Acute Liver Support Series: Acetaminophen Overdose in the ICU

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The Pre-brief

If you had to pick one reason for patients ending up in the ICU for Acute Liver Failure (ALF), it would be acute acetaminophen (APAP) overdose. While the differential diagnosis for ALF includes many entities, APAP overdose constitutes more than 50% of cases of acute liver failure in the developed world and remains one of the leading causes of liver failure that needs acute transplantation (1).  The burden of disease is severe, but fortunately many patients can recover with timely critical care support as well as early administration of antidote.

The Transfer Center is Calling You. Time to Accept an Admission:

A 48 year old male arrives in your ICU as a transfer/ referral from an outside hospital for liver transplant evaluation in the setting of Tylenol overdose. 2 days prior to arrival at your facility he presented to the referring hospital’s ED because his family was concerned about a social media post about “Saying goodbye.” He did not report anything to the emergency department staff, though was intoxicated with an alcohol level of 230 mg/dL. Family reports he has no history of alcoholism, and also reported finding several empty bottles of medications, though it’s unclear how much of anything he took. Initial labs revealed mild transamonitis, negative ASA and fentanyl, positive opiates and an APAP level of 200 mcg/mL, for which he was started on an N-acetylcysteine infusion and admitted under suicide precautions. Within 8 hours of admission his repeat APAP level had climbed to 350 mcg/dL, and within 2 days of admission he has developed oliguric kidney injury, hepatic encephalopathy requiring intubation, and 0.08 mcg/kg/min of norepinephrine with vasopressin to maintain a MAP >65 mmHg. His ammonia has increased to 200 mg/dL, for which the OSH team has started lactulose. His INR climbed to 5.0, and his bilirubin was 13 mg/dL. His family remained supportive and involved at the time of transfer and desires that all care possible be rendered.

With the patient in your ICU, what medical stabilization is possible? Does he need a new liver?

APAP Poisoning:

The mechanism of toxicity in APAP overdose has been one of the most well described pathways in acute medicine. For the fellows and residents reading, yes it will be on your boards. Figure 1 shows the familiar pathway seen in nearly every toxicology and pharmacology textbook: the pathologic transformation of excess APAP into toxic metabolites (NAPQI) that then precipitates liver necrosis, and the all-important balance of neutralizing glutathione. If the reader desires a deeper dive into APAP toxicity, we advise review of some of the sources in our reference section (2-3). 

Normally the liver can deal with acetaminophen via glucuronidation and/or glutathione neutralization of NAPQI (toxic metabolite). In overdoses, glutathione supply is exhausted and leads to a buildup of toxin, which then directly causes hepatitis and hepatic necrosis. NAC (N-acetylcysteine) when administered as an antidote replenishes glutathione, which can deplete NAPQI or prevent critical build-up. Source: Wikipedia commons

The clinical manifestations for the critically ill patient with APAP overdose stems from the central nature of the liver’s effects on the entire body. Unlike other kinds of “single organ failure,” when the liver acutely fails there tends to be massive inflammatory cascades that spring into motion, similar to what is seen in ACLF (see prior post on this). The classic natural history of Tylenol overdose is initial liver injury followed by multi-organ dysfunction failure and cardiovascular collapse (1-4). This natural history is well codified in a familiar table that separates the illness into the classic 4 phases of disease (Table 1). Assuming early/ aggressive support and antidote administration, even the direst of overdose patients can make it to convalescence without need for transplant and/or death (1-4). This last part is important for intensivists or supporting clinicians: APAP overdose patients can look hopelessly sick. On top of their coagulopathies and liver disease they commonly develop distributive shock, encephalopathy, ATN that requires renal replacement therapy, and cerebral edema. Most patients, however, are usually young and actually do relatively well if supported aggressively and early with critical care intervention and antidote, with a transplant-free survival exceeding 65% (4).

N-acetylcysteine Dosing: Do you have the NAC for it?

Without fail, the most important part of ALF management in APAP overdose is early antidote. NAC acts to replete glutathione reserves and is most efficacious when used as early as possible (1, 3) For this reason, ANYONE who comes in as with suicide attempt/ ideation as well as ANY overdose patient MUST be screened with a Tylenol level. APAP is in basically every over-the-counter remedy, and most overdose cases involve 2 or more substances (5). It is also important to remember that the number 1 cause of most toxicity deaths is opiate toxicity (6). One of the most widely available and most often implicated prescription narcotic is Percocet (oxycodone PLUS APAP). 

NAC initiation and maintenance dosing

The tricky part about NAC for intensivists is figuring out when to use higher dose regimens as well as figuring out the correct duration of therapy. Initial dosing of N-acetylcysteine in the Emergency Department or the ICU is pretty standard: A bolus dose of 150 mg/kg followed by an infusion of 12.5 mg/kg/hr for 4 hours. The standard Prescott protocol then has a maintenance dose of 6.25 mg/kg/hr until discontinuation. That shakes out to about 319 mg/kg for the first 24 hours, and then an additional 150 mg/kg/day. That regimen, which was the original protocol used for FDA approval, was based on an assumed dose of acutely ingested 16 grams of acetaminophen (3). 

But what if the patient in question had a massive overdose? What if their initial APAP level after 4 hours of ingestion was 100 mcg/mL (clearly toxic based on nomogram studies), but on recheck their APAP level is now 200…or 250? What if their initial APAP level is >300…or over 500 mcg/mL? While a relatively small number of patients qualify as “massive” overdoses, it is always possible that either history may have been incomplete (i.e. the duration of ingestion may have been longer and allowed for multiple ingestions) or coingestants may have slowed peristalsis and increased absorption (e.g. opiate or alcohol effects). As initial APAP levels climb above 250 mcg/mL, the risk of increased hepatotoxicity as measured by lab derangements in case reports and case reviews increases on the order of 10-20 fold (3). As such, in cases where APAP levels are significantly elevated or begin to cross nomogram lines upward, there may well be an indication for higher doses of NAC dosing beyond the initial bolus (Table 2). 

Figure 2. Standard Acetaminophen Nomogram (source Wikimedia Commons). When levels exceed the solid “treatment line,” relative to estimated time from ingestion, treatment with NAC is strongly recommended.
Table 2A. Alternative concentrations/ dosing regimens for N-acetylcysteine. While the Prescott regimen was intended for an assumed dose of 16 gm of APAP, patients may have intentionally dosed with much higher doses. The 2x, 3x, and 4x dose infusions would potentially address initial overdoses of 32, 48, and 64 Gm of initial APAP, respectively. Source Material: Hendrickson et al. Clin Pharm 2019 (7).
Table 2B. In massive overdose, the initial APAP level may be much higher than the standard toxicity line depicted in Figure 2. Initial 4-hour levels may be the key to understanding the size of the overdose, and therefore the right concentration/ dose of NAC. Source: Hendrickson 2019.

NAC infusion discontinuation

Discontinuation of NAC infusion can take variable amounts of time, and primarily revolves around normalization of lab values. Typically the cut-points on discontinuation are:

  • APAP level of 0
  • PT of 25-30 seconds
  • Normalization of LFTs
  • Resolution of Hepatic Encephalopathy

Since most liver centers are quite conservative on this point, ALL of these endpoints are recommended to be met before discontinuing NAC. 

Other Supportive Measures:

Most patients with severe APAP overdose benefit from early medical management and critical care support and do not require much more than watchful waiting. Patients often require renal support, vasopressor therapy, intubation, and transfusions to meet standard endpoints of resuscitation and perfusion markers. In a large review of a US-based liver failure registry, APAP overdoses enjoyed a transplant free survival rate of 65% . Critical Care support of ALF from APAP overdose resembles standard support of any critically ill patient, but specifically should emphasize a few things specifically:

  • Timely renal replacement therapy when needed for standard indications or to bring down very high ammonia levels (7). 
  • Intubation for pulmonary compromise or airway protection
  • Normalization of electrolyte abnormalities and fluid balance
  • Close monitoring of neurologic status with low threshold to diagnose and treat cerebral edema and elevated Intracranial Pressures.
  • Standard transfusion targets (8, 9):
    • Hemoglobin/ hematocrit >7 gm / 25 %
    • Platelets > 50
    • Fibrinogen >100
    • INR and PT typically remains elevated; FFP not indicated for normalization of values

As we continue segments on liver support, each of these standard practices will be discussed in greater detail. SCCM has also created a document specifically for guiding clinicians taking care of ALF and ACLF as well (8). 

Acute Transplant: When NAC is not enough

Sometimes the answer to liver failure is, well, to get a new liver. A nice review of a US registry of liver failure cases conducted in the Lancet found that about half of all cases were due to APAP toxicity, and about 9% of those cases required transplant to survive (3). While psychosocial circumstances weigh heavily in terms of assessing transplant candidacy, a history of suicide attempt does not outright disqualify most patients, even if it is the index reason for their overdose. Table 3 references the Kings College Criteria for Liver Severity.  As is always the case with acute transplants, there is a fine line between “too sick” and “not sick enough” when it comes to the operating room (OR). It’s gonna be a discussion, and if the patient needs a liver, their best shot at getting to the OR in time is the best medical stabilization as possible. 

Table 3. Kings College Criteria for Liver Transplantation selection. Patients with acute liver failure in APAP overdose who satisfy either numbered grouping have predicted survivals of <20% and should be evaluated for transplant.

A key distinction in considering Table 3 is your own ability to marshal resources in your own clinical setting. While satisfaction of Table 3’s criteria may imply need for transplant evaluation (and certainly it does not necessarily guarantee listing patients for transplant) fulfillment of even some of these criteria is likely grounds for expeditious transfer from community centers to a liver center (2,3).  If you practice at a liver transplant center, then hepatology, transplant surgery and the OR are just down the hall/ only a phone-call away. However, if your patient with massive tylenol overdose is in the community setting, it is probably best not to hold off because of pH cut-off. Referral from the community should occur as early as possible, especially when multi-system organ dysfunction becomes evident (or honestly when any of the criteria in Table 3 are met).

Case Resolution

Upon arrival to the receiving hospital his repeat APAP level remained at 200 mcg/dL and his ammonia remained at 213 mg/dL, and so the decision was made to increase his NAC infusion to “2x” infusion rate of 12.5 mg/kg/hr. Since he was not responding to any stimuli with sedatives weaned. Ocular Nerve Sheath Diameters measured at the bedside with ultrasound revealed distended optic nerves, and so a head CT was performed which showed mild cerebral edema (though no stroke or herniation was present). Hepatology and transplant surgery were consulted immediately, though they advised medical optimization before listing for transplant, especially given concern for neurologic injury. Hyperosmolar therapy with hypertonic saline and mannitol were used to temporize his intracranial hypertension and continuous renal replacement therapy was initiated both to mitigate acidosis as well as improve clearance of ammonia. On his 7th day of ICU care, he began to follow commands, and his vasopressor requirements steadily decreased as his acid-base disturbances normalized. He was extubated on ICU day 11, and after his LFTs and INR approached normal values, NAC was discontinued. He was discharged to acute rehab on hospital day 20 and three months later he was seen in the clinic having regained much of his kidney and liver function. At 6 months he no longer required dialysis and was living at home in the care of his family.

The Debrief

APAP overdose in the ICU is a scary thing, but it’s also something most ICUs can handle (or at least temporize). Most of these patients if given early and aggressive therapy can make it to a very acceptable and high quality level of survivorship. 

  1. Reasons to transfer early to a liver center include
    1. Multi-organ system dysfunction and/or cardiovascular collapse
    2. Massive Overdose
    3. Refractory acidosis
  2. Watch out for the neurologic sequelae of acute liver failure:
    1. Screen for intracranial hypertension syndromes
    2. Treat with hyperosmolar therapy when needed
    3. Mitigate Ammonia levels >150 aggressively, considering CRRT early in their hospital course
  3. Be Patient and Aggressive. Especially when young, even massive overdoses that look terribly sick can bounce back.

References

  1. Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013 Dec 26;369(26):2525-34. doi: 10.1056/NEJMra1208937. PMID: 24369077.
  2. Erik S. Fisher, Steven C. Curry. Evaluation and treatment of acetaminophen toxicity. Editors: Anup Ramachandran, Hartmut Jaeschke. Advances in Pharmacology. Academic Press, Volume 85, Ch 10. 2019. Pages 263-272, ISBN 9780128167595.
  3. Hendrickson RG. What is the most appropriate dose of N-acetylcysteine after massive acetaminophen overdose? Clin Toxicol (Phila). 2019 Aug;57(8):686-691. doi: 10.1080/15563650.2019.1579914. Epub 2019 Feb 19. PMID: 30777470.
  4. Stravitz RT, Lee WM. Acute liver failure. Lancet. 2019 Sep 7;394(10201):869-881. doi: 10.1016/S0140-6736(19)31894-X. PMID: 31498101.
  5. Bauer LK, Brody JK, León C, Baggett TP. Characteristics of Homeless Adults Who Died of Drug Overdose: A Retrospective Record Review. J Health Care Poor Underserved. 2016;27(2):846-859.  
  6. Holly Hedegaard, M.D., Arialdi M. Miniño, M.P.H., and Margaret Warner, Ph.D. Drug Overdose Deaths in the United States, 1999–2018. NCHS Data Brief, No. 356. January 2020. https://www.cdc.gov/nchs/data/databriefs/db356-h.pdf
  7. Cardoso FS, Gottfried M, Tujios S, Olson JC, Karvellas CJ; US Acute Liver Failure Study Group. Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure. Hepatology. 2018 Feb;67(2):711-720. doi: 10.1002/hep.29488. Epub 2017 Dec 26. PMID: 28859230
  8.  Nanchal R, Subramanian R, Karvellas CJ, Hollenberg SM, Peppard WJ, Singbartl K, Truwit J, Al-Khafaji AH, Killian AJ, Alquraini M, Alshammari K, Alshamsi F, Belley-Cote E, Cartin-Ceba R, Dionne JC, Galusca DM, Huang DT, Hyzy RC, Junek M, Kandiah P, Kumar G, Morgan RL, Morris PE, Olson JC, Sieracki R, Steadman R, Taylor B, Alhazzani W. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary and Renal Considerations: Executive Summary. Crit Care Med. 2020 Mar;48(3):415-419.
  9. O’Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA Clinical Practice Update: Coagulation in Cirrhosis. Gastroenterology. 2019 Jul;157(1):34-43.e1.

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