A 22-year-old female was brought to the Emergency Department by a friend after ingesting approximately forty 325 mg acetaminophen tablets in an apparent suicide attempt four hours previously. She denied taking any other drugs or alcohol and had no known health problems. She now complains of epigastric distress and nausea, but has not vomited and has no other symptoms. On examination she is slightly diaphoretic and pale. Her vital signs are a BP of 110/60, HR 100, RR 16/min, and temperature 37 C. The rest of her examination is unremarkable.
1) Is this a potentially toxic dose of acetaminophen?
2) What would your initial management be?
3) What would you do if she ingested the same quantity over a 6 hour period?
4) What should the management be if she presented 24 hours post-ingestion?
Can the Rumack normogram be used if she ingested "Extended Relief" ( sustained release ) Tylenol
Acetaminophen
Acetaminophen is rapidly absorbed from the GI tract with peak plasma levels usually occurring at 2 hours and almost always by 4 hours. Once absorbed, acetaminophen is metabolized by the liver by glucoronidation (60%), sulfation (30 %), and a small amount (4 - 7 %) is excreted unchanged in the urine. Neither acetaminophen itself nor these metabolites are toxic. However, usually about 4 % of the ingested dose is metabolized by hepatic P450 mixed-function oxidase to an active toxic intermediate metabolite (NAPQI) which is normally detoxified by conjugation with glutathione. In overdose situations, this glutathione is rapidly depleted, and free unconjugated NAPQI binds covalently to various hepatocellullar macromolecules, producing a centrilobular hepatic necrosis, which can progress to fulminant hepatic failure.
The signs and symptoms of acetaminophen poisoning can be divided into 4 clinical phases.
- Stage 1 occurs between 0 to 24 hours and is manifested by nausea, anorexia, vomiting and diaphoresis. However, acetaminophen is one of the few drugs where the patient may appear normal with no signs and symptoms for the first 24 hours, despite the ingestion of a toxic dose. Thus all patients who present with a potential overdose of any sort should have an acetaminophen level drawn to rule out co-toxicity with acetaminophen.
Stage 2 occurs between 24 to 72 hours and is characterized by right upper quadrant pain, elevation of transaminases and the PT. There may also be deterioration of renal function.
Stage 3 is from 72 to 96 hours and is characterized by the sequelae of centrilobular hepatocellular necrosis including hepatic encephalopathy, bleeding diathesis, hypoglycemia and possible death.
Stage 4 begins at 4 days to 2 weeks during which complete resolution of hepatic dysfunction occurs if damage in phase 3 is not irreversible. In summary, acetaminophen toxicity is important because early symptoms may be subtle, and the onset of hepatotoxicity, the major manifestation, is delayed by several days following the ingestion. Failure to recognize and treat toxicity early results in significant morbidity and mortality.
The first acetaminophen level should be drawn at 4 hours post-ingestion, as levels done before this are uninterpretable because absorption and distribution of the drug may not be complete. If the patient presents greater than 24 hours post-ingestion, the level could be zero despite toxicity so liver function tests should be drawn. If a decision is made to admit and treat the patient then a CBC, PT, PTT, BUN, Creatinine, electrolytes, bilirubin, and transaminases should be drawn and repeated every 24 hours until discharge.
To interpret the serum acetaminophen level, the time of ingestion must be established as accurately as possible and the level plotted on the Rumack-Matthew normogram. When in doubt, choose the earliest possible time of ingestion (the worst case scenario). The normogram is based on single ingestion in time thus if the patient took the pills over many hours (multiple ingestions in time) choose the time when the first pills were ingested, which again is the conservative worst case scenario.
The treatment of acetaminophen overdose is relatively straightforward. As always, the first priority is assessment and stabilization of Airway, Breathing, and Circulation keeping in mind that a majority of adult overdoses are mixed overdoses. Abnormalities in vital signs or mental status usually indicate the presence of another toxin or disease state in addition to the acetaminophen ingestion. Because acetaminophen is so rapidly absorbed from the GI tract, gastric emptying is probably beneficial during the first two hours only, and activated charcoal during the first four hours post-ingestion. However, when treating a mixed ingestion, these measures might be appropriate for the coingestant even if they are not expected to be of benefit for acetaminophen.
N-acetylcysteine (NAC or Mucomyst) is the specific antidote for acetaminophen toxicity. NAC given before 8 hours post-ingestion eliminates mortality and brings morbidity to a few percent (the 8-hr window). Its efficacy diminishes beyond 8 hours, and diminished further beyond 16 hours post-ingestion. Failure to recognize and treat acetaminophen toxicity within 16 hours results in significant morbidity and mortality. NAC can be withheld pending a drug level if the results will be available within this 8-hour period. It should be given on spec if the ingestion occurred between 8 - 16 hours and then continued if the level is within toxic range.
The indications for NAC in the acute overdose are:
- Toxic level of acetaminophen on the normogram
- Ingestion > 140 mg/kg with no level available within 8 hours
- Elevated LFT’s with history of acetaminophen ingestion
- Acetaminophen induced hepatic injury
When in doubt due to multiple ingestion over time or an uncertain initial time of ingestion, give 24 hours of NAC, then check the liver function tests. The NAC can be safely discontinued if they are normal as all patients with abnormal LFT’s get them by 24 hours post ingestion.
The 24-hr protocol for NAC iv is:
150 mg/kg bolus over 15 minutes
50 mg/kg over 4 hours
100 mg/kg over 16 hours.
NAC should also be initiated even beyond 24 hours if there are toxic levels of acetaminophen or evidence of overt hepatotoxicity. In addition to its traditional mechanisms of action as a glutathione substitute, which binds NAPQI, NAC may also have an antioxidant effect and an effect on the hepatic microcirculation to improve hepatocellular oxygenation. There is now evidence that the late (> 24 hours) administration of NAC decreases mortality and morbidity in acetaminophen induced fulminant hepatic failure and that NAC should be continued until recovery occurs. It should not be forgotten that liver transplantation is a viable option in severe cases.
Acetaminophen
Poor prognostic signs ( early indicators )
pH < 7.3
Cr > 330
PT > 1.8 normal
grade III/IV encephalopathy
- time to APAP ( 8< 16 < 24 H )
- high bili is inversely correlated ( have to live longer to get level up )
- chronic alcoholics generally have low glutathione stores, revved up P450, poor nutritional stores, but no solid date that alcoholics are at increased risk, use the same normogram for each
- liver enzymes usually do not increase for 24 hours in APAP hepatitis, peaks at 3 - 4 days, then drops rapidly if regenerating liver, drops slowly in burnt out liver
PT and bili will lag behind but continue to go sky high
Pathophysiology
- APAP - glucoronidation ( 60 % )
sulphation ( 30 % ) - major route in kids
unchanged in urine ( 6 % )
all the above are non-toxic
P450 - NAPQI + glutathione - urine ( more in alcoholics, phenobarb, DPH )
- NAPQI - electrophilic, oxidant produced by P450
binds to hepatocytes leading to cell lysis with release of transaminases
centrolobular necrosis ( highest metabolic activity and furthest distance from periportal blood supply
detoxified by conjugation with glutathione and excreted in urine as cysteine and
mercapturic acid conjugates
Clinical phases
1) 0 - 24 hours
n,v,anorexia, pallor, malaise, diaphoresis if large amounts
may appear normal
2) 24 - 72 hrs
becomes better ( symptomology less pronounced )
RUQ pain, elevation of LFT and PT
deterioration of renal fn, but low BUN due to decreased hepatic urea formation
3) 72 - 96 hrs
centrilobular hepatocellular necrosis
hepatic encephalopathy, bleeding diathesis, hypoglycemia
coagulation defects, jaundice, renal failure, myocardial pathology
ARF, possible death
4) 4 days - 2 weeks
complete resolution of hepatic dysfn
Diagnosis
- level at 4 hours then repeat Q4H
- CBC, SMAC, LFT, bili, glucose, PT, PTT, INR
- if toxic, repeat q 24 h
Normogram
- based on single ingestion in time
- rapidly absorbed ( 30 - 120 minutes )
- peak usually at 2 hours, almost always by 4 hours
- line has nothing to do with APAP metabolism, only with prognostic implications
- already has 25 % error margin built in
- don’t belong on normogram
multiple ingestion in time
unknown time period
1) late with abnormal LFT and APAP level 0 = Rx
2) takes more than 150 mg/kg ( 12.5 gm ) in 24 hr period
3) assume all taken at pt A to assume worse case senario
4) toxic dose is 7.5 gm ( 140 mg/kg in adults )
- when in doubt about multiple ingestants give 24 hrs of NAC, then check LFT, d/c if normal
- all pt with abnormal LFT get them by 24 hrs
Indications for NAC
Acute
- toxic level
- ingestion > 140 mg/kg with no level available within 8 hours
- elevated LFT’s with Hx of APAP ingestion
- APAP induced hepatic injury
Chronic
- Hx of more than recommended daily dose for several days and
elevated LFT
persistant vomiting
serum level inconsistant with therapeutic dose
- Prescott suggested in 1971 that pats with hepatic necrosis almost always had a T1/2 greater than 4 hours but not known how NAC changes pharmacokinetics ( !st order ) ; the administration of NAC in uncertain cases takes precedance
- when time not known, treat if PT, LFT are up with a positive level
Treatment
- ABC - abnormalities suggsest co-ingestants
- gastric emptying - probably of little benefit after 2 hours ( unless co-ingestant )
- charcoal- inhibits absorption if given within 4 hours
- NAC before 8 hours eliminates mortality and brings morbidity to few % ( 8 hr window )
give on spec if ingestion between 8 - 16 hours
as soon as possible for every patient
toxic range on normogram
more aggressive with alcoholics
- keep giving until better in severe intox ( no arbitrary time frame )
- benign drug, no time is too late
NAC
1) acts as glutathione substitute
2) enhances synthesis of glutathione, regenerates glutathione
3) enhances metabolism through sulfation pathway(sulphation is sulphur dependant and may serve as a sulphur donor)
4) antioxidant
has sulfhydryl groups and binds directly
increased hepatic blood flow and O2 extraction
may interefere with WBC migration in the liver
- 20 hr protocol :
150 mg/kg bolus over 15 minutes
50 mg/kg over 4 hrs
100 mg/kg over 16 hrs
- 48 hr protocol
140 mg/kg
70 mg/kg q4h x 48 hrs
References: Acetaminophen
1) Keays R, Harrison P, et al: Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: A prospective controlled trial. Br Med J 303:1026-1029, 1991
2) Harrison P, Keays R, et al: Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet 1:1572-1753, 1990
3) Harrison P, Wendon J et al: Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med: 324:1852-1857,1991
4) Douglas DR, et al: A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs. Regular Tylenol). Acad Emerg Med 103(8):740, 1996