Evidence for the changing regimens of acetylcysteine

Abstract

Paracetamol overdose prior to the introduction of acetylcysteine was associated with significant morbidity. Acetylcysteine is now the mainstay of treatment for paracetamol poisoning and has effectively reduced rates of hepatotoxicity and death. The current three-bag intravenous regimen with an initial high loading dose was empirically derived four decades ago and has not changed since. This regimen is associated with a high rate of adverse effects due mainly to the high initial peak acetylcysteine concentration. Furthermore, there are concerns that the acetylcysteine concentration is not adequate for 'massive' overdoses and that the dose and duration may need to be altered. Various novel regimens have been proposed, looking to address these issues. Many of these modified regimens aim to decrease the rate of adverse reactions by slowing the loading dose and thereby decrease the peak concentration. We used a published population pharmacokinetic model of acetylcysteine to simulate these modified regimens. We determined mean peak and 20 h acetylcysteine concentrations and area under the under the plasma concentration-time curve to compare these regimens. Those regimens that resulted in a lower peak acetylcysteine concentration have been shown in studies to have a lower rate of adverse events. However, these studies were too small to show whether they are as effective as the traditional regimen. Further research is still needed to determine the optimum dose and duration of acetylcysteine that results in the fewest side-effects and treatment failures. Indeed, a more patient-tailored approach might be required, whereby the dose and duration are altered depending on the paracetamol dose ingested or paracetamol concentrations.

Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand

“…The standard three‐bag intravenous weight‐based dosage regimen (150 mg/kg body weight over 15–60 min, then 50 mg/kg over 4 h and 100 mg/kg over 16 h; 300 mg/kg total) developed in the 1970s was empirically derived and not subject to dose ranging studies . This regimen has proven to be highly efficacious when compared with no treatment, but it causes frequent adverse reactions and the dosing regimen is complex and prone to error . A two‐bag acetylcysteine regimen slows the initial loading dose and simplifies the protocol (ie, 200 mg/kg over 4 h followed by 100 mg/kg over 16 h).…”

Outcomes from massive paracetamol overdose: a retrospective observational study

“…The decision to treat acute, non‐staggered, paracetamol overdose is based principally on measured plasma paracetamol concentrations, taken at least 4 h after ingestion . International guidelines differ in their recommendations as to threshold paracetamol concentrations for treatment on nomograms, but once these have been exceeded, acetylcysteine dosing regimens are very similar throughout the world . The dose of acetylcysteine is determined only by patient weight, and does not vary according to other factors including the dose of paracetamol taken, plasma paracetamol concentration, time to presentation, and/or co‐ingestion of other drugs.…”

“…NAPQI can be detoxified to cysteine and mercapturate conjugates by glutathione, with organ injury resulting once stores of the latter become depleted . Consequently, pharmacokinetic studies were performed in healthy individuals to determine the level of glutathione depletion over a range of paracetamol concentrations, and a dose of acetylcysteine selected that would match this on a stoichiometric basis .…”

How to treat paracetamol overdose and when to do it

“…A formal RCT may require too many patients to be feasible given funding limitations and alternative approaches such as international observational studies with historical controls may be needed. Ultimately, a more patient-tailored approach might be necessary in which the dose and duration are altered depending on the plasma paracetamol concentration and dose ingested [8].…”