Clinical Effects
USES: Acetaminophen is a mild analgesic and antipyretic. It is available as a non-prescription single ingredient product, in many non-prescription combination products, and in prescription combination products (usually with an opioid). PHARMACOLOGY: The exact mechanism of action is not known. Acetaminophen inhibits cyclooxygenase and this likely is responsible for at least some clinical effects. TOXICOLOGY: In overdose, the usual metabolic pathways are overwhelmed, and acetaminophen is metabolized by CYP2E1 to a reactive metabolite. This metabolite can be detoxified by conjugation with glutathione, but when hepatic glutathione stores are depleted, the metabolite binds to macromolecules in the hepatocyte causing cell death and hepatic necrosis. EPIDEMIOLOGY: Acetaminophen overdose is very common, and there are several hundred deaths from acetaminophen poisoning annually in the United States. MILD TO MODERATE TOXICITY: For the first day after ingestion, patients may be asymptomatic, or only develop nausea, vomiting and abdominal pain. Elevation of serum transaminase (ALT, AST) may begin to develop about 24 hours after ingestion and can range from mild to marked (greater than 10,000 international units/L) with few other signs or symptoms. Aminotransferase elevations generally peak 2 to 3 days after ingestion. SEVERE TOXICITY: Liver failure, including coagulopathy and hepatic encephalopathy, will occur. Patients may also have renal injury. Massive overdose (initial serum concentration greater than 500 mcg/mL) can produce coma, hyperglycemia and lactic acidosis In patients who survive the overdose, both hepatic and renal function return to normal. ADVERSE EFFECTS: Generally rare. Some patients may have gastrointestinal upset.
Treatment of Acetaminophen
Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Patients who present with a potential ingestion of more than 150 mg/kg or 7.5 g (whichever is less) must have a serum acetaminophen concentration determined. If the time of ingestion is known and the acetaminophen concentration is measured between 4 and 20 hours post-ingestion, the patient can be risk stratified using the Rumack-Matthew Nomogram. If it is not possible to measure the serum acetaminophen concentration in a timely manner (results available within 2 hours), start treatment with acetylcysteine . Patients who have an acetaminophen above the possible toxicity line (the line starting at 150 mcg/mL at 4 hours) should be treated with acetylcysteine. Patients who present with a history suggestive of acetaminophen exposure and an unknown time of ingestion should be treated with acetylcysteine if they have a detectable serum acetaminophen concentration OR if they have elevated serum transaminases. There is some debate as to the effect of coingestion of medications that decrease gastrointestinal motility (anticholinergic and opioids) may have on the reliability of a 4-hour acetaminophen concentration for risk stratification. Some experts recommend obtaining a second acetaminophen concentration 8 hours postingestion and starting acetylcysteine if either concentration is above the possible toxicity line. Similar recommendations have been made regarding sustained release acetaminophen products. MANAGEMENT OF SEVERE TOXICITY: Patients who present late after an acute acetaminophen ingestion (greater than 36 hours) may have significant liver injury and even liver failure (INR greater than 1.5, acidosis or encephalopathy). Intubate patients with altered mental status and resuscitate hypotensive patients with crystalloid and adrenergic vasopressors. Treat coagulopathic patients who are bleeding with fresh frozen plasma. Patients with renal failure may require renal replacement therapy. Administer intravenous acetylcysteine to all patients with liver injury. Patients with hepatic encephalopathy, acidosis or significant coagulopathy (INR greater than 5) should be evaluated for liver transplantation. Patients who present early following a massive ingestion (serum acetaminophen concentration greater than 500 mcg/mL) may have coma, metabolic acidosis and hyperglycemia with normal serum transaminases. These patients generally recover with supportive care (airway management, fluid resuscitation) and early acetylcysteine therapy.
Decontamination: PRE-HOSPITAL: Consider activated charcoal in the pre-hospital setting if the patient is awake and can protect their airway. Pre-hospital ipecac should be avoided as it may interfere with oral acetylcysteine therapy. HOSPITAL: Administer activated charcoal for all substantial, recent ingestions if the patient is awake and can protect their airway. Retrospective data suggest that administration of activated charcoal up to 2 hours post-ingestion decreases the proportion of patients who will require acetylcysteine therapy.
Antidote: Acetylcysteine should be administered to any patient at risk for hepatic injury (either serum acetaminophen concentration above the possible toxicity line on the Rumack-Matthew Nomogram, or history of ingesting more than 150 mg/kg or 7.5 g (whichever is less) and serum concentration not available or time of ingestion not known) and to patients who have hepatic injury and a history of acetaminophen overdose. ORAL: 140 mg/kg loading dose followed by 70 mg/kg every 4 hours. The FDA-approved protocol is for 72 hours (17 maintenance doses); however, many toxicologists will stop therapy early in patients who do not develop toxicity and may continue therapy beyond 72 hours for patients who develop significant toxicity. Please contact your local poison center for guidance. INTRAVENOUS: 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hour infusion. The FDA-approved protocol is for 16 hours of treatment at 6.25 mg/kg/hr (a total of 100 mg/kg). However, many toxicologists recommend checking serum transaminases and serum acetaminophen concentration prior to stopping therapy. If the transaminases are elevated or if the serum acetaminophen concentration is still detectable, the maintenance infusion is often continued until acetaminophen is not detectable and liver enzymes and INR are improving, and the patient is clinically improving. Contact your local poison center for guidance. LIVER FAILURE: Treat patients with liver failure with intravenous acetylcysteine 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hour infusion until resolution of encephalopathy, decreasing serum transaminase, and improving coagulopathy.
Monitoring of patient: Patients who present early (within 8 hours of ingestion) only require a serum acetaminophen determination. In those patients who require acetylcysteine treatment, liver enzymes, serum electrolytes, and renal function should be monitored. Patients who present with an unknown time of ingestion or more than 8 hours after an ingestion should have a serum acetaminophen determination, electrolyte measurements, renal function tests, liver enzymes, and an INR.
Enhanced elimination procedure: Hemodialysis clears acetaminophen, but it is not routinely used, since acetylcysteine is an effective antidote.
Patient disposition: HOME CRITERIA: For inadvertent ingestions, children who have ingested less than 200 mg/kg and adults who have ingested less than 150 mg/kg (maximum of 7.5 g) may be managed at home. OBSERVATION CRITERIA: Patients who have non-toxic acetaminophen concentrations can be discharged with appropriate psychiatric care after an appropriate observation period.
ADMISSION CRITERIA: Patients who require treatment with acetylcysteine are generally admitted to the hospital. Patients with acute liver failure should be admitted to an ICU and may require transfer to a facility with liver transplant criteria. CONSULT CRITERIA: Contact your poison center for patients who have an unknown time of ingestion, and elevated serum transaminases or a detectable serum acetaminophen concentration. Contact a liver transplant center for patients with hepatic encephalopathy, acidosis or severe coagulopathy.
Range Of Toxicity
TOXICITY: ADULT: greater than 150 mg/kg OR more than 7.5 g, whichever is less. PEDIATRIC: greater than 200 mg/kg or 10 g, whichever is less. THERAPEUTIC DOSE: ADULT: 650 to 1000 mg every 4 hours up to 4 g/day. PEDIATRIC: 10 to 15 mg/kg every 4 hours up to 60 mg/kg/day.
USES: Acetaminophen is a mild analgesic and antipyretic. It is available as a non-prescription single ingredient product, in many non-prescription combination products, and in prescription combination products (usually with an opioid). PHARMACOLOGY: The exact mechanism of action is not known. Acetaminophen inhibits cyclooxygenase and this likely is responsible for at least some clinical effects. TOXICOLOGY: In overdose, the usual metabolic pathways are overwhelmed, and acetaminophen is metabolized by CYP2E1 to a reactive metabolite. This metabolite can be detoxified by conjugation with glutathione, but when hepatic glutathione stores are depleted, the metabolite binds to macromolecules in the hepatocyte causing cell death and hepatic necrosis. EPIDEMIOLOGY: Acetaminophen overdose is very common, and there are several hundred deaths from acetaminophen poisoning annually in the United States. MILD TO MODERATE TOXICITY: For the first day after ingestion, patients may be asymptomatic, or only develop nausea, vomiting and abdominal pain. Elevation of serum transaminase (ALT, AST) may begin to develop about 24 hours after ingestion and can range from mild to marked (greater than 10,000 international units/L) with few other signs or symptoms. Aminotransferase elevations generally peak 2 to 3 days after ingestion. SEVERE TOXICITY: Liver failure, including coagulopathy and hepatic encephalopathy, will occur. Patients may also have renal injury. Massive overdose (initial serum concentration greater than 500 mcg/mL) can produce coma, hyperglycemia and lactic acidosis In patients who survive the overdose, both hepatic and renal function return to normal. ADVERSE EFFECTS: Generally rare. Some patients may have gastrointestinal upset.
Treatment of Acetaminophen
Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Patients who present with a potential ingestion of more than 150 mg/kg or 7.5 g (whichever is less) must have a serum acetaminophen concentration determined. If the time of ingestion is known and the acetaminophen concentration is measured between 4 and 20 hours post-ingestion, the patient can be risk stratified using the Rumack-Matthew Nomogram. If it is not possible to measure the serum acetaminophen concentration in a timely manner (results available within 2 hours), start treatment with acetylcysteine . Patients who have an acetaminophen above the possible toxicity line (the line starting at 150 mcg/mL at 4 hours) should be treated with acetylcysteine. Patients who present with a history suggestive of acetaminophen exposure and an unknown time of ingestion should be treated with acetylcysteine if they have a detectable serum acetaminophen concentration OR if they have elevated serum transaminases. There is some debate as to the effect of coingestion of medications that decrease gastrointestinal motility (anticholinergic and opioids) may have on the reliability of a 4-hour acetaminophen concentration for risk stratification. Some experts recommend obtaining a second acetaminophen concentration 8 hours postingestion and starting acetylcysteine if either concentration is above the possible toxicity line. Similar recommendations have been made regarding sustained release acetaminophen products. MANAGEMENT OF SEVERE TOXICITY: Patients who present late after an acute acetaminophen ingestion (greater than 36 hours) may have significant liver injury and even liver failure (INR greater than 1.5, acidosis or encephalopathy). Intubate patients with altered mental status and resuscitate hypotensive patients with crystalloid and adrenergic vasopressors. Treat coagulopathic patients who are bleeding with fresh frozen plasma. Patients with renal failure may require renal replacement therapy. Administer intravenous acetylcysteine to all patients with liver injury. Patients with hepatic encephalopathy, acidosis or significant coagulopathy (INR greater than 5) should be evaluated for liver transplantation. Patients who present early following a massive ingestion (serum acetaminophen concentration greater than 500 mcg/mL) may have coma, metabolic acidosis and hyperglycemia with normal serum transaminases. These patients generally recover with supportive care (airway management, fluid resuscitation) and early acetylcysteine therapy.
Decontamination: PRE-HOSPITAL: Consider activated charcoal in the pre-hospital setting if the patient is awake and can protect their airway. Pre-hospital ipecac should be avoided as it may interfere with oral acetylcysteine therapy. HOSPITAL: Administer activated charcoal for all substantial, recent ingestions if the patient is awake and can protect their airway. Retrospective data suggest that administration of activated charcoal up to 2 hours post-ingestion decreases the proportion of patients who will require acetylcysteine therapy.
Antidote: Acetylcysteine should be administered to any patient at risk for hepatic injury (either serum acetaminophen concentration above the possible toxicity line on the Rumack-Matthew Nomogram, or history of ingesting more than 150 mg/kg or 7.5 g (whichever is less) and serum concentration not available or time of ingestion not known) and to patients who have hepatic injury and a history of acetaminophen overdose. ORAL: 140 mg/kg loading dose followed by 70 mg/kg every 4 hours. The FDA-approved protocol is for 72 hours (17 maintenance doses); however, many toxicologists will stop therapy early in patients who do not develop toxicity and may continue therapy beyond 72 hours for patients who develop significant toxicity. Please contact your local poison center for guidance. INTRAVENOUS: 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hour infusion. The FDA-approved protocol is for 16 hours of treatment at 6.25 mg/kg/hr (a total of 100 mg/kg). However, many toxicologists recommend checking serum transaminases and serum acetaminophen concentration prior to stopping therapy. If the transaminases are elevated or if the serum acetaminophen concentration is still detectable, the maintenance infusion is often continued until acetaminophen is not detectable and liver enzymes and INR are improving, and the patient is clinically improving. Contact your local poison center for guidance. LIVER FAILURE: Treat patients with liver failure with intravenous acetylcysteine 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hour infusion until resolution of encephalopathy, decreasing serum transaminase, and improving coagulopathy.
Monitoring of patient: Patients who present early (within 8 hours of ingestion) only require a serum acetaminophen determination. In those patients who require acetylcysteine treatment, liver enzymes, serum electrolytes, and renal function should be monitored. Patients who present with an unknown time of ingestion or more than 8 hours after an ingestion should have a serum acetaminophen determination, electrolyte measurements, renal function tests, liver enzymes, and an INR.
Enhanced elimination procedure: Hemodialysis clears acetaminophen, but it is not routinely used, since acetylcysteine is an effective antidote.
Patient disposition: HOME CRITERIA: For inadvertent ingestions, children who have ingested less than 200 mg/kg and adults who have ingested less than 150 mg/kg (maximum of 7.5 g) may be managed at home. OBSERVATION CRITERIA: Patients who have non-toxic acetaminophen concentrations can be discharged with appropriate psychiatric care after an appropriate observation period.
ADMISSION CRITERIA: Patients who require treatment with acetylcysteine are generally admitted to the hospital. Patients with acute liver failure should be admitted to an ICU and may require transfer to a facility with liver transplant criteria. CONSULT CRITERIA: Contact your poison center for patients who have an unknown time of ingestion, and elevated serum transaminases or a detectable serum acetaminophen concentration. Contact a liver transplant center for patients with hepatic encephalopathy, acidosis or severe coagulopathy.
Range Of Toxicity
TOXICITY: ADULT: greater than 150 mg/kg OR more than 7.5 g, whichever is less. PEDIATRIC: greater than 200 mg/kg or 10 g, whichever is less. THERAPEUTIC DOSE: ADULT: 650 to 1000 mg every 4 hours up to 4 g/day. PEDIATRIC: 10 to 15 mg/kg every 4 hours up to 60 mg/kg/day.
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Unknown - Wednesday, 20 April 2011
