Safety of acetylcysteine: a scoping review of iatrogenic overdose cases and their associated complications.

INTRODUCTION

Acetylcysteine is the standard antidote for acetaminophen (paracetamol) toxicity and is widely considered safe when administered appropriately. However, an increasing number of case reports have documented serious adverse outcomes following its improper administration, including cerebral edema, hemolytic uremic syndrome, and death. As acetylcysteine is increasingly utilized for roles beyond acetaminophen overdose, its broader application introduces more opportunity for error. This review aims to systematically evaluate published cases of iatrogenic acetylcysteine overdose to characterize the risks, patterns of error, and outcomes associated with these events.

METHODS

We conducted a scoping review of peer-reviewed literature describing iatrogenic acetylcysteine overdose. Articles were identified using Covidence through a comprehensive search of MEDLINE and additional databases. Search terms and strategy were guided by medical subject heading analysis. Included cases reported dosing or infusion-related errors that led to clinical deterioration. Cases involving known side effects (e.g., anaphylactoid reactions without overdose) or abnormal lab values without clinical toxicity were excluded. Extracted variables included dosing protocol, route, type of error, timing of events, complications, and neurological outcomes utilizing the modified Rankin scale, when available.

RESULTS

A total of 16 reports met the inclusion criteria, with 14 describing toxicity from acetylcysteine overdose itself (analytic set) and two describing hyponatremia resulting from excess diluent volume. Among the 14 toxic overdose patients, 85.7% were female (mean age 18 years). Errors stemmed from the electronic medical record, pharmacy, provider, and nursing errors. Of the 14 reported acetylcysteine overdoses, 10 included sufficient information to analyze outcomes stratified by acetylcysteine exposure. Acetylcysteine exposure ≥1000 mg/kg was significantly associated with cerebral edema (P = 0.0476). Among the five patients who developed seizures, four (80%) had received ≥1000 mg/kg of acetylcysteine. However, this exposure was not significantly associated with seizure occurrence (P = 0.52). Death and severe disability, hemolytic uremic syndrome, and functional outcomes were not significantly different by dose threshold. Functional outcomes revealed a bimodal distribution: most patients either recovered fully or died, with a minority experiencing persistent deficits. Among the six fatal cases, four occurred in patients receiving three-bag regimens, and two occurred in those receiving two-bag protocols.

DISCUSSION: The significant association between acetylcysteine exposure ≥1000 mg/kg and cerebral edema underscores the importance of early recognition and intervention, particularly given the substantial lag period before clinical decline. Additionally, the predominance of multi-level system failures rather than one isolated error highlights the need for safeguards beyond protocol revision alone. As acetylcysteine expands to indications beyond toxicologic emergencies, these findings reinforce the importance of implementing additional safety measures across clinical settings.

CONCLUSION

Iatrogenic acetylcysteine overdose is associated with high morbidity and mortality, with cerebral edema at very large doses contributing to rapid clinical deterioration, and frequently, death. In patients who survive longer, complications such as hemolytic uremia syndrome were observed. Evidence from this review supports the consideration of safety-focused changes in acetylcysteine administration protocols, including the adoption of simplified dosing regimens, improved electronic medical records, safeguards, and early targeted interventions. Standardizing monitoring protocols may further mitigate preventable harm in both traditional and expanded use cases.