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

The 150 Rule

• Toxic dose is 150 mg/kg
• Give NAC if level is >150 mcg/mL four hours post-ingestion
• Initial loading dose of NAC is 150 mg/kg IV (140mg/kg PO)

Pharmacology

Mechanism of action

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

Pharmacokinetics

• 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)
• E - Conjugated and unconjugated excreted through kidneys

Toxicology

Pathophysiology

• 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

Clinical Features

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

Work-Up

1. APAP level
2. Chemistry
   1. Metabolic acidos seen w/ extremely large ingestion
3. LFT
4. PT/PTT/INR
5. Acetaminophen level: 4 hours post ingestion and repeat in 4 hours
6. ASA levels and other co-ingestants

Diagnosis

1. APAP level
   1. Obtain 4hrs post-ingestion
   2. Obtaining multiple levels is rarely indicated in the absence of hepatotoxicity
2. Nomogram (see below)
   1. Only indicated for single, acute ingestion occurring <24hr prior to presentation

Rumack-Matthew Nomogram

• 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)

Treatment

• Very important to identify time of ingestion

<4hr after ingestion

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

Between 4-24hr after ingestion

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

Unknown or >24hr after ingestion

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

Chronic Ingestion

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

Overdose in Pregnancy

• Both IV or oral NAC may be used in pregnant patients with Acetaminophen toxicity.
  • IV formulation may be preferred to increase fetal NAC concentrations

Extended release overdose

• 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.

Disposition

• 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

King's College Criteria

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

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

• other predictors of APAP-induced hepatic failure include:

1. lactate>3.5 4hrs after fluid resusciation
2. phos>3.8 at 48hrs, OR
3. APACHE II >15

External Links

• MDCalc - Acetaminophen Overdose & NAC Dosing
• MDCalc - King's College Criteria for Acetaminophen Toxicity