Toxicology Talks with Toxijawn

A Massive Problem

Author: Vincent Basile, DO, Emergency Medicine Resident PGY1
Fellow: Alexis Cates, DO, Medical Toxicology Fellow PGY6
Faculty: James Krueger, MD, Medical Toxicology / Emergency Medicine Attending

The Case.

A young adult female is transferred to your ICU after being found down at home by her parents. The patient initially presented to the ED with unresponsiveness following what was thought to be a seizure.  The patient was found with an empty bottle of “Tylenol Extra Strength” in the patient’s room (formulation: 500 mg Acetaminophen). The bottle was reported to have 500 pills, though it is unclear how many the patient consumed.  A total possible calculated dose of acetaminophen is 250,000 mg.

The patient was subsequently intubated due to persistently altered mental status and respiratory failure.  Her initial acetaminophen level was reported to be >600 mcg/mL.  The patient remained intubated in the ICU.  You wonder- is this a massive acetaminophen ingestion?

Learning Point 1: Massive Acetaminophen Overdose

**Disclaimer:  This case is not meant to discuss acetaminophen (APAP) in its entirety.  This discussion will focus on massive acetaminophen overdose.  For a basic understanding of acetaminophen toxicity, consider reading the Goldfrank’s Toxicologic Emergencies Chapter on Acetaminophen or the Internet Book of Critical Care (IBCC) Acetaminophen Toxicity by Josh Farkas (Acetaminophen toxicity) 

●     No true standard definition of a massive acetaminophen toxicity, but some commonly used cut offs are exposure to  >500 mg/kg body weight of acetaminophen or a measurable acetaminophen concentration above the “300 line” of the Rumack-Matthew nomogram.

●     With massive acetaminophen overdose, patients may develop mitochondrial dysfunction before hepatotoxicity.  The toxicity pattern does not always follow classic acetaminophen toxicity.

●     Altered mental status and the presence of a large lactic acidosis are features that help distinguish from toxicity due to lower ingested doses.

●     Acute kidney injury is often seen.  This can be for multiple reasons, but CYP2E1 (one of the metabolism pathways of acetaminophen) is present in the kidneys, and could allow for NAPQI (toxic metabolite) production in the kidneys.

The Case Continued.

In the ICU, the patient was maintained on high-dose N-acetylcysteine infusion.  She was given a dose of fomepizole.  She also required vasopressors to maintain blood pressure. Calcium gluconate and sodium bicarbonate were administered, in addition to magnesium, for electrolyte disturbances.  

Due to the massive ingestion and concern for progression towards hepatotoxicity and potentially hepatic failure, the patient underwent a full work-up for evaluation for a liver transplant.  This included a CT scan of the patient’s abdomen and pelvis.  This showed a concern for a hyperdensity in the stomach.  You are concerned for slowed motility of the GI tract, leading to ileus and poor elimination of the medication through the gut pathways.  This also brought up the concern of not just an ileus but perhaps the formation of a pharmacobezoar or undigested pill matter still being absorbed in the gut, as evident on the CT scan.  You begin to brainstorm your next steps.

Over the course of the patient’s first 24 – 36 hours in the hospital, serum acetaminophen levels showed several rises and falls, resulting in two different peaks.  This is in spite of aggressive treatments.  The decision was made to perform intermittent hemodialysis to allow for removal of the parent compound of acetaminophen.  Unfortunately, even after a session of intermittent hemodialysis, the patient’s acetaminophen level rose to a third peak, albeit at a lower level than initially obtained.  The ongoing absorption of the xenobiotics from the gut was likely to be blamed.  You wonder if there is anything else you can do for this patient?

Learning Point 2: Treatments

• There are a variety of interventions that one can consider in a massive acetaminophen ingestion that may stray from usual protocol 
  • For all massive acetaminophen ingestions, consider contacting your local poison control center and/or medical toxicologist for guidance 
• Gastrointestinal Decontamination
  •  Activated charcoal may have benefit in adsorbing remnant xenobiotic in the stomach, but elimination through whole bowel irrigation may be useful in the right setting (though, there are obvious contraindications such as obstruction or unrelieved ileus)
  • Gastric lavage carries a risk of aspiration and is not currently routinely recommended
    

• N-acetylcysteine (NAC) continues to be the standard of care in acetaminophen toxicity, and has been proven to reduce morbidity and mortality, including the risk of hepatotoxicity.
  • A basic protocol is 21 hours which can be continued indefinitely when indicated.
  • There are a variety of parameters that have been cited as indications to discontinue a NAC infusion.  Consideration of patient condition, repeat acetaminophen concentrations and evaluation of trend of liver function should occur prior to discontinuation.
  • Continuous NAC infusions above standard dosing may be considered to prevent hepatotoxicity in these massive acetaminophen ingestions.
    • These higher doses of NAC may be initiated but depend on the serum concentration of acetaminophen
      • >300 mcg/mL [APAP] = 12.5 mg/kg/hr of NAC infusion
      • >450 mcg/mL [APAP] = 18.75 mg/kg/hr NAC infusion
      • >600 mcg/mL [APAP] = 25 mg/kg/hr NAC infusion
        
• Hemodialysis can be considered in certain situations, but not in place of NAC.  NAC should be initiated or continued through this process (and the rate must be doubled to keep up with it’s own removal by hemodialysis). 
  • Intermittent hemodialysis is preferred due to larger volume removed over time
  • The following are some instances where hemodialysis can be considered, though clinical judgment may be used in certain circumstances:

1.    NAC is not administered and [APAP] >1000 mcg/mL on day 1 or >800 mcg/mL on day 2

2.    NAC is not administered and the patient is persistently altered, metabolic acidosis, elevated lactate and [APAP] >700 mcg/mL on day 1 or >500  mcg/mL on day 2

3.    NAC is administered and the patient is persistently altered, has a metabolic acidosis, elevated lactate and [APAP] >900 mcg/mL on day 1 or >800 mcg/mL on day 2

• Fomepizole may help to prevent the formation of NAPQI, the toxic metabolite of APAP
  • Works by preventing the formation of NAPQI from APAP by binding to active site of CYP2E1 in the CYP450 system of the liver
  • Also shown to decrease c-jun-N-terminal kinase signaling, which would normally increase mitochondrial oxidative damage
  • Limited data on use in massive overdose, but shown improved outcomes when used in conjunction in NAC
  • Dosing typically recommended at 15mg / kg every 12 hours
    
• Liver Transplant
  • Often required with massive overdose due to irrecoverable hepatotoxicity
  • King’s college criteria is the most commonly used calculation to determine who should be evaluated for liver transplant

A last note on the case.

The patient remained on a high-dose NAC infusion and vasopressors to maintain blood pressure for a few days.  Consideration was given to whole bowel irrigation, gastric lavage and bedside endoscopy removal of xenobiotic from the more proximal GI tract.  Unfortunately, the patient expired due to ongoing multi-organ dysfunction.

Summary of Learning points:

●     A level above the “300 line” of the Rumack-Matthew nomogram is generally used to define massive acetaminophen overdose

●     Altered mental status and elevated lactic acidosis are common features

●     Increasing serum [APAP] is associated with highly increased risk of hepatotoxicity

●     Massive overdoses may lead to consideration of higher doses of NAC via infusion, and are based on acetaminophen concentrations

●     Hemodialysis, fomepizole, and gastrointestinal decontamination can be considered as adjuncts to treatment, in addition to NAC infusion

●     If liver transplant criteria met in patients with massive acetaminophen ingestions, evaluation by hepatology and transplant hepatology is required 

References

1. Marc Ghannoum, Sara Kazim, Ami M. Grunbaum, Eric Villeneuve & Sophie Gosselin (2016): Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics, Clinical Toxicology, DOI: 10.1080/15563650.2016.1175006.
2. Nelson, L.S, et al. (2019). Goldfrank’s Toxicologic Emergencies. Journal of Emergency Medicine. (11). Pgs472-491.
3. Chrøis, K. M., Larsen, S., Pedersen, J. S., Rygg, M. O., Boilsen, A. E. B., Bendtsen, F., & Dela, F. (2020). Acetaminophen toxicity induces mitochondrial complex I inhibition in human liver tissue. Basic & clinical pharmacology & toxicology, 126(1), 86-91.
4. Hendrickson, R. G. (2019). What is the most appropriate dose of N-acetylcysteine after massive acetaminophen overdose?. Clinical Toxicology, 57(8), 686-691.
5. Gosselin, S., Juurlink, D. N., Kielstein, J. T., Ghannoum, M., Lavergne, V., Nolin, T. D., … & EXTRIP Workgroup. (2014). Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clinical toxicology, 52(8), 856-867.
6. Shah, K. R., & Beuhler, M. C. (2020). Fomepizole as an Adjunctive Treatment in Severe Acetaminophen Toxicity. The American journal of emergency medicine, 38(2), 410-e5.
7. Christophersen, A. B., Levin, D., Hoegberg, L. C. G., Angelo, H. R., & Kampmann, J. P. (2002). Activated charcoal alone or after gastric lavage: a simulated large paracetamol intoxication. British journal of clinical pharmacology, 53(3), 312-317.