Acetaminophen overdose is common in the pediatric population. N-acetylcysteine (NAC) is effective at preventing liver injury in most patients when started shortly after the overdose. Delays to therapy increase risk of hepatotoxicity and liver failure that may necessitate organ transplant. Animal studies have demonstrated fomepizole may provide added benefit in acetaminophen overdose because of its ability to block the metabolic pathway that produces the toxic acetaminophen metabolite and downstream inhibition of oxidative stress pathways that lead to cell death. Several adult case reports describe use of fomepizole in patients at higher risk for poor outcomes despite NAC. We describe a case of a 7-month-old female who presented in acute liver failure with persistently elevated acetaminophen concentration secondary to repeated supratherapeutic doses of acetaminophen to manage fever. Fomepizole and NAC antidotes were used in the management of the patient. She fully recovered despite demonstrating multiple markers of poor outcome on initial presentation. Although randomized trials are lacking, this case suggests that fomepizole may safely provide additional benefit in pediatric patients at risk for severe acetaminophen toxicity.
Acetaminophen (APAP) is the leading cause of acute liver failure in pediatric patients in the United States.1 N-acetylcysteine (NAC) therapy, when initiated within 10 hours following an acetaminophen overdose, effectively limits hepatotoxicity by replenishing glutathione stores, minimizing the impact of the toxic metabolite, N-acetyl-para-benzoquinone imine (NAPQI).2,3 Despite NAC treatment, some patients may progress to develop severe liver injury, especially in cases of massive or late presenting overdose. Fomepizole has traditionally been used to treat toxic alcohols by blocking alcohol-dehydrogenase; however, it has also been demonstrated to inhibit CYP2E1, which is the primary hepatic cytochrome that is responsible for NAPQI formation.4 In massive overdose, fomepizole may help prevent toxicity by blocking the production of toxic metabolites.5 Further, animal studies have demonstrated the potential for fomepizole to block the c-Jun N-terminal kinase pathway, thereby limiting a cascade of cellular events that lead to oxidative stress and, ultimately, cell death.6 Given these complementary mechanisms, it has been postulated that fomepizole may be effective in treating APAP toxicity even after complete metabolism of the parent compound. Although severe APAP induced liver injury is uncommon in young pediatric patients, the frequency of APAP use and dosing errors place them at high risk. This case report describes the use of fomepizole in addition to increased NAC dosing in an infant with acute liver failure related to a repeated supratherapeutic overdose of acetaminophen.
Case
A 7-month-old female infant presented to a community hospital with fever, vomiting, and cough. At the index visit, she was diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute otitis media. She was discharged with prescriptions for azithromycin, acetaminophen, and ibuprofen.
Five days later, the infant returned to the emergency department with signs of worsening vomiting and lethargy. At this second visit, the infant’s mother reported the infant received 5 mL or 160 mg of children’s liquid acetaminophen every 4 hours since the initial visit (99 mg/kg daily for 5 days) and ibuprofen with unclear dose and frequency. On examination, the infant was noted to be hypotonic with vital signs in the normal range for age. Laboratory work up revealed an acetaminophen concentration of 239.6 mcg/mL with associated severe hepatotoxicity as manifested by elevations in aspartate transaminase (AST) (25 133 IU/L; normal range, 26–55 IU/L), alanine transaminase (ALT) (16 837 IU/L, normal range 11–30 IU/L, and international normalized ratio (INR) (4.95, no reference range). Her venous pH was 7.42 and creatinine 0.3 mg/dL with bicarbonate of 22 mEq/L. Lactate was not obtained. Intravenous NAC was started using the 3-bag protocol (150 mg/kg over 1 hour, followed by 50 mg/kg over 4 hours, followed by terminal bag of 100 mg/kg over 16 hours).7 Under poison center guidance, the terminal bag dose was increased from 6.25 to 12.5 mg/kg per hour. The infant was then transferred to the local pediatric hospital.
Within 8 hours of arrival at the pediatric hospital, the infant’s clinical status worsened. The infant’s acetaminophen remained elevated at 189.8 mcg/mL, with a calculated half-life of 26.4 hours assuming first order kinetics (Fig 1). Additionally, venous pH declined to 7.23 with associated bicarbonate of 15.7 mmol/L; INR had risen to 5.1. At this time, the regional poison center recommended fomepizole and it was initiated at 15 mg/kg intravenously. Peripheral phlebotomy became increasingly difficult. To facilitate placing central access, the primary team attempted to reverse coagulopathy with fresh-frozen plasma and platelets, 500 mg aminocaproic acid, and 3 mg of intravenous vitamin K. The infant remained encephalopathic. Ultimately, the infant was transferred to a pediatric liver transplant center.
The graph depicts change in APAP concentration and AST and ALT. The second AST and ALT concentrations were greater than 27 300 and 11 700 IU/L, respectively. The green dotted line indicates the start of NAC and the purple dotted line indicates start of fomepizole.
The graph depicts change in APAP concentration and AST and ALT. The second AST and ALT concentrations were greater than 27 300 and 11 700 IU/L, respectively. The green dotted line indicates the start of NAC and the purple dotted line indicates start of fomepizole.
At the transplant center, the infant was comanaged by the liver transplant and pediatric intensive care teams. Although the patient did not meet immediate transplant criteria because of concomitant SARS-CoV-2 infection, a transplant work-up was initiated. Additional studies identified coinfection with norovirus on stool polymerase chain reaction. Alternative etiologies of liver failure were excluded, including autoimmune diseases, other viral infections, and systemic inflammatory disease.
The treating team continued fomepizole and NAC therapy and liver transaminases, and functional tests steadily improved (Table 1). Fomepizole was continued for 4 additional doses of 10 mg/kg every 12 hours until APAP concentration was less than 1 mcg/mL and NAC continued at a rate of 12.5 mg/kg per hour until the patient met the regional poison center NAC stop criteria (negative acetaminophen concentration, INR under 2, and AST peak and decline to under 1000 IU/L). N-acetylcysteine was stopped after 81 hours of infusion on hospital day 4. The patient additionally received vitamin K for coagulopathy and lactulose and rifaximin for hyperammonemia.
Peak Laboratory Values Daily Across Hospital Course and Medical Therapies Provided Each Hospital Day
| Admission Info | Laboratory Data | Medical Therapy | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hospital | Hospital Day | APAP mcg/mL | AST IU/L | ALT IU/L | Venous pH | INR | Ammonia mcmol/L | Total Bilirubin (direct) mg/dL | NAC | Fomepizole | Lactulose | Rifaximin | Vitamin K |
| Receiving ER | 0 | 239.6 | 25 133 | 16 837 | NA | 4.95 | NA | 2.3 | X | — | — | — | — |
| Children's Hospital | 1 | 189.8 | >27 300 | >11 700 | 7.23 | 5 | NA | 2.9 (2.3) | X | X | — | — | X |
| Transplant Center | 1 | 92 | 9320 | 8233 | 7.37 | 3.9 | 172 | 4.7 (2.9) | X | X | X | — | X |
| 2 | 50 | 6583 | 7667 | NA | 3.8 | 156 | 6.6 (4) | X | X | X | X | X | |
| 3 | 5 | 1799 | 4875 | NA | 3.1 | 101 | 10.6 (NA) | X | X | X | X | X | |
| 4 | <1 | 660 | 3209 | NA | 1.6 | 69 | 10.5 (7.5) | X | — | X | X | X | |
| 5 | 1 | 265 | 2442 | NA | 1.1 | 51 | 7.9 (NA) | — | — | X | X | — | |
| 6 | 2 | 216 | 2403 | NA | 1 | 43 | 7.5 (5.5) | — | — | X | — | — | |
| Admission Info | Laboratory Data | Medical Therapy | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hospital | Hospital Day | APAP mcg/mL | AST IU/L | ALT IU/L | Venous pH | INR | Ammonia mcmol/L | Total Bilirubin (direct) mg/dL | NAC | Fomepizole | Lactulose | Rifaximin | Vitamin K |
| Receiving ER | 0 | 239.6 | 25 133 | 16 837 | NA | 4.95 | NA | 2.3 | X | — | — | — | — |
| Children's Hospital | 1 | 189.8 | >27 300 | >11 700 | 7.23 | 5 | NA | 2.9 (2.3) | X | X | — | — | X |
| Transplant Center | 1 | 92 | 9320 | 8233 | 7.37 | 3.9 | 172 | 4.7 (2.9) | X | X | X | — | X |
| 2 | 50 | 6583 | 7667 | NA | 3.8 | 156 | 6.6 (4) | X | X | X | X | X | |
| 3 | 5 | 1799 | 4875 | NA | 3.1 | 101 | 10.6 (NA) | X | X | X | X | X | |
| 4 | <1 | 660 | 3209 | NA | 1.6 | 69 | 10.5 (7.5) | X | — | X | X | X | |
| 5 | 1 | 265 | 2442 | NA | 1.1 | 51 | 7.9 (NA) | — | — | X | X | — | |
| 6 | 2 | 216 | 2403 | NA | 1 | 43 | 7.5 (5.5) | — | — | X | — | — | |
—, medical therapies not used; NA, not available - indicates the test was not performed; X, medical therapies used.
On hospital day 4, the infant had worsened agitation and a CT head was obtained and negative. She returned to her mental status baseline on hospital day 5 and transferred to the general floor. The patient was discharged to follow up with hepatology in her home state on hospital day 8.
Discussion
Repeated supra-therapeutic ingestions (RSTI) of APAP often lead to the most severe outcomes in patients.8 Animal studies have demonstrated that hepatic injury begins when glutathione stores have decreased to roughly 30% of normal.9 Although NAC therapy alone has been overwhelmingly successful in treating patients with APAP toxicity via glutathione repletion, there remain patients who develop hepatic injury despite early administration of NAC.2 Further, in patients who present with massive ingestion, late after acute overdose, or following RSTIs, some mathematical models suggest that the standard dose of NAC may be insufficient.10 Fomepizole has recently garnered interest in the treatment of APAP toxicity because it acts to block the production of NAPQI, as well as potentially limits oxidative stress via the c-Jun N-terminal kinase pathway.6,11 This case highlights the use of increased NAC dosing and fomepizole in the treatment of a 7-month-old who presented with liver failure in the setting of an RSTI.
There are no randomized controlled trials in humans that demonstrate additional benefit from fomepizole in combination with NAC for APAP overdose. In mice, fomepizole outperforms NAC in models of massive APAP overdose with prolonged APAP metabolism.6 The translation and application of these findings to humans is challenging given absorption, metabolism, and toxicity of APAP occur at slower rates. The safety of fomepizole has been well established in adults and young children in the setting of toxic alcohols.12–14 Nonetheless, the use of fomepizole in APAP poisoning has thus far been limited to adolescents and adult patients.15 To our knowledge, this is the youngest patient so far treated with fomepizole specifically for APAP toxicity.
The initial decision to institute fomepizole therapy was driven by the potential mechanistic advantages outlined above. The patient presented with liver failure, which implies significant glutathione depletion, and had a prolonged calculated APAP half-life in excess of 24 hours. For context, the APAP half-life in infants and children following 15 mg/kg of intravenous APAP is 1.5 to 4.2 hours.16 Prolonged half-life reflects reduced metabolism and clearance capacity and prognostically correlates to severity of liver injury despite NAC.17 Additionally, the patient’s impaired metabolic profile mimicked the scenario in which fomepizole demonstrated superior hepatoprotection in animals.6 When fomepizole was initiated, the patient had already displayed an alarming trajectory, meeting King’s College Criteria by pH. King’s College Criteria (pH <7.3 after fluid resuscitation or INR >6.5, Creatinine >3.3 mg/dL and grade 3 or 4 encephalopathy) is a sensitive early predictor for mortality without transplant in APAP overdose.18,19 Our patient was evaluated for transplantation; however, she recovered with the described interventions. Although it is impossible to conclude that fomepizole was crucial to the patient’s recovery, it adds to the growing body of data that suggests that fomepizole improves outcomes in the most severe cases of APAP toxicity.
This case also brings attention to the frequent medication-dosing errors in pediatrics. APAP is widely used in young children and dosing errors are unfortunately common, both in the hands of parents and prescribing providers alike.20 Weight-based mathematical errors; awareness of daily maximum dosages; confusion surrounding units (milliliter or household teaspoon); lack of labeled dosing for children under 2 years; and lack of dosing syringes with over-the-counter preparations have all been implicated in serious overdoses. The reported overdose in this case was just shy of the consensus recommendation for hospital referral in the under 6 age group (100 mg/kg per day for 72 hours or greater).21 Therefore, it is reasonable to assume that reported dosing was an underestimation or the patient was uniquely susceptible to APAP toxicity, such as when suffering from a viral illness, with decreased oral intake and increased catabolism, which can excessively deplete antioxidants.22 Additionally, SARS-CoV-2 infection has been connected to liver injury in children and potentially contributed to disease severity.23
This case also highlights how chronic exposures with therapeutic intent carry higher risk. Among children with APAP induced liver failure, RSTI is more common and carries an increased risk of death and transplant.24 Evolving symptoms from accidental APAP overdose are often delayed and may be misattributed to the primary illness. NAC is often started late in these cases, rendering it potentially less effective. Organ transplant in this age group carries obvious lifetime morbidity and organ availability for this age group is limited.25 Given the need for adjunctive therapies in these circumstances, ongoing clinical investigation of fomepizole is warranted.
Exploring the benefit of fomepizole in pediatric patients is valuable given the frequency of overdose in this population and the morbidity associated with transplantation. The mechanistic advantages and safety of fomepizole make it a reasonable consideration in cases of severe acetaminophen toxicity. However, randomized control trials are necessary to validate its safe and effective use in conjunction with NAC. Further, it would be important to target future investigations to patients at risk for poor outcomes under the current standard of care.
Drs Pepin and Matsler conceptualized the case report, analyzed patient data, and drafted the initial manuscript; Drs Fontes and Flaherty obtained consent from the patient and collated patient data; Drs Heard and Monte assisted with conceptualizing the case report and interpretation of patient data; and all authors critically reviewed and revised the manuscript for important intellectual content, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: Rocky Mountain Poison and Drug Safety has received an investigator-initiated grant from McNeil Consumer Healthcare Division to conduct a clinical trial investigating fomepizole and N-acetylcysteine for acetaminophen poisoning in adults (NCT05517668). No authors received financial support through this grant.
Comments
Fomepizole Therapy for Acetaminophen-Induced Liver Failure in an Infant
We read the recent case report by Pepin, et al. with great interest and great respect for the life-saving care provided for this infant (1). The authors highlight the use of fomepizole in a 7-month-old with hepatotoxicity after repeated supratherapeutic acetaminophen administration to treat symptoms of COVID. We join other experts in the field who have adopted this antidote into practice for management of massive and severe acetaminophen poisoning.
Although this paper adds to the growing body of literature surrounding fomepizole use in pediatric acetaminophen poisoning, we are hesitant to agree with the authors conclusion that this case suggests fomepizole may safely provide additional benefit in these cases. Although the authors acknowledge that it is impossible to conclude that fomepizole was crucial to the patient’s recovery, we would add that it is impossible to determine whether fomepizole had any influence at all. It is equally likely that this child recovered from acetylcysteine alone (1, 2, 3). Although it there did not appear to be any toxicity from fomepizole in this case, and we agree that this drug is likely safe in pediatrics, a single case, even with a positive outcome, hardly constitutes evidence of safety in pediatric patients at risk for severe acetaminophen toxicity (4,5,6).
We believe that this article makes a substantial contribution in raising awareness of medication dosing errors and their sequelae in pediatrics, the high-risk nature of repeated supratherapeutic acetaminophen overdose, and the need for further exploration of the benefit and safety of fompeizole in pediatric acetaminophen poisoning.
Respectfully
Hannah Hays
Marcel Casavant
Prashant Joshi
References
1. Pepin L, Matsler N, Fontes A, Heard K, Flaherty BF, Monte AA. Fomepizole Therapy for Acetaminophen-Induced Liver Failure in an Infant. Pediatrics. 2023 Oct 1;152(4):e2022061033. doi: 10.1542/peds.2022-061033. PMID: 37681263.
2. Rumack BH, et al. Acetaminophen overdose in young children: treatment and effects of alcohol and other additional ingestants in 417 cases. Am J Dis Child. 1984:138:428-433
3. Heard K, Bui A, Mlynarchek SL, Green JL, Bond GR, Clark RF, Kozer E, Koff RS, Dart RC. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases. Am J Ther. 2014 May-Jun;21(3):174-83. doi: 10.1097/MJT.0b013e3182459c53. PMID: 22407198; PMCID: PMC3374904.
4. Brent J. Fomepizole for the treatment of pediatric ethylene and diethylene glycol, butoxyethanol, and methanol poisonings. Clin Toxicol (Phila). 2010;48)5):401-406
5. Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009;360(21)2216-2223.
6. Rasamison R, Besson H, Berleur MP, et al. Analysis of fomepizole safety based on a 16-year post-marketing experience in France. Clin Toxicol (Phila). 2020;58(7):742-747