ST segment elevation secondary to paracetamol overdose

Paracetamol is the most common drug employed in self-poisoning in the UK, with 25,000 admissions from paracetamol poisoning recorded in 2001 alone [Morgan et al. 2005]. The toxic effects of paracetamol on the hepatic and renal systems are well documented, but it is less publicized that paracetamol and its metabolites can have toxic effects on other organ systems including the myocardium [Jones and Prescott, 1997]. We present a case of paracetamol poisoning causing toxic myocardial damage.

Case report

A 68-year-old woman self-presented 12 h after taking a 25-g paracetamol overdose. She had no past medical history of note and was not currently taking any medications. Clinically she was asymptomatic but was noted to be mildly hypotensive. Serum paracetamol level at presentation was 23 mg/l (reference range: 10–20 mg/l at 4 h post-ingestion), but other blood results including arterial blood gases were unremarkable.

A routine electrocardiogram (ECG), performed to look for evidence of concomitant tricyclic antidepressant ingestion, showed widespread ST-elevation (Figure 1a). Her symptoms were not suggestive of myocardial infarction or pericarditis but the ST changes were new when compared with an ECG from 6 months previously (Figure 1b). An urgent echocardiogram was obtained showing global hypokinesia consistent with a moderate degree of systolic left ventricular impairment.

Figure 1.

Patient ECGs. (a) ECG on admission showing widespread ST-elevation. (b) ECG 6 months prior to admission. (c) ECG day 6 of admission showing widespread deep T-wave inversion suggestive of subendocardial injury. ECG, electrocardiogram.

Information from the regional drugs and therapeutics team suggested there had been rare reports of ST change secondary to paracetamol overdose. After discussion, the patient was commenced on N-acetylcysteine and transferred to the coronary care unit for expectant management. She remained clinically well and the N-acetylcysteine infusion was continued for 24 h. Liver function, clotting and renal function tests remained normal but a troponin T assay was elevated at 0.241 µg/l (reference range: <0.01 µg/l) and creatine kinase peaked at 503 U/l (reference range: 26–192 U/l) on day 2 of her admission, consistent with myocardial necrosis. The ST segment elevation resolved spontaneously within 36 h without the appearance of Q waves, but her ECG continued to evolve over the next several days with deep T-wave inversion consistent with subendocardial injury (Figure 1c). Repeat echocardiography demonstrated improvement of ventricular function essentially to normal by day 4 of admission.

On day 6, the patient underwent coronary angiography. The coronary tree was widely patent with minor irregularities only in the proximal left anterior descending and right coronary arteries (Figure 2). Left ventricular angiography confirmed minor antero-apical hypokinesia with an overall well-preserved ejection fraction. Following psychiatric review, the patient, who remained clinically well throughout, was discharged home the following day on an angiotensin-converting enzyme inhibitor, with follow up planned in the clinic.

Figure 2.

Right and left coronary artery angiograms demonstrating minor irregularities only in a widely patent coronary tree.

Discussion

Dysrhythmias and abnormalities of the ST-segment or T-wave frequently occur in paracetamol poisoning in comatose encephalopathic patients, with the cause of the ECG changes at least partly related to the severe metabolic changes [Armour and Slater, 1993; Weston et al. 1976]. However, ST–T-wave changes in nonencephalopathic patients have been documented, and our case report describes a patient who had ST-segment changes without any evidence of hepatotoxicity, metabolic derangement or encephalopathy.

This presentation however appears to be rare, with the first description in 1968 by Pimstone and Uys [1968], and only isolated cases in the literature subsequently. A further case in 1987 described a 15-year-old girl whose ECG 12 h after paracetamol overdose showed gross widespread ST-depression and T-wave inversion [Wakeel et al. 1987]. Her overdose eventually resulted in death and postmortem examination revealed focal myocardial infiltrates of neutrophils and left ventricular dilatation suggesting a toxic myocarditis. A third case was documented in 1993 describing a 29-year-old man with significant paracetamol overdose who was found to have an abnormal ECG in the absence of hepatic encephalopathy [Armour and Slater, 1993].

To date, there has not been any systematic investigation of cardiotoxicity in patients presenting with paracetamol overdose, as many will be asymptomatic and hence the prevalence of this condition is unknown. Importantly however, it has been suggested that some unexplained deaths associated with paracetamol poisoning may have been due to cardiac arrhythmias, which have been documented in conjunction with ST-T-wave changes [Armour and Slater, 1993].

Potential mechanisms for paracetamol cardiotoxicity have been postulated. One hypothesis suggests that myocardial injury occurs as a result of a similar mechanism to that of hepatic damage, with paracetamol partly converted to a toxic metabolite, N-acetyl-p-benzoquinonimine, which is normally inactivated by reduction with glutathione and acts as a direct toxin on the myocardium [Armour and Slater, 1993]. Interestingly, paracetamol itself has also been shown to bind covalently to proteins in both liver and cardiac tissue with subsequent alteration of protein structure and function, potentially precipitating cytokine release and tissue injury [Lacour et al. 2005; Bulera et al. 1996]. Another possible mechanism is that paracetamol causes depletion of sulphydryl groups on the nitrate receptor in vascular smooth muscle. It is suggested that this paracetamol-induced depletion of sulphydryl groups might interfere with nitrous oxide metabolism, and thereby lead to coronary ischaemia [Armour and Slater, 1993]. Importantly, these proposed mechanisms would suggest that cardiotoxicity may be mitigated by N-acetylcysteine treatment in a similar fashion to liver injury.

As a corollary to its toxic potential, a burgeoning literature has also demonstrated the cardioprotective capacity of paracetamol in ischaemia-reperfusion syndromes. At concentrations of 45–50 µg/ml, well below the clinically toxic doses of ≥300 µg/ml, paracetamol can reduce tissue injury by preventing opening of the mitochondrial permeability transition pore and reducing apoptosis [Hadzimichalis et al. 2007; Merrill et al. 2001]. This dose-dependent preconditioning effect is clearly different to the mechanisms involved in paracetamol cardiotoxicity, reinforcing the concept of paracetamol’s therapeutic window, and demonstrating a novel property of this widely used drug.

Although clinically apparent cardiotoxicity in paracetamol poisoning is rare, the cardiotoxic potential of this common drug of overdose should not be overlooked. Routine ECGs on poisoning victims may suffice to risk stratify individuals and guide clinicians on consideration of further therapy.