Acetaminophen toxicity
Pathophysiology
-APAP (n-acetyl-p-aminophenol) OD disrupts metabolic pathways in liver
-Usual APAP metabolism from CYP450 includes toxic metabolite N-acetyl-benzoquinonimine (NAPQI)
-In excessive amounts, depletion of glutathione --> accumulation of NAPQI --> liver injury
-N-acetylcysteine (NAC) increases availability of glutathione thus prevents accumulation of NAPQI
-Additional effects of NAC: Antioxidant effects, microcirculatory changes (improved tissue oxygenation)
-Activated charcoal: Adsorbs (and prevents absorption of) acetaminophen
-Adsorbs (and prevents absorption of) N-acetylcysteine
Risk Factors for Toxicity
-Hepatic disease, alcoholics, geriatric: chronic toxicity
-Toxicity enhanced with inducers of CYP450 (alcoholics, drugs), poor nutrition (lower glutathione stores)
Kinetics
-t1/2: 4 hrs in OD, otherwise 1-3 hrs
-Usual maximum daily recommended dose: 2.6 g/day
-Toxic dose 140mg/kg; 10g or 200mg/kg; 4g or 100mg/kg in high risk pt
Metabolism: CYP450 dependent
-Children with less of cytochrome; less likely to suffer effects of toxicity
Symptoms
-Phase 1 (0-24 hrs): asymptomatic, N/V, abd. tenderness, diaphoresis
-Phase 2 (24-72 hrs): asymptomatic, LFT's & coagulation tests, Cr may begin to incr.
-Phase 3 (72-124 hrs): PEAK hepatotoxicity, hepatic necrosis, jaundice, encephalopathy, renal failure, death, pancreatitis (hyperamylasemia)
--Seen in 18% of overdoses
-Phase 4 (5-14 d): recovery
W/U
Laboratory testing
-Lytes, BUN/Cr, glucose: metabolic acidos seen w/ extremely large (> 75 g, > 10 g peds) ingestion, renal function
-LFT's: AST usually incr. first; may rise over 10,000
-Monitor qd x3 with bilirubin
-Coagulation studies: indicator of liver function; monitor qD x3
-Acetaminophen level: 4 hours post ingestion and repeat in 4 hours
-Estimated ingestion >150 mg/kg and 8 hr post ingestion may start NAC while awaiting levels
-Rumack-Matthews nomogram guide for Tx in acute overdose; do not use for chronic ingestions or late ingestions
Toxic levels
-4 hr level >150 mcg/mL [993 umol/L]
-6 hr >110 mcg/mL [728 umol/L]
-8 hr >75 mcg/mL [496.5 umol/L]
-24 hr >4.5 mcg/mL [29.8 umol/L]
Acetaminophen half-life > 4 hr also may indicate toxicity
Extended release preparations (Tylenol7 "Extended Relief")
-Bi-layer caplet; each layer contains 325 mg acetaminophen
-One layer "immediate release," second layer "extended release" (up to 8 hrs; 95% released by 5 hrs)
-Peak blood levels with therapeutic doses @ 1-2 hrs; may be longer after overdose
-Requires serial levels (x2-3) as will drop and can be misleading
-Cannot use nomogram
-If suspicious, treat with NAC
-Does not qualify for new shorter course 48 hr NAC therapy
Treatment
Call poison control
1. ABCs, IV, O2, monitor
-Decrease absorption
-Do not induce emesis
2. Gastric lavage if < 1 hr post-ingestion
3. Activated charcoal if < 3 hr post-ingestion or if other coingestants
-Does not interfere with NAC administration
4. Antidote: N-acetylcysteine (NAC or Mucomyst)
-Obtain acetaminophen level at least 4 hrs after ingestion (if uncertain time, obtain level immediately and then 4hrs later; determine 1/2 life)
-Wait for level before initiating therapy if level will return within 8 hrs post-ingestion
-Plot on Rumack-Matthew nomogram; if acetaminophen level in non-toxic range, NAC not indicated
-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:
PO:
-140 mg/kg PO load
-70 mg/kg PO q4hr x17 doses additional; dilute to 5% soln
IV:
-Loading dose 150 mg/kg in 200 mL D5W over 60 min
-Second (maintenance) dose 50 mg/kg in 500 mL D5W over 4 hrs
-Third dose 100 mg/kg in 1000 mL D5W over 16 hrs
--Virtually 100% effective if given < 8 hr post-ingestion; less effective if 16-24 hr post-ingestion
--May still be useful > 24 hr post-ingestion with fulminant hepatic failure
--Do not stop when acetaminophen concentrations fall to 0: free radicals are still causing hepatic damage
--In pts who develop hepatic injury, NAC tx should be continued until liver function improves
5. May require strong anti-emetic (ondansetron 0.15 mg/kg IV, metoclopramide 20-40mg IV) or NGT if severe vomiting
6. Increase elimination
-Charcoal hemoperfusion
--Also effective in removing acetaminophen
--Not useful in usual clinical circumstances
--Indicated when pt. has fulminant hepatic encephalopathy with significant levels of acetaminophen present
7. Follow acetaminophen levels q4h, LFT, Coags
8. Evaluate potential need for liver transplant: pH<7.25, Cr >2.5, INR >4.5
Disposition
Psych hold
Admit
-Pre-school child with ingestions > 200 mg/kg
-Older child, adult w/ingestion >150 mg/kg or a total dose of 7.5 g
-Liver function abnormalities
-Delayed presentation or requirement for NAC therapy
Discharge
-Asymptomatic pts. w/o need of NAC therapy