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Acetaminophen Toxicity Author: Susan E Farrell, MD; Chief Editor: Asim Tarabar, MD Updated: Feb 6, 2012 Background Because acetaminophen (APAP) is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world (contained in >100 products), it is reported by the American Association of Poison Control Centers to be one of the most common pharmaceuticals associated with both intentional and unintentional poisoning and toxicity. Acetaminophen toxicity is the most common cause of hepatic failure requiring liver transplantation in Great Britain. In the United States, APAP toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and is the second most common cause of liver failure requiring transplantation. Acetaminophen is also known as paracetamol and N -acetyl-p-aminophenol (APAP). This agent is available in the United States as 325-mg and 500-mg immediate-release (IR) tablets, and as a 650-mg extended-release (ER) preparation marketed for the treatment of arthritis. Various children's dissolvable, chewable, suspension, and elixir formulations of APAP are available. Acetaminophen is a component of many over-the-counter (OTC) cold and analgesic medications and prescription combinations, including codeine-acetaminophen (Tylenol #3) and oxycodone-acetaminophen (Percocet). In an attempt to decrease the risks of potential APAP toxicity in the United States, a number of pharmaceutical regulatory changes have been introduced. In 2009, the US Food and Drug Administration (FDA) required that nonprescription and prescription APAP-containing medications provide information regarding the risks of APAP-induced hepatotoxicity.[1, 2] The FDA is considering the removal of APAP from some popular analgesic combination products (Vicodin) and possibly decreasing the recommended maximum daily dose. The FDA is also considering other changes to APAP-related recommendations, including the following: Safe daily dose for healthy individuals Safe daily dose in chronic liver disease Safe daily dose when used with alcohol Appropriate dose for efficacy Package size restrictions Pediatric dosing Acetaminophen narcotic combinations In January 2011, the FDA announced it was asking manufacturers of prescription APAP combination products to limit the maximum amount of the drug in these products to 325 mg per tablet, capsule, or other dosage unit.[3] The FDA believes that such a limitation will reduce the risk of hepatoxicity, liver failure, and death related to APAP overdose.[3] See also Liver Transplants, Liver Transplantation, Pediatric Acetaminophen Toxicity, Pediatric Liver Transplantation, and Transfusion Requirements in Liver Transplantation. Etiology and Pathophysiology Production of the toxic metabolite of acetaminophen (APAP), N -acetyl-p-benzoquinone imine (NAPQI), in excess of an adequate store of conjugating glutathione, is associated with hepatocellular damage, necrosis, and hepatic failure. Additional mechanisms of acetaminophen-induced toxicity are also postulated. Currently, the maximum recommended daily dose of APAP is 4 g in adults and 90 mg/kg in children. Toxicity is associated with a single acute APAP ingestion of 150 mg/kg or approximately 7-10 g in adults. The ingested amount at which toxicity may occur may be lower in the settings of chronic ethanol use or diminished nutritional states, fasting, or viral illness with dehydration, or if substances or medications that are known to induce the activity of the APAP-metabolizing cytochrome P (CYP) oxidative enzymes are concurrently being ingested. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small. Acetaminophen APAP is rapidly absorbed from the stomach and small intestine and primarily metabolized by conjugation in the liver to nontoxic, water-soluble compounds that are eliminated in the urine. In acute overdose or when the maximum daily dose is exceeded over a prolonged period, metabolism by conjugation becomes saturated, and excess APAP is oxidatively metabolized by the CYP enzymes (CYP2E1, 1A2, 2A6, 3A4) to the reactive metabolite NAPQI. NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and is renally excreted. Under conditions of excessive NAPQI formation, or a reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins, forming NAPQI-protein adducts. This causes an ensuing cascade of oxidative damage and mitochondrial dysfunction. The subsequent inflammatory response propagates hepatocellular injury, death, and centrilobular (zone III) liver necrosis. Similar enzymatic reactions occur in extrahepatic organs, such as the kidney, and can contribute to some degree of extrahepatic organ dysfunction. The antidote for APAP poisoning is N -acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. This agent is a precursor of glutathione and, as such, increases the concentration of glutathione available for the conjugation of NAPQI. NAC also enhances sulfate conjugation of unmetabolized APAP, functions as an antiinflammatory and antioxidant, and has positive inotropic effects. In addition, NAC increases local nitric oxide concentrations and promotes microcirculatory blood flow, enhancing local oxygen delivery to peripheral tissues. The microvascular effects of NAC therapy are associated with a decrease in morbidity and mortality, even when NAC is administered in the setting of established hepatotoxicity. NAC is maximally hepatoprotective when administered within 8 hours of an acute APAP ingestion. When indicated, however, NAC should be administered, regardless of the time since the overdose. Therapy with NAC has been shown to decrease mortality rates in latepresenting patients with fulminant hepatic failure, even in the absence of measurable serum APAP levels. Prognosis With aggressive supportive care and antidotal therapy, the mortality rate associated with acetaminophen (APAP) hepatotoxicity is less than 2%. If correctly treated in a timely manner, most patients do not suffer significant sequelae; thus, patients who survive should be expected to have a return of normal hepatic function. Case series report that fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or the need for liver transplantation occurs in less than half of these patients. Patients with chronic ethanol use or diminished nutritional status may be at increased risk for morbidity because of deficient glutathione stores and a subsequent inability to conjugate and detoxify NAPQI. Patients who use substances that are known to induce the activity of the APAP-metabolizing oxidative cytochrome P (CYP) enzymes, CYP2E1, CYP1A2, CYP2A6, or CYP3A4, may be at increased risk of morbidity due to the enhanced production of NAPQI. Agents and substances that induce CYP enzyme activity are numerous but include rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, chronic ethanol ingestion, and tobacco use. Pediatric patients younger than 5 years appear to fare better than adults after acute APAP poisoning, perhaps owing to a greater capacity to conjugate APAP through sulfation, enhanced detoxification of NAPQI, or greater glutathione stores. However, as no controlled studies have supported an alternative pediatric-specific therapy, treatment in children should be the same as in adults. A number of screening measurements have been studied as prognostic indicators of poor outcome after APAP ingestion, subsequently necessitating liver transplantation. The most widely used of these predictors are the King’s College Criteria, which have been wellvalidated for the prediction of poor outcome and need for liver transplantation after an isolated APAP overdose. The criteria consist of the following laboratory abnormalities, any one of which should prompt urgent transplantation consultation: pH less than 7.30 after fluid resuscitation Creatinine level greater than 3.3 mg/dL Prothrombin time (PT) greater than 1.8 time control or PT greater than 100 seconds or international normalized (INR) greater than 6.5) Grade III or higher encephalopathy Other prognostic screening tools that have been studied in regard to prediction of the need for liver transplantation include the Acute Physiology and Chronic Health Evaluation II (APACHE II) score of a patient on the first hospital day.[4] This study found that the APACHE II score was found to be accurate but cumbersome to apply. Alternative early predictors also include changes in serum phosphate, an indirect representation of the balance between the development of renal failure and hepatic regeneration. Serum phosphate concentrations greater than 1.2 mmol/L measured at 48-96 hours after overdose were sensitive and specific for increased mortality.[5] Finally, elevations in blood lactate have also been studied as prognostic indicators after acute APAP overdose.[6] Blood lactate levels greater than 3.5 mmol/L before fluid resuscitation or greater than 3 mmol/L after fluid resuscitation were found to be sensitive and specific indicators of survival. In comparison with the King’s College Criteria, there was not significant difference in the time to early identification of patients who required transplantation. In summary, a number of laboratory and clinical findings can facilitate the early identification of patients who have overdosed on APAP and will be at high risk of death without liver transplantation. A number of these indicators require further study. For those patients who develop critical illness, consult a regional poison control center for guidance and consider early transfer and consultation with a transplantation center. Patient Education Because acetaminophen (APAP) is commonly considered an innocuous over-the-counter (OTC) drug, it is important to advise patients of the potential risks associated with the inappropriate use of APAP. Educate parents of the proper APAP dosing for children and the danger associated with misusing various APAP preparations of different concentrations (eg, infant suspension vs pediatric elixir, pediatric vs adult suppositories). Because the infant suspension (drops) is a more concentrated formulation than the elixirs (100 mg/mL vs 32 mg/Ml, respectively), misuse can be a potential source of therapeutic error. Parents should always be given clear dose and formulation instructions based on the age and weight of the child. Parents should also be instructed to carefully examine OTC medications that may contain APAP in combination formulations. Educate patients of the increased potential for renal toxicity associated with concurrent APAP and nonsteroidal anti-inflammatory drug (NSAID) analgesic use, or chronic ethanol use. For patient education information, see Acetaminophen (Tylenol) Poisoning and Poisoning. The US Food and Drug Administration (FDA) has patient and caregiver education resources through its Consumer Health Information Website. History and Physical Examination The clinical course of acetaminophen (APAP) toxicity generally is divided into 4 phases. Physical examination findings may vary, depending on the phase of toxicity. Clinical evidence of end-organ toxicity is often delayed 24-48 hours after an acute ingestion. Because antidotal therapy is most effective when initiated within 8 hours after an ingestion, it is important to obtain an accurate history of the time(s) of ingestion, the quantity, and the formulation of APAP ingested. In addition, the history should include any co-ingestants, which may delay APAP absorption (eg, anticholinergic drugs or opioids). The serum APAP concentration is the basis for diagnosis and treatment, even in the absence of symptoms. After a single ingestion, N -acetylcysteine (NAC) therapy is guided by the serum APAP concentration. See the image below. Semilogarithmic plot of plasma acetaminophen levelSemilogarithmic plot of plasma acetaminophen levels vs time. From: Rumack BH, Matthew H. Acetaminophen Poisoning and Toxicity. Pediatrics. 1975 (55)871-876. Phase 1 (0-24 h) Patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise. Physical examination may reveal pallor and diaphoresis. A subclinical rise in serum transaminase levels begins approximately 12 hours after an acute ingestion. Phase 2 (18-72 h) Patients generally develop right upper quadrant abdominal pain, anorexia, nausea, and vomiting. Right upper quadrant tenderness, tachycardia, and hypotension may be present. There is a continued rise in serum transaminase levels. Phase 3 (72-96 h) Patients may have continued nausea and vomiting, abdominal pain, and a tender hepatic edge. Hepatic necrosis and dysfunction are associated with jaundice, coagulopathy, hypoglycemia, and hepatic encephalopathy. Acute renal failure develops in some critically ill patients. Death from multiorgan failure may occur. Phase 4 (4 d to 3 wk) Patients who survive critically illness in Phase 3 have complete resolution of symptoms and complete resolution of organ failure. Diagnostic Considerations The diagnosis of acetaminophen (APAP) ingestion and potential toxicity is based on obtaining a history of APAP ingestion and the measurement of a potentially toxic serum APAP concentration. Acetaminophen ingestion should be considered as a potential cause of illness in patients who present with hepatic dysfunction of unknown etiology. The differential diagnosis for the clinical presentation of a patient with suspected APAP toxicity includes such conditions as vomiting of unclear etiology, hepatic failure and acute liver failure of unknown etiology, and hepatorenal syndrome. Differential Diagnoses Acute Tubular Necrosis Amatoxin Toxicity in Emergency Medicine Bacterial Gastroenteritis Ethanol-Induced Hepatitis Other Hepatotoxic Exposures Pancreatitis Pediatric Amatoxin Toxicity Peptic Ulcer Disease Viral Gastroenteritis Viral Hepatitis in Emergency Medicine Approach Considerations Obtain an electrocardiogram in order to exclude the presence of cardioactive substances/coingestants. In females of childbearing age, obtain levels of human chorionic gonadotropin (HCG).[7] Acetaminophen crosses the placenta, and the fetal liver is able to elaborate NAPQI by 14 weeks of gestation. A delay in treating pregnant patients with antidotal therapy is associated with fetal demise. Obtain a type and cross-match in the event of coagulopathy and active bleeding. Perform a urinalysis to assess the presence of proteinuria and hematuria, which may be seen with acute tubular necrosis, sometimes occurring in conjunction with hepatic failure. Obtain an arterial blood gas evaluation. A pH of less than 7.3 is one laboratory indicator predictive of mortality. Consider computed tomography (CT) scanning of the brain in patients with altered mental status. This study may reveal cerebral edema in patients with late presentation and encephalopathy. If clinically indicated, abdominal ultrasonography may reveal mild hepatic enlargement in late-presenting patients. Gastric lavage has no proven efficacy in isolated acetaminophen (APAP) overdose. Pediatric Acetaminophen Toxicity Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Timothy E Corden, MD Updated: Sep 23, 2011 Background It is not surprising that acetaminophen toxicity is a relatively common occurrence, particularly in children, given that this drug is the most widely used analgesic-antipyretic medication taken by people in the United States and around the world.[1] Since the 1950s, the availability of acetaminophen in over-the-counter (OTC) preparations and the contraindication of pediatric use for aspirin-containing products have made acetaminophen one of the most commonly used drugs in pediatric medicine. Acetaminophen is available in more than 200 OTC and prescription medications as a single agent or in combination with other pharmaceuticals. Numerous formulations and preparations are also available and include liquids, tablets, caplets, capsules, and suppositories in immediate-release and sustained-release forms. Acetaminophen, or paracetamol, is also known by its chemical name, N -acetyl-p aminophenol (APAP). It has an excellent safety profile when administered in proper therapeutic doses, but hepatotoxicity can occur with misuse and overdoses. N -acetylcysteine (NAC) is an effective antidote for acetaminophen-induced hepatotoxicity due to an acute overdose, especially if administered within 8-10 hours after ingestion.[2] Acetaminophen (APAP) metabolism is illustrated in the image below. Acetaminophen metabolism. Acetaminophen metabolism. Not only is acetaminophen (APAP) the drug most commonly ingested in overdoses, it is also a common co-ingestant. Owing to its widespread availability and the underestimation of its potential toxicity, acetaminophen (APAP) poisoning is the most common cause of acute liver failure and overdose deaths. In Great Britain, acetaminophen (APAP) toxicity is cited as the most common etiology of hepatic failure requiring liver transplantation. Overdose with this agent can present at any age. A therapeutic misadventure typically occurs in patients younger than 1 year when caregivers give improper doses of a medication that contains acetaminophen (APAP) to a child. An accidental poisoning (unintentional ingestion) can occur in toddlers and young children. Older patients (eg, teenagers and adults) may overdose with intent to do self-harm. See also Acetaminophen Toxicity, Pediatric Liver Transplantation, Liver Transplantation, and Transfusion Requirements in Liver Transplantation. Pathophysiology Therapeutic oral doses of acetaminophen (APAP) are rapidly absorbed by the gastrointestinal (GI) tract, with body serum levels peaking at 0.5-2 hours postingestion. Therapeutic levels are 10-20 mcg/mL (66-132 mcmol/L). Serum peak levels occur after an overdose within 4 hours postingestion for an immediate-release preparation. Co-ingestion with drugs that delay gastric emptying (such as opiates, anticholinergic agents) or ingestion of an acetaminophen (APAP) extended-release formulation may increase the peak serum level to more than 4 hours postingestion. The elimination half-life of acetaminophen is estimated to be 2-4 hours. Metabolism of acetaminophen (APAP) is primarily hepatic. The liver metabolizes more than 90% of an acetaminophen (APAP) dosage to sulfate and glucuronide conjugates, which are water soluble and are then eliminated in the urine. Sulfation is the primary metabolic pathway in children aged 12 years and younger. Glucuronidation predominates in adolescents and adults. Two percent of an acetaminophen (APAP) dose is excreted unchanged by the kidneys. The remaining acetaminophen (APAP) is metabolized by the hepatic cytochrome P450 (CYP450) system to form a reactive, highly toxic metabolite known as N -acetyl-p benzoquinone imine (NAPQI) (see the following image). Glutathione binds NAPQI, enabling the excretion of nontoxic mercapturate conjugates in the urine. Acetaminophen metabolism. Acetaminophen metabolism. Therapeutic doses of acetaminophen (APAP) do not cause hepatic injury; however, because hepatic glutathione stores are depleted (by 70-80%) in an overdose, NAPQI cannot be detoxified and covalently binds to the lipid bilayer of hepatocytes, causing hepatic centrilobular necrosis. Necrosis primarily occurs in this hepatic region due to the greater production of NAPQI by these cells. Glutathione stores to enable metabolism of this toxic metabolite are replaced by sulfhydryl compounds from the diet (eg, fruits and vegetables) or from drugs, such as the antidote, N -acetylcysteine (NAC). Age, diet, liver disease, and medical conditions (eg, malnutrition due to prolonged fasting, gastroenteritis, chronic alcoholism, or human immunodeficiency virus (HIV) disease) affect glutathione stores in the body. Ethanol and drugs such as isoniazid (INH), rifampin, phenytoin, phenobarbital, barbiturates, carbamazepine, trimethoprim-sulfamethoxazole (TMP-SMX), and zidovudine induce CYP2E1 enzymes (part of the CYP450 system). Activation of the cytochrome system increases the production of NAPQI and, therefore, can increase the risk of hepatocellular injury in patients who ingest these agents. Herbal supplements may also play a role in amplifying the risk for acetaminophen (APAP)–induced hepatic injury. Etiology Production of N -acetyl-p -benzoquinone imine (NAPQI) by the cytochrome P (CYP) system is the cause of liver toxicity in acetaminophen (APAP) overdose. Maximum APAP dosages The maximum daily adult dose of acetaminophen (APAP) is 4 g with a recommended dosage of 352-650 mg every 4-6 hours or 1 g every 6 hours. For children younger than 12 years and/or less than 50 kg in weight, the maximum daily dosage of acetaminophen (APAP) is 80 mg/kg (not to exceed a cumulative daily dose of 2.6 g). Therapeutic weight-based oral dosing for children younger than 12 years is 10-15 mg/kg every 4-6 hours with a maximum of 5 doses per 24-hour period. Weight-based rectal suppository dosing for children is higher at 15-20 mg/kg per dose. Minimum APAP dosages In adults, the minimum toxic dose of acetaminophen (APAP) for a single ingestion is 7.5-10 g. Single ingestions of 12 g or higher have high potential for hepatotoxicity. In children, the minimum toxic dose of acetaminophen (APAP) for a single acute ingestion is 150 mg/kg. Medical toxicologists recommend increasing this threshold to 200 mg/kg in healthy children aged 1-6 years. Children in this age group are less susceptible to hepatotoxicity due to acute acetaminophen (APAP) poisoning because of their relatively larger hepatic mass (ie, ratio of organ weight to total body weight), which efficiently eliminates and detoxifies N -acetyl-p -benzoquinone imine (NAPQI). Toxic APAP dosages Children who have acutely ingested 250 mg/kg or more of acetaminophen (APAP) pose significant concern for acetaminophen (APAP)-induced hepatotoxicity. Patients who ingest more than 350 mg/kg develop severe hepatotoxicity, if they are not appropriately treated. In June 2009, the US Food and Drug Administration (FDA) announced requirements for nonprescription and prescription medication to provide new information regarding acetaminophen (APAP)–induced hepatotoxicity.[3, 4, 5] Additionally, the FDA is: (1) examining possible removal of acetaminophen (APAP) from some popular analgesic combination products (eg, Vicodin) and/or lowering the maximum cited daily dose, and (2) evaluating whether changes need to be made for acetaminophen (APAP) regarding the following: Safe daily dose for healthy individuals Safe daily dose in patients with chronic liver disease Safe daily dose when ingested concurrently with alcohol Appropriate dose for efficacy Package size restrictions Pediatric dosing Acetaminophen (APAP) narcotic combinations In January 2011, the FDA announced it was asking manufacturers of prescription acetaminophen (APAP) combination products to limit the maximum amount of the drug in these products to 325 mg per tablet, capsule, or other dosage unit.[6] The FDA believes such a limitation will reduce the risk of hepatoxicity from acetaminophen (APAP) overdosing, an ingestion that could lead to liver failure, liver transplantation, and death.[6] Prognosis The proper medical use of the antidote N -acetylcysteine (NAC) has significantly lowered the mortality rate of patients with acetaminophen (APAP) toxicity. Most patients do not have clinically significant sequelae if they are treated in a timely manner with antidotal therapy and appropriate supportive care. In acute exposures, mortality and morbidity rates are lower in young children (≤5 y) than in older children, adolescents, and adults. The cause for this age-related difference is unclear but may be due to an increased capacity for conjugation with sulfate, an increased supply and regeneration of glutathione stores, lower ingested doses, or a greater likelihood to vomit after an acute ingestion. Patients with acetaminophen (APAP) levels below the possible line for hepatotoxicity on the Rumack-Matthew nomogram may be discharged home after they are medically cleared. If the ingestion occurred with an intent to harm oneself, a thorough psychosocial and/or psychiatric evaluation is indicated before the patient can be discharged from the hospital. Patient Education Inform parents and caregivers of the risks associated with acetaminophen (APAP) overdose in children and adolescents and that this drug, although it is safe when dosed properly, can cause harm if misused. Educate parents and caregivers about the proper dose of acetaminophen (APAP) in children based on weight, and inform them that various preparations have different concentrations of acetaminophen (APAP). Adult formulations of this agent should not be used to treat children. Also educate parents and caregivers that many over-the-counter (OTC) cold and cough preparations contain acetaminophen (APAP). Therefore, they should carefully read medication labels before they give these preparations to children. Give parents and caregivers information, including the toll-free phone numbers for the National Poison Control Center hotline (1-800-222-1222) and their regional Poison Control hotline. For patient education information, see (Tylenol) Poisoning and Poisoning. The US Food and Drug Administration (FDA) has patient and caregiver education resources through its Consumer Health Information Website.[7, 6]


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