An Abbreviated IV Acetylcysteine Regime for Acute APAP Toxicity. Short, Sweet, and…. Safe?

These authors propose the initial bolus dose of NAC to be infused over a longer period (2 hours vs 15 min) followed by a maintenance infusion delivered over 12 hours in contrast to the traditional 24. They theorized that these modifications would reduce the amount of adverse reactions, primarily due to the initial rate at which NAC is infused and at the same time, limit the duration of treatment required. In a 2X2 factorial design, the authors also examined the effects of ondansetron on the rates of adverse reactions in both the traditional and modified NAC regimes.

From September 2010 to December 2012, 222 patients underwent randomization at three different UK hospitals. The authors found that both the modified dosing regiment and ondansetron prophylaxis decreased the rate of vomiting and retching in patients undergoing treatment for acute APAP intoxication. More impressively the modified dose regime seemed to dramatically reduce the incidence of serious anaphylactoid reactions from a frighteningly high 31% to 5%.

As far as safety is concerned there was no difference between the traditional and modified dosing regimes in the number of patients with an elevation in AST levels or microRNA miR-122 harpega(a more sensitive marker of hepatic injury as per the authors’ claims). There was an interesting increase in both AST levels and microRNA miR-122 levels in those given ondansetron when compared to placebo. Though this did not translate into any long term hepatic injuries and it is unclear if this increase was just noise secondary to the small sample size, the authors warn against its prophylactic use before further studies are performed to assess its safety.

Given that the Rumack-Mathews Nomogram was designed to be highly sensitive at the cost of its specificity, and very few patients above treatment threshold go on to clinically relevant hepatic toxicity, it is hard to say how many of these patients actually benefited from treatment. In addition 30% of this population were under the 4 hr 200mg/L level and were only treated because of the recent changes in the UK guidelines to lower the treatment threshold to 100mg/L. Due to the poor specificity and small sample size, it is difficult to truly assess the safety of this refined protocol. Using surrogate endpoints thought to be more sensitive for hepatic injury like a 50% rise in AST  (in contrast to the more traditional measurement of AST > 1000 IU) and microRNA miR-122, may provide us with some idea of efficacy, but does not answer the more pressing question. Are the patients treated with this modified regime at a higher risk for clinically relevant hepatic injury? This would require a much larger study population.