None listed
Conditions
Brief summary
Recently, in New Zealand, intravenous paracetamol has become available, and is used for postoperative pain control after major operations. However there are a number of concerns regarding the safety of paracetamol: firstly paracetamol is toxic in overdose because of a toxic metabolite, produced by a minor metabolic pathway; secondly this toxic metabolite is detoxified using glutathione, a substance that may be deficient in fasted patients; and thirdly the major metabolic pathways of paracetamol may be inhibited by cytokines (released by tissue inflammation) resulting in an increase in the toxic metabolite produced by the minor pathway. This raises the possibility of an increased risk of hepatotoxicity in this vulnerable group of patients. Interleukin 1b is known to inhibit the expression of a number of Phase I, Phase II and transporter genes, some of which are involved in paracetamol metabolism. In cultured hepatocytes, expression of UGT1A1 and UGT2B3 mRNA is reduced by IL-6, even in the presence of an inducer (dexamethasone). Exposure to IL-6, and to a lesser extent IL-1b, was associated with decreased expression of sulfotransferases in cultured hepatocytes. In animal models interferon-? has been shown to down regulate P-glycoprotein. In critically ill children with sepsis, CYP activity is reduced in association with increased levels of interleukin 6. Phenytoin metabolism (CYP2C9) is decreased in association with elevated IL-6. In patients with heart failure, reduced activity of CYP1A2 was associated with increased IL-6, and reduced CYP2C19 was associated with increased TNF-a, but CYP2D6 and CYP2E1 were not affected by either cytokine. However, in human hepatocyte cultures, CYP2E1 mRNA had decreased expression under the influence of interferon-?, but had increased expression with IL-4. The down-regulation of hepatic metabolism may be influenced by enzyme induction and species, in addition to being cytokine specific.
Interventions
Intravenous paracetamol, 1g, is given 6 hourly for 3 days in adult patients undergoing major abdominal surgery
Sponsors
Dunedin School of Medicine, University of Otago
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
20 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Adults undergoing major abdominal surgery
Exclusion criteria
Exclusion criteria: history of past or present ethanol or substance misuse; nutritional deficiency; hepatic disease, including history of hepatitis B or C; previous adverse reaction to paracetamol; comedication with enzyme inducing or inhibiting drugs, including barbiturates, phenytoin and rifampicin.
Outcome results
None listed