Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine

Context: Paracetamol (acetaminophen) overdose is a common reason for emergency hospital admission in the UK and the leading cause of acute liver failure in the Western world. Currently, the antidote acetylcysteine (NAC) is administered at a dose determined only by body weight without regard for the body burden of paracetamol. Objective: To determine whether higher plasma paracetamol concentrations are associated with increased risk of liver injury despite prompt treatment with intravenous NAC. Methods: Patients admitted to hospital for treatment with intravenous NAC following a single acute paracetamol overdose entered the study if NAC was commenced within 24 h of drug ingestion (N = 727 hospital presentations). Based on the plasma paracetamol concentration at first presentation to hospital, a series of nomograms were created: 0-100, 101-150, 151-200, 201-300, 301-500 and over 501 mg/L. The primary endpoints were acute liver injury (ALI - peak serum ALT activity >150 U/L and double the admission value) and hepatotoxicity (peak ALT > 1000 U/L). Results: ALI and hepatotoxicity were more common in patients with higher admission plasma paracetamol concentrations despite NAC treatment (ALI: nomogram 0-100: 6%, 101-150: 3%, 151-200: 3%, 201-300: 9%, 301-500: 13%, over 501 mg/dL: 27%. p < 0.0001). This dose-response relationship between paracetamol concentration and ALI persisted even in patients treated with NAC within 8 h of overdose (nomogram 0-100: 0%, 101-150: 0.8%, 151-200: 2%, 201-300: 3.6%, 301-500: 12.5%, over 501mg/L: 33%. p < 0.0001) and in patients with normal ALT activity at first presentation (nomogram: 0-100: 0%, 101-150: 1.2%, 151-200: 1.5%, 201-300: 5.3%, 301-500: 10.8% p < 0.0001). Discussion: Patients with increased concentrations of plasma paracetamol at hospital presentation are at higher risk of liver injury even when intravenous NAC is promptly administered before there is biochemical evidence of toxicity. Conclusion: This study supports theoretical concerns that the current intravenous dose of NAC may be too low in the setting of higher paracetamol exposure.