ACETAMINOPHEN-REPEATED SUPRATHERAPEUTIC

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Acetanilide, 4-hydroxy-
2) APAP
3) 4'-Hydroxyacetanilide
4) N-acetyl-p-aminophenol
5) N-(4-Hydroxyphenyl)acetamide
6) Paracetamolum
7) Paracetamol
8) CAS 103-90-2

Available Forms Sources

1) INTRAVENOUS

a) 10 mg/mL in a single-use 100 mL vial for injection (Prod Info OFIRMEV(TM) intravenous infusion, 2010).

2) ORAL

a) Capsules: 500 mg (Prod Info acetaminophen oral capsules, 2007)
b) Liquid: 160 mg/5 mL (Prod Info CHILDREN'S SILAPAP oral liquid, 2006)
c) Solution: 80 mg/0.8 mL, 160 mg/5 mL, 500 mg/15 mL (Prod Info TYLENOL(R) oral concentrated infant drops, 2009; Prod Info TYLENOL(R) SORE THROAT DAYTIME oral solution, 2007; Prod Info acetaminophen oral solution, 2002)
d) Suspension: 80 mg/0.8 mL (Prod Info TYLENOL(R) INFANTS' DROPS oral suspension, 2006)
e) Tablets: 325 mg and 500 mg; 80 mg and 160 mg (chewable); 650 mg (extended release) (McNeil-PPC, 2010; McNeil-PPC, 2010; Prod Info JR. TYLENOL(R) meltaway oral tablets, 2007; Prod Info TYLENOL(R) oral tablets, 2006; Prod Info QUICKMELTS(TM) oral tablets, 2004)

3) RECTAL

a) Suppository: 120 mg, 325 mg, 650 mg (Prod Info Acephen(TM) rectal suppositories, 2009; Prod Info ACEPHEN(TM) rectal suppositories, 2006; Prod Info ACEPHEN(TM) rectal suppositories, 2006a)

1) Acetaminophen is an analgesic and antipyretic agent used for the treatment of mild to moderate pain and for the reduction of fever (Prod Info TYLENOL(R) oral, 2010; Prod Info OFIRMEV(TM) intravenous infusion, 2010).
2) It is also used for moderate to severe pain in patients also receiving opioids adjunctively (Prod Info OFIRMEV(TM) intravenous infusion, 2010).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Acetaminophen is a non-opioid analgesic and antipyretic medication found in many over-the-counter and prescription products. "Chronic" or "repeated supratherapeutic" acetaminophen ingestion is defined as repetitive ingestion of more than the recommended maximum daily dose. Repeated supratherapeutic ingestions of acetaminophen are usually unintentional occurring in patients with acute or chronic pain syndromes or repeated dosing in ill children.
B) PHARMACOLOGY: Acetaminophen is used primarily as an antipyretic and analgesic. Its effects are mediated through the central nervous system.
C) TOXICOLOGY: In therapeutic doses, about 90% of acetaminophen is conjugated in the liver to nontoxic metabolites (glucuronides and sulfates). A small portion (less than 5%) is conjugated by cytochrome P450 CYP2E1 to a toxic metabolite, N-acetyl-p-benzo-quinone imine (NAPQI). This metabolite is further conjugated by glutathione, and eliminated by the kidneys. In toxic doses, the usual metabolic pathways are overwhelmed; acetaminophen is shunted to the cytochrome P450 pathway, and glutathione stores are depleted. Cellular injury and hepatic necrosis occur as NAPQI accumulates. Renal toxicity may develop in patients with hepatic toxicity, either due to cytochrome P450 activity in the kidneys causing direct renal damage, or due to hepatorenal syndrome in patients with fulminant hepatic failure.
D) EPIDEMIOLOGY: Acetaminophen poisoning is very common and can be severe. However, the incidence of serious acetaminophen toxicity after repeated doses is negligible and appears to only follow massive dosing or prolonged excessive dosing.
E) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Toxicity can range from asymptomatic ALT elevation to malaise, nausea, vomiting, abdominal pain, and hepatotoxicity.
2) SEVERE TOXICITY: Jaundice, hypoglycemia, coagulopathy, renal failure, fulminant hepatic failure and encephalopathy.
3) Presentation following chronic acetaminophen overdose typically includes 4 phases: (1) anorexia, nausea, vomiting, malaise and diaphoresis; (2) first phase signs resolve, replaced by right upper quadrant pain, liver enlargement, oliguria in some patients, elevated bilirubin and hepatic enzyme levels, and prolonged prothrombin time; (3) about 3 to 5 days into the course, anorexia, nausea, vomiting, and malaise reappear along with signs of hepatic failure (jaundice, hypoglycemia, coagulopathy, encephalopathy) and sometimes renal failure and cardiomyopathy; (4) either recovery or progression to death due to liver failure finally occurs. Presentation with central nervous system depression, shock, hypothermia, and metabolic acidosis may also occur rarely, after very large ingestions.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Patients with dehydration may have tachycardia.

0.2.20)

A) Intravenous (IV) acetaminophen is classified as an FDA pregnancy category C. Acetaminophen crosses the placental barrier; fetal blood levels will probably be as high as those of the mother. Maternal ingestion of recommended doses of acetaminophen does NOT appear to present a risk to the fetus or nursing infant. In animal fertility studies, there was an increased percentage of abnormal sperm in male offspring and a decreased number of mating pairs producing a fifth litter, which suggests the possibility of cumulative acetaminophen toxicity after chronic use of the drug near the upper limit of daily dosing. There was also evidence of reduced testicular weight, spermatogenesis, and fertility in males and reduced implantation sites in females.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Stop acetaminophen therapy. The vast majority of repeated supratherapeutic ingestions of acetaminophen can be managed with symptomatic and supportive care. Treatment should be initiated with n-acetylcysteine if the patient’s acetaminophen concentration is greater than or equal to 20 mcg/mL and/or if liver enzymes are elevated. Patients should be treated for a minimum of 12 hours (at least 20 hours if the acetaminophen concentration or liver enzymes are very high). After 12 to 20 hours, an acetaminophen concentration should be checked along with liver enzymes. If the patient’s acetaminophen concentration is undetectable, liver enzymes have clearly declined and are approaching normal, and the patient is at baseline mental status and is clinically well, and n-acetylcysteine can be stopped; however, if all the prior criteria are not met, n-acetylcysteine must be continued.

B) MANAGEMENT OF SEVERE TOXICITY

1) Aggressive symptomatic and supportive care in addition to n-acetylcysteine therapy must be undertaken in severe toxicity. Intubate patients with respiratory compromise or encephalopathy. Maintain blood pressure with IV fluids and pressors if needed. Call your local poison center and or transplant team for assistance to help you decipher if your patient meets criteria for transplant.

C) DECONTAMINATION

1) Administer activated charcoal in a substantial ingestion occurring within 2 hours (consider later if extended release preparations) and if the patient is able to protect his or her airway.

D) AIRWAY MANAGEMENT

1) Perform aggressive airway protection in patients with signs of encephalopathy or CNS depression if concomitant drugs like opioids are ingested.

E) ANTIDOTE

1) NAC therapy should be initiated as soon as possible. Administer NAC therapy until ALL criteria have been met:

a) The liver enzymes have clearly peaked and declined
b) Patient is at his/her baseline mental status
c) Acetaminophen is non-detectable

1) Both oral and IV n-acetylcysteine are equally efficacious.
2) ADULT REGIMEN: INTRAVENOUS N-ACETYLCYSTEINE (ACETADOTE(R))

a) Loading dose: 150 mg/kg in 200 milliliters of 5% dextrose infused over 60 minutes
b) Maintenance Infusion #1- 50 mg/kg in 200 milliliters of 5% dextrose over 4 hours (12.5 mg/kg/hr)
c) Maintenance Infusion #2:100 mg/kg in 1000 milliliters of 5% dextrose (6.25 mg/kg/hr) until treatment endpoint

3) ADULT REGIMEN: ORAL N-ACETYLCYSTEINE (MUCOMYST(R))

a) Loading dose: 140 mg/kg diluted to a 5% solution
b) Maintenance dose: 70 mg/kg diluted to a 5% solution every 4 hours until treatment endpoints are met.

4) PEDIATRIC (PATIENTS LESS THAN 40 KG): INTRAVENOUS N-ACETYLCYSTEINE (ACETADOTE(R))

a) PEDIATRICS (PRECAUTIONS): Standard intravenous dosing can cause hyponatremia and seizures secondary to large amounts of free water. To avoid this complication, the manufacturer has recommended the following dosing guideline:

1) Patients greater than 20 kg to less than 40 kg: Loading dose: 150 mg/kg in 100 mL of diluent administered over 60 minutes. Dose 2: 50 mg/kg in 250 mL of diluent administered over 4 hours. Dose 3: 100 mg/kg in 500 mL of diluent administered over 16 hours.
2) Patients 20 kg or less: Loading dose: 150 mg/kg in 3 mL/kg of body weight of diluent administered over 60 minutes. Dose 2: 50 mg/kg in 7 mL/kg of body weight of diluent administered over 4 hours. Dose 3: 100 mg/kg in 14 mL/kg of body weight of diluent administered over 16 hours.

5) PEDIATRIC REGIMEN: ORAL N-ACETYLCYSTEINE (MUCOMYST(R))

a) Loading dose: 140 mg/kg diluted to a 5% solution
b) Maintenance dose: 70 mg/kg diluted to a 5% solution every 4 hours until treatment endpoints are met.

6) NAC should be continued until all criteria are met. Patients should be treated for a minimum of 12 hours. Consultation with a medical toxicologist/poison center is recommended before changes (based on liver AST/ALT, coagulation (INR) function, acetaminophen concentration) in the duration of therapy are made.
7) Adverse events include anaphylactoid reactions and errors in dosing regimens.

F) ANTIEMETIC

1) Patients may require aggressive antiemetic therapy (Adults: metoclopramide 1 to 2 mg/kg IV, or ondansetron 2 to 8 mg IV; Pediatrics: ondansetron 0.1 to 0.15 mg/kg IV) to ensure that NAC is retained when given orally. If recurrent vomiting develops, switch to intravenous dosing.

G) PATIENT DISPOSITION

1) HOME MANAGEMENT: Patients under age 6 can be managed at home if the ingestion is inadvertent and: a) less than 200 mg/kg over a single 24 hour period, or b) less than 150 mg/kg per 24-hour period for the preceding 48 hours or c) less than 100 mg/kg per 24-hour period for the preceding 72 hours or longer. Patients age 6 or older can be managed at home if the ingestion is inadvertent and: a) less than 200 mg/kg or 10 g (whichever is less) over a single 24 hour period, or b) less than 150 mg/kg or 6 g (whichever is less) per 24-hour period for the preceding 48 hours or longer. In patients with conditions that are purported to increase susceptibility to acetaminophen toxicity (eg alcoholism, isoniazid use, prolonged fasting) the dose of acetaminophen considered safe to manage at home should be reduced to less than 4 g or 100 mg/kg (whichever is less) per day.
2) OBSERVATION CRITERIA: Patients under age 6 should be sent to a healthcare facility for evaluation if the ingestion is: a) 200 mg/kg or more over a single 24 hour period, or b) 150 mg/kg or more per 24-hour period for the preceding 48 hours or c) 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer. Patients age 6 or older should be sent to a healthcare facility for evaluation if the ingestion is: a) at least 200 mg/kg or 10 g (whichever is less) over a single 24 hour period, or b) at least 150 mg/kg or 6 g (whichever is less) per 24-hour period for the preceding 48 hours or longer. In patients with conditions that are purported to increase susceptibility to acetaminophen toxicity (eg alcoholism, isoniazid use, prolonged fasting) the dose of acetaminophen considered potentially toxic should be reduced to at least 4 g or 100 mg/kg (whichever is less) per day. All patients with deliberate overdose should be sent to a healthcare facility Asymptomatic patients with normal liver enzymes and an acetaminophen concentration below 20 mcg/mL may be discharged.
3) ADMISSION CRITERIA: Patients who are symptomatic, have elevated liver enzymes or an acetaminophen concentration above 20 mcg/mL should be admitted for NAC therapy.
4) CONSULT CRITERIA: Consult a toxicologist for all questions regarding dosing, necessity or duration of therapy. Have a low threshold to consult a toxicologist if you think your patient might need a transplant.

H) PITFALLS

1) Failing to identify a patient with repeated supratherapeutic ingestion of acetaminophen.
2) Utilizing the Rumack-Matthew Nomogram to risk stratify this type of patient.
3) Inappropriately stopping N-Acetylcysteine therapy.

I) PHARMACOKINETICS

1) Acetaminophen is rapidly absorbed with peak concentrations occurring within 30 to 120 minutes. Delayed absorption may occur with sustained-release products or with coingestions that slow the gastrointestinal tract (eg, opioids, anticholinergics). The elimination half-life is 1 to 3 hours.

J) TOXICOKINETICS

1) The absorption and half-life of acetaminophen may be prolonged with very large doses or when the patient develops liver failure.

K) DIFFERENTIAL DIAGNOSIS

1) Includes other agents or disorders which can cause hepatocellular necrosis including amanita phalloides, carbon tetrachloride, phenytoin, valproic acid and isoniazid, viral hepatitis.

Range Of Toxicity

1) ADULTS: More than one ingestion during a period exceeding 8 hours, resulting in a cumulative dose of greater than 4 g per 24 hours.
2) PEDIATRIC: Patients under 6 years of age:

a) 200 mg/kg or more over a single 24-hour period, or
b) 150 mg/kg or more per 24-hour period for the preceding 48 hours, or
c) 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer

3) PEDIATRIC: Patients older than 6 years of age:

a) At least 10 g or 200 mg/kg, whichever is less, over a single 24-hour period, or
b) At least 6 g or 150 mg/kg, whichever is less, per 24-hour period for the preceding 48 hours or longer

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Patients with dehydration may have tachycardia.

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPOTHERMIA: Transient hypothermia has been reported in adults following therapeutic doses of acetaminophen and in overdose (Van Tittelboom & Govaerts-Lepicard, 1989).
2) FEVER: Infants typically present with repeated supratherapeutic acetaminophen ingestion in response to a febrile illness, often with an associated decrease in oral intake (Smilkstein, 1998).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) Scleral icterus occurs if hepatic injury develops (Lane et al, 2002).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) In a retrospective study of 24 patients with hepatic failure following acetaminophen poisoning, 8 developed severe lung injury (non-cardiogenic pulmonary edema) and one had mild to moderate injury. Pulmonary artery occlusion pressures were normal, systemic vascular resistance was low, pulmonary artery pressure was mildly increased and pulmonary vascular resistance was low (Baudouin et al, 1995).

1) Patients with pulmonary injury were more likely to have increased intracranial pressure and circulatory failure, more severe hepatic coma scores on admission, and had a higher mortality rate (8 of 9 (89%) vs 2 of 15 (13%)) than did patients without lung injury (Baudouin et al, 1995).

Neurologic

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) Hepatic encephalopathy may develop in patients with severe liver injury (Miles et al, 1999). Hypoglycemia may also contribute to mental status changes in patients with severe liver injury.

B) DROWSY

1) WITH THERAPEUTIC USE

a) Lethargy (Glasgow Coma Scale 13) was reported in a 54-year-old woman after chronically ingesting one 500 mg acetaminophen gel cap, as well as a combination medication containing hydrocodone and 500 mg of acetaminophen, every 3 to 4 hours for 6 to 8 weeks for treatment of persistent leg, back, and neck pain (total acetaminophen daily dose of 5 to 6.5 g). The patient recovered following N-acetylcysteine administration (Lane et al, 2002).

2) WITH POISONING/EXPOSURE

a) Infants may present with lethargy in addition to a febrile illness (Waseem et al, 2003; Henretig et al, 1989; Bauer et al, 1999).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 5-month-old infant developed seizures secondary to severe hypoglycemia (dextrostix measured 29 mg/dL) after chronically ingesting 200 mg/dose of acetaminophen every 4 hours for 4 days. The seizures resolved after intravenous administration of glucose (Waseem et al, 2003).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) Gastrointestinal irritability may develop following repeated supratherapeutic ingestions with nausea, vomiting and abdominal pain (Dart et al, 2000). In children, an acute prodromal illness with fasting and/or vomiting is common preceding repeated supratherapeutic acetaminophen-induced liver failure (Waseem et al, 2003; Miles et al, 1999).
2) Risk of upper gastrointestinal complications is increased in patients using a daily dose of 2 grams or greater of acetaminophen. This risk appears to be independent of treatment duration (Garcia-Rodriguez & Hernandez-Diaz, 2001).

B) PANCREATITIS

1) Hyperamylasemia and pancreatitis have occurred in a small number of patients, generally developing 2 to 3 days after the last dose (Mofenson et al, 1991; Caldarola et al, 1986; Gilmore & Touvras, 1977; Coward, 1977). Clinical signs of pancreatitis may be obscured by gastrointestinal symptoms and hepatitis (Hord et al, 1992).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) PEDIATRIC

a) For repeated ingestions, the precise dose of acetaminophen and the time course of ingestion required to produce hepatotoxicity are unknown. In children, repeated ingestion of more than 90 to 100 mg/kg/day, for more than 3 days in duration, may lead to liver injury and has been a cause of fulminant hepatic failure in children (Ranganathan et al, 2006; Liu et al, 2005; Muniz et al, 2004; Nogen & Bremner, 1978; Agran et al, 1983; Clark et al, 1983; Swetnam & Florman, 1984; Smith et al, 1986; Blake et al, 1988; Henretig et al, 1989; Smilkstein et al, 1989; Turchen et al, 1989; Penna & Buchanan, 1991; Calvert & Linder, 1978; Kozer et al, 2001a). Despite apparently low acetaminophen levels, severe hepatotoxicity in children has been observed (Ward et al, 2001).
b) After multiple doses, neonates and infants are capable of forming the reactive intermediate metabolite that results in hepatocellular damage. Infants have an immature glucuronide conjugation system, but the rate constant for the sulfation metabolic pathway is larger than in older children (Arana et al, 2001).
c) Doses lower than 150 mg/kg/day in children (140 mg/kg/day in a 4-year-old and 108 mg/kg/day in a 12-year-old) have resulted in serious hepatotoxicity (Hynson & South, 1999; Miles et al, 1999).
d) Following repeated supratherapeutic acetaminophen dosing in children, very high transaminase levels are common, but disproportionately low total bilirubin levels are typical in acetaminophen-induced hepatotoxicity (Waseem et al, 2003; Miles et al, 1999). Children with acetaminophen-induced liver failure generally have an acute non-specific prodromal illness with prolonged fasting and/or vomiting followed by encephalopathy, coagulopathy, very high transaminase levels and disproportionately low total bilirubin levels.
e) Hepatotoxicity after chronic acetaminophen overdosage has been observed in children. Rarely, pediatric hepatotoxicity has been reported with acetaminophen doses less than 150 mg/kg per day (Hynson & South, 1999). More than 90 mg/kg/day is generally considered potentially hepatotoxic.
f) REPEATED OVERDOSE: A 5-year-old girl received 500-mg acetaminophen suppositories every 3 hours for a total of 17 suppositories (8.5 grams) within a 48-hour period. Laboratory tests indicated severe liver damage. At 72 hours after the first acetaminophen dose, the child died (Bauer et al, 1999).
g) CASE REPORT: A 3-year-old girl received sevoflurane anesthesia for an appendectomy and an average acetaminophen dose of 100 mg/kg/day rectally for 4 days (before and after surgery). She developed hepatic failure and was in coma state III to IV on day 5. Following NAC IV therapy, the child recovered, with hepatic biochemistry nearing normal levels by day 11. It was suggested the cause of hepatic failure was multiple: fasting, large acetaminophen dose, and sevoflurane exposure (Bruun et al, 2001).
h) CASE REPORT: A 16-year-old girl intentionally ingested, over a 72-hour period, 50 tablets of a cold medication containing acetaminophen (total amount acetaminophen ingested, 25 g), and subsequently developed abdominal pain and tenderness, hepatic tenderness, asterixis, and extremity clonus. Laboratory analysis revealed elevated liver enzyme levels and an acetaminophen level of 33 mcg/mL. With n-acetylcysteine administration and supportive care, the patient gradually recovered and was discharged 7 days after admission (Kirages et al, 2003).
i) CHRONIC OVERDOSE: Chronic ingestion of greater than 140 mg/kg/day for 2 to 3 days has been associated with hepatotoxicity in infants and children (Ranganathan et al, 2006; Waseem et al, 2003; Blake et al, 1988; Smilkstein et al, 1989a; Turchen et al, 1989; Henretig et al, 1989; Smith et al, 1986; Douidar et al, 1994; Rivera-Penera et al, 1997; Luria et al, 1996; Heubi et al, 1998).
j) In one infant with fulminant hepatic failure due to chronic acetaminophen, liver biopsy revealed total necrosis of hepatocytes with lymphocytic infiltrations; the viable hepatocytes were located in the periportal area without evidence of regeneration (Liu et al, 2005).
k) CASE REPORT: A 4-day-old infant presented to the emergency department with lethargy, dehydration, and poor responsiveness to stimulation. On hospital day 1, the patient also developed recurrent seizures that were successfully treated with phenobarbital. Laboratory analysis revealed elevated serum creatinine and liver enzyme concentrations, and an elevated prothrombin time (51.9 sec; normal, 10.1 to 15.9 sec). Prior to presentation, the patient, who had been circumcised at 2 days of age, had been receiving acetaminophen 80 mg (26 mg/kg) every 4 hours for the first 24 hours following circumcision, then 40 mg (13 mg/kg) every 4 hours for the next 2 days. Sixteen hours after the last dose, the patient's serum acetaminophen concentration was 109.8 mcg/mL (therapeutic range, 10 to 30 mcg/mL). Following treatment with a 20-hour intravenous N-acetylcysteine infusion protocol, the patient gradually recovered with normalization of his laboratory values, and he was subsequently discharged without apparent sequelae (Walls et al, 2007).

2) ADULT

a) CHRONIC OVERDOSE: There are a number of reports of hepatotoxicity developing after ingestions of 2.6 to 12 grams of acetaminophen per day for 1 to 8 days in adults, most of whom chronically abused ethanol (Barker et al, 1977; Monteagudo & Folb, 1987; McClain et al, 1980; Leist et al, 1985; Seeff et al, 1986; Kartsonis et al, 1986; Baeg et al, 1988; Foust et al, 1989; Wooton & Lee, 1990; Kumar & Rex, 1991; Eriksson et al, 1992; Sivaloganathan et al, 1993) Zimmerman & Maddrey, 1995; (Schueler & Harper, 1995; Leach et al, 1998; Bauer et al, 1999; Stevenson et al, 2001).
b) Blood levels and urine metabolites were not documented in most of these cases, and the reported amount ingested was based entirely on patient recall.
c) Other confounding factors such as starvation and use of other enzyme-inducing drugs existed in some patients, and abdominal complaints preceded the acetaminophen ingestion in some others. It is not clear that acetaminophen was solely responsible for the development of hepatotoxicity in all of these cases.
d) CASE REPORT: A 54-year-old woman developed scleral icterus, mild jaundice, and elevated liver enzyme levels (peak AST 7816 Units/L, peak ALT 3066 Units/L) after chronically ingesting a total daily dose of 5 to 6.5 grams acetaminophen for 6 to 8 weeks for treatment of persistent leg, back, and neck pain. The patient did not appear to have any associated risk factors (no alcohol use, no illicit drug use, no history of hepatitis, and no history of blood transfusions). The patient recovered following administration of N-acetylcysteine and supportive care (Lane et al, 2002).
e) THERAPEUTIC DOSES

1) The best available evidence suggests that hepatotoxicity does NOT develop, even in "susceptible" individuals (alcoholics) after short-term therapeutic doses. In controlled prospective trials, hepatotoxicity did not develop in alcoholics receiving 4 grams/day. Susceptibility to acetaminophen toxicity may exist for selected groups; further research is needed to more accurately identify the ingested dose (Dart, 2002). In a very small number of cases hepatotoxicity developed with acetaminophen therapy at doses less than 4 grams/day when taken for greater than 4 days in patients with no other risk factors for toxicity; however, this is very unusual (Bolesta & Haber, 2002). Following supratherapeutic dosing with acetaminophen, peak acetaminophen levels correlate poorly with liver dysfunction, morbidity and mortality. These patients usually present later and the diagnosis is often delayed (Gyamlani & Parikh, 2002).
2) STUDY: Of 78 patients in an alcohol detoxification unit who received acetaminophen (dose range from 325 milligrams to 52,650 milligrams over 13 days), none developed clinical evidence of hepatic injury. Twenty-nine of these 78 patients had transaminase levels drawn after acetaminophen administration and the transaminase levels were not elevated in any of them (Cienki et al, 1995).
3) STUDY: In a randomized, prospective, blinded, placebo-controlled study of 60 chronic alcoholics, administration of therapeutic doses of acetaminophen (1000 milligrams 4 times a day for two days) were not associated with an increase in AST, ALT, or INR or clinical evidence of liver disease. The study had an 80% probability of detecting a difference of at least 20 International Units/L in AST or ALT (Kuffner et al, 1997).
4) STUDY: In another randomized, prospective, blinded, placebo-controlled study of 200 chronic alcoholics, administration of 1000 milligrams of acetaminophen 4 times a day for 2 days was not associated with an increase in AST, ALT or INR, or clinical evidence of liver disease. The study had a 95% probability of detecting a difference of at least 15 International Units/L in mean AST or ALT (Kuffner et al, 1999). In a randomized, placebo-controlled trial of alcoholics, with no recent acetaminophen ingestion and no evidence of hepatic dysfunction, maximal therapeutic doses of acetaminophen for 2 days had no effect on the development of hepatotoxicity. The authors stated that a reduced acetaminophen dose in the alcoholic patient was NOT supported by this study.
5) STUDY: In a randomized placebo-controlled trial, 145 healthy volunteers received either a placebo, 1 of 3 acetaminophen/opioid regimens, or acetaminophen alone. All of the acetaminophen-containing regimens included 4 grams of acetaminophen daily for 14 days. The incidence of maximum ALT levels greater than 3 times the upper limit of normal with any of the acetaminophen-containing regimens ranged from 31% to 44%, as compared with the placebo group in which none of the volunteers had an ALT level that was greater than 3 times the upper limit of normal. Only 1 patient in the placebo group exhibited a maximum ALT level that was greater than 2 times the upper limit of normal, compared with 53% of the subjects receiving acetaminophen. In the placebo group, 38% of subjects developed an ALT above the upper limit of normal compared with 76% of the subjects receiving acetaminophen. Ethnicity and diet, both known to affect serum aminotransferase concentrations, were not controlled in this study (Watkins et al, 2006).
6) CASE REPORTS: Hepatotoxicity from chronic therapeutic doses of acetaminophen has been suggested by several case reports but has not been clearly established. Factors which may increase susceptibility have been present in most reported cases (alcoholism, depleted glutathione from chronic illness, concomitant ingestion of enzyme inducers, underlying diseases). The history of amount ingested in these cases was based entirely on patient recall (Benson, 1983a; Zimmerman & Maddrey, 1995; Gould et al, 1997; Schiodt et al, 1997).
7) CASE SERIES: Of 118 young adults with measles, significantly higher numbers of patients treated with acetaminophen had elevated AST and ALT levels compared to those treated with dipyrone (Ackerman et al, 1989). Higher acetaminophen doses (5.8 to 11.6 g over 2 to 8 days) were associated with impaired liver function (Ackerman et al, 1989).
8) CASE REPORTS: A few reports of hepatotoxicity from therapeutic doses of acetaminophen in patients without chronic alcohol use exist; most are associated with chronic use of acetaminophen, and the history of the amount ingested is based entirely on patient recall (Johnson & Tolman, 1977; Maddrey, 1987; Eriksson et al, 1992).
9) IDIOSYNCRATIC acute hepatitis has been reported following therapeutic acetaminophen in two patients with melanoma treated with high-dose interferon-alpha. Other causes of acute liver injury were excluded. After stopping both drugs, liver function tests normalized after 1 month. On acetaminophen rechallenge, aminotransferase levels increased suddenly the day after rechallenge (Fabris & Palma, 2001).
10) CASE REPORT: A 53-year-old severely malnourished woman with cancer developed severe hepatotoxicity 4 days after beginning paracetamol (acetaminophen) for postoperative analgesia. The patient was also fasting during this time. Her liver enzymes levels were elevated and she developed severe nausea, upper abdominal pain and tender hepatomegaly. Her signs and symptoms resolved within 4 weeks after discontinuing paracetamol use. Despite an inadvertent rechallenge with paracetamol, administered at a lower dose (1.3 to 2.6 grams/day up to 3 times per week) for several weeks, there was no recurrence of hepatic abnormalities (Kurtovic & Riordan, 2003).
11) Total parenteral nutrition (TPN): TPN may diminish patients' hepatic reserve, particularly infants and toddlers, making them more susceptible to hepatotoxicity from chronic acetaminophen usage.

a) Hepatotoxicity was reported in a toddler given normal doses of acetaminophen for 4 days. History was significant for premature birth, requiring TPN for several months. The patient died of fulminant liver failure. A liver biopsy was consistent with drug-induced hepatic injury and TPN-induced hepatic changes (Pershad et al, 1999a).

12) CASE REPORT: A 92-year-old woman developed acute hepatotoxicity after receiving IV acetaminophen 1 gram every 6 hours for 5 days following surgery for a bowel obstruction. The patient's renal function was normal and, at the beginning of acetaminophen therapy, her AST and ALT levels were 24 and 10 international units/L, respectively. However, on day 5 of therapy, her AST and ALT levels significantly increased to 4698 and 3914 International Units/L, respectively. There was no history of ethanol abuse and titers for viral or infectious hepatitis were negative. Serum acetaminophen-hepatic protein adducts (APAP-CYS), were measured at 4.81 mcM on day 5. Following IV acetylcysteine therapy and discontinuation of acetaminophen, the patient's liver enzyme levels gradually decreased and she was discharged on day 8 with an AST and ALT of 333 and 1024 International Units/L, respectively, and an APAP-CYS of 0.95 mcM (Seifert et al, 2015).

a) APAP-CYS is formed from an acetaminophen-oxidized reactive intermediate that binds to cellular hepatic proteins, and is believed to be a specific biomarker of acetaminophen exposure with concentrations that directly correlate to acetaminophen-induced hepatotoxicity (Seifert et al, 2015).

Genitourinary

3.10.2)

A) RENAL FAILURE SYNDROME

1) Acute renal insufficiency may occur in a small number of patients in severe cases and may be independent of liver injury (Campbell & Batlis, 1992; (Curry et al, 1982). Renal failure is usually reversible but may last for several weeks and require hemodialysis. Acute renal failure is more often associated with hepatic injury (Lane et al, 2002; Prescott, 1983; Prescott et al, 1982; Monteagudo & Folb, 1987; Chan et al, 1995; Brotodihardjo et al, 1992; Katzir et al, 1995; Eguia & Materson, 1997). A case report described hepato-renal failure in a 48-year-old woman following self-medication with acetaminophen and Tylox(R) (containing acetaminophen) for flu symptoms. The patient died due to fulminant hepatic failure (Stevenson et al, 2001).

B) PAPILLARY NECROSIS

1) No association was found between consumption of acetaminophen-containing analgesics and the incidence of renal papillary necrosis in a retrospective case-control investigation of 1189 patients (McCredie & Stewart, 1988).
2) In a retrospective review of 180 patients with end-stage renal disease, five patients were identified in whom excessive consumption of acetaminophen (greater than 1 kg) may have contributed to the development of renal papillary necrosis (Segasothy et al, 1988).
3) A case-control study of 554 hospitalized adults with recently diagnosed primary chronic renal disease and 516 non-hospitalized controls found an association between daily use of acetaminophen and increased risk of renal disease (odds ratio 1.05 to 9.8).

a) There was no relationship with total dose and confounding factors were not evaluated. This finding should be considered tentative until confirmed by other studies (Sandler et al, 1989).

C) UREMIA

1) CHRONIC RENAL FAILURE: In a study of 716 patients with end-stage renal disease (ESRD) and 361 control subjects, ingestion of more than 104 acetaminophen tablets/year or 1000 tablets/lifetime was associated with an increased risk of ESRD. A similar effect was not found for salicylate. Ingestion of more than 5000 NSAID tablets/lifetime was also associated with an increased risk of ESRD (Perneger et al, 1994).
2) Limitations of this study include the fact that the estimated lifetime amount ingested for all medications was based entirely on patient recall with no attempt at validation, combination products were not considered, and exposure was defined as number of tablets ingested rather than ingested dose (Horowitz et al, 1995). In addition, there was no attempt to correct for preexisting diseases such as mild renal insufficiency, diabetes or hypertension which predispose to renal failure and might be independently associated with acetaminophen use (Faich, 1995; Nelson, 1995).

Acid-Base

3.11.2)

A) ACIDOSIS

1) Metabolic acidosis is common in patients developing fulminant hepatic failure (Liu et al, 2005). An arterial pH of 7.3 is associated with an increased mortality in patients with acetaminophen-induced fulminant hepatic failure.

Dermatologic

3.14.2)

A) JAUNDICE

1) WITH THERAPEUTIC USE

a) Mild jaundice with scleral icterus occurred in a 54-year-old woman, who chronically ingested a total daily of 5 to 6.5 grams acetaminophen for 6 to 8 weeks for treatment of persistent leg, back, and neck pain (Lane et al, 2002).

Endocrine

3.16.2)

A) HYPOGLYCEMIA

1) Hypoglycemia may develop 2 to 4 days following severe repeated supratherapeutic acetaminophen dosing with associated hepatic failure (Miles et al, 1999; Smilkstein, 1998).
2) CASE REPORT: A 5-month-old infant developed severe hypoglycemia (dextrostix measured 29 mg/dL) approximately 2 days after chronically ingesting 200 mg/dose of acetaminophen every 4 hours for several days. The hypoglycemia resolved following intravenous administration of glucose (Waseem et al, 2003).
3) CASE REPORT: A 58-day-old girl presented with severe hypoglycemia (glucose 6 mg/dL) and acute hepatic failure after receiving 98 mg/kg/day of acetaminophen for 24 hours(Muniz et al, 2004).

Reproductive

3.20.1)

3.20.2)

A) RESPIRATORY SYSTEM EFFECTS

1) A randomized controlled trial by the Peer Education in Pregnancy Study suggests that acetaminophen use during middle to late pregnancy may be related to wheezing during the first year of an infant’s life. Study subjects (n=345) were questioned at four different times during their pregnancy. Exposure to acetaminophen was defined as the mother having taken the medication at least once during the first trimester, middle pregnancy, late pregnancy, or postpartum. A total of 70% of the women had used acetaminophen at least once during their pregnancy (40.1% first trimester, 38.1% middle pregnancy, 49% late pregnancy, and 59.9% in either middle or late pregnancy). Development of respiratory symptoms in the children of the study subjects was defined as any positive response to a series of questions regarding wheezing, coughing, breathing problems, hospital visits and admission for breathing problems, and asthma from week 4 through month 9 of life. Respiratory symptoms were commonly reported (33% wheezing, 21.5% wheezing that disturbed sleep, 65.4% coughing that disturbed sleep, 33.9% ER visit for respiratory problem, 10.1% hospitalized for a respiratory problem, 4.6% were diagnosed with asthma). Multivariate analyses of respiratory end points in relation to acetaminophen use during pregnancy demonstrated a 70% increased risk of wheezing and 130% increased risk of wheezing that disturbed sleep by 1 year of age. However, further analysis demonstrated that the increase in a child's risk for respiratory symptoms is only statistically significant with middle to late pregnancy use of acetaminophen. The impact of acetaminophen use on other respiratory symptoms was not statistically significant (Persky et al, 2008).

B) LACK OF EFFECT

1) In a large population-based, prospective, cohort of women with live born singletons (n=26,424), there was no increased risk of congenital malformations in infants born to mothers who were exposed to oral acetaminophen during the first trimester compared with a control group of mothers and children not exposed; the incidence of congenital malformations was 4.3%, which is similar to the incidence in the general population (Prod Info OFIRMEV(R) intravenous injection, 2013).
2) In a population-based, case-control study from the National Birth Defects Prevention Study, there was no increased risk of major birth defects in infants with prenatal acetaminophen exposure during the first trimester (n=11,610) compared with a control group (n=4500) (Prod Info OFIRMEV(R) intravenous injection, 2013).
3) MUSCULAR VENTRICULAR SEPTAL DEFECTS (mVSDs): A study analyzed data from the Centers for Disease Control and Prevention's National Birth Defects Prevention Study (NBDPS) and found no significant association between acetaminophen or NSAID use and the development of muscular ventricular septal defects (mVSDs). Exposure to acetaminophen or NSAIDs was defined as taking either medication at least once during the first trimester or one month before pregnancy to delivery. The researchers also analyzed the association between febrile illness and the development of mVSD, with febrile illness defined as a fever greater than or equal to 100 degrees Fahrenheit. There were 168 cases and 692 controls included in the study. The two case groups evaluated were: all mVSD infants (included those infants with other minor cardiac defects or noncardiac defects; n=168) and those with isolated mVSDs (n=133). Acetaminophen use was high in both groups with 62% cases and 57% controls reporting use during the first trimester, and 77% cases and 72% controls reporting use anytime from one month prior to pregnancy to delivery. The use of NSAIDs was lower with 18% cases and 19% controls reporting use during the first trimester, and 29% cases and 30% controls reporting use anytime from one month prior to pregnancy to delivery. There was also no correlation found between exposure to acetaminophen or NSAIDs during a febrile episode and the development of mVSD. The patients in all groups could not provide detailed information on the frequency or duration of use of either acetaminophen or NSAIDs (Cleves et al, 2004).
4) There is no clear evidence that acetaminophen is teratogenic. Researchers studied 123 pregnant women who received prescriptions for acetaminophen during pregnancy and/or 30 days before conception compared with 13,327 controls who did not receive acetaminophen prescriptions. More than twice as many malformations were found in the acetaminophen group, but the type of malformations did not indicate a causal link. No evidence of altered fetal growth was found with acetaminophen use during pregnancy (Thulstrup et al, 1999).
5) There is no clear evidence that either acetaminophen or N-acetylcysteine is teratogenic (Riggs et al, 1989; McElhatton et al, 1990; McElhatton et al, 1990a).

3.20.3)

A) ADHD

1) Acetaminophen use during pregnancy was associated with an increased risk of hyperkinetic disorders (HKD), attention-deficit/hyperactivity disorder (ADHD), or ADHD-like behaviors according to a Danish National cohort study. More than half of all mothers reported acetaminophen use during pregnancy (n=36,187). Children exposed to acetaminophen at any point during pregnancy were at a 37% increased risk of hospital-diagnosed HKD. A 29% increase in the need for ADHD medications and a 13% increased risk in ADHD-like behaviors at age 7 were also observed. Risk increased in patients with acetaminophen use during more than one trimester, especially later in the pregnancy, and with increased frequency during pregnancy. A significant and consistently higher risk of HKD and ADHD was observed with the increased number of weeks of use. The risk of HKD diagnosis almost doubled in children exposed for greater than or equal to 20 weeks during pregnancy, and the risk of receiving ADHD medications increased by over 50%. These results were not altered by maternal inflammation, infection during pregnancy, mental status of the mother, or other potential confounders (Liew et al, 2014).
2) Exposure to acetaminophen significantly increased the risk of ADHD symptoms in children aged 7 to 11 years, in a clinical study. Children who were exposed to acetaminophen during pregnancy scored an average of 0.8 to 1.1 points higher on the Strength and Difficulties Questionnaire. Symptom categories included emotion, conduct, hyperactivity, peer esteem, and prosocial. Acetaminophen was compared to antiinflammatories, aspirin, antacids, and antibiotics, all of which did not produce a significant increased risk in ADHD symptoms (Thompson et al, 2014).

B) PREGNANCY CATEGORY

1) Oral acetaminophen has been classified as FDA pregnancy category B (Prod Info TYLENOL(R) oral, 2010). IV acetaminophen has been classified as FDA pregnancy category C (Prod Info OFIRMEV(R) intravenous injection, 2013).

C) PLACENTAL BARRIER

1) Acetaminophen crosses the placenta, but documented fetal death or hepatotoxicity from maternal overdose is rare. In the absence of fetal distress, induction of labor or termination of pregnancy based on maternal acetaminophen toxicity is not indicated (Smilkstein, 1998).
2) Pregnant patients with chronic supratherapeutic acetaminophen ingestions should receive NAC therapy using the same indications as in non-pregnant patients. The neonate should also receive NAC if delivered prior to the completion of maternal NAC therapy, or if there is evidence of hepatic injury or the acetaminophen level in cord blood is measurable at the time of delivery.
3) CASE REPORT: A 27-week pregnant 23-year-old woman developed liver failure following 2 days of supratherapeutic acetaminophen use. She required an emergent C-section for fetal distress, with the baby expiring soon after delivery. Cord blood showed an acetaminophen level of 19.1 mcg/mL and AST less than 6 units/L. Following NAC intravenous therapy and extracorporeal hemodiabsorption postpartum, the patient eventually recovered, with a course complicated by pancreatitis and wound dehiscence (Chu et al, 2001).

D) HEPATIC FAILURE

1) CASE REPORT: After taking an unknown amount of acetaminophen during pregnancy, an 18-year-old primigravida woman presented at 33 weeks gestation with intrauterine fetal death and an initial diagnosis of acute hepatic failure secondary to acute fatty liver of pregnancy. Due to markedly elevated liver transaminases, acetaminophen serum levels of 34 mg/L and later 19.2 mg/L, and liver biopsy results showing fatty liver of pregnancy with superimposed centrilobular hepatocellular coagulative necrosis, a diagnosis of acetaminophen toxicity was suspected. After inducing labor, a stillborn fetus (death, to 2 days prior to delivery) with normal morphology was reported. A liver transplant was performed on the third postpartum day (Gill et al, 2002).
2) CASE REPORT: A 22-year-old woman, approximately 20 weeks pregnant, developed fulminant hepatic failure following chronic supratherapeutic ingestion of acetaminophen, 6 g daily for 2 weeks. She presented with right upper quadrant abdominal pain. Initial laboratory data revealed elevated liver enzymes (AST 1064 units/L, ALT 1436 units/L), a total bilirubin level of 2.8 mg/dL, and an acetaminophen concentration of 31.5 mcg/mL. Over the next 24 hours, the patient's condition deteriorated, with development of somnolence and confusion, consistent with stage III hepatic encephalopathy. Repeat laboratory analysis revealed continued increase in liver enzymes (AST greater than 2250 units/L, ALT greater than 3000 units/L) and an acetaminophen concentration of 35 mcg/mL. Liver transplantation was determined to be the course of action. In accordance with the family, the pregnancy was continued. Following transplant, the patient developed bleeding from the hepatic arterial anastomosis requiring reoperation. Immunosuppressive therapy post-transplant was adjusted to avoid any teratogenic effects. Postoperatively the patient also developed hemolytic anemia and thrombocytopenia, secondary to graft-versus-host disease, which resolved following administration of high-dose prednisone therapy. On postoperative day 6, the fetus developed ascites and pericardial effusion. On postoperative day 14 (23 weeks gestation), a fetal ultrasound indicated mild, but progressive, ventriculomegaly, and a repeat ultrasound on day 17 demonstrated hydrocephalus, subarachnoid fluid, cavum septum pellucidum compression, and lateral herniation of the brain, indicative of severe brain injury incompatible with life. The pregnancy was terminated (Franko et al, 2013).

E) LACK OF EFFECT

1) MISCARRIAGE: Use of acetaminophen during the first 20 weeks of pregnancy was not associated with a 20% increased risk of miscarriage over nonuse in a study of 1055 women. Use of products containing acetaminophen, such as Vicodin(R) and Tylenol with Codeine(R) were also included in the analysis. In the same study, NSAID and acetylsalicylic acid use was associated with an increase in miscarriage risk (Li et al, 2003).
2) CASE REPORT: Acetaminophen overdose occurred in a 26-year-old female at 36 weeks gestation. The patient was admitted 4.5 hours after ingestion of acetaminophen and promptly placed on the Rocky Mountain Poison and Drug Center protocol for acetaminophen overdose. The patient was successfully treated and delivered a healthy infant girl at 42 weeks gestation. This report indicates that if treatment is begun early and response is rapid, maternal and fetal outcome may be good (if occurring in the third trimester) (Byer et al, 1982). At this time, it is unknown how much acetaminophen is passed to the fetus following a maternal overdose. The capability of the fetus to handle acetaminophen is also unknown. If the acetaminophen depletes fetal glutathione stores or saturates sulfate conjugation, reactive metabolites would be available to cause fetal liver damage.

3.20.4)

A) BREAST MILK

1) There are no studies of IV acetaminophen use in nursing mothers. With oral acetaminophen exposure, the daily acetaminophen dose in nursing infants was calculated as approximately 1% to 2% of the maternal dose according to data from more than 15 nursing mothers (Prod Info OFIRMEV(R) intravenous injection, 2013). Acetaminophen is distributed in the breast milk in amount ranging from 0.1% to 1.85% of the maternal dose (Prod Info Tylenol(R), 1999).
2) Acetaminophen appears to partition into the milk of lactating mothers with peak concentrations of 10 to 15 mcg/mL one to two hours following an oral dose of 650 mg. Neither acetaminophen nor its metabolites were detected in nursing infants' urine (Berlin et al, 1980; Bitzen et al, 1981).
3) CASE REPORT: A skin rash was observed in a 2-month-old breastfed infant whose mother had been receiving acetaminophen 1 g at bedtime for 2 days. The rash was maculopapular and appeared on the baby's upper trunk and face; withdrawal of acetaminophen in the mother resulted in subsidence of the rash in approximately 24 hours. Two weeks later, a similar rash occurred in the infant following a 1-g dose of acetaminophen to the mother (Matheson et al, 1985). Toxicity to the neonate during lactation or due to neonatal use may be limited by immaturity of metabolic pathways.
4) Although acetaminophen appears in breast milk, the concentration does not appear sufficient to result in a pharmacologically significant dose to the breastfeeding infant (Anon: Committee on Drugs & American Academy of Pediatrics, 1994; Berlin et al, 1980a; Bitzen et al, 1981).

B) LACK OF EFFECT

1) Maternal ingestion of recommended doses of acetaminophen does not appear to present a risk to the nursing infant.

3.20.5)

A) ANIMAL STUDIES

1) As part of the National Toxicology Program, fertility assessments were conducted in animals via a continuous breeding study. No effects on fertility parameters were evident in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison. There was no effect on sperm motility or sperm density in the epididymis; however, there was a significant increase in the percentage of abnormal sperm in animals consuming 1.7 times the MHDD (based on a body surface area comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing (Prod Info OFIRMEV(R) intravenous injection, 2013).
2) There was evidence of reduced testicular weight, spermatogenesis, and fertility in males and reduced implantation sites in females when given acetaminophen at doses that were 1.2 times the MHDD or greater (based on body surface area). The duration of treatment was associated with an increase in these adverse effects. The clinical significance of this study is unknown (Prod Info OFIRMEV(R) intravenous injection, 2013).

Carcinogenicity

3.21.3)

A) LACK OF EFFECT

1) No association was found between consumption of acetaminophen-containing analgesics and the incidence of cancer of the renal pelvis, ureter, or bladder in a retrospective case-control investigation in 1189 patients (McCredie & Stewart, 1988).
2) In a case-controlled study, patients who ingested acetaminophen were at a decreased risk of developing ovarian cancer (Cramer et al, 1998).

Genotoxicity

Hematologic

3.13.2)

A) THROMBOCYTOPENIC DISORDER

1) Thrombocytopenia has been reported in rare incidences of chronic acetaminophen overdose (Fischereder & Jaffe, 1994; Thornton & Losowsky, 1990).

B) INTERNATIONAL NORMALIZED RATIO

1) Increased INR and PTT is common in patients with fulminant hepatic failure from chronic supratherapeutic use of acetaminophen (Liu et al, 2005; Waseem et al, 2003; Miles et al, 1999; Smilkstein, 1998).

C) AGRANULOCYTOSIS

1) CASE REPORT: A 19-year-old patient who overdosed on 12 grams of acetaminophen over 2 days presented with plasmacytosis and thrombocytosis along with life-threatening agranulocytosis which was followed by a leukemoid reaction (Gursoy et al, 1996).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Always monitor vital signs and mental status in all patients.
B) STABLE PATIENT: Acetaminophen level and liver enzymes, consider checking acetyl salicylic acid level, electrolytes, and ECG in patients with an intentional exposure.
C) UNSTABLE PATIENT: CBC, electrolytes, renal function tests, ABG/VBG, acetaminophen level, liver enzymes, PT/INR, urinalysis, lactate, acetyl salicylic acid level, ECG, chest x-ray, and head CT if encephalopathic.

4.1.2)

A) TOXICITY

1) In symptomatic patients or patients with a history of repetitive, supratherapeutic ingestion, serum acetaminophen levels should be obtained. When the acetaminophen serum concentration is measurable, NAC should be instituted immediately. Some authors suggest that if the laboratory used cannot measure acetaminophen concentrations below 10 mcg/mL (greater than 66.16 Standard International Units (micromole/L)), then NAC should be administered until at least 24 hours after the last dose of acetaminophen (Donovan et al, 1999).

a) Interpretation of acetaminophen levels is difficult in chronic overdoses; the acetaminophen nomogram cannot be applied. The Rumack-Matthew nomogram is designed to be used for single acute ingestions. It is NOT helpful in determining the need for NAC in chronic ingestions.

B) BLOOD/SERUM CHEMISTRY

1) Obtain AST, ALT, and PT or INR levels to determine whether liver injury has occurred, particularly in symptomatic patients or patients with acetaminophen serum levels greater than 10 mcg/mL (greater than 66.16 Standard International Units (micromole/L)).

a) Serum AST on presentation may have prognostic implications in these patients, those with AST < 50 units/L will likely do well with NAC therapy, those with AST greater than 1000 units/L on presentation are at higher risk of death.

1) In a prospective series of 249 patients with repeated supratherapeutic acetaminophen ingestion, serum AST concentration on admission was less than 50 units/L in 126 patients and none of these patients went on to develop hepatotoxicity (defined as aminotransferase of greater than 1000 units/L). There were 37 patients with AST concentration of greater than 1000 units/L on presentation; 5 died and one underwent liver transplantation (Daly et al, 2004).

2) A small number of patients may experience kidney injury following chronic high doses of acetaminophen. Obtain serum electrolyte levels, BUN, and creatinine in order to assess changes in electrolytes and kidney injury in patients with hepatotoxicity. Generally renal and hepatic toxicity develop concurrently.

a) If evidence of liver injury, monitor glucose (for hypoglycemia) and amylase (for pancreatitis) levels. Hypoglycemia may be seen 2 to 4 days post-ingestion with severe chronic overdoses and hepatic failure.
b) Monitor serum ammonia in patients with evidence of encephalopathy.

3) Febrile children given supratherapeutic acetaminophen dosing (80 to 180 mg/kg/day) were shown to have reduced antioxidant status and erythrocyte glutathione levels after therapy. These changes may indicate a risk for hepatotoxicity (Kozer et al, 2001).

C) ACID/BASE

1) Monitor arterial blood gases for acidosis in patients with severe hepatic injury.

D) COAGULATION STUDIES

1) Prothrombin time or INR may be used to determine whether liver injury has occurred (Singer et al, 1995). Some authorities start prophylaxis against hepatic encephalopathy if the prothrombin ratio rises above 3.

a) Acetaminophen does not interfere with the prothrombin time assay (van der Steeg et al, 1995 & 1995a).

Methods

1) ELISA (FOR CHRONIC TOXICITY): An antigenic biomarker called 3-(cystein-S-yl)-acetaminophen protein adducts (3-Cys-A) can be quantitated by a competitive inhibition enzyme-linked immunosorbent assay (ELISA) in cases of suspected chronic acetaminophen toxicity (Webster et al, 1996).
2) RECOMMENDED METHODS: HPLC and a fluorescence polarization immunoassay are recommended methods for analysis of samples for acetaminophen. Other methods, including colorimetrics and other immunoassays, are used, but results may be affected by interfering compounds and may not be accurate at low concentrations.
3) ABBOTT TDX FLUORESCENCE POLARIZATION IMMUNOASSAY: Rapid, easy to perform, free of interferences from other drugs, and results correlate well with those of HPLC through a wide range of concentrations (Edinboro et al, 1991).
4) EMIT(R) ASSAY: When compared with HPLC analysis of the same samples in 2 laboratories, had correlation coefficients of 0.984 (n=98) and 0.964 (n=54) (Syva Company, 1984).
5) ALPHA-GST ENZYME IMMUNOASSAY (HEPKIT): is available for determination of serum alpha-glutathione S-transferase (aGST), with a turn-around-time of less than 3 hours. Serum aGST appears to be a more sensitive measurement of subclinical hepatic injury than AST following acetaminophen overdose (Sivilotti et al, 1999).

1) HIGH PRESSURE LIQUID CHROMATOGRAPHY (HPLC): Also an accurate although somewhat more labor intensive method of analysis through a wide range of serum concentrations without interference from other drugs (Blair & Rumack, 1977; Duffy & Byers, 1979).
2) Gas chromatography is also a reliable method.
3) Ion-pair liquid-liquid extraction of samples prior to reversed-phase ion-pair isocratic HPLC may increase resolution when compared with simple direct injection of urine or protein precipitated plasma samples (Kamali & Herd, 1990).

1) COLORIMETRIC: The results obtained from some colorimetric assays may be unreliable. Methods that depend on acid hydrolysis of the sample prior to extraction do not distinguish between parent drug and metabolites, and may overestimate acetaminophen concentrations by as much as 700% compared with HPLC (Stewart et al, 1979).

a) Another colorimetric assay overestimates actual drug concentration at levels below 50 mcg/mL (Duffy & Byers, 1979).

2) FERRIC REDUCTION METHOD: The ferric reduction colorimetric method appeared reasonably reliable at acetaminophen levels of 50 mcg/mL and 200 mcg/mL with a sufficiently low cost to benefit ratio. It may be appropriate for small hospitals that perform tests infrequently (Bridges et al, 1983).
3) COLORIMETRIC ASSAY: A colorimetric technique for determination of acetaminophen in serum and plasma (50 to 450 mcg/mL) has been reported (Patel & Morton, 1988).

a) Eight of 178 drug/drug combination products tested interfered significantly with the quantitative assay. All of these were able to be corrected in order to arrive at a semiquantitative value for acetaminophen concentration.

4) RAPID ACETAMINOPHEN METER: A meter using one drop of whole blood, and providing results within 30 seconds, correlated strongly with simultaneous HPLC or TDx assay analysis in 61 samples (Shannon et al, 1989).
5) URINE: A rapid urinary screen for acetaminophen with modification to avoid false-negative results was described (Ray et al, 1987; Buttery et al, 1988).
6) TISSUE: A method to detect acetaminophen-protein adducts in biological samples was reported (Roberts et al, 1987; Potter et al, 1989; Pumford et al, 1989).

a) Measuring acetaminophen-protein adducts in serum or hepatic tissue may help determine the etiology of hepatotoxicity of unknown cause (Bania et al, 1992).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who are symptomatic, have elevated liver enzymes or an acetaminophen concentration above 20 mcg/mL should be admitted for NAC therapy.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients under age 6 can be managed at home if the ingestion is inadvertent and: a) less than 200 mg/kg over a single 24 hour period, or b) less than 150 mg/kg per 24-hour period for the preceding 48 hours or c) less than 100 mg/kg per 24-hour period for the preceding 72 hours or longer. Patients age 6 or older can be managed at home if the ingestion is inadvertent and: a) less than 200 mg/kg or 10 g (whichever is less) over a single 24 hour period, or b) less than 150 mg/kg or 6 g (whichever is less) per 24-hour period for the preceding 48 hours or longer (Dart et al, 2006).
B) In patients with conditions that are purported to increase susceptibility to acetaminophen toxicity (eg alcoholism, isoniazid use, prolonged fasting) the dose of acetaminophen considered safe to manage at home should be reduced to less than 4 g or 100 mg/kg (whichever is less) per day (Dart et al, 2006).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a toxicologist for questions regarding dosing, necessity or duration of therapy. Have a low threshold to consult a toxicologist if you think your patient might need a transplant.
B) Consultation with a liver transplant center may be required if the following signs develop (Mutimer et al, 1994; Vale, 1992; Janes & Routledge, 1992; Harrison et al, 1990a; O'Grady et al, 1991; O'Grady et al, 1989; O'Grady et al, 1988):

1) Acidosis, pH less than 7.3
2) Encephalopathy, grade III or IV
3) Renal insufficiency (creatinine higher than 3.4 mg/dL)
4) Coagulopathy: PT greater than 35 to 40 seconds (without treatment with coagulation factors), or rapidly rising.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients under age 6 should be sent to a healthcare facility for evaluation if the ingestion is: a) 200 mg/kg or more over a single 24 hour period, or b) 150 mg/kg or more per 24-hour period for the preceding 48 hours or c) 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer. Patients age 6 or older should be sent to a healthcare facility for evaluation if the ingestion is: a) at least 200 mg/kg or 10 g (whichever is less) over a single 24 hour period, or b) at least 150 mg/kg or 6 g (whichever is less) per 24-hour period for the preceding 48 hours or longer (Dart et al, 2006).
B) In patients who may be more susceptible (ie, alcoholic, concomitant isoniazid use, prolonged fasting), referral should be considered at lower levels; more than 4 g or 100 mg/kg per day, whichever is less (Dart et al, 2006).
C) All patients with deliberate overdose should be sent to a healthcare facility.
D) Asymptomatic patients with normal liver enzymes and an acetaminophen concentration below 20 mcg/mL may be discharged.

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) Most patients will NOT require pre-hospital decontamination following repeated supratherapeutic oral doses unless the last dose is recent and very substantial. Infants and children who have received repeated supratherapeutic doses via the rectal route will NOT require pre-hospital decontamination. One dose of activated charcoal should be given without a cathartic if substantial ingestion has occurred within previous few hours.

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) SUMMARY

1) Gastrointestinal decontamination is generally not a priority as this is a CHRONIC ingestion. One dose of activated charcoal should be given without a cathartic if substantial ingestion has occurred within previous few hours.

B) ACTIVATED CHARCOAL

1) Acetaminophen is well adsorbed by activated charcoal (Bainbridge et al, 1977; Van de Graff et al, 1982) and is most effective if given within one hour of ingestion of a liquid formulation (Anderson et al, 1999).
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) GENERAL TREATMENT

1) DEFINITION of REPEATED SUPRATHERAPEUTIC DOSING:

a) ADULTS: Excessive chronic acetaminophen ingestion can be defined as ingestion of greater than manufacturers' maximum recommended daily dose of 4 grams. However, liver toxicity following chronic acetaminophen dosing is related to both dose and duration of exposure (beyond 24 hours). Therefore, concern for liver injury in patients 6 years of age and older should be considered for those who ingest at least 10 grams or 200 mg/kg (whichever is less) over a single 24-hour period, or at least 6 grams or 150 mg/kg per day (whichever is less) for a 48-hour period or longer (Dart et al, 2006).
b) CHILDREN: It has been recommended that ingestions of 200 mg/kg or more over a single 24-hour period, or 150 mg/kg or more per 24-hour period for the preceding 48 hours, or 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer constitute repeated supratherapeutic dosing in children (Dart et al, 2006).
c) Theoretically, it should be possible at some dose and dosing interval (currently undefined) to achieve a steady-state acetaminophen concentration capable of depleting glutathione to the extent that hepatotoxicity could occur.

2) The incidence of serious acetaminophen toxicity after repeated supratherapeutic doses is low and usually appears to only follow massive dosing or prolonged excessive dosing. Most patients are asymptomatic and do NOT need treatment unless risk factors (eg, preexisting hepatic disorder, HIV infection) are present.
3) Obtain an acetaminophen plasma concentration as soon as possible after presentation. If acetaminophen concentrations in plasma samples are below the level of detection and liver enzymes are not elevated, treatment with n-acetylcysteine is not recommended (Smilkstein, 1998; Smilkstein, 1991).
4) If there is detectable acetaminophen in initial plasma samples and/or liver enzymes are elevated, treatment with n-acetylcysteine is recommended.
5) Serum AST on presentation may have prognostic implications in these patients, those with AST less than 50 units/L will likely do well with NAC therapy, those with AST greater than 1000 units/L on presentation are at higher risk of death.

a) In a prospective series of 249 patients with repeated supratherapeutic acetaminophen ingestion, serum AST concentration on admission was less than 50 units/L in 126 patients and none of these patients went on to develop hepatotoxicity (defined as aminotransferase of greater than 1000 units/L). There were 37 patients with AST concentration of greater than 1000 units/L on presentation; 5 died and one underwent liver transplantation (Daly et al, 2004).

6) PATIENT HISTORY CONSIDERATIONS

a) There are no established guidelines for determining the risk for development of hepatotoxicity in these patients (Smilkstein, 1998; Smilkstein, 1991).
b) Factors in the patient's history that should be elicited are (Smilkstein, 1991):

1) The number and timing of doses (especially of the last dose).
2) The amount ingested in each dose and the total overall dose.
3) Whether or not chronic alcoholism or chronic ingestion of inducers of cytochrome P-450 (such as phenobarbital/phenobarbitone) are involved.
4) Whether factors which would deplete hepatic glutathione stores (alcoholism, starvation, chronic illness) are involved.

c) It is advisable to discuss all such cases with a medical toxicologist or Poison Control Center, as firm guidelines for patient evaluation and treatment have NOT been established (Smilkstein, 1991); care must be individualized for each such patient.
d) In a prospective cohort study of febrile children (n=44) who received repeated supratherapeutic acetaminophen doses (greater than 60 mg/kg/day; mean total daily dose, 92 mg/kg/day) for greater than 48 hours, no correlation was found either between the time since the last dose or the total daily dose and the serum drug concentration(Kozer et al, 2002).

7) There are no conclusive data on the proper evaluation and management of patients chronically ingesting amounts of acetaminophen in excess of recommended doses (Kozer & McGuigan, 2002). Treatment recommendations are somewhat controversial and are based on the following data:

a) In two case series (one retrospective, one prospective) of patients with acetaminophen-induced fulminant hepatic failure following acute ingestion:
b) Treatment with the 20-hour intravenous N-acetylcysteine protocol started between 10 to 80 hours after ingestion was associated with less mortality and morbidity (Keays et al, 1991; Harrison et al, 1990).
c) N-acetylcysteine was well tolerated by these patients (Keays et al, 1991; Harrison et al, 1990).
d) In patients with acetaminophen-induced hepatic failure following acute ingestion, administration of intravenous NAC (20 hour protocol) starting 15 to 36 hours post-ingestion increased oxygen delivery and consumption.
e) The increased use of oxygen may be responsible for the beneficial effects noted in this setting (Harrison et al, 1991).
f) Because these studies did not address the issue of chronic ingestion, it is not possible to draw conclusions regarding the use of N-acetylcysteine in the setting of chronic ingestion and fulminant hepatic failure.
g) However, administration of N-acetylcysteine is probably safe and may be beneficial in such cases.

B) ACETYLCYSTEINE

1) INDICATIONS: Patients with an initial acetaminophen serum concentration above 20 mcg/mL or with evidence of liver injury (elevated PT/INR, AST, or ALT, or right upper quadrant pain) should be treated with NAC (Jones, 2000; Howland, 1998; Smilkstein, 1998).

a) It is recommended that NAC be given to those patients who develop hepatic failure believed to be associated with repeated supratherapeutic ingestions of acetaminophen and therefore, cannot be risk stratified by the Rumack-Matthew Nomogram (Wolf et al, 2007).
b) If serum liver enzymes are normal and acetaminophen serum concentration is undetectable, the patient does not need NAC therapy.

2) Atypical poisonings include both patients with multiple, intentional overdoses within 24 hours and patients who misused acetaminophen for pain over more than one day. Within the second group, these patients are often alcoholic and present very late and hepatic injury is generally well established prior to admission. There is no current accepted standard by which to determine admission and treatment in these groups. It is recommended that NAC be administered in these atypical presentations until 24 hours have passed since the last ingestion (Donovan et al, 1999). If there is no detectable serum acetaminophen and no clinical or biochemical evidence of hepatotoxicity at 24 hours since the last ingestion, NAC can be discontinued. NAC should be continued in patients with detectable acetaminophen concentrations at 24 hours or biochemical evidence of hepatotoxicity. Other clinicians recommend treatment for a minimum of 36 hours after the last ingested dose (Dart et al, 2000; Smilkstein, 1998; Howland, 1998).
3) NOMOGRAM: In cases of chronic overdose, the Rumack-Matthew Acetaminophen Nomogram cannot be applied. Interpretation of acetaminophen serum concentrations following chronic overdose is difficult (Dart & Rumack, 1993; Smilkstein, 1991).
4) NAC PHARMACOKINETICS: Oral NAC is rapidly absorbed, but bioavailability is low (10% to 30%) due to significant first-pass metabolism. NAC has a relatively small volume of distribution (0.5 L/kg). Steady-state plasma concentration following a continuous infusion is approximately 35 mg/L. Severe liver damage does not appear to affect elimination of NAC (Howland, 1998).
5) TREATMENT

a) Based on clinical studies that support a shortened course for NAC therapy (Betten et al, 2007), it appears reasonable to obtain an acetaminophen concentration along with liver enzymes at approximately 12 hours after initiation of NAC (or 20 hours if the initial acetaminophen concentration or liver enzymes are very elevated). This is based on further studies that suggest liver injury from an acetaminophen repeated supratherapeutic ingestion is most often apparent at the time of patient presentation. If the patient's 12 or 20 hour acetaminophen concentration is less than 10 mg/L (66 mcmol/L), liver enzymes have clearly declined and are approaching normal and the patient is at baseline mental status and is clinically well, NAC can be stopped, and this may allow for early discharge of the patient. However, if all the criteria are not met, NAC should be continued (Daly et al, 2004; Howland, 1998; Smilkstein, 1998).

6) ORAL NAC STANDARD PROTOCOL

a) LOADING DOSE: Give 140 mg/kg NAC as a 5% solution.

1) DILUTION: NAC is available as a 20% and 10% solution and should be diluted to 5% in a soft drink, juice, or water for oral or nasogastric administration:

TABLE: NAC DOSE/PREPARATION 20% NAC
BODY WEIGHT (kg)	20% NAC SOLUTION (mL)	GRAMS	DILUENT (mL)	5% SOLUTION (Total mL)

100 to 109	75	15	225	300
90 to 99	70	14	210	280
80 to 89	65	13	195	260
70 to 79	55	11	165	220
60 to 69	50	10	150	200
50 to 59	40	8	120	160
40 to 49	35	7	105	140
30 to 39	30	6	90	120
20 to 29	20	4	60	80

b) MAINTENANCE DOSE: 70 mg/kg every 4 hours, starting 4 hours after the loading dose, for a total of 17 doses.

1) DILUTION:

TABLE: NAC DOSE/PREPARATION 20% NAC
BODY WEIGHT (kg)	20% NAC SOLUTION (mL)	GRAMS	DILUENT (mL)	5% SOLUTION (Total mL)

100 to 109	37	7.5	113	150
90 to 99	35	7	105	140
80 to 89	33	6.5	97	130
70 to 79	28	5.5	82	110
60 to 69	25	5	75	100
50 to 59	20	4	60	80
40 to 49	18	3.5	52	70
30 to 39	15	3	45	60
20 to 29	10	2	30	40

2) If the patient weighs less than 20 kg, calculate the dose of acetylcysteine. Each mL of 20% acetylcysteine solution contains 200 mg of acetylcysteine (Prod Info acetylcysteine oral solution, solution for inhalation, 2007).

c) DOSE CONTINUATION: If liver or renal injury is not improving, continue NAC beyond the standard 72 hours (oral) or 20 hours (intravenous) protocol until improvement of liver and renal function occurs.
d) ANTIEMETIC THERAPY (Adults): Metoclopramide 1.0 to 2.0 mg/kg intravenously plus prochlorperazine 10 mg given intravenously. May add diphenhydramine 25 to 50 mg intravenously to this regimen. Alternatively, ondansetron 8 mg intravenously may be used if. If recurrent vomiting develops, switch to intravenous administration.

7) INTRAVENOUS NAC

a) 21-HOUR INTRAVENOUS PROTOCOL: This is the FDA-approved standard dosing regimen used in Europe (Prescott protocol). NAC is used for prophylaxis/prevention of acetaminophen-induced hepatic injury. LOADING DOSE: 150 milligrams/kilogram in 200 milliliters of 5% dextrose, infuse intravenously over 60 minutes. MAINTENANCE DOSE: 50 milligrams/kilogram in 500 milliliters of 5% dextrose, infuse intravenously over 4 hours followed by 100 milligrams/kilogram in 1000 milliliters of 5% dextrose, infuse intravenously over 16 hours (Prod Info Acetadote(R), 2004; Prescott et al, 1979).
b) Acetadote(R) is available in 30 mL (200 mg/mL) single dose glass vials(Prod Info ACETADOTE(R) IV injection, 2006).

Body Weight		Loading Dose 150 mg/kg in 200 mL 5% Dextrose over 60 minutes
(kg)	(Ib)	Acetadote (mL)
100	220	75
90	198	67.5
80	176	60
70	154	52.5
60	132	45
50	110	37.5
40	88	30

Body Weight		Second Dose 50 mg/kg in 500 mL 5% Dextrose over 4 hours
(Kg)	(Ib)	Acetadote (mL)
100	220	25
90	198	22.5
80	176	20
70	154	17.5
60	132	15
50	110	12.5
40	88	10

Body Weight		Third Dose 100 mg/kg in 1000 mL 5% Dextrose over 16 hours
(kg)	(Ib)	Acetadote (mL)
100	220	50
90	198	45
80	176	40
70	154	35
60	132	30
50	110	25
40	88	20

Body Weight		Second Dose 50 mg/kg in 500 mL 5% Dextrose over 4 hours
(Kg)	(Ib)	Acetadote (mL)
100	220	25
90	198	22.5
80	176	20
70	154	17.5
60	132	15
50	110	12.5
40	88	10

Body Weight		Third Dose 100 mg/kg in 1000 mL 5% Dextrose over 16 hours
(kg)	(Ib)	Acetadote (mL)
100	220	50
90	198	45
80	176	40
70	154	35
60	132	30
50	110	25
40	88	20

Body Weight		Third Dose 100 mg/kg in 1000 mL 5% Dextrose over 16 hours
(kg)	(Ib)	Acetadote (mL)
100	220	50
90	198	45
80	176	40
70	154	35
60	132	30
50	110	25
40	88	20

c) In patients who develop hepatic injury secondary to acetaminophen, NAC therapy should be continued until liver function improves.
d) To obtain more information, you can contact: Cumberland Pharmaceuticals, Inc at 1-866-767-5077.
e) PEDIATRIC DOSING

1) PEDIATRICS (PRECAUTIONS): Standard intravenous dosing can cause hyponatremia and seizures secondary to large amounts of free water. To avoid this complication, the manufacturer has recommended the following dosing guideline (Prod Info ACETADOTE(R) IV injection, 2008):

a) Patients greater than 20 kg to less than 40 kg: Loading dose: 150 mg/kg in 100 mL of diluent administered over 60 minutes. Dose 2: 50 mg/kg in 250 mL of diluent administered over 4 hours. Dose 3: 100 mg/kg in 500 mL of diluent administered over 16 hours.
b) Patients 20 kg or less: Loading dose: 150 mg/kg in 3 mL/kg of body weight of diluent administered over 60 minutes. Dose 2: 50 mg/kg in 7 mL/kg of body weight of diluent administered over 4 hours. Dose 3: 100 mg/kg in 14 mL/kg of body weight of diluent administered over 16 hours.

Body Weight		Loading Dose 150 mg/kg over 60 minutes
(kg)	(Ib)	Acetadote(R) (mL)	5% Dextrose or 1/2 normal saline (mL)
30	66	22.5	100
25	55	18.75	100
20	44	15	60
15	33	11.25	45
10	22	7.5	30

Body Weight		Second Dose 50 mg/kg over 4 hours
(kg)	(Ib)	Acetadote(R) (mL)	5% Dextrose or 1/2 normal saline (mL)
30	66	7.5	250
25	55	6.25	250
20	44	5	140
15	33	3.75	105
10	22	2.5	70

Body Weight		Third Dose 100 mg/kg over 16 hours
(kg)	(Ib)	Acetadote(R) (mL)	5% Dextrose or 1/2 normal saline (mL)
30	66	15	500
25	55	12.5	500
20	44	10	280
15	33	7.5	210
10	22	5	140

Body Weight		Second Dose 50 mg/kg over 4 hours
(kg)	(Ib)	Acetadote(R) (mL)	5% Dextrose or 1/2 normal saline (mL)
30	66	7.5	250
25	55	6.25	250
20	44	5	140
15	33	3.75	105
10	22	2.5	70

Body Weight		Third Dose 100 mg/kg over 16 hours
(kg)	(Ib)	Acetadote(R) (mL)	5% Dextrose or 1/2 normal saline (mL)
30	66	15	500
25	55	12.5	500
20	44	10	280
15	33	7.5	210
10	22	5	140

Body Weight		Third Dose 100 mg/kg over 16 hours
(kg)	(Ib)	Acetadote(R) (mL)	5% Dextrose or 1/2 normal saline (mL)
30	66	15	500
25	55	12.5	500
20	44	10	280
15	33	7.5	210
10	22	5	140

2) CASE REPORT: Approximately 9 hours after the initiation of 20-hour intravenous NAC therapy, a 3.5-year-old female (13 kg) with acetaminophen poisoning (concentration 1701 mcmol/L) developed hyponatremia (118 mmol/L) and tonic-clonic seizures; the 20-hour intravenous NAC protocol as outlined by the manufacturer suggested a loading dose of 11.25 mL of 20% NAC mixed with 40 mL of 5% dextrose for administration over 15 minutes; maintenance infusion: 3.75 mL of NAC in 500 mL of 5% dextrose over 4 hours, followed by 7.5 mL of NAC in 1 L of 5% dextrose over 16 hours. Following supportive care the child made a complete neurological recovery (Sung et al, 1997).
3) If the protocol were completed, this patient would have received 1540 mL of 5% dextrose over 20.25 hours. The authors recommended that if the 20-hour IV protocol is chosen, instead of using an absolute volume in which to dilute the NAC, a final concentration of 40 mg/mL (1 mL of 20% NAC with 4 mL of diluent (5% dextrose) to obtain a final volume of 5 mL with a concentration of 40 mg/mL) should be used. This process will avoid both sudden decreases in serum sodium and fluid overload in small children (Sung et al, 1997).
4) 10 preterm newborns (gestational age range 25 to 31 weeks; weight 500 to 1380 grams): In one study, no adverse effects were observed during IV infusion with acetylcysteine at a mean rate of 8.4 mg/kg/h for 24 hours (Prod Info Acetadote(R), 2004).
5) 6 newborns (gestational age range 26 to 30 weeks; weight from 520 to 1335 grams): In another study, no adverse effects were observed during IV infusion acetylcysteine at a rate of 0.1 to 1.3 mg/kg/h for 6 days (Prod Info Acetadote(R), 2004).
6) CASE REPORT: A 4-year-old girl (20 kg) was given NAC infusion (150 mg/kg IV) followed by an infusion of 10 mg/kg/hr for 32 hours after receiving acetaminophen 2400 mg over 72 hours, then receiving acetaminophen 2800 mg over the next 17 hours (140 mg/kg/17 hours). The patient was discharged after 7 hospital days with near normal liver function tests (Hynson & South, 1999).

f) DOSE CONTINUATION

1) If liver injury is not substantially improved, continue oral or intravenous NAC until liver function is normal or at the patient's baseline.

g) ADVERSE REACTIONS WITH IV DOSE: If a rash develops, temporarily discontinue infusion and administer diphenhydramine intravenously (adult, 25 to 50 mg; pediatric, 1 to 2 mg/kg up to adult dose). Typically the rash resolves within 1 hour. Restart intravenous NAC. Subsequent doses may require pretreatment with diphenhydramine. If anaphylactoid reaction (hypotension, angioedema, bronchospasm) occurs, NAC should be discontinued and anaphylactoid reaction treated appropriately. Further use of NAC intravenously is relatively contraindicated (Bailey & McGuigan, 1998; Reynard et al, 1992; Smilkstein et al, 1991). Anaphylactoid reactions seen after IV dosing are not noted after oral therapy and may be either rate related or related to high serum NAC concentrations.

8) PROTHROMBIN INDEX

a) A decrease in the prothrombin index (which corresponds to an increase in prothrombin time or INR) has been reported following administration of IV NAC for treatment of patients with paracetamol poisoning who did not exhibit signs of hepatocellular injury. The time of the decrease appeared to be associated with the start of the NAC infusion instead of with the ingestion of paracetamol. Because prothrombin time is measured as a prognostic indicator in patients with paracetamol (acetaminophen) poisoning, the concern is that the decrease in prothrombin index may be misinterpreted as a sign of liver failure. The authors conclude that patient management decisions should not be based solely on the measurement of this value (Schmidt et al, 2002; Pol & Lebray, 2002).

C) PATIENT CURRENTLY PREGNANT

1) CONCLUSION: Pregnant patients with a history of repeated supratherapeutic dosing with a detectable concentration of acetaminophen should be treated with NAC and delivery should not be induced in attempts to prevent fetal acetaminophen toxicity.

a) Administering NAC to the mother as soon as possible after the last dose may be the most effective means of preventing hepatotoxicity in mother and fetus (Riggs et al, 1989).
b) If the neonate is delivered prior to the completion of NAC therapy, or if the neonate has evidence of hepatic injury or there is detectable acetaminophen in cord blood at the time of delivery, the child should also receive NAC therapy.

D) HEPATIC FAILURE

1) Supportive measures should be instituted in the event that signs of hepatic failure develop.
2) HEMOPERFUSION: Although one study demonstrated an increased survival rate (16 of 23 patients) following early hemoperfusion, more controlled clinical studies need to be performed before this procedure can be considered a routine treatment for acetaminophen-induced hepatic failure (Gimson et al, 1982).
3) TRANSPLANTATION

a) Liver transplantation has a definite but limited role in the management of patients with hepatic failure from acetaminophen toxicity (Larsen et al, 1995; Makin et al, 1995). Reliable prognostic indicators for fatal outcome are needed, since those patients who recover without transplantation have complete recoveries (Harrison et al, 1990); Tournaul et al, 1992.
b) A meta-analysis was conducted that compared the different prognostic criteria that were used to determine the need for liver transplantation in patients with fulminant hepatic failure secondary to acetaminophen poisoning. The criteria that was analyzed included King's criteria (pH less than 7.3 or a combination of prothrombin time (PT) of greater than 100 sec plus creatinine of greater than 300 mcmol/L plus encephalopathy grade 3 or greater), pH less than 7.3 only, PT greater than 100 secs only, PT greater than 100 secs plus creatinine greater than 300 mcmol/L plus encephalopathy grade 3 or greater, an increase in PT day 4, factor V of less than 10%, APACHE II score of greater than 15, and Gc-globulin less than 100 mg/L.

1) Overall, in the meta-analysis, King's criteria had moderate sensitivity at 69% (range, 55% to 100%), as compared with the other criteria analyzed, but it had high specificity at 92% (range, 43% to 100%). Further analysis, utilizing Q values (a Q value of 1 reflects a perfect test and a Q value of 0.5 reflects an uninformative test) showed that the ability of the King's criteria to distinguish between patients requiring transplantation and those who do not seems limited, with a Q value of 0.61. However, using likelihood ratios, as an alternative method for evaluating the accuracies of diagnostic criteria (the greater the positive likelihood ratio and the lower the negative likelihood ratio, the better the criteria), the King's criteria had a positive:negative likelihood ratio of 12.33:0.29, indicating that it is a fairly accurate prognostic indicator.
2) In comparison, the APACHE score greater than 15 criteria had a sensitivity of 81% and a specificity of 92% on the first day of patient's admission. The APACHE criteria also had the highest positive and lowest negative likelihood ratios of any criteria analyzed in the meta-analysis (16.4:0.19), however, the APACHE criteria was evaluated in only one study. Because there was only one study available, the authors concluded that further studies are needed to evaluate the efficacy of APACHE II score criteria, and in the interim, King's criteria should be used as the standard criteria, despite its moderate sensitivity (Bailey et al, 2003).

c) During a multicenter prospective study, involving 275 patients with acute liver failure following acetaminophen poisoning, King's criteria for liver transplantation was compared with the use of the APACHE II score to determine the best prognostic indicator of outcome. King's criteria was met on admission in only 40 patients (19 died without transplant and 6 underwent transplant). Of the 235 patients who did not meet King's criteria, 163 patients survived without a transplant, 55 died without receiving a liver transplant, and 17 underwent transplantation, yielding low sensitivity, but high specificity (26% and 92%, respectively). With the APACHE II score system, 216 patients were divided into two groups, APACHE II scores less than 20 and APACHE II scores of 20 or greater. Transplant-free survival was significantly lower in the 20 or greater group as compared with the less than 20 group (43% vs 92%; p less than 0.0001). Also, the 20 or greater group underwent transplantation more frequently than the less than 20 group (13% vs 1%, p=0.002), resulting in higher sensitivity than King's criteria, but with slightly lower specificity (68% and 87%, respectively). Overall, based on the results of this study, the use of the APACHE II scores appeared to provide a more accurate assessment of outcome (Larson et al, 2005).

4) HEMODIABSORPTION: A 27-week pregnant patient presenting with acetaminophen-induced fulminant hepatic failure (due to supratherapeutic dosing) underwent 2 courses of extracorporeal hemodiabsorption (HD) because of worsening liver toxicity despite NAC therapy. This resulted in both numerical and clinical improvement in hepatic toxicity. It is suggested to employ this technique as a bridge to liver transplant and may benefit patients who fail NAC therapy (Chu et al, 2001).

E) RENAL FAILURE SYNDROME

1) Continuous hemofiltration may be preferable to intermittent hemodialysis in patients with acetaminophen induced hepatic and renal failure. Use of intermittent hemodialysis is associated with increases in intracranial pressure in these patients due to both cytotoxic and vasogenic cerebral edema. Continuous arteriovenous hemofiltration was associated with a smaller increase from baseline ICP in a group of patients with acetaminophen induced hepatic and renal failure in one study (Davenport et al, 1991).
2) Continuous veno-venous hemofiltration was used in a case of acetaminophen toxicity in an alcoholic patient presenting with liver and renal failure. Oral NAC therapy was initiated. Following aggressive supportive therapy, the patient recovered (Agarwal & Farber, 2002).

Enhanced Elimination

1) Forced diuresis, hemodialysis, and charcoal hemoperfusion are of little value in preventing acetaminophen hepatotoxicity (Winchester et al, 1985; Gimson et al, 1982a).

1) If oliguric renal failure, refractory acidosis, or fluid and electrolyte changes occur, hemodialysis may be indicated (Hall & Rumack, 1986).
2) Hemodialysis may be useful as an adjunct in treating hyperammonemia associated with hepatic encephalopathy or in patients with consistently elevated plasma acetaminophen concentrations (Williams, 1973).

1) Hemoperfusion removes only small amounts of acetaminophen from the body and has not been shown to be of benefit in repeated supratherapeutic dosing (Gazzard et al, 1974).
2) Patients presenting early after the last ingestion have been shown to do well with NAC therapy and are unlikely to benefit from hemoperfusion, even after extremely large ingestions (Smilkstein et al, 1989a).
3) Late hemoperfusion is not likely to be of benefit since the toxic metabolites are intrahepatic and are not likely to be removed by hemoperfusion.

Abstracts

Case Reports

1) A 7-month-old developed hepatotoxicity after iatrogenic administration of 467 mg/kg within 26 hours. She was treated with oral NAC beginning 11 hours after the last dose and recovered (Smilkstein et al, 1989a).
2) An 11-month-old received 70 mg/kg/dose every 4 hours for 32 hours. She was admitted 4 hours after the last dose with vomiting, lethargy and irritability, developed hepatotoxicity and recovered with supportive care (Henretig et al, 1989).
3) A 7-month-old developed hepatotoxicity after receiving 456 mg/kg per rectum over 3 days. Acetaminophen level 4 hours after the last dose was 72 mcg/mL (Smith et al, 1986).

1) PREGNANCY: A 31-year-old took 1200 mg acetaminophen, 240 mg codeine, 1400 mg carisoprodol, and 2275 mg aspirin daily throughout her pregnancy. An infant with hepatic damage and coagulopathy was born at 35 weeks gestation and suffered an intracranial hemorrhage during delivery (Kurzel, 1990).

1) A 6-year-old who received 143 mg/kg/day for 3 days died despite NAC therapy. Antecedent and concurrent illnesses including varicella, cryptococcal lymphadenitis, and hepatitis B, may have contributed to the fatal outcome (Blake et al, 1988)
2) A 5-year-old and an 8-year-old died after one week of chronic salicylate and acetaminophen overdose up to 6 grams/day. Presenting manifestations resembled Reye's syndrome, with a serum acetaminophen level of 215 mcg/mL 6 hours after the last dose in the 5-year-old (Turchen et al, 1989a).

Range Of Toxicity

Summary

1) ADULTS: More than one ingestion during a period exceeding 8 hours, resulting in a cumulative dose of greater than 4 g per 24 hours.
2) PEDIATRIC: Patients under 6 years of age:

3) PEDIATRIC: Patients older than 6 years of age:

a) At least 10 g or 200 mg/kg, whichever is less, over a single 24-hour period, or
b) At least 6 g or 150 mg/kg, whichever is less, per 24-hour period for the preceding 48 hours or longer

Therapeutic Dose

7.2.1)

A) ROUTE OF ADMINISTRATION

1) INTRAVENOUS

a) WEIGHT OF 50 KG OR MORE: The recommended dose is 1000 mg every 6 hours or 650 mg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 1000 mg; maximum daily dose is 4000 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).
b) WEIGHT OF LESS THAN 50 KG: The recommended dose is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 15 mg/kg or 750 mg; maximum daily dose is 75 mg/kg/day or 3750 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).

2) ORAL

a) For analgesia and antipyresis, the recommended oral dose is 650 to 1000 milligrams every 4 to 6 hours as needed, up to a maximum of 4 grams/day (Prod Info TYLENOL(R) REGULAR STRENGTH oral tablets, 2007; Prod Info TYLENOL(R) EXTRA STRENGTH chewable oral tablets, oral tablets, rapid-release oral gelcaps, oral geltabs, oral caplets, oral cool caplets, oral liquid, 2007).

3) RECTAL

a) For analgesia and antipyresis, the recommended dose is 650 milligrams administered as a rectal suppository every 4 to 6 hours is recommended, not to exceed 4 grams in 24 hours (Prod Info ACEPHEN(TM) rectal suppositories, 2006).

7.2.2)

A) ROUTE OF ADMINISTRATION

1) INTRAVENOUS

a) 2 to 12 years: The recommended dose is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 15 mg/kg or 750 mg; maximum daily dose is 75 mg/kg/day or 3750 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).
b) 13 years or older and weighing less than 50 kg: The recommended dose is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 15 mg/kg or 750 mg; maximum daily dose is 75 mg/kg/day or 3750 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).
c) 13 years or older and weighing 50 kg or more: The recommended dose is 1000 mg every 6 hours or 650 mg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 1000 mg; maximum daily dose is 4000 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).

2) ORAL

a) 2 to 3 years: The recommended dose is 160 milligrams (mg) orally every 4 hours as needed, up to a maximum dose of 800 mg/24 hours (Prod Info acetaminophen oral suspension, 2006).
b) 4 to 5 years: The recommended dose is 240 milligrams orally every 4 hours as needed, up to a maximum dose of 1.2 grams/24 hours (Prod Info CHILDREN'S TYLENOL(R) oral flavor-creator liquid, oral dye-free liquid, meltaway oral tablets, oral suspension, 2007).
c) 6 to 8 years: The recommended dose is 320 milligrams orally every 4 hours as needed, up to a maximum dose of 1.6 grams/24 hours (Prod Info CHILDREN'S TYLENOL(R) oral flavor-creator liquid, oral dye-free liquid, meltaway oral tablets, oral suspension, 2007).
d) 9 to 10 years: The recommended dose is 400 milligrams orally every 4 hours as needed, up to a maximum dose of 2 grams/24 hours (Prod Info CHILDREN'S TYLENOL(R) oral flavor-creator liquid, oral dye-free liquid, meltaway oral tablets, oral suspension, 2007).
e) 11 years: The recommended dose is 480 milligrams orally every 4 hours as needed, up to a maximum dose of 2.4 grams/24 hours (Prod Info CHILDREN'S TYLENOL(R) oral flavor-creator liquid, oral dye-free liquid, meltaway oral tablets, oral suspension, 2007).
f) 12 years and older: The recommended dose is 650 to 1000 milligrams orally every 4 to 6 hours as needed, up to a maximum dose of 4 grams/24 hours (Prod Info TYLENOL(R) REGULAR STRENGTH oral tablets, 2007; Prod Info TYLENOL(R) EXTRA STRENGTH chewable oral tablets, oral tablets, rapid-release oral gelcaps, oral geltabs, oral caplets, oral cool caplets, oral liquid, 2007).

3) RECTAL

a) TERM INFANTS: The recommend starting dose of rectal acetaminophen for term infants is 30 milligrams/kilogram (mg/kg) followed by 20 mg/kg every 6 to 8 hours. The maximum daily dose of rectal acetaminophen for term infants is 90 mg/kg (Van Lingen et al, 1999).
b) 3 to 6 years: The recommended dose is 120 milligrams (mg), administered as a rectal suppository, every 4 to 6 hours as needed, up to a maximum dose of 720 mg/24 hours (Prod Info ACEPHEN(TM) rectal suppositories, 2006).
c) 6 to 12 years: The recommended dose is 325 milligrams, administered as a rectal suppository, every 4 to 6 hours as needed, up to a maximum dose of 2 grams/24 hours (Prod Info ACEPHEN(TM) rectal suppositories, 2006).
d) 12 years and older: The recommended dose is 650 milligrams, administered as a rectal suppository, every 4 to 6 hours as needed, up to a maximum dose of 4 grams/24 hours (Prod Info ACEPHEN(TM) rectal suppositories, 2006).

Minimum Lethal Exposure

1) A 5-year-old girl received a 500-mg acetaminophen suppository every 3 hours for a total of 17 suppositories (8.5 grams) within a 48-hour period. Laboratory tests at this time showed severe liver damage. At 72 hours after the first acetaminophen dose, the child died (Bauer et al, 1999).
2) A 3.5-year-old child died of hepatic and renal failure after 24 hours of excessive acetaminophen therapy. The patient received 720 milligrams every 3 hours, for a total of 5.04 grams. Fourteen hours after her last dose, the acetaminophen serum level was 53 milligrams/liter. Liver biopsy revealed centrilobular necrosis typical of massive acute acetaminophen overdose (Nogen & Bremner, 1978).

Maximum Tolerated Exposure

1) It has been recommended that ingestions of 200 mg/kg or more over a single 24-hour period, or 150 mg/kg or more per 24-hour period for the preceding 48 hours, or 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer constitute repeated supratherapeutic dosing in children (Dart et al, 2006).

a) In patients who may be particularly susceptible (ie, concomitant isoniazid administration, prolonged fasting) referral after ingestions of 4 grams or 100 mg/kg per day (whichever is less) should be considered (Dart et al, 2006).

2) A minimum toxic threshold dose in children, based on reported experience, is 175 milligrams/kilogram over 2 to 4 days, especially in the setting of fever and decreased oral intake (Sztajnkrycer & Bond, 2001).
3) An 11-month-old child was admitted to the emergency department following inadvertent dosing of 650 milligrams acetaminophen rectally every 4 hours for 8 doses (total acetaminophen 580 milligrams/kilogram, averaging 420 milligrams/kilogram/24 hours). Eleven hours after the last dose, an acetaminophen serum level of 240 milligrams/liter was reported. The child recovered with supportive care only (Henretig et al, 1989).
4) A 22-month-old child was admitted with significantly elevated liver aminotransferase levels following inadvertent dosing of 650 milligrams rectally. She received 10 suppositories (650 milligrams each) over 3 days, a total dose of 6.5 grams or 520 milligrams/kilogram, averaging 174 milligrams/kilogram/day. Acetaminophen serum level 30 hours after the last dose was 19.8 milligrams/liter. The patient recovered following 17 doses of oral NAC (Henretig et al, 1989).
5) A case report described a 15-month-old child who developed fulminant hepatitis and encephalopathy following treatment with acetaminophen at an estimated dosage of 150 milligrams/kilogram/day for 4 days. The serum acetaminophen level was first determined at about 30 hours after the last reported dose and was zero. The patient recovered with supportive care (Agran et al, 1983).
6) A 10-month-old infant developed fulminant hepatic failure after taking 750 mg acetaminophen (125 mg/kg/day) for 4 days and 1000 mg of acetaminophen (150 mg/kg/day) for 2 days. The serum acetaminophen concentration, approximately 15 hours after the last dose of acetaminophen was 55 mcg/mL. The patient recovered following NAC therapy, administered about 47 hours after the last acetaminophen dose (Liu et al, 2005).
7) The following table summarizes the dosing history and outcome of pediatric cases of hepatotoxicity following repeated supratherapeutic acetaminophen dosage.

TABLE: CHRONIC PEDIATRIC ACETAMINOPHEN OVERDOSE
AGE	DAILY DOSE	DURATION	TREATMENT	OUTCOME
4 days	480 mg first 24 hours, then 240 mg	2 days	NAC	recovery
6 week	540 mg	2 days	NAC	recovery
7 week	180 mg	6 days	supportive	recovery
7 mo	152 mg/kg	3 days	supportive	recovery
7 mo	467 mg/kg	26 hours	NAC	recovery
10 mo	125 mg/kg for 4 days and 150 mg/kg for 2 days	6 days	NAC	recovery
11 mo	420 mg/kg	32 hours	supportive	recovery
15 mo	150 mg/kg	4 days	supportive	recovery
18 mo	148 mg/kg	2 days	supportive	recovery
20 mo	up to 2.7 g	7 days	supportive	recovery
22 mo	174 mg/kg	3 days	NAC	recovery
36 mo	4 g	6 days	supportive	death
3.5 yr	336 mg/kg	24 hours	supportive	death
4 yr	140 mg/kg	4 days	NAC	recovery
5 yr	up to 6 g	1 week	NAC	death
6 yr	143 mg/kg	3 days	NAC	death
8 yr	up to 6 g	1 week	NAC	death
12 yr	up to 108 mg/kg	6 days	supportive	recovery

1) In adults, a repeated supratherapeutic ingestion of acetaminophen occurs when there is more than one ingestion during a period exceeding 8 hours, resulting in a cumulative dose of greater than 4 g per 24 hours (Alhelail et al, 2011; Daly et al, 2004). However, liver toxicity following chronic acetaminophen dosing is related to both dose and duration of exposure (beyond 24 hours). Therefore, concern for liver injury in patients 6 years of age and older should be considered for those who ingest at least 10 grams or 200 mg/kg (whichever is less) over a single 24-hour period, or at least 6 grams or 150 mg/kg (whichever is less) for a 48-hour period or longer (Dart et al, 2006).

a) In patients who may be particularly susceptible (alcoholic, isoniazid, prolonged fasting) referral after ingestions of 4 grams or 100 mg/kg per day (whichever is less) should be considered (Dart et al, 2006).

2) In one anecdotal case of chronic acetaminophen poisoning in an adult, a 36-year-old woman survived ingestion of approximately 30 grams acetaminophen over 36 hours. She developed acute renal failure in the absence of severe hepatotoxicity (Curry et al, 1982).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) PEDIATRIC

a) Acetaminophen serum level of 240 milligrams/liter was reported 11 hours after the last dose following inadvertent dosing of 650 milligrams rectally every 4 hours for 8 doses in an 11-month-old child (Henretig et al, 1989).
b) Acetaminophen serum level of 19.8 milligrams/liter was reported 30 hours after the last dose following inadvertent dosing of 10 suppositories (650 milligrams each) over 3 days in a 22-month-old child (Henretig et al, 1989).
c) In a fatality, acetaminophen serum level of 53 milligrams/liter was reported 14 hours after the last dose in a 3.5-year-old girl who had received 720 milligrams every 3 hours, for a total of 5.04 grams (Nogen & Bremner, 1978).
d) An acetaminophen level of 78.5 mcg/mL was reported in a 5-month-old infant who inadvertently received approximately 200 mg/dose every 4 hours (total dose of 162 mg/kg/day) for several days (Waseem et al, 2003).
e) An acetaminophen level of 287 mcg/mL was reported in a 58-day-old girl who inadvertently received multiple unknown doses of acetaminophen; her parents were instructed to give the infant acetaminophen 80 mg (16.32 mg/kg/dose or 97.9 mg/kg/day) every 4 hours for fever. Following NAC, intravenous dextrose, and supportive therapy for hepatotoxicity, she recovered without further sequelae (Muniz et al, 2004).
f) A 4-day-old infant, who had been circumcised at 2-days-old, developed hepatic failure after receiving acetaminophen 80 mg (26 mg/kg) every 4 hours for 24 hours, followed by 40 mg (13 mg/kg) every 4 hours for 2 days. Sixteen hours after the last dose, the patient's serum acetaminophen concentration was 109.8 mcg/mL (therapeutic range 10 to 30 mcg/mL) (Walls et al, 2007).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (ORAL)MOUSE:

a) 338 mg/kg ((RTECS, 2000))

2) LD50- (SUBCUTANEOUS)MOUSE:

a) 310 mg/kg ((RTECS, 2000))

3) LD50- (ORAL)RAT:

a) 1944 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) When approximately 70% of glutathione stores are depleted, NAPQI binds covalently with the protein macromolecules in the hepatocytes and causes cell death and zone 3 (centrilobular or distal acinar) degeneration of the liver (Mitchell et al, 1974; Prescott, 1983).
2) In humans the hepatic supply of reduced glutathione and 3-phosphoadenosine 5'-phosphosulfate starts to be depleted after administration of 0.5 to 3 grams acetaminophen (Slattery et al, 1987).
3) ANIMAL/IN VITRO STUDIES: In acetaminophen-toxic mice, anti-acetaminophen antibodies were initially located in cells proximal to the central vein, indicating that damage started there, and then spread out through zone 3 (centrilobular or distal acinar) (Bartolone et al, 1989a).

a) Researchers purified a 58-kilodalton protein from mice with acetaminophen-induced hepatotoxicity. This protein was identified with an affinity purified antibody to acetaminophen adducts, and was found only in damaged tissues (Bartolone et al, 1989).

4) FREE RADICAL INJURY: Based on an in vitro study of cultured hepatocytes, it was postulated that hydroxyl radicals generated by an iron catalyzed Haber-Weiss reaction mediates the cell injury produced by acetaminophen (Kyle et al, 1987).

a) Deferoxamine decreased acetaminophen-induced hepatotoxicity, mortality and depressed malonaldehyde formation without affecting glutathione depletion or reducing covalent binding of acetaminophen to liver proteins in a rat model. This suggests that acetaminophen-induced hepatotoxicity is related to free radical injury catalyzed by iron (Sakaida et al, 1995).

5) SECONDARY INJURY: Secondary microcirculatory changes (neutrophil activation and microvascular plugging) that exacerbate the original acetaminophen-induced hepatic injury and extend necrosis through ischemic infarction of the periacinar region has been proposed as a mechanism of acetaminophen-induced hepatotoxicity (Jaeschke & Mitchell, 1989).

a) It was also speculated that a potent antioxidant such as NAC may protect through an action on neutrophils to restore microcirculatory blood flow (Mitchell, 1988).
b) In a rat model, pretreatment with drugs which interfere with macrophage function prevented acetaminophen-induced hepatotoxicity without affecting acetaminophen metabolism, suggesting that macrophages contribute to acetaminophen-induced hepatic necrosis (Laskin et al, 1995).

6) PROSTAGLANDINS: Mice treated with xylitol or sodium chloride (to stimulate prostaglandin synthesis) after overdose with 400 mg/kg acetaminophen developed increased ALT and AST, and reduced hepatic glutathione.

a) Aspirin (25 mg/kg) and indomethacin (10 mg/kg), cyclooxygenase inhibitors, were found to be hepatoprotective in mice (Ben-Zvi et al, 1990).

7) MITOCHONDRIAL RESPIRATION: It was found that both acetaminophen and NAPQI were independently capable of inhibiting mitochondrial respiration in rats (Esterline et al, 1989).

a) NAPQI caused non-specific, irreversible damage, while acetaminophen was specific for NAD-linked mitochondrial substrates which were unaffected by hepatic glutathione levels and were readily reversible.
b) Clinical effects in these rats due to inhibited mitochondrial respiration included metabolic acidosis, hyperglycemia and coma (Esterline & Ji, 1989).

8) CYTOCHROMES: An in vitro study of highly purified rat liver P450 enzymes showed that certain cytochromes were primarily responsible for formation of specific reactive metabolites (Harvison et al, 1988).

a) Cytochrome P450UT-A, present only in male rats, catalyzed reactive intermediate formation 25 times faster than the female-specific cytochrome, which may explain the increased sensitivity of male rats to acetaminophen as compared with females.
b) NAPQI was formed at significantly higher rates by isoenzymes not inducible by phenobarbital, suggesting that NAPQI and 3-hydroxyacetaminophen are not formed from a common intermediate.

9) CALCIUM REGULATION: Interference in hepatic calcium regulation is reported as an early event that occurs in mice that may contribute to acetaminophen-induced injury and cell death (Corcoran et al, 1987).

1) ANIMAL STUDY: Administration of acetaminophen (600 mg/kg orally) to mice resulted in proximal tubular necrosis. The mechanism was postulated to be most dependent on cytochrome P450 activation and subsequent covalent binding of reactive metabolites (Emeigh Hart et al, 1991).

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

References

General Bibliography

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ACETAMINOPHEN-REPEATED SUPRATHERAPEUTIC

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