Acetaminophen (APAP) is a widely used analgesic and antipyretic agent among adults and children worldwide. In therapeutic doses, it is effective and well tolerated. Nevertheless, due to it being freely available over-the-counter, safety concerns arise. Multiple cases of poisoning with APAP have been reported, raising a need for a reversal agent. N-acetylcysteine (NAC), available orally (PO), and intravenously (IV), prevents the detrimental effects of APAP poisoning if used appropriately. Administering NAC in an inappropriate manner, as with other medications, is associated with an increased risk of adverse effects as well as a substantial increase in hospitalization and healthcare costs.
Based on a review of prospective and retrospective studies, several symptoms following NAC administration appeared consistently, such as anaphylactoid reactions with IV administration (rash, flushing, and pruritis), chest pain, hypotension, as well as gastrointestinal and respiratory symptoms. Such symptoms are in alignment with those reported in various studies, and it is of note that children suffer from detrimental side effects due to incorrect dosing of IV NAC.
Schmidt et al. observed the risk factors for the development of such side effects following NAC administration. About 529 patients were admitted due to APAP poisoning and treated with NAC; 45 of whom developed side effects due to NAC, and 18 developed systemic side effects. Of these patients, the side effects were more severe in those who had asthma, are chronic alcoholics, or were receiving enzyme-inducing anticonvulsants. Moreover, a prospective case-controlled study of 64 patients treated with NAC infusion concluded that patients who had low plasma APAP levels, zero levels, delayed hospital admission, or were classified as being high-risk patients were more likely to develop anaphylactoid reactions to NAC, making them at high risk of developing NAC adverse events.
Due to variations in the acquisition costs and length of treatment between IV versus PO NAC and which of them is more cost-effective, a cohort study by Martello et al. concluded that the cost of hospitalization was significantly lower with IV NAC compared to PO NAC ($7,607.82 versus $18,287.63, respectively; P < 0.001). Additionally, the average length of hospitalization favored IV NAC when compared to PO NAC (four days versus seven days, respectively; P < 0.001). With that being said, it is important to note the preparation costs associated with IV administration. Additionally, NAC utilization for all patients with APAP overdose is not cost effective.
To our knowledge, there is no published data assessing the use of NAC for acute APAP overdose in patients presenting to the emergency department in Saudi Arabia. Thus, we aim to decrease the unwanted adverse effects and costs associated with the inappropriate use of NAC, decrease unnecessary treatment and hospitalization and develop an evidence-based protocol for administering NAC for acute APAP ingestion.
A cross-sectional study was conducted during the period from June 2015 to November 2018 at King Saud University Medical City (KSUMC) to primarily determine the percentage of patients that were appropriately prescribed NAC. The secondary objectives are to determine the number of incidents when a NAC was indicated inappropriately, the number of patients who received an incorrect regimen/dose of NAC, and the number of incidents of inappropriate NAC therapy duration. Patients initiated on NAC secondary to acute APAP overdose in the emergency department were included in the study. Any patient with insufficient history or laboratory data to determine the appropriateness of therapy was excluded. The data collection process included the following: demographic data, dose of APAP ingested, time of APAP ingestion, dose of NAC, time of NAC received, route of administration, APAP concentration, hepatic function (AST, ALT, and bilirubin), coagulation profile (INR and PT), renal function (creatinine and BUN), electrolytes, and ammonia.
The appropriateness of prescribing NAC for acute APAP overdose (including the appropriate regimen, indication, and duration) was assessed based on a developed, validated, evidence-based protocol for administering NAC for acute APAP ingestion [see Figures 1 and 2]. NAC is considered appropriately prescribed if it was given with correct regimen (dose and rate of administration), correct indication, and correct duration of therapy. Descriptive statistics were reported as frequencies and percentages using IBM SPSS Statistics. This study was ethically approved by the institutional ethical review board at KSUMC (Ref.No. 19/017/IRB).
A total of 29 patients were enrolled in this study. The majority of participants were female (75.9%), with no drastic difference in age (51.7% being adults versus 48.3% paediatrics). Most participants ingested APAP as a tablet (93.1%), and only 6.9% reported multiple APAP ingestions. Of the 29 participants, the majority arrived at the hospital within 1 to 4 hours of APAP ingestion (51.7%). Refer to Table 1 for more details on patient demographics.
Table 2 summarizes the primary outcome of the study, being the percentage of patients that were appropriately prescribed NAC. Results showed that of the 29 patients included, 14 (48.2%) were appropriately prescribed NAC, while 15 (51.7%) were prescribed NAC inappropriately; nine of which were adults, and six were pediatrics. All used NAC regimens were solely intravenous (IV) regimens.
As for the secondary outcomes, Figure 3 represents the number of patients that were prescribed NAC for an inappropriate indication. Seven patients ingested <150 mg/kg or <10 g of APAP (whichever is lower), four patients received NAC in <4 hours after ingesting ≥150 mg/kg or ≥10 g of APAP (whichever is lower), three patients ingested ≥150 mg/kg or ≥10 g of APAP (whichever is lower) with a non-toxic APAP level on R-M Nomogram after 4–24 hours of APAP ingestion, and one patient did not receive NAC despite the ingestion of ≥150 mg/kg or ≥10 g of APAP (whichever is lower) and a toxic APAP level on R-M Nomogram after 4–24 hours of APAP ingestion.
APAP overdose represents a major health concern globally and should be adequately managed with NAC when indicated. Our results showed that around half of our study population received NAC with no proper indication; most of which received it without ingesting the 150 mg/kg or 10 g threshold for APAP toxicity. Additionally, the most non-indicated NAC (n = 15) was associated with either higher or lower dose/rate of administration (n = 11). In contrast, around half of our subjects showed in the emergency department within 1–4 hours of APAP ingestion, which provides time for clinicians to assess the case before the therapeutic decision. This unnecessary use of NAC puts patients at an unwarranted risk of acquiring detrimental adverse events due to NAC administration, including but not limited to gastrointestinal symptoms with the oral route and anaphylactoid reactions with the IV route.
The incidence of such events is relatively determined by multiple factors. For example, anaphylactoid reactions are commonly observed with lower APAP levels, which was hypothesized by the proportionate decrease in histamine release with the APAP dose. Furthermore, a slower infusion rate upon NAC administration was also associated with a lower presentation of such reactions. Toxicologists have recommended a 60-min infusion rate rather than 15 min; following such a recommendation showed a numerically lower incidence of anaphylactoid reactions with the former group compared to the latter, although no statistical difference was observed.
It has been reported that the prevalence of anaphylactoid reactions in Saudi Arabia ranges from 0.05% to 2%; 0.04% to 3.1% of which are drug-induced and accountable for one in every 4,000 emergency department visits. This puts an unnecessary burden on the emergency department that may be adjusted upon correct administration of medications. Among all patients administered NAC, 3% experienced anaphylactoid reactions. Considering the severity of such events, this number is alarming, highlighting the need for an appropriate treatment guideline on the use of NAC.
Issuing a standardized protocol on the proper administration of NAC is crucial to the safety of patients as well as maintaining the quality of healthcare systems. Thus, a proposed one was developed accordingly, as shown in Figure 1. The APAP levels need not be taken before the 4-hour margin; after which they may be plotted on the R-M Nomogram if the results can be made available in less than 8 hours. Consecutively, NAC is to be administered when toxic levels are reported. This recommendation also applies when the patient presents at an unknown time or after the 24-hour margin. Additionally, NAC may be initiated immediately if the patient presents 8 to 24 hours post ingestion. A decision on continuation or discontinuation is to be made as soon as the APAP level results are available. This protocol clearly highlights the importance of APAP levels and the timing of ingestion as well as NAC administration in appropriately managing patients with APAP overdose. This was seen among our study sample, as the majority of patients were administered NAC with non-toxic APAP levels (n = 7, 46.66%), and a decent number of patients were also administered NAC at an inappropriate timing, being <4 hours post-APAP ingestion (n = 4, 26.67%). Despite some patients ingesting a toxic amount of APAP, their APAP level on the R-M Nomogram after 4 to 24 hours was not toxic (n = 3, 20%), thus not qualifying them for NAC administration. However, they inappropriately received NAC upon admission. In addition, a patient ingested a toxic level of APAP and had a toxic level on the R-M Nomogram (n = 1, 6.67%); however, NAC was not administered as indicated. Similarly in a single-centred study in the United States, 21 out of 56 patients (35.5%) were started on IV NAC <4 hours post-APAP ingestion. Additionally, around 15 (26.8%) of the patients were initiated on IV NAV while their APAP level on the R-M Nomogram after 4 to 24 hours was not toxic. Therefore, healthcare providers should be extremely vigilant on observing the three mentioned parameters (i.e., APAP level, timing of ingestion, and timing of NAC administration), making this protocol simpler for the management of such patients.
Not only will following such a protocol have a dramatic effect on the safety of patients and their outcomes, it will also have a massive impact on healthcare costs. More than $ 250,000 was unnecessary healthcare costs (hospital stay, laboratory, and medication costs) of IV NAC administration when it was given inappropriately to 20 out of 56 patients with acute APAP overdose. The cost of one NAC vial is 102.1 Saudi Riyals ($ 27.23), and the total cost of the medication itself if it is given to a 70 kg person within a 21-hour IV regimen is 612.6 Saudi Riyals ($ 163.36). Such a cost excludes the cost of bed occupation, facility usage, different healthcare charges, and laboratory costs.
There are a few limitations to this study. Due to the fast-paced environment of the emergency department, poor documentation was an issue, and given the retrospective design of this study, we were confined to the information provided in the medical records. This, in turn, resulted in the small sample size of our study. With that being said, our study is the first of its kind, providing a relevant benchmark for this topic and paving the way for future research.
Improper NAC administration appears to be a significant issue among patients with APAP overdose. The utilization of a protocol for the management of APAP overdose will reduce the unwanted adverse events associated with NAC administration, saving its benefits for only warranted patients. Additionally, it will dramatically impact healthcare costs associated with NAC administration. Future research with a larger sample size is highly encouraged.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
This work was supported by the College of Prince Sultan Bin Abdulaziz for Emergency Medical Services Research Center, Deanship of Scientific Research, King Saud University, Saudi Arabia
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