To the Editor:
We read the case report ‘Massive acetylcysteine overdose associated with cerebral edema and seizures’Citation1 with interest; we believe that readers may benefit from further case details, comparison with other NAC dosing error cases, and the clinical perspective of the medical toxicologists caring for the patient as the case unfolded; along with its medico-legal consequences.
The poison center (PC) recommended to the initial hospital empiric treatment based on an acetaminophen overdose history with N-acetylcysteine (NAC) 150 mg/kg followed by 15 mg/kg/h using a 30 mg/cc NAC infusion. This dose is used (in an attempt) to limit dosing errors and encompass all acetaminophen toxic patients; not just the acute, early presenting ones. This explains the use of the 3% NAC solution by the hospital. The nurse reported the dose as ‘50 cc/h × 4 h, followed by 100 cc/h × 16 h’. Since this is not a NAC dose, an attempt was made by the specialists to clarify. Despite significant resistance of hospital staff because of Health Insurance Portability and Accountability Act (HIPAA) a pharmacist eventually erroneously reported the dose as identical to the Acetadote® dosing.
When the patient developed status epilepticus, the PC was contacted for advice. An important piece of laboratory data not presented in the original case report was an international normalized ratio (INR) of 2.5 at the time of the seizures. This, combined with an alanine aminotransferase (ALT) increase to 121 IU/L along with the belief that the NAC dosing was correct, prompted the medical toxicologist to recommend restarting the NAC infusion. It is known that IV NAC elevates the INR,Citation2 and in cases of NAC overdose this INR elevation appears to be more significant; the INR was 2.1 in the nearly identical IV NAC dosing error (same dose, same 3% NAC solution) published in the 2008 National Poison Data System fatality reports.Citation3
During the ensuing litigation proceedings, all of the PC specialists involved in the case were required to provide testimony; the case documentation of attempts to verify the dose were critical in these discussions, and the PC was eventually not named in the suit.
Because IV NAC errors are becoming frequent, the PC began tracking and recommending serum osmolality after NAC overdoses as a potential prognostic tool; the seizures may have an osmolar component, and one of the fatality reviewers from reference 3 was incredulous that an IV NAC overdose could occur without elevated serum osmolality. Many dosing errors were detected; the two most significant were as follows: one PC patient who received IV NAC of 150 mg/kg/h for 8 h had serum osmolality assessed 20 min after infusion termination with normal serum osmolality and no osmolar gap; they were asymptomatic before and after the infusion was stopped. Another PC patient received IV NAC at 150 mg/kg followed by 100 mg/kg/h for 8 h; they developed nausea and seizures but the NAC was terminated before the seizures started; they did not have an elevated serum osmolality at the time of seizure onset and recovered without sequelae.
Despite popular rhetoric, when medical errors occur, even after the ‘dust settles’, there is rarely an altruistic approach to disclosure. The toxicologists who managed the case reportCitation1 were instructed by their risk management group not to write this case up; we are grateful that the author was able to present the case in full. A similar problem occurred with the 2008 NPDS death,Citation3 in this case, although institutional review board (IRB) approval was obtained, the legal department of the hospital where the death occurred forbade any further publication, ever. Thankfully, the death abstract contained all the important details; the only ones omitted were that she had persistent vomiting several hours leading up to the seizures, her elevated INR (2.1) led to the restarting of the NAC because of concerns for hepatic injury due to acetaminophen, and her post mortem aortic blood was negative for all organic bases, neutrals and acids.
It appears that the clinical factors suggesting a NAC overdose are the presence of an elevated INR along with unexpected agitation, persistent nausea, confusion or seizures, and this should be considered even if the dose is believed to be correct. Additionally, if the dosing error is recognized, and the NAC is stopped before the onset of seizures, the outcomes may be better than if the NAC is continued after seizures develop. It is hoped that as IV NAC use continues at its unprecedented rate, that overdoses of IV NAC are shared whenever possible with the medical toxicology community.
Declaration of interest
The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper.
References
- Heard K, Schaeffer TH. Massive Acetylcysteine overdose associated with cerebral edema and seizures. Clin Toxicol 2011; 49(5):423–425.
- Schmidt LE, Knudsen TT, Dalhoff K, Bendtsen F. Effect on Acetylcysteine on Prothrombin index in paracetamol poisoning without hepatic injury. Lancet 2002; 360:1151–1152.
- Bronstein AC, Spyker DA, Cantilena LR Jr. Green JL, Rumack BH, Giffin SL. 2008 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 27th Annual Report. Clin Toxicol 2009; 47(10):979–1178 (Abstract number ‘Addenda’).