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.

Keywords: acetylcysteine; antidote; overdose; paracetamol.

Figure 1

Percentage [95% confidence interval (CI)] of patients with adverse reaction, as reported in various retrospective and prospective studies. *Prospective study. All other studies are retrospective

Figure 2

Acetylcysteine infusion (mg kg^–1) and cumulative acetylcysteine dose (g) in a 70 kg patient vs. time, for the traditional and newly proposed regimens. (A) Traditional regimen (15 min or 60 min loading). (B) Modified 12‐h regimen 38. (C) Two‐bag (4‐h loading) regimen 37, 48. (D) Oakley et al. (1 h loading followed by 10mg/kg/h for 20 h) 50. (E) Johnson et al. (1 h loading followed by 14mg/kg/h for 20 h) 49. (F) 48‐hour intravenous regimen 52. Note: The 48‐h intravenous regimen has a different scale for the acetylcysteine cumulative dose and time.

Figure 3

Simulated acetylcysteine concentrations vs. time for the traditional and proposed acetylcysteine regimens. (A) Traditional protocol (loading over 15 min); the scale of the y‐axis is larger in (A) than in (B) to (G). (B) Loading over 60 min. (C) Modified 12‐h protocol 38. (D) Two‐bag loading protocol, 200 mg kg^–1 over 4 h 37, 48. (E) Johnson et al. (1 h loading followed by 14mg/kg/hr for 20 h). 50. F) Oakley et al. (1 h loading followed by 10mg/kg/hr for 20 h). 49. (G) 48‐h intravenous protocol 52; graph simulated to 60 h as a longer infusion of acetylcysteine. Note: for (A) to (G), the time of infusion commences at 4 h post‐ingestion.