This case demonstrates potential difficulties with intravenous NAC as demonstrated by an anaphylactoid reaction. In addition, this case highlights the potential problems of compounding intravenous NAC and demonstrates the dose-dependent nature of the anaphylactoid reaction.
Anaphylactic and anaphylactoid reactions are similar because of the massive release of histamine resulting in hypotension, bronchospasm, pruritus, angioedema, and rash. Anaphylactic reactions are an antibody-mediated mast cell degranulation, which require prior sensitization and production of the IgE antibody. In contrast, anaphylactoid reactions are non-immunogenic and thus do not require previous sensitization. Given the lack of tryptase elevations, non-mast cell sources of histamine likely play an important role in anaphylactoid reactions [4]. It was the recognition of anaphylactoid reactions associated with the intravenous formulation of NAC that precipitated an infusion change in the packet insert, lengthening the infusion time from 15 min to 60 min for the loading dose.
Risk factors for anaphylactoid reactions include atopy, asthma, drug allergy, and low plasma acetaminophen levels, with our patient having the latter [5]. Asthma is one of the better-described risk factors with previous reports of severe anaphylactoid reactions and respiratory distress following intravenous NAC [6]. As for the cardiac manifestations noted in this report, only two other cases reported ECG changes with intravenous NAC. One involved ST depression and T wave inversion, which temporally resolved with antihistamine administration [7]. The other report documents asystole, which responded to precordial thump and intramuscular epinephrine [8]. The current report is unique in the myocardial ischemia associated with intravenous NAC, especially given his only known risk factor for coronary artery disease was smoking.
Many controversies still exist concerning which formulation is more appropriate. Oral administration is thought to improve drug efficacy given its immediate delivery to the liver and the first-pass effect. However, oral formulations have the disadvantage of potential poor tolerance and adherence given the nausea and vomiting associated with administration [9]. In comparison, intravenous formulations have more serious side effects, greater potential for compounding errors, and have been associated with hyponatremia in the pediatric population [10]. Several severe complications from intravenous NAC have been reported, including several fatalities, one in association with asthma [11]. In addition, adverse drug reactions were associated with compounding errors and higher rates of infusion [3].
NAC medication errors are typically classified into the three major categories of systemic calculation, mixing, and measuring errors. These errors with NAC are well described, with systemic calculation errors occurring in 5% of cases, mixing errors in 9%, and measuring errors in 3% [12]. Reports of errors have been reported to be as high as 33% of patients receiving intravenous NAC, with 18.6% having a delay or interruption in therapy for greater than 1 h [13]. Smaller delays in therapy may cause greater elevation in transaminases, increased length of stay, or more serious sequelae. One patient had a delay in her therapy secondary to an anaphylactoid reaction, which may have contributed to her hepatic failure, as the patient ultimately received an orthotopic liver transplant [14].
In an attempt to decrease NAC medication errors, some advocate for a one-bag method as opposed to a three-bag method. The three-bag method mixes a separate bag for each dose during the FDA-approved intravenous NAC protocol. This requires three different volumes and three different concentrations. The alternative one-bag method reduces the likelihood of compounding errors and also reduces delays in administration because nursing staff is not waiting for the pharmacy to deliver the second and third bags. However, this method does require the nursing staff to change the infusion rates, which does provide another potential source for an infusion error.
Previously, both 15-min and 1-h infusions of the loading dose have been used. Both protocols are equally effective for acetaminophen poisoning, but given the dose-dependent relationship of anaphylactoid reactions, 1-h infusions attempt to limit serious reactions. In addition, some have suggested a ceiling weight of 110 kg for obese patients given the volume of distribution, which also reduces the dose received [15]. In pediatric patients, hyponatremia can complicate the intravenous administration given the free water delivery associated with the treatment protocol [10].