appearance typical for the type 1 Brugada ECG pattern (Fig. 1). Cardiac biomarker Troponin I was elevated at 0.13 ng/mL (normal range 0.00–0.09) on arrival to the hospital. Given the ST segment elevation and positive Troponin I, an emergent coronary angiogram was performed to exclude a thrombotic coronary occlusion. The angiogram revealed only mild coronary artery disease without significant lesions. The patient remained hemodynamically stable throughout his hospital stay, and an echocardiogram revealed no wall motion abnormality or structural heart disease. Digoxin, phenytoin, and ethanol levels were negative. Serum sodium and potassium concentrations were 142 mEq/L and 4.5 mEq/L, respectively. A comprehensive urine drug screen,
" C 2010, The Authors. No claim to original US government works
PACE
2010
1
COLE, ET AL.
Figure 1. ECG on admission showing characteristic changes of Brugada type 1 ECG pattern.
including high-performance liquid chromatography, was negative except for tramadol and its metabolite. Specifically, cocaine, propoxyphene, antidysrhythmics, or tricyclic antidepressants were not present. The serum tramadol level was markedly elevated at 8,663 ng/mL (therapeutic values 100–1,500), as well as the level of its metabolite, mono-O-desmethyl tramadol (M1), at 1,485 ng/mL (maximum therapeutic level 200). Serial ECGs showed gradual resolution of the acute findings with a decrease in J-point elevation in V1 and V2 with resolution of coving of the ST segments (Fig. 2). There was persistent J-point elevation with terminal notching of the QRS in V3 and V4, consistent with early repolarization. The patient was discharged in good condition on hospital day 3. No arrhythmias were noted during
his hospitalization. An electrophysiology study to uncover Brugada ECG pattern was discussed with the patient, but he did not wish to pursue further evaluation. Discussion We report a case of a Brugada type 1 ECG pattern caused by an isolated tramadol overdose. ECG findings in the Brugada syndrome are frequently linked to a decrease in inward sodium current due to dysfunctional sodium channels.4 Many sodium-channel blocking agents are known to either unmask or induce this ECG pattern.3 The ECG pattern on admission in our patient was discovered in the context of an intentional overdose of tramadol. In vitro blockade of sodium-channels by tramadol has been
Figure 2. ECG taken subsequently, prior to discharge, showing resolution of specific findings noted in V1and V2 that are characteristic of Brugada ECG pattern.
2
2010
PACE
TRAMADOL OVERDOSE AND BRUGADA ECG PATTERN
demonstrated at high concentrations.5 Additional evidence supporting tramadol causing sodiumchannel blockade includes compound action potential reduction in amphibian sciatic nerves exposed to tramadol6 and the use of tramadol in humans for local anesthesia.7 Sodium-channel blockade is an established method to uncover the Brugada pattern.8 Multiple other conditions are associated with a Brugada ECG pattern. These include fever,9 hyperkalemia,10 hyponatremia,11,12 cocaine toxicity,13 and overdose with phenytoin14 or tricyclic antidepressants.2 Our patient had none of these conditions, which could potentially influence the ECG findings noted. Though usual doses of tramadol have not been implicated in development of Brugada ECG pattern, the very high serum level of tramadol in our patient likely resulted in sodiumchannel blockade and the manifestation of the Brugada ECG pattern. The ECG findings noted in V1 and V2, which are characteristic of Brugada ECG pattern, resolved with time, presumably as the serum tramadol concentration decreased.
To our knowledge, this is the first case report associating tramadol toxicity with the Brugada ECG pattern. Other conditions capable of causing ST elevation in the right precordial leads include variants of normal, left-ventricular hypertrophy, leftbundle branch block, acute anteroseptal infarction or ventricular aneurysm, myocarditis, pericarditis, pulmonary embolism, and right ventricular infarction.15 The typical Brugada ECG pattern, however, has a characteristic appearance only infrequently confused with the above conditions. It is unclear if patients with Brugada ECG pattern associated with various conditions outlined above increases the risk of ventricular arrhythmias. Conclusion Tramadol overdose should be included in the growing list of conditions and drugs associated with the Brugada ECG pattern. This case is of particular clinical relevance given that tramadol is a frequent cause of drug poisoning.16
References 1. Stork CM, Redd JT, Fine K, Hoffman RS. Propoxyphene-induced wide QRS complex dysrhythmia responsive to sodium bicarbonate– a case report. J Toxicol Clin Toxicol 1995; 33:179–183. 2. Akhtar M, Goldschlager NF. Brugada electrocardiographic pattern due to tricyclic antidepressant overdose. J Electrocardiol 2006; 39:336–339. 3. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, et al. Brugada syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005; 111:659–670. 4. Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. The Brugada syndrome: Clinical, electrophysiologic and genetic aspects. J Am Coll Cardiol 1999; 33:5–15. 5. Haeseler G, Foadi N, Ahrens J, Dengler R, Hecker H, Leuwer M. Tramadol, fentanyl and sufentanil but not morphine block voltageoperated sodium channels. Pain 2006; 126:234–244. 6. Katsuki R, Fujita T, Koga A, Liu T, Nakatsuka T, Nakashima M, Kumamoto E. Tramadol, but not its major metabolite (mono-Odesmethyl tramadol) depresses compound action potentials in frog sciatic nerves. Br J Pharmacol 2006; 149:319–327. 7. Altunkaya H, Ozer Y, Kargi E, Ozkocak I, Hosnuter M, Demirel CB, Babuccu O. The postoperative analgesic effect of Tramadol when used as subcutaneous local anesthetic. Anesth Analg 2004; 99:1461–1464. 8. Hudson CJ, Whitner TE, Rinaldi MJ, Littman L. Brugada electro-
PACE
9. 10. 11.
12. 13. 14.
15. 16.
2010
cardiographic pattern elicited by inadvertent flecainide overdose. Pacing Clin Electrophysiol 2004; 27:1311–1313. Ott P, Freund NS. Brugada-pattern ekg in a febrile patient. J Emerg Med 2007; 33:281–282. Kovacic JC, Kuchar DL. Brugada pattern electrocardiographic changes associated with profound electrolyte disturbance. Pacing Clin Electrophysiol 2004; 27:1020–1023. Mok NS, Tong CK, Yuen HC. Concomitant-acquired Long QT and Brugada syndromes associated with indapamide-induced hypokalemia and hyponatremia. Pacing Clin Electrophysiol 2008; 31:772–775. Tamene A, Sattiraju S, Wang K, Benditt DG. Brugada-like electrocardiography pattern induced by severe hyponatraemia. Europace 2010; 12:905–907. Bebarta VS, Summers S. Brugada. Electrocardiographic pattern induced by cocaine toxicity. Ann Emerg Med 2007; 49:827–829. Al Aloul B, Adabag AS, Houghland MA, Tholakanahalli V. Brugada pattern electrocardiogram associated with supratherapeutic phenytoin levels and the risk of sudden death. Pacing Clin Electrophysiol 2007; 30:713–715. Wang K, Asinger RW, Marriott JHL. ST Segment elevation in conditions other than acute myocardial infarction. N Engl J Med 2003; 349:2128–2135. Shadnia S, Soltaninejad K, Heydari K, Sasanian G, Abdollahi M. Tramadol intoxication: A review of 114 cases. Hum Ex Toxicol 2008; 27:201–205.
3
