Acetaminophen, Acetylcysteine, and Anaphylaxis With a Twist
History
A 15 year-old male, with a past medical history of intermittent asthma, presents with a chief complaint of diffuse abdominal pain, nausea, and two episodes of non-bloody, non-bilious emesis. His symptoms began five hours prior to arrival, and are not accompanied by diarrhea, constipation, genitourinary, urologic, or musculoskeletal symptoms. He provides limited history and appears tearful. On direct questioning, he endorses that he attempted suicide the night prior by taking a “handful of ibuprofen.” He does not know the exact number of pills, but estimates somewhere between 50 and 100, and does not know the dose strength. His mother, a clinical pharmacist, believes they were 200 mg tablets, and that there were no other pills in the house. The patient endorses feelings of depression in the prior month, and blames himself for his father having fallen off a roof (without injury) two years prior. He attends high school and is up-to-date on his vaccinations. He is a non-smoker, does not use alcohol, and endorses occasional marijuana use. His only medication is an albuterol inhaler as needed.
Physical Exam
Initial vital signs: BP 122/82, HR 68 BPM, Temp 98.6 F, RR 20, and SpO2 100% on room air. Physical exam is notable for RUQ and LUQ tenderness without peritoneal signs. There are no scars or superficial cuts. He is tearful, but alert and oriented to person, place, and time.
Results and Management
The patient was placed on a cardiorespiratory monitor. Workup consisted of an EKG plus typical toxicologic labs, and consultation from poison control.
His EKG showed normal intervals and aVR morphology. Labs were notable for an acetaminophen level of 27 ug/mL and a slight elevation in transaminases, with AST 56 IU/L, and ALT 62 IU/L. On further questioning, the patient confessed that multiple types of pills were taken. Ingestion occurred at 2:00 AM, 14 hours prior to arrival. Given the poor history and elevated acetaminophen level, treatment based on the Rumack-Matthew nomogram (Figure 1) was felt to be beneficial.
Figure 1: Rumack-Matthew nomogram for acetaminophen ingestion.
The patient’s mother was concerned about his history of asthma, and her knowledge that NAC can cause bronchospasm; however, the benefits of treatment were felt to outweigh the risks. He was started on a standard 21-hour protocol, with a loading dose followed by two tapering doses.
Approximately one hour after the initial loading dose, the patient began to experience wheezing, a diffuse urticarial rash over the face, neck, shoulders, and thorax, and oral angioedema. He also became tachycardic. Given concern for a severe allergic reaction, bronchospasm, and possibly anaphylaxis, the infusion of NAC was held and he was treated with nebulized albuterol, IV diphenhydramine, IM epinephrine, IV normal saline, and IV corticosteroids. He was monitored in the emergency department for three hours, although his reaction resolved within 30 minutes.
Disposition and Resolution
The decision to restart NAC was considered, weighing the risk of possible anaphylaxis against the benefit of NAC to minimize potential hepatic insult. Given the low acetaminophen level, a repeat drug level and hepatic function panel were sent to inform this decision. These repeat labs came back with an undetectable acetaminophen level (now at 15 hours post-ingestion) and unchanged transaminase levels. NAC was not restarted on the basis of presumed completion of metabolism. The patient was admitted to the pediatric intensive care unit for monitoring, serial drug levels, and hepatic function panels. No further treatment was required during hospitalization. He was transferred to the psychiatry service on hospital day three for inpatient management of suicidal ideation and major depressive disorder. He did well with therapy and was discharged.
Case Discussion
This case illustrates elements of toxicity from two common over-the-counter medications, complicated by an adverse reaction to a life-saving treatment. Acetaminophen toxicity is a common emergency department phenomenon, and while ibuprofen is generally well-tolerated, it can cause toxicity at high doses.
Acetaminophen is metabolized by the liver via two pathways. First, conjugation to sulfate or glucuronide, which generates non-toxic metabolites, and second, via the CYP450 system, which generates a toxic free-radical metabolite, N-acetyl-P-benzoquinone (NAPQI). NAPQI is neutralized by glutathione (Figure 2).
Figure 2: Acetaminophen metabolism.
When acetaminophen is consumed in toxic doses, the pathways leading to nontoxic metabolites are overwhelmed and the accumulation of NAPQI depletes glutathione. In turn, the liver is unable to eliminate free oxygen radicals via glutathione, resulting in oxidative damage and mild, moderate, or fulminant liver failure if glutathione is not regenerated.
Patients are typically asymptomatic until 24-48 hours after an acute ingestion. Single doses over 150-200 mg/kg in healthy children pose significant risk of hepatotoxicity. Symptoms initially are nonspecific, with nausea, vomiting, and malaise, and can progress over a course of days to weeks to liver failure, recovery, or death. Treatment depends on the level of ingestion, the time from ingestion, and the presence of hepatic damage, but generally consists of gastric decontamination within the first hour after ingestion, oral or intravenous NAC, and supportive care. [1]
Ibuprofen, a non-steroidal anti-inflammatory drug, acts on cyclooxygenase enzymes to prevent conversion of arachidonic acid to prostaglandins and thromboxane, disrupting the gastric mucosal barrier and renal blood flow. At toxic doses, it can cause nausea, abdominal pain, gastritis, and renal failure. In severe presentations, acidosis and electrolyte disturbances are seen. The therapeutic window of ibuprofen is broad; toxicity typically does not occur until doses reach the 200-400 mg/kg range. Even in such cases, it is often mild and self-resolving with supportive care. The patient in this case likely consumed less than 100-200 mg/kg, which is unlikely to cause significant symptoms. His nausea, vomiting, malaise, and abdominal pain were likely secondary to gastric irritation from both ingestions in the early phase. [2]
NAC can be given orally or intravenously to manage acetaminophen overdose. Considerations for route depend on the severity of presentation and patient tolerance to PO medications. The duration of treatment varies by route. With IV, which was chosen for our patient due to poor PO tolerance and limited clarity around the time and quantity of ingestion, a loading dose (150 mg/kg administered over one hour) is then followed by tapered IV infusions over the next twenty hours (50 mg/kg administered over four hours, and 100 mg/kg administered over sixteen hours).
Unfortunately, NAC administration can be complicated by anaphylactoid reactions. These reactions are commonly limited to cutaneous symptoms of flushing and pruritus, with bronchospasm, angioedema, and shock occurring in <2% of patients. [3] Yarema and colleagues found in 2018 that 75.4% of anaphylactoid reactions to NAC fall within the cutaneous category. Of the total reactions observed, 95.4% of them occurred within the first five hours of treatment, which correlates with the delivery of high concentrations of drug. Female gender was associated with a more severe reaction, while higher serum acetaminophen concentrations were associated with less severe reactions. [4]
Pakravan et al further researched the mechanism of this reaction in 2008. They found that levels of serum histamine correlated with reaction severity, but that regardless of severity, there was no increase in serum tryptase or inflammatory cytokines. This suggests a non-mast-cell source of histamine and thus, a non-IgE-mediated reaction. This distinguishes the reaction from true anaphylaxis, however, the final common histaminergic pathways are similar, making clinical differentiation nearly impossible and arguments for different treatments in the initial stage largely academic. [5]
The pathophysiology of anaphylaxis and anaphylactoid reactions stems from the effect of histamine on vascular and bronchial smooth muscle leading to cutaneous vasodilation and third-spacing (hives, rash, pruritis), bronchospasm (wheezing), and reduced systemic vascular resistance (tachycardia, hypotension). Reversing this pathophysiology and providing supportive care is accomplished through intramuscular epinephrine (increases systemic vascular resistance and decreases bronchoconstriction), intravenous H1/H2 blockers (decreases vasodilation and third-spacing), nebulized beta-agonists (relieves bronchospasm), intravenous glucocorticoids (anti-inflammatory), and intravenous fluids (intravascular resuscitation, increases cardiac output). [7]
Yamamoto et al researched the frequency of occurrence as related to the treatment timeline, finding that the reaction will most commonly occur during the initial loading dose (61%), that a smaller fraction will occur over the next four hours (37%), and that the least frequent fraction occurs during the terminal taper (2%). [6]
Regardless, this anaphylactoid reaction prompts considerations about appropriate treatment and, if stopped, how and whether or not to restart the drug. The reaction itself, even when severe, typically does not necessitate cessation of therapy. A common approach to managing the reaction includes temporarily holding the infusion, initiating the normal anaphylactic countermeasures, then restarting the infusion at half of the previous rate after symptom control. Generally, the ongoing infusion is well-tolerated once histaminergic blockade is in place. This off-target effect has no effect on the critical reaction of regenerating hepatic glutathione stores. NAC is very effective at preventing fulminant hepatic failure, even in severe cases of overdose, and restarting treatment should be a high priority.
In this case, the patient’s parents refused to restart the medication given his severe reaction. He had not been previously exposed to NAC, which suggests that his reaction was likely anaphylactoid as opposed to anaphylaxis. His acetaminophen level at 14 hours had scored onto the lowest acceptable treatment line on the Rumack-Matthew nomogram and his liver function was only notable for a minimal-mild elevation in transaminases. Given the lower concern for severe toxicity, and repeat labs demonstrating an undetectable acetaminophen level with no appreciable change in hepatic function, the parents and treatment team were comfortable without restarting it in this case.
Lastly, an additional complication of NAC relates to coagulopathy. Sandilands et al reported elevations in INR in association with NAC treatment; however, an initial rise in INR, assuming it stabilizes, is not indicative of progressive liver failure. Elevations typically stabilize around an INR of 1.3, which is not concerning for increased risk of bleeding. [8]
In summary, treatment with NAC may be complicated by histamine-mediated anaphylactoid reactions, which are commonly limited to cutaneous reactions easily treated with histamine antagonists. Severe reactions may necessitate adjunct treatment from inhaled or intravenous beta-agonists, intramuscular beta-agonists, intravenous glucocorticoids, and fluids. True anaphylaxis requires previous sensitization. Unless extenuating circumstances or clinical context exist, NAC should be restarted after treating the reaction. Elevations in INR are common and do not imply liver failure unless they continue to rise.
Faculty Reviewer: Dr. Jane Preotle
References
Farrell SE, Miller MA. Acetaminophen Toxicity. Wolters Klewer, eMedicine. Updated 22 Jan 2018. Accessed 24 Sep 2018.
Wiegand TJ, Schlamovitz GZ. Nonsteroidal Anti-inflammatory Drug Toxicity. Wolters Klewer, eMedicine. Updated 20 Dec 2017. Accessed 16 Sep 2018.
Blackford MG, Felter T, Gothard MD, Reed MD. Assessment of the clinical use of IV and oral NAC in the treatment of acute acetaminophen poisoning in children: a retrospective review. Clin Ther. 2011; 33(9):1322-30 (ISSN: 1879-114X)
Yarema M, Chopra P, Sivilotti MLA, et. Al. Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning. J Med Toxicol. 2018 Jun;14(2):120-127. Doi: 10.1007/s13181-018-0653-9.
Pakravan N, Waring WS, Sharma S et. Al. Risk Factors and Mechanisms of Anaphylactoid Reactions to Acetylcysteine in Acetaminophen Overdose. J Clin Tox 2008 Jun;46:697-702.
Yamamoto T, Spencer T, Dargan PL, Wood DM. Incidence and management of N-acetylcysteine-related anaphylactoid reactions during the management of acute paracetamol overdose. Eur J Emerg Med. 2014 Feb;21(1):57-60. doi: 10.1097/MEJ.0b013e328364eb22.
Bailey B, McGuigan MA. Management of Anaphylactoid reactions to IV N-acetylcysteine. Ann Emerg Med. 1998 Jun;31(6):710-5.
Sandilands EA, Bateman DN. Adverse reactions associated with acetylcysteine. Clin Toxicol (Phila). 2009 Feb;47(2):81-8.