Via Research Recognition Day 2024 VCOM-Carolinas

Clinical Case-Based Reports

Multiorgan Failure Secondary to Intentional Acetaminophen Overdose-induced Methemoglobinemia MohamedAbutineh, OMS-III, Chirag Lodha, OMS-III, George Mitchell, D.O. Cleveland Clinic Indian River Hospital, Vero Beach, FL

Introduction/Background

Hospital Course

Conclusions

• A 21-year-old man presented to the ED via EMS with intentional overdose of Wellbutrin, two pill bottles of acetaminophen, and an unknown amount of bleach. • The patient was emergently intubated, and there was no evidence of esophagitis on EGD. • Poison control was contacted, and N-acetylcysteine (NAC) was initiated due to acetaminophen overdose. • The exact time of acetaminophen ingestion was unknown, but transaminases were initially normal. • Transaminases became abnormal 48 hours later (well after NAC administration), and the patient developed severe anion gap metabolic acidosis. • Despite normal transaminases upon admission, the patient's lactic acid levels were elevated, leading to suspicion of methemoglobinemia. • Methemoglobinemia was confirmed to be elevated, potentially explaining tissue ischemia, and methylene blue was administered as the antidote. • The liver transplant team was consulted and agreed with poison control in excluding acetaminophen-induced liver injury. • Due to unexplained elevated lactic acid and multisystem organ failure, the family elected for a Do Not Resuscitate (DNR) status. • The patient expired 4 days later with multisystem organ failure. Pathophysiology of Acetaminophen Toxicity: • Metabolism of APAP primarily occurs through glucuronidation, leading to the formation of NAPQI. • Failure to eliminate NAPQI promptly results in oxidative damage, disrupting signal transduction pathways, increasing mitochondrial permeability, and hindering ATP production through oxidative phosphorylation. • This contributes to tissue damage, and anaerobic glycolysis prevails, leading to lactic acid accumulation, a crucial aspect of acetaminophen-induced toxicity. 1 • Timely administration of N-acetylcysteine (NAC) is a well established protective measure. • NAC significantly reduces the risk of hepatotoxicity and mortality associated with acetaminophen overdose. 2 Methemoglobinemia in Acetaminophen Toxicity (Figure 1). • Methemoglobinemia, often overlooked, introduces a critical element to the clinical presentation. • It oxidizes hemoglobin iron from its ferrous (Fe2+) to ferric (Fe3+) state, impairing oxygen dissociation and resulting in tissue hypoxia. • The consequent failure to deliver oxygen triggers anaerobic metabolism, leading to lactate accumulation and potentially causing lactic acidosis. • Methylene blue serves as the definitive treatment for methemoglobinemia, restoring hemoglobin to its oxygen-carrying ferrous state 3 . Context: Although it is known that acetaminophen toxicity may result in methemoglobinemia, it is completely underappreciated in the literature . This diagnosis requires a high index of clinical suspicion because it can result in lactic acidosis and multiorgan failure secondary to tissue ischemia. Case Report

Figure 1. Graphic of methemoglobinemia mechanism 4

• This case reveals intricate dynamics of acetaminophen toxicity, involving interconnected mechanisms and often-overlooked consequences. • Acetaminophen induces hepatotoxicity through N-acetyl-p-benzoquinone imine (NAPQI), causing oxidative damage, disrupting signal transduction, and promoting anaerobic glycolysis with lactic acid accumulation. • Timely N-acetylcysteine (NAC) administration is crucial for restoring redox balance and mitigating hepatotoxicity and mortality risks. • I n this case NAC was administered immediately upon presentation and in our opinion along with the opinion with the poison control center and liver transplant team likely mitigated toxic acetaminophen liver injury, further supporting another mechanism of liver failure (such as ischemic hepatopathy secondary to methemoglobinemia). • Methemoglobinemia , an additional consequence, triggers tissue hypoxia and ischemia and fosters lactate accumulation, contributing to lactic acidosis. • T he patient's atypical presentation , with delayed transaminase elevation and unexplained lactic acidosis despite NAC, revealed the connection to methemoglobinemia. • Methylene blue administration as an antidote, prompted by elevated methemoglobin levels, did not prevent multiorgan failure and death. • We presume that the acute kidney injury in this case was secondary to the ischemic hepatopathy , which has been shown in animal studies to result in renal reperfusion injury 5 . • This case challenges the underestimation of the role of methemoglobin in acetaminophen toxicity, urging a shift in clinical awareness to consider nuanced interactions involving methemoglobinemia and lactic acidosis. • In conclusion, the case underscores the intertwined nature of acetaminophen toxicity, methemoglobinemia, and lactic acidosis, emphasizing the need for a comprehensive perspective among healthcare providers in managing acetaminophen overdose.

Figure 2. Clinical progression/timeline

Table 1. Relevant Labs

References

1.Chiew, A. L., & Buckley, N. A. (2021). Acetaminophen Poisoning. Critical care clinics, 37(3), 543 – 561. https://doi.org/10.1016/j.ccc.2021.03.005 2.Jaeschke H. (2015). Acetaminophen: Dose-Dependent Drug Hepatotoxicity and Acute Liver Failure in Patients. Digestive diseases (Basel, Switzerland), 33(4), 464 – 471. https://doi.org/10.1159/000374090 3.Sahu, K. K., George, S. V., & Siddiqui, A. D. (2020). Systematic Review of Methemoglobinemia in Acetaminophen Poisoning. QJM : monthly journal of the Association of Physicians, hcaa174. Advance online publication. https://doi.org/10.1093/qjmed/hcaa174 4.Lee, K. W., & Lee, J. B. (2013). Antidote for acquired methemoglobinemia: methylene blue. Journal of the Korean Medical Association, 56(12), 1084 – 1090. 5.Lee, H. T., Park, S. W., Kim, M., & D'Agati, V. D. (2009). Acute kidney injury after hepatic ischemia and reperfusion injury in mice. Laboratory investigation; a journal of technical methods and pathology, 89(2), 196 – 208. https://doi.org/10.1038/labinvest.2008.124

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2024 Research Recognition Day