Acetaminophen toxicity

Background

• Recommended maximum total daily dose:
  • Adults: 3gm
  • Peds: 75mg/kg
• Toxic dose
  • >10gm or >200mg/kg as single ingestion or over 24hr period OR
  • >6gm or >150mg/kg per 24hr period x2d
• Peak serum levels seen within 2hr

Pathophysiology

• APAP toxic metabolite NAPQI usually quickly detoxified by glutathione
  • In overdose, glutathione runs out, NAPQI accumulates -> liver injury
• NAC increases availability of glutathione

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. Hepatic 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)
   1. Clinical improvement and recovery (7-8d) OR
   2. Deterioration to multi-organ failure and death OR
   3. Continued deterioration

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

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

Toxic levels

1. 4 hr level >150 mcg/mL [993 umol/L]
2. 6 hr >110 mcg/mL [728 umol/L]
3. 8 hr >75 mcg/mL [496.5 umol/L]
4. 24 hr >4.5 mcg/mL [29.8 umol/L]

Acetaminophen half-life > 4 hr also may indicate toxicity

Extended Release (Tylenol7 "Extended Relief")

1. Bi-layer caplet; each layer contains 325 mg acetaminophen
2. One layer "immediate release," second layer "extended release" (up to 8 hrs; 95% released by 5 hrs)
3. Peak blood levels with therapeutic doses @ 1-2 hrs; may be longer after overdose
4. Requires serial levels (x2-3) as will drop and can be misleading
5. Cannot use nomogram
6. If suspicious, treat with NAC
7. Does not qualify for new shorter course 48 hr NAC therapy

Treatment

1. Call poison control
2. ABCs, IV, O2, monitor
3. Decrease absorption
   1. Do not induce emesis
   2. Gastric Lavage if < 1 hr post-ingestion
4. Activated Charcoal if < 3 hr post-ingestion or if other coingestants
   1. Does not interfere with NAC administration
5. Antidote: N-acetylcysteine (NAC or Mucomyst)
   1. Obtain acetaminophen level at least 4 hrs after ingestion (if uncertain time, obtain level immediately and then 4hrs later; determine 1/2 life)
   2. Wait for level before initiating therapy if level will return within 8 hrs post-ingestion
   3. Plot on Rumack-Matthew nomogram; if acetaminophen level in non-toxic range, NAC not indicated
   4. If level will not return within 8 hrs post-ingestion, give first dose of NAC empirically with suspected toxic ingestion; discontinue therapy if level non-toxic

If toxic:

1. NAC
   1. PO:
      1. 140 mg/kg PO load
      2. 70 mg/kg PO q4hr x17 doses additional; dilute to 5% soln
   2. IV (Acetadote)
      1. Loading dose 150 mg/kg in 200 mL D5W over 60 min
      2. Second (maintenance) dose 50 mg/kg in 500 mL D5W over 4 hrs
      3. Third dose 100 mg/kg in 1000 mL D5W over 16 hrs
   3. Virtually 100% effective if given < 8 hr post-ingestion; less effective if 16-24 hr post-ingestion
   4. May still be useful > 24 hr post-ingestion; even with fulminant hepatic failure
   5. Do not stop when acetaminophen concentrations fall to 0: free radicals are still causing hepatic damage
   6. In pts who develop hepatic injury, NAC tx should be continued until liver function improves (follow LFT's)
   7. May require strong anti-emetic (ondansetron 0.15 mg/kg IV, metoclopramide 20-40mg IV) or NGT if severe vomiting
2. Increase elimination
   1. Charcoal hemoperfusion
      1. Also effective in removing acetaminophen
      2. Not useful in usual clinical circumstances
      3. Indicated when pt. has fulminant hepatic encephalopathy with significant levels of acetaminophen present
3. Follow acetaminophen levels q4h, LFT, Coags
4. Evaluate potential need for liver transplant: pH<7.25, Cr >2.5, INR >4.5

Disposition

1. Psych hold
2. Admit
   1. Pre-school child with ingestions > 200 mg/kg
   2. Older child, adult w/ingestion >150 mg/kg or a total dose of 7.5 g
   3. Liver function abnormalities
   4. Delayed presentation or requirement for NAC therapy
3. Discharge
   1. Asymptomatic pts. w/o need of NAC therapy

The "140" Rule

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

Rumack-Matthew Nomogram