acute acetaminophen toxicity, general overview

This week I got called about a woman with severe toxicity presumably from an acute overdose of extra-strength tylenol. She was prescribed 240 tablets of vicodin ES (which has 750 mg/tablet) two weeks prior, and the bottle was empty at the time she was brought in by medics. I'm not sure how many of these she took on the day of the overdose, but her liver functions were already out, her creatinine was up, and, most surprisingly, her bicarb was 6 (pH 6.98 initially). She was transferred to another center for possible emergency liver transplant...i am not sure what the outcome was as of yet. More about this case later, below is a general discussion of tylenol and related products, which in the tox world remain the most common overdose overall and the number one toxicologic killer in industrialized countries.

Here are the basics of acetaminophen overdose...if you haven't seen at least one in the last month, consider yourself due for one on your next shift...  

1. The “Rule of 150.” Toxic dose is generally 150 mg/kg ( or at least 7.5 gms per day in adults); toxic level is (depending on the reference) 150-200 mg/L at 4 hrs, and declining from there with a 4-hr half life. NAC loading dose is also 150 mg/kg.
2. The Rumack-Mattew nomogram (reproduced below) is useful in ACUTE,  SINGLE IMMEDIATE-RELEASE OVERDOSES (not for chronic or multiple ingestions). Opioids and benadryl—don’t seem to affect nomogram utility! See the nomogram below, it demonstrates that the toxic level decreases with time. It begins at 4 hrs after ingestion, so levels done prior to this time are not useful for determining whether to treat with the antidote, NAC. (However, if the level is zero and the clinical suspicion is low, then a stat level rules out toxicity).
3. For extended release product overdoses, the manufacturer recommends 2 levels, 4-6 hrs apart; if either one crosses the line then treat as a toxic ingestion and give NAC.
4. Major clinical effects: vomiting (but remember, many severely overdosed patients can be virtually asymptomatic for 2-3 days); fulminant hepatic failure; pancreatitis, acute renal failure; metabolic acidosis and sedation characterize MASSIVE ACUTE OVERDOSE (for example 50-100 gram ingestions)
5. Liver toxicity is centrilobular necrosis (maybe some apoptosis) due to a compound called NAPQI (this is a free radical quickly eliminated by glutathione reductase until glutathione stores are depleted); renal toxicity is due to free radicals from tubular prostaglandin synthetase or p450-mediated NAPQI; pancreatitis is rare, not due to NAPQI, and thus not helped by NAC.
   
6. N-acetylcysteine, or NAC is the antidote for acetaminophen. NAC effects: regenerates glutathione by donating sulfhydryl groups, which allow NAPQI detoxification; directly inactivates NAPQI; converts NAPQI back to acetaminophen; acts to increase hepatic microcirculation and attenuate free radical damage.
   
7. NAC DOSE: loading dose is 150 mg/kg PO or IV; PO dose is given as 70 mg/kg every 4 hours; IV dose can be same as PO dose or continuous infusion over 20 hrs (use loading dose over 15 minutes, then 50 mg/kg over 4 hours; then 100 mg/kg over 16hrs). There is also a protocol for continuous infusion when using the newer formulation of NAC (trade name, Acetadote), which uses 3 concentrations in 3 bags given over 20 hours. Contact your pharmacy for the details on preparation. Keep in mind that the "older" formulation of NAC can be used IV if a 22-micron pyrogen filter is used in line of the infusion...a minority of patients experience histaminergic effects such as itching and bronchospasm, which can should be treated with antihistamines/steroids/slowing the infusion. There is no credible evidence that NAC causes anaphylaxis, so do not withhold treatment in someone who needs it!
8. WHEN TO START NAC: level is above the 150 ng/mL line on the nomogram (or 200 depending on clinician’s comfort level and accuracy of history); if late presentation, can start NAC if AST ALT are elevated even if acetaminophen level is nondetectable.
   
9. WHEN TO STOP NAC: Acetaminophen level is nondetectable AND AST/ALT/INR are normal. Some clinician s will discontinue NAC if liver functions are slightly abnormal but show a trend towards normalizing, esp if patient has chronic liver disease. In severe toxicity and liver failure, continue NAC at maintenance doses until transplantation or death.
   
10. In general, oral NAC is the most direct way to the liver via portal circulation; IV NAC risks metabolism before reaching hepatic circulation. However, IV is preferred if patient is vomiting, GI tract is not well perfused (e.g. shock); pregnancy (to ensure placental delivery). PO NAC is foul to taste and smell; if patient vomits within 1 hr of swallowing a dose, then redose with antiemetics or use the IV formulation.