Changing paradigms of paracetamol poisoning

The overall objective of this thesis was to identify and examine areas for improvement in the management of paracetamol poisoning. Paracetamol is one of the commonest drugs taken in overdose in Australia and a common cause of acute liver injury in Western countries. Management of paracetamol poisoning includes assessment for the need of antidote (acetylcysteine) administration and decontamination in patients at risk of toxicity. Management in most follows standard guidelines and in those receiving early acetylcysteine are at very low risk of developing acute liver injury. However, circumstances were arising when some patients were developing acute liver injury despite early acetylcysteine. In this thesis we firstly review the evidence for the current assessment and treatment of paracetamol poisoning and identified risk factors associated with treatment failure. This allowed us to identify and examine those patient groups that were at higher risk of acute liver injury with standard treatment protocols such as massive and modified-release paracetamol overdose. However, these cases were uncommon so a means to recruit these patients from many centres was required. The Australian Toxicology Monitoring study (ATOM) is a prospective observational study that recruits patients from calls to two poisons information centres and five clinical toxicology units. An arm of ATOM the Australian Paracetamol Project (APP) recruited an enriched dataset of problematic paracetamol poisoning. From APP three studies form a part of this thesis. ATOM-2 investigated massive immediate-release paracetamol ingestion and found increased acetylcysteine dose and early decontamination decreases the risk of liver injury. ATOM-3 investigated modified-release paracetamol ingestion and found many required prolonged treatment and some developed liver injury despite early acetylcysteine treatment. The results of these studies subsequently resulted in change to the national guidelines for the management of these patients. ATOM-5 examined a new biomarker paracetamol-protein adducts and showed that it can be used to stratify patients at low and high risk of acute liver injury. This thesis shows that recruitment of patients from many centres can be performed to examine uncommon and problematic overdoses