Refractory shock and asystole related to tramadol overdose

Abstract

Introduction. Tramadol use is largely considered safe. However, several lethal cases of tramadol intoxication were reported, suggesting an underestimated toxicity. We report for a tramadol overdose case in combination with other central nervous system depressants, leading to refractory shock requiring extracorporeal life support. Case report. A 33-year-old man was admitted in our intensive care unit for drug intoxication with coma, seizures, and hypotension without signs of heart failure. A few hours later, he developed a ventricular tachycardia, followed by a brief cardiac arrest in asystole with refractory shock requiring an extracorporeal life support, vasopressors, and hemofiltration. With this aggressive support, his overall status gradually improved. Repeated echocardiography showed an improvement in the cardiac function. The patient was weaned off extracorporeal life support on day eight and discharged on day 12. On admission, a urine analysis, using gas chromatography-mass spectrometry, showed high peaks of tramadol and desmethyltramadol with the presence of hydroxyzine, gabapentine, and clonazepam. The tramadol blood concentration measured by the high-performance liquid chromatography method-diode array detector was 23.9 mg/L, much higher than many previously reported fatal overdoses. No other drugs with potential cardiac toxicity, such as beta-blockers, calcium antagonists, antiarrythmic, antidepressants, meprobamate, or other xenobiotics were detected. Conclusion. This case illustrates that tramadol overdose may cause refractory shock and asystole when taken in combination with CNS depressants, and reminds all physicians to be vigilant with regard to the potential toxic effects of tramadol.

Keywords:

• Tramadol
• Asystole
• Extracorporeal life support

Introduction

Tramadol is a centrally acting analgesic commonly used in the treatment of moderate to severe pain. It has a low affinity to μ-opioid receptors and inhibits the reuptake of serotonin and norepinephrine neurotransmitters. Tramadol use is largely considered safe by physicians. The most common reported side effects are dizziness, nausea, constipation, and headache. However, tramadol toxicity may be underestimated. Some non-lethal cases of respiratory depression, seizures, and serotonin syndrome have been reported with tramadol (1–2). Several deaths have also been reported when tramadol was ingested alone in overdose (3–5), or when it was ingested with others drugs (6–8), particularly with central nervous system (CNS) depressants like benzodiazepine (9–11). We report a case of a tramadol overdose in combination with other CNS depressants, leading to refractory shock and asystole requiring extracorporeal life support (ECLS).

Case report

A 33-year-old man with a history of depression was found in his residence unconscious with seizures, hypotension, and hypoglycaemia (50 mg/dL). Several empty packages of tramadol, hydroxyzine, gabapentin, and clonazepam were found suggesting a maximal ingestion of 10 g, 6 g, 1 g, and 80 mg, respectively. He was intubated and mechanically ventilated. Thiopental, intravenous glucose, and fluid loading were administered and the patient was transferred to our intensive care unit.

On admission, the patient had a Glasgow Coma Scale score of 3 with seizures, mydriasis, and no pupillary reflexes. His blood pressure was 63/38 mmHg, pulse 85 beats/minute, and temperature 35.9°C. Cardiac and pulmonary auscultation detected no abnormalities. Chest x-ray showed opacities in the lower lobes of the lungs. An electrocardiogram (ECG) showed sinus rhythm with a complete right bundle-branch block and QTc of 480 msec. An electroencephalogram (EEG) showed continuous generalized epileptiform discharge. Cranial computer tomography was normal. An echocardiogram showed a good left ventricular ejection fraction, estimated at 56%. Initial blood tests results were serum glucose 162 mg/dL, arterial pH 7.4, PaO2/FiO2 ratio 350, HCO3- 18 mmol/L (normal 24–30), lactate 2.2 mmol/L (normal 0.5–1.6), creatinine 22 mg/dL (normal 5.8–11.6), urea 16 mg/dL (normal 15.3–34.6), aspartate aminotransferase 15 U/L (normal 5–35), alanine aminotransferase 13 U/L (normal 5–45), gamma glutamyl transferase 10 U/L (normal 5–55), total bilirubin 0.6 mg/dL (normal 0.054–0.92), albumin 27 g/L (normal 39–55), hemoglobin 10.3 g/dL, platelet count 171,000/mm³, leukocyte count 8,240/mm³, activated partial thromboplastin time 28 seconds (normal 25–39 seconds), cardiac troponin I 0.01 μg/L (normal <0.04), creatine kinase 332 U/L (normal 20–171), and myoglobin 1281 μg/L (normal 25–90).

Despite an aggressive therapy consisting of thiopenthal under EEG control, fluid loading, vasopressors, assisted ventilation, and tight glycemic control, the patient dramatically deteriorated. Twelve hours after admission, he developed sudden ventricular tachycardia necessitating defibrillation. This was followed a few minutes later by a brief period of asystole, with restoration of spontaneous circulation after 3 mg of epinephrine. No evident explanation for this sudden cardiac arrest was found; no ischemia on the successive ECG, no acute metabolic abnormalities, no hypoglycemia, no problem with ventilator, or medication error. A repeat echocardiogram showed a hypokinetic left ventricular with a 25% estimated ventricular ejection fraction. An ECLS device was implanted using a femoral approach with pre-heparinized percutaneous cannula (12). The pump speed was increased to approximately 2500 - 3000 rpm to obtain a flow of 2.5 L/m². Vasopressors were infused to maintain a mean systemic arterial pressure higher than 70 mmHg. Continuous venovenous hemofiltration was used to treat the acute renal failure and to regulate the intravascular volume and the overall fluid balance.

The patient's overall status gradually improved and over the following hours the vasopressor support and the ventilator settings could be appropriately adjusted. Repeated echocardiography showed an improvement in the cardiac function (Table 1). The patient was weaned off hemofiltration on day four, off vasopressors and ECLS on day eight, and off assisted ventilation on day 11. He was discharged with moderate cerebral disability on day 12.

Table 1. Clinical and laboratory results

	Hour O	Hour 4	Hour 12	Day 1	Day 3	Day 8	Day 12
APACHE II / SAPS II^$				36/74
LOD score^$$				13	6	5	3
Coma Glasgow Score	3	3	3	3	10	11	15
Mydriasis	Yes	Yes	Yes	Yes	No	No	No
Seizure	Yes	Yes	Yes	No	No	No	No
EEG: continuous generalized epileptiform discharge	Yes	Yes	No	No	No	–	Normal
PA mmHg	63/38	84/60	0/0	82/64	130/88	140/90	155/112
Heart rate	85	110	0	109	90	100	88
ECG	RBBB	–	Asystole	Sinusal	Sinusal	Sinusal	Sinusal
Vasopressors	No	Yes	Yes	Yes	Yes	No	No
Continuous venovenous hemofiltration	No	No	No	Yes	Yes	No	No
Extra corporeal life support (ECLS)	No	No	Yes	Yes	Yes	No	No
Left ventricular ejection fraction	–	56%	25%	–	25%	45%	50%
Chest x-ray	Lower lobes opacities	–	–	Bilateral alveolar intertitial syndrome	Bilateral alveolar intertitial syndrome	Basal opacities	Normal
FIO2	70%	100%	100%	60%	60%	45%	21%
ECLS FIO2				50%	21%
PaO2 (mmHg)	245	272	150	154	213	129	–
pH	7,40	7,43	7,37	7,23	7,48	7,37	–
HCO3- (mmol/l)	18	20	18	9.6	22	21	–
Lactate (mmol/l)	2,2	1,4	1.7	10.3	2,2	0,6	–
Na / K (mmol/l)	133/4,8	133/3,7	134/4,4	139/3,2	140/3,6	146/3,9	150/4
Creatinine (mg/dl)	22	19	35	25	27	32	18
Urea (mg/dl)	16	23	31	35	50	121	80
Myoglobin (μg/l)	1281	–	735	725	–	–	–
CK (U/l)	332	–	1684	1390	–	–	–
Troponin Ic (μg/l)	0,01	–	0,36	1,31	–	–	–

^$APACHE II, acute physiology and chronic health evaluation type II (13) and SAPS II, simplified acute physiology score II are severity scores (14) calculated within the first 24 hours of ICU admission are used to predict the risk of death.

^$$The logistic organ dysfunction system provides (15) a means to assess patients in the intensive care unit for severity of organ dysfunction. LOD score = (neurologic score) + (cardiovascular score) + (renal score) + (pulmonary score) + (hematologic score) + (hepatic score). Range 0 to 22.

On admission, the results of routine toxicological analysis of the blood using an immunoenzymatic method was negative for ethanol, benzodiazepine, acetaminophen (paracetamol), salicylic acid, barbiturates, and tricyclic antidepressants. Gas chromatography-mass spectrometry (GC-MS) analysis of the urine identified significant peaks of tramadol and desmethyltramadol - reported to have a higher affinity for the μ-opioid receptors than the parent drug - with small quantities of hydroxyzine, gabapentine and clonazepam. No other drug or xenobiotic was detected. Repeated measures of tramadol and desmethyltramadol blood concentrations were performed by the high-performance liquid chromatography method - diode array detector (HPLC-DAD). Tramadol and desmethyltramadol blood concentrations were performed on blood taken on admission and at 12, 31, 72, 88, and 110 hours later (Fig. 1). On admission, tramadol concentration was 23.9 mg/L (therapeutic range 0.1–0.8 mg/L) and persisted above therapeutic concentrations for three days. The peak desmethyltramadol concentration was at 12 hours after admission, at the time of cardiac arrest.

Fig. 1. Tramadol and desmethyltramadol blood concentrations.

Discussion

We report the first case of tramadol overdose in combination with CNS depressants leading to refractory shock and asystole managed with ECLS. In previously reported tramadol fatalities (3–11) in combination with other drugs, death occurred when tramadol blood concentrations ranged from 0.03 to 134 mg/L. In cases where authors ascribed the death to tramadol, blood concentrations ranged from 9.6 to 134 mg/L. The tramadol blood concentration of 23.9 mg/L was 30 times the upper limit of normal therapeutic range of 0.1 to 0.8 mg/L (16), 15 times the toxic level (1–2 mg/L) (10), and 10 times the 2 mg/L possible lethal concentration reported by the Internationnal Association of Forensic Toxicologists (17), much higher than the average post-mortem femoral blood tramadol concentration of 6.1 mg/l in five people whose deaths were attributed solely to tramadol overdoses (5).

Hydroxyzine, gabapentin, and clonazepam were also detected in urine by GC-MS in combination with tramadol. Unfortunately, no quantitative measurements were made because they were detected in small quantities. Although they probably contributed to the patient's CNS depression and hypotension, it is unlikely that these drugs were involved in the cardiac arrest because none of them is known to cause cardiac toxicity. No adverse cardiac events following massive ingestion of gabapentin and clonazepam (18) or hydroxyzine intoxication have been reported.

No drugs with potential cardiac toxicities (e.g., beta-blockers, calcium antagonists, antiarrythmic, antidepressants, meprobamate, or other xenobiotics) were detected in the patient's urine by GC-MS, suggesting that the shock and the asystole observed could be explained by tramadol ingestion alone or interactions between tramadol and other drugs. No adverse cardiac event has been reported concerning interaction between gabapentin, hydroxyzine, and tramadol. In previous reports focusing on tramadol fatalities, benzodiazepine intoxication was frequently associated suggesting potential pharmacokinetic interaction between tramadol and benzodiazepine (9–10). Although this interaction was not well documented, tramadol could interact with benzodiazepine by increasing the CNS depression with an additive or synergic effect (19). However, no cardiac toxicity has been reported with this association. A serotonin syndrome could be suspected in out patient. Tramadol is known to induce or to precipitate severe serotonin syndrome when taken alone or with serotoninergic antidepressant drugs via an inhibition of central reuptake of serotonin and norepinephrine neurotransmitters (20). Recently, a case of severe serotonin syndrome induced by tramadol and antidepressants, leading to refractory shock and death, was reported (11). Several of our patient's finding (coma, seizure, mydriasis, shock) are common to serotonin syndrome. However, these features are not specific and our patient did not have clinical signs that would support this diagnosis (such as tremor, hyper-reflexia, muscular rigidity, tachycardia, and hyperthermia). Whether or not direct cardiac toxicity can be caused by high doses tramadol is unclear. There are no published human reports but experimental studies have reported that high doses of tramadol (bolus injections of 5 to 10 mg/kg) significantly decreased cardiac contractility (21–22) or caused cardiac depression (23). Moreover, it was reported that the tissue distribution of tramadol was not different between the peripheral blood and heart, with a high sequestration of tramadol in heart tissue (4). Furthermore, the cardiac arrest occurred at the time of the highest desmethyltramadol concentration, the main active metabolite of tramadol.

Conclusion

This case illustrates the fact that tramadol overdose may cause a refractory shock and asystole when taken in combination with CNS depressants. The mechanisms of this failure are, at this time, unexplained. This case should remind all physicians to be vigilant with regard to the potential toxic effects of tramadol.