Acetaminophen toxicity

Background

Recommended maximum total daily dose:
- Adults: 4g/day
- Peds: 75mg/kg/day
Toxic dose
- >10gm or >200mg/kg as single ingestion or over 24hr period OR
- >6gm or >150mg/kg per 24hr period x2d
- 200 mg/kg in healthy children 1-6 yoa
Serum levels may not reach peak until up to 4 hours post-ingestion

Poorly understood
Possibly through inhibition of Cyclooxygenase-3 (COX-3)
- Decreases synthesis of prostaglandins
Antipyresis through inhibition of hypothalamic heat center

A - Rapid and near complete absorption
D - Vd = 0.95 L/kg
M - T 1/2 = 1.5-2hrs
- 40-60% - Glucuronidation
- 20-40% - Sulfuronidation
- 5-10% - Metabolism through CYP450 (Forms NAPQI)^[1]
E - Conjugated and unconjugated excreted through kidneys

APAP toxic metabolite NAPQI usually quickly detoxified by glutathione stores in liver
- In overdose, glutathione runs out, NAPQI accumulates -> liver injury
NAC increases availability of glutathione
- NAC is a precursor

Stage 1 (first 24hr)
- Mild N/V/malaise
- Hypokalemia (a/w high 4-hr level)
Stage 2 (days 2-3)
- Improvement in symptoms
- RUQ abdominal pain
- Elevated transaminases
- Elevated bilirubin, PT (if severe)
Stage 3 (days 3-4)
- Recurrence of N/V
- Acute liver necrosis -> liver failure
- Jaundice
- Coagulopathy
- Encephalopathy (esp w/ massive ingestions)
- Acute renal failure (1-2%; usually after hepatic failure is evident)
- Pancreatitis (rare)
Stage 4 (after day 5, up to 2 weeks)
- Clinical improvement and recovery (7-8d) OR
- Deterioration to multi-organ failure and death OR
- Continued deterioration

Rumack-Matthew Nomogram (use correct units!)

APAP level
- Obtain 4hrs post-ingestion
- Obtaining multiple levels is rarely indicated in the absence of hepatotoxicity

Only indicated for single, acute ingestion occurring <24hr prior to presentation
- Not useful for chronic ingestion (patients who take supratherapeutic doses for several days) or if time of ingestion is unknown
Make sure you use the correct units!
Dotted line should be used for those at higher-risk of liver toxicity (eg alcoholics, those on enzyme-inducing drugs)

GI decontamination
- Activated Charcoal if <3 hr post-ingestion (no role for multidose activated charcoal)
- Gastric Lavage if high-morbidity coingestants and <1 hr post-ingestion
Send 4hr APAP level
- Toxic level: Give NAC
- Nontoxic level: No treatment necessary

Send APAP level
- If level will be available within 8hr post-ingestion: wait for level before treating
- If level will not be available within 8hr post-ingestion: do not wait for level before treating
  - Discontinue treatment if level returns non-toxic

Consider GI decontamination for unknown ingestion time
Give 1st dose of NAC
Send APAP level, LFT, coags
- APAP level >10 OR elevated transaminases? If yes then continue NAC
  - pH <7.3 or PT >100 or Cr >3.3 or AMS? If yes refer to liver transplant unit
- APAP level and LFT both normal? If yes then stop NAC (treatment not indicated)

Initiate NAC in any patient with evidence of ongoing hepatotoxicity (lft abnormalities) OR 'positive' tylenol level (>20 mcg/mL)
If patient has normal LFT and 'negative' tylenol level (<20 mcg/mL), NAC treatment NOT required

Both IV or oral NAC may be used in pregnant patients with Acetaminophen toxicity. ^[3]
- IV formulation may be preferred to increase fetal NAC concentrations

Extended-release acetaminophen (Tylenol ER) consists of acetaminophen 325 mg in immediate release (IR) form surrounding a matrix of acetaminophen 325 mg
- Several studies show that the elimination of ER and IR APAP preparations is nearly identical after 4 hours. However, some case reports have documented APAP levels that are above the potential toxicity and treatment line on the nomogram as late as 11-14 hours after the ingestion of the ER preparation.
- Recommended management includes the measurement of 4-, 6-, and 8-hour APAP concentrations. Begin NAC therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin NAC therapy.

Consider discharge for asymptomatic pts who do not require NAC
Admission if requiring NAC or other ingestions, injuries
Transfer to transplant center based on above criteria
Psych consult if pt has suicidal ideation
In subacute toxicity, AST/ALT ratio of < 0.4 has sen of 99% for resolving hepatic injury^[4]

Criteria for predicting fulminant hepatic failure, and thus referral to transplant center^[5]
PPV 70-90% and sensitivity 69%
includes:

pH<7.3 or lactate>3 at 12hrs after full fluid resuscitation, OR all of the following:
Cr>3.4
INR>6.5
grade 3 or 4 Hepatic Encephalopathy

↑ Hendrickson RG, Bizovi KE. Acetaminophen. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th ed. New York: McGraw-Hill; 2002:523-543. (Textbook chapter)
↑ Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002 Dec 17; 137(12): 947-54.
↑ Heard KJ. Acetylcysteine for acetaminophen poisoning. N Eng J Med. 2008;359(3):285-292. (Review)
↑ Mcgovern AJ, et al. Can AST/ALT ratio indicate recovery after acute paracetamol poisoning? Clin Toxciol. 2015; 53:164-167.
↑ Bailey B, et al. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003; 31(1):299-305.