Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents

INTRODUCTION — Since its clinical introduction in 1950, acetaminophen (N-acetyl-p-aminophenol; APAP; paracetamol) has become the most widely used analgesic and antipyretic in the United States. The popularity of acetaminophen among pediatricians increased when concerns were raised about an association between aspirin and Reye syndrome.

Acetaminophen is available in hundreds of over-the-counter and prescription medications. Although it is remarkably safe when used at therapeutic doses, acute acetaminophen overdose (defined as any pattern of acetaminophen ingestion as long as the serum concentration can be measured within 24 hours of swallowing the first dose) has been recognized to cause fatal and nonfatal hepatic necrosis since 1966 [1,2]. In addition, repeated supratherapeutic doses can cause hepatotoxicity in children with certain risk factors, including decreased oral intake [3-5].

The clinical manifestations and diagnosis of acetaminophen poisoning in children and adolescents will be presented here. The evaluation of acetaminophen poisoning in adults and the management of acetaminophen poisoning in children, adolescents, and adults is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Acetaminophen (paracetamol) poisoning: Management in adults and children".)

EPIDEMIOLOGY — Acetaminophen remains a major cause of overdose in children throughout the world. In the United States, pediatric acetaminophen exposures account for approximately 30,000 reports to the National Poison Data System annually [6]. The outcome of acetaminophen poisoning in children and adolescents is nearly always good if the antidote, acetylcysteine, is administered within 8 to 10 hours of ingestion. Mortality is rare in children and adolescents. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Acetylcysteine administration and monitoring'.)

Patterns of exposure — The potential for toxicity from acetaminophen overdose in children and adolescents largely depends upon the circumstances surrounding the exposure.

Intentional — Intentional acetaminophen ingestions are more prevalent among older children and adolescents. These ingestions tend to be single event, high-dose ingestions. The suicidal intent of these ingestions may be disclosed by the child or adolescent after ingestion, or discovered only through toxicologic screening. Children and adolescents who ingest acetaminophen as a suicide gesture may underestimate its toxicity and more frequently develop hepatotoxicity than young children with exploratory ingestions [7]. (See "Suicidal behavior in children and adolescents: Epidemiology and risk factors" and "Approach to the child with occult toxic exposure".)

Intentional poisoning of infants with acetaminophen has been reported in cases of child abuse and is also associated with significant toxicity [8,9].

Unintentional — Unintentional ingestions are more common among younger children. These ingestions may occur through "exploratory" hand to mouth behavior [10] or inappropriate dosing [11-13], even under medical supervision [14-16].

Exploratory — The vast majority of exploratory ingestions (ie, ingestion of unsecured medication by young children) involves small doses and often can be managed without referral to an emergency department [17,18]. Significant morbidity and mortality rarely occur [3-5,19,20].

Inappropriate dosing by a caregiver — In contrast with exploratory ingestions, inadvertent repeated supratherapeutic overdose of acetaminophen in young children is the most frequent cause of severe acetaminophen toxicity or death in this age group [3-5,19]. Diagnosis of these unintentional ingestions due to inappropriate dosing may be delayed, since the symptoms and signs are nonspecific and may mimic those of the acute illness for which acetaminophen was being administered. The history of ingestion is also often difficult to obtain because parents or caregivers may be reluctant to acknowledge that they made an error that contributed to their child's illness. Per manufacturer recommendations, the use of weight to select the best dose is preferred although the use of age is an acceptable alternative.

Inappropriate dosing may occur in the following circumstances:

●When adult acetaminophen formulations are administered to children (eg, substitution of 325 or 500 mg tablet for 80 or 160 mg tablet) (table 1) [5].

●Through misreading (or unclear) instruction guidelines for liquid preparations (eg, substituting the infant drop formulation [100 mg/mL] for the less concentrated elixir or syrup [32 to 33 mg/mL]) (table 1). This type of error has decreased in the United States since the concentrated infant drop formula was discontinued in 2011 [21].

●Through "intentional" overdose, when parents or caregivers perceive that effective therapy has not been achieved with pediatric formulations (eg, 160 mg per 5 mL) in the appropriate dose (10 to 15 mg/kg) and increase the frequency or dosage of acetaminophen [4,5,22], or combine acetaminophen with other antipyretics [23], exceeding dose and duration on product labeling.

●There are reports suggesting that some conditions may predispose children to liver injury from therapeutic acetaminophen doses. However, many of these reports are of low quality and lack sufficient information for a formal causality assessment [24]. Putative risk factors are starvation, postoperative condition, inborn errors of metabolism and CYP2E1 induction by other medications such as rifampin and isoniazid.

●By consuming multiple acetaminophen-containing products concurrently (ie, prescription products and nonprescription products or single substance and combination products).

A profile of the child who may be at increased risk for hepatotoxicity from repeated supratherapeutic acetaminophen dosing at home has been derived from case series. Characteristic features include a sick child who is younger than two years of age and is exposed in one of the following ways [5,11,19,25-27]:

●Dosing that exceeds more than 90 mg/kg per day of acetaminophen for more than one day (eg, only 20 percent greater than the maximum recommended daily dose of 75 mg/kg)

●Administration of multiple doses of adult-strength preparations

●Administration of acetaminophen suppositories

Although hepatoxicity has been reported in a few children who received multiple therapeutic doses of acetaminophen [5], the ascertainment of dose through parent or caregiver recall in these cases is questionable. Furthermore, a study of therapeutic dosing in a group of 100 hospitalized children and adolescents who received therapeutic doses of acetaminophen (greater than or equal to six doses of 10 to 15 mg/kg per dose over a 48-hour period) and were at risk for acetaminophen toxicity due to decreased oral intake failed to find any hepatotoxicity attributable to acetaminophen [28]. Thus, the likelihood of toxicity from multiple therapeutic doses of acetaminophen in the majority of children appears low.

Iatrogenic intravenous overdose — Intravenous acetaminophen has been available in the United Kingdom since 2003 and was available for use in the United States in 2010 [29]. Tenfold iatrogenic overdoses have been described in hospitalized young children receiving intravenous acetaminophen for pain relief [30]. The typical error occurs when the dose in mg is mistakenly given as the volume in mL. Other errors include human error when determining the volume to infuse by pump, duplicated doses, and intravenous injection of the oral suspension [29].

Treatment is controversial and consultation with a poison control center or medical toxicologist is strongly advised if a child receives a single intravenous acetaminophen dose ≥90 mg/kg actual total body weight (TBW) or a cumulative dose ≥150 mg/kg TBW during 24 hours [2]. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Patient with Iatrogenic intravenous overdose' and 'Additional resources' below.)

PHARMACOKINETICS AND TOXICOKINETICS — Acetaminophen (paracetamol) is available in a variety of oral formulations, rectal suppositories, and an intravenous preparation. Toxicity, consisting primarily of hepatotoxicity, occurs when a large portion of the toxic, highly reactive, electrophilic intermediated, N-acetyl-p-benzoquinoneimine is produced after acetaminophen overdose. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Biochemical toxicity'.)

Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract, with peak serum concentrations reached from one-half to two hours after a therapeutic oral dose [31]. Peak serum concentrations are reached within four hours in most cases of overdose of immediate-release preparations. However, following high-risk overdose (>30 grams), overdose of extended-release preparations [32-34] or with co-ingestions that delay gastric emptying [35], peak serum concentrations may be delayed beyond four hours. The various suppository preparations have different absorption characteristics and reach peak concentration at variable times [36-38].

Elimination half-lives range from two to four hours for all acetaminophen preparations. However, elimination may appear to be prolonged for extended-release preparations because of prolonged tablet dissolution and absorption [33,39]. Elimination is delayed in cases with hepatotoxicity; serum half-lives greater than four hours are considered a marker of poor prognosis [40]. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation".)

The metabolism of acetaminophen at therapeutic (figure 1) and toxic doses is discussed in detail separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Biochemical toxicity'.)

Risk factors in children — Liver damage caused by excess N-acetyl-p-benzoquinoneimine (NAPQI) can occur in four circumstances (figure 1) [41-45]:

●Excessive intake of acetaminophen

●Decreased capacity for glucuronidation or sulfation

●Increased cytochrome P450 (CYP2E1) activity

●Depletion of glutathione stores

A number of risk factors may influence the propensity of acetaminophen to cause hepatotoxicity in children through the mechanisms listed above, including patient age, pattern of ingestion, nutritional status, concomitant use of CYP2E1-inducing drugs, comorbid illnesses, and genetic background [3,46]. These factors, summarized briefly below, are discussed in detail separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Clinical factors that may influence toxicity'.)

●Age – Following acute overdose, children younger than six years of age appear to be less susceptible to hepatotoxicity than older children and adults [47-52]. The reasons for this are unclear, but several hypotheses have been proposed:

•Compared with adults, infants and young children are believed to have greater capacity for conjugation with sulfate [49,51,53]. Adult patterns of metabolism are reached between 10 and 12 years of age [3].

•Young children are likely protected by an increased supply and regeneration of glutathione [51,54].

•Young children have a greater propensity to vomit after acetaminophen ingestion [49,52].

●Repeated excessive dosing – In both children and adults, repeated administration of supratherapeutic doses is associated with greater morbidity and mortality than an acute overdose [4,55]. Repeated supratherapeutic dosing is often associated with other risk factors for hepatotoxicity, such as fasting or delayed presentation. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Inappropriate therapeutic dosing'.)

●Nutritional status – Fasting or malnutrition depletes hepatic stores of glucuronide and/or glutathione, leading to increased microsomal metabolism of acetaminophen and accumulation of free NAPQI, respectively, predisposing to hepatic injury (figure 1) [56-62]. Patients at greatest risk appear to be those who consume multiple excessive doses rather than an acute overdose. This scenario is common among children suffering from an acute febrile illness, who may receive multiple doses or prolonged duration of acetaminophen.

●Comorbidities – Intercurrent or febrile illness appears to predispose some children to hepatotoxicity after multiple supratherapeutic doses [63,64]. The mechanism is not clear. It is speculated that intercurrent or febrile illnesses lower the threshold for hepatic injury, alter the clearance of acetaminophen [63], or are associated with other risk factors for hepatotoxicity (eg, decreased oral intake) [3].

Patients with Gilbert syndrome may be predisposed to hepatotoxicity because of impaired glucuronidation [65,66]. However, studies are not consistent and at least one study reports that the pattern of metabolites in urine of patients with Gilbert syndrome is similar to normal subjects [67]. (See "Gilbert syndrome".)

Patients with chronic liver disease usually have low cytochrome oxidase enzyme activity, which may be protective following acetaminophen overdose, even though the elimination half-life may be prolonged [68,69].

●Medications and co-ingestants – Concomitant use of agents that induce CYP2E1 enzymes can cause hepatotoxicity in the absence of overt acetaminophen overdose and may worsen outcome when an intentional overdose has occurred. Examples of such agents include ethanol, isoniazid, and rifampin [70,71].

In addition, drugs that compete for glucuronidation pathways (eg, trimethoprim-sulfamethoxazole and zidovudine) may potentiate acetaminophen hepatotoxicity by increasing the CYP2E1-dependent metabolism of acetaminophen [72]. However, there are no systematic studies that demonstrate a consistent increased associated risk with these medications.

●Genetic background – Polymorphisms in the cytochrome oxidase enzyme system may contribute to diminished or excessive oxidative metabolism of acetaminophen, and thereby affect predisposition to hepatic injury [73,74]. However, there are no systematic studies that demonstrate a consistent increased associated risk with known genetic variants.

DOSAGE FORMS — Acetaminophen is available in the following preparations (table 1):

●Immediate-release for oral administration (eg, liquids, caplets, capsules, tablets)

●Immediate release suppositories

●Sustained-release oral tablets (eg, bilayer tablets of Tylenol Extended Relief) formulations

●Intravenous formulation (10 mg/mL concentration)

Among the oral formulations, the concentration may range from 32 to 33 mg/mL (syrups, elixirs) for liquid preparations in the United States, and the strength may range from 80 to 650 mg for pills, capsules, or suppositories. Although the 100 mg/mL infant formulation was discontinued in the United States in 2011, it is still available in some countries. Given the variety of formulations and range of doses within similar formulations (eg, chewable tablets), the potential for unintentional overdose due to confusion over concentration and frequency is high [75].

TOXIC DOSE — The therapeutic dose of acetaminophen for children younger than 12 years is 10 to 15 mg/kg per dose, every four to six hours, not to exceed five doses per 24-hour period (maximum daily dose 75 mg/kg). The therapeutic dose for children 12 years and older and adults is 325 to 1000 mg per dose every four to six hours (maximum daily dose 4 g). Therapeutic serum concentrations range from 10 to 20 mcg/mL (66 to 132 micromol/L).

The toxic dose may vary among individuals according to baseline glutathione levels and other factors (see 'Risk factors in children' above) but in general:

●The minimal toxic dose for an acute ingestion is 150 mg/kg for a child or 7.5 to 10 g for an adult [76]. Referral for emergency department evaluation is generally recommended for acute ingestions greater than 200 mg/kg in children younger than six years of age or 10 g, whichever is less. (See 'Acute overdoses' below.)

●Toxicity is likely to occur with acute ingestions greater than 250 mg/kg or ingestions of greater than 12 g in a 24-hour period [77,78].

●Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity (defined as peak aspartate aminotransferase [AST] or alanine aminotransferase [ALT] concentrations greater than 1000 international units/L) unless treated [77]. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children".)

●In repeated supratherapeutic overdose (eg, multiple oral or rectal doses amounting to a supratherapeutic dose of acetaminophen), the minimum toxic threshold for children appears to be 150 to 175 mg/kg per day over two to four days, particularly in the setting of a febrile illness and decreased oral intake [3-5]. (See 'Repeated supratherapeutic ingestion' below.)

CLINICAL MANIFESTATIONS — The initial manifestations of acute acetaminophen poisoning in children and adolescents are often mild and nonspecific, and do not predict subsequent hepatotoxicity [79]. Nonetheless, clinicians must promptly recognize acetaminophen poisoning in order to minimize subsequent morbidity and mortality because acetylcysteine, the antidote for acetaminophen, is most effective if administered within 8 to 10 hours of ingestion [80-82].

Acute exposures — The clinical course of acute exposures (defined as any pattern of acetaminophen ingestion as long as the serum concentration can be measured within 24 hours of swallowing the first dose [2]) is often divided into four sequential stages. These stages (table 2) are described in detail separately and include the following (see "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation"):

●Stage I (up to 24 hours after overdose) – Asymptomatic but less commonly: nausea, vomiting, and, in patients with very large doses, lethargy and malaise

●Stage II (24 to 72 hours after overdose) – Right upper quadrant pain, elevation in liver aminotransferases, and prothrombin time (PT)/international normalized ratio of PT (INR), and, in severe cases, evidence of nephrotoxicity (elevated blood urea nitrogen, creatinine, oliguria) and/or pancreatitis (elevated serum amylase, lipase)

●Stage III (72 to 96 hours) – Evidence of hepatic failure and, in severe cases, kidney failure and multi-organ failure; death most commonly occurs in this stage

●Stage IV (4 to 14 days) – Recovery

Patients with high-risk ingestions (typically >350 mg/kg or >30 grams) can develop altered mental status and a metabolic acidosis with hyperlactemia early (ie, within eight hours) following ingestion [83]. Toxicity is from the acetaminophen itself (ie, parent compound) instead of the metabolites, likely from mitochondrial dysfunction and not liver injury. Management follows similar principles, but activated charcoal may be given in a delayed fashion, an increased acetylcysteine dose may be warranted, and hemodialysis may be recommended in some cases [2]. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'High-risk patients'.)

Repeated supratherapeutic ingestion — Diagnosis of repeated supratherapeutic toxicity is often difficult and requires the combination of astute history-taking and recognition of typical clinical and laboratory abnormalities. Clinicians must specifically ask about acetaminophen ingestion (including dose and frequency of administration) because patients and caregivers may not include it when asked about potentially toxic drugs. Signs and symptoms are insidious in onset, often nonspecific, and easily confused with alternative diagnoses (eg, viral syndrome). Serum concentrations of acetaminophen in this setting do not correlate with toxicity [55].

Establishing the diagnosis of repeated supratherapeutic acetaminophen poisoning frequently involves exclusion of other causes of clinical hepatitis. (See 'Differential diagnosis' below.)

EVALUATION AND DIAGNOSIS — The need for emergency department evaluation of children and adolescents with acetaminophen intoxication varies depending upon the age of the child and the maximum possible ingested dose. Most pediatric acetaminophen exposures are low-dose exposures that do not require medical attention [18]. Consultation with a regional poison control center is encouraged when making triage decisions. (See 'Regional poison control centers' below.)

Acute overdoses — Because most children and adolescents with acute acetaminophen overdose are asymptomatic at presentation, the history of exposure largely determines the need for medical evaluation, laboratory testing, and treatment. An acute overdose is defined as any pattern of acetaminophen ingestion as long as the serum concentration can be measured within 24 hours of swallowing the first dose [2].

●Prehospital triage – Prehospital evaluation involves determination of the maximal possible dose, pattern of ingestion, and whether the child has any risks for hepatotoxicity (eg, fasting, coingestion of other drugs, underlying medical conditions). Consultation with a poison control center (see 'Regional poison control centers' below) is helpful in assessing the need for emergency referral, particularly if the ingested product contains other pharmaceuticals, such as opiates (eg, acetaminophen with codeine or oxycodone, antihistamine, etc) or is an extended-release product. Some health care providers may choose to refer children younger than six years of age with acute acetaminophen exposures that are less than 200 mg/kg, especially when significant uncertainty exists concerning the maximum ingested acetaminophen dose and/or the patient's weight.

Consensus guidelines developed by America’s Poison Centers and based upon observational studies suggest that children and adolescents who meet the following criteria after acute overdose be referred to an emergency department for evaluation of acetaminophen toxicity [84]:

•Exposure to 200 mg/kg or 10 g, whichever is less, acutely or over 24 hours

•Ingestion of an unknown amount of acetaminophen

•Ingestion of acetaminophen with intent for self-harm

•Known exposure to acetaminophen with signs of toxicity (eg, vomiting, right upper quadrant pain, altered mental status)

●History – The evaluation of the child or adolescent with acetaminophen intoxication should include as much detail about the ingestion as possible.

•When did the ingestion occur?

•How much acetaminophen was ingested? (The strength or concentration of acetaminophen in the product of concern must be carefully delineated) (table 1).

•Was the child or adolescent taking acetaminophen on a regular basis (including in over-the-counter preparations)?

•Was the ingestion intentional with a desire for self-harm?

•Does the child or adolescent have any underlying medical problems or take any medication on a regular basis?

•Does the child or adolescent have symptoms (nausea, vomiting, diaphoresis, pallor, lethargy, malaise, right upper quadrant pain, hepatomegaly)?

●Physical examination – Most children with acute acetaminophen overdoses present for care soon after ingestion and are asymptomatic with a normal physical examination. Examination of children with acetaminophen intoxication should include evaluation for encephalopathy, jaundice, right upper quadrant pain, liver enlargement and/or tenderness, and bleeding. Because the clinical manifestations of acetaminophen intoxication occur in distinct stages (table 2), the examination must be repeated over time.

The clinical features of toxic metabolic encephalopathy are discussed separately. (See "Acute toxic-metabolic encephalopathy in children".)

Repeated supratherapeutic ingestion — Consensus guidelines developed by America’s Poison Centers and based upon observational studies suggest that children and adolescents who meet the following criteria be referred to an emergency department for evaluation of acetaminophen toxicity after the following supratherapeutic exposures [84]:

●150 mg/kg or 6 g, whichever is less, per 24-hour period over 48 hours

●In children less than six years of age, 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer

●Children with conditions that predispose to acetaminophen toxicity (eg, fasting, liver disease) with an ingestion of 100 mg/kg or 4 g, per 24-hour period, whichever is less

We obtain an acetaminophen concentration, aspartate aminotransferase (AST), alanine aminotransferase (ALT), prothrombin time (PT)/international normalized ratio of PT (INR), and bilirubin in children who have received multiple excessive doses of acetaminophen if they have any of the following [2]:

●If ingestion period was ≤ 24 hours – Ingestion of greater than 200 mg/kg/day (or >10 g/day if this is lower) of acetaminophen.

●If ingestion period was 24 to 48 hours – Ingestion of greater 150 mg/kg/day (or >6 g/day if this is lower) of acetaminophen.

●If ingestion period > 48 hours – Ingestion of greater 100 mg/kg/day (or >4 g/day if this is lower) of acetaminophen.

●Abdominal pain or right upper quadrant tenderness, nausea, vomiting, jaundice, ill appearing, or mental status changes.

The Revised Rumack-Matthew nomogram for acetaminophen poisoning should not be used to determine the risk of toxicity. The Revised Rumack-Matthew nomogram was derived from patients who had ingested doses within 24 hours of measurement of the serum acetaminophen concentration so it cannot be used for risk stratification of patients who have multiple ingestions over more than 24 hours [2]. The last dose cannot be used as a surrogate for single-point ingestions because earlier exposure may have caused hepatic injury [3]. If the aminotransferases are elevated, the patient should have renal function and international normalized ratio measured.

Elevation of AST or ALT indicates hepatic injury, regardless of the serum acetaminophen concentration and treatment with acetylcysteine should be provided. As an example, of 249 patients over the age of 12 years who had received more than 4 g per 24 hours of acetaminophen, 15 percent with AST of 50 to 1000 international units/L developed liver toxicity and 16 percent with serum AST >1000 international units/L died or received liver transplants [85].

Children who have residual acetaminophen (>20 mcg/mL [66 micromol/L]) but normal AST and ALT and a history suggestive of acetaminophen overdose may also be at risk for hepatic injury and warrant antidotal therapy with acetylcysteine.

Consultation with a regional poison control center (see 'Regional poison control centers' below) or a medical toxicologist can help in tailoring duration of therapy and monitoring disease progression. The management of these children is discussed separately. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Patient with reliable history and repeated supratherapeutic ingestion'.)

Laboratory evaluation — All patients with a history of acetaminophen overdose should undergo measurement of serum acetaminophen concentration. In patients who are expected to develop hepatic toxicity based upon history and initial serum acetaminophen concentration, additional laboratory tests include ALT, AST, electrolytes, blood urea nitrogen (BUN), creatinine. These studies should also be performed in patients who ingested repeated supratherapeutic doses. In addition, ill-appearing patients or those with altered mental status need blood gas analysis to determine serum pH, serum lactate, prothrombin time (PT)/international normalized ratio of PT (INR), and bilirubin to quantify hepatic dysfunction. (See "Approach to the child with occult toxic exposure".)

Acetaminophen concentration — Following an acute ingestion, the risk of toxicity is best predicted by relating the time of ingestion to the serum acetaminophen concentration. The dose history helps guide treatment decisions, but it is not sufficient evidence on which to base treatment after an acute overdose. Most studies have found only weak correlation between the amount of acetaminophen reportedly ingested and the serum concentration measured [10,86,87].

For an acute overdose, the serum acetaminophen concentration should be measured as soon as possible as long as at least four hours have passed since the start of the ingestion. There is limited utility to serum concentrations measured less than four hours after ingestion [88]. The concentration should be plotted on the Revised Rumack-Matthew nomogram to determine the need for acetylcysteine therapy (figure 2). While there is universal agreement that acetylcysteine is effective for the prevention of hepatic injury when administered soon after acetaminophen overdose, the exact guidelines for the initiation of treatment vary throughout the world. The Rumack-Matthew nomogram (four hour concentration of 150 mg/L) has been used in the United States for more than 30 years and is the author's preferred tool to guide treatment because of its safety and efficacy [89,90]. Other guidelines have also been published [91,92].

A concentration at or above the line that starts at 300 mg/L at four hours on the Revised Rumack-Matthew Treatment nomogram (figure 2) suggests a high-risk ingestion [2]. Consultation with a regional poison control center (see 'Regional poison control centers' below) or a medical toxicologist is strongly encouraged as these patients may need an increased dose of acetylcysteine and may benefit from delayed activated charcoal administration. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'High-risk patients'.)

Although the peak concentration after an intravenous overdose will occur sooner than after oral ingestion, a four-hour concentration is still recommended [30]. Until more experience with intravenous acetaminophen overdose is obtained, the clinician is encouraged to contact a regional poison control center for assistance with assessment and management of these patients. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Patient with Iatrogenic intravenous overdose' and 'Additional resources' below.)

Following an ingestion that involves an extended-release formulation (labeled for use on an eight-hour basis) or a co-ingestion with an anticholinergic agent or opioid, the Revised Rumack-Matthew nomogram can be used to assess risk if the concentration is at or above the treatment line (ie, therapy with acetylcysteine is indicated) [2]. A repeat concentration is not needed if the concentration was ≤10 mcg/mL (66 micromol/L). Following an extend-release ingestion, if the concentration obtained between 4 to 12 hours after ingestion is below the treatment line but >10 mcg/mL (66 micromol/L), we measure another concentration four to six hours after the first measurement. Following a co-ingestion with an anticholinergic agent or opioid, if the acetaminophen concentration measured 4 to 24 hours after ingestion is below the treatment line but >10 mcg/mL, we measure another concentration four to six hours after the first measurement. The second concentration is plotted versus the number of hours since the ingestion and if either concentration is above the treatment line, acetylcysteine is indicated.

Observational evidence from Australia suggests that ingestion of modified release products may increase the risk of delayed or multiple peak serum concentrations and that these patients are at increased risk for prolonged absorption and need for prolonged treatment [93]. This product is different than the modified release product available in the United States and Canada. However, given the risk of prolonged absorption, early treatment and poison center consultation is warranted for these cases.

Most clinical chemistry laboratories report the plasma acetaminophen concentrations in mcg/mL rather than micromol/L. The units should be confirmed to ensure proper plotting on the Revised Rumack-Matthew nomogram for acetaminophen poisoning. To convert mcg/mL to micromol/L, multiply by 6.62.

Serum acetaminophen concentrations obtained before four hours may be useful in detecting occult acetaminophen ingestions in patients who do not (or cannot) provide an ingestion history. However, because concentrations obtained before four hours may not represent peak concentrations, they should be repeated at four hours [79], and the four-hour concentration plotted on the Revised Rumack-Matthew nomogram. A nondetectable concentration measured between two to four hours after ingestion typically excludes risk for significant toxicity; consultation with a poison center or medical toxicologist is recommended if the decision is made to not obtain a concentration at four hours in this situation [2]. (See 'Regional poison control centers' below.)

Serum acetaminophen concentrations obtained more than 24 hours after ingestion are difficult to interpret. Patients with an unknown time of ingestion and a serum acetaminophen concentration >10 mcg/mL (66 micromol/L) and/or elevation of aminotransferases are usually treated with acetylcysteine. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Patient with unreliable history'.)

Measuring a screening serum acetaminophen concentration is recommended for all patients with a history of overdose or altered mental status thought to be caused by overdose (see "General approach to drug poisoning in adults"). However, in some cases, there is no practical way to ascertain the time of ingestion, making it impossible to use the Revised Rumack-Matthew nomogram for risk stratification. In these situations, our approach, for patients in whom an acute ingestion has occurred is to narrow the ingestion time to a specific window (eg, the patient had been continually observed until 12 hours prior to admission so the ingestion could not have occurred more than 12 hours ago), it may be possible to construct a worst possible scenario and plot the measured serum concentration using the "last known time prior to ingestion" as the time of ingestion.

Acetaminophen-protein adducts — The oxidation of acetaminophen by hepatic enzymes forms a reactive metabolite that may bind to hepatic proteins. This hepatic acetaminophen-protein adduct is released into serum and can be quantified. Quantification of these adducts may be helpful in determining if acetaminophen is responsible for acute liver injury [94-96]. However, the test is not widely available and has most commonly been used to retrospectively determine the cause of acute liver failure.

DIFFERENTIAL DIAGNOSIS — The history of acetaminophen ingestion may or may not be known. Unlike many other etiologies of hepatitis, acetaminophen-induced hepatitis is acute in onset and progresses rapidly; in severe exposure with delayed presentation or untreated with acetylcysteine, it is characterized by marked elevation of plasma aminotransferases (greater than 3000 international units/L) and is associated with a rising prothrombin time (PT). In cases of occult exposure, the differential diagnosis includes other causes of hepatic failure:

●Viral hepatitis (hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus, cytomegalovirus, varicella) – Viral hepatitis usually can be distinguished from acetaminophen-induced liver injury by aminotransferases that are almost always less than 3000 international units/L and positive serology. (See "Overview of hepatitis A virus infection in children", section on 'Diagnosis' and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Clinical manifestations'.)

●Ischemic hepatitis ("shock liver") – Ischemic hepatitis typically follows a period of severe, prolonged hypotension. Other features suggestive of ischemic hepatitis include an early rise in serum lactate dehydrogenase (LDH), a ratio of serum alanine aminotransferase (ALT) to LDH <1.5 early in the course, and a rapid fall in serum aminotransferase concentrations after the initial rise. (See "Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy", section on 'Diagnosis'.)

●Inborn errors of metabolism (eg, Wilson disease, alpha-1 antitrypsin deficiency, fatty acid oxidation abnormalities) – These diseases tend to progress slowly and are typically associated with elevations in plasma aminotransferases that are less than 1000 international units/L. Characteristic associated findings and specific testing can confirm the diagnosis. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnostic evaluation' and "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis'.)

●Drug- or toxin-induced hepatitis – A variety of toxic agents can cause acute hepatitis, which in many circumstances may be clinically indistinguishable from acetaminophen poisoning (table 3). Known exposure to these agents, absence of any history of acetaminophen exposure, and no clinically detectable serum acetaminophen help establish the diagnosis.

●Hepatobiliary disease – Most children with hepatobiliary disease have a history of biliary atresia, long-term requirement for hyperalimentation, or predisposition to pigmentary gallstones (eg, sickle cell anemia, hemolytic anemia).

●Reye syndrome – Reye syndrome is a rare cause of rapidly progressive encephalopathy with hepatic failure that often begins several days after apparent recovery from a viral illness, especially varicella or influenza A or B. This disease has virtually disappeared in concert with advisories not to use salicylates in febrile children. The liver pathology typically shows steatosis rather than the centrilobular necrosis that is characteristic of acetaminophen poisoning. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

●Patterns of exposure – The majority of acetaminophen overdoses in children younger than six years of age involve acute ingestions that are typically exploratory and have a low likelihood for serious toxicity. Multiple supratherapeutic doses of acetaminophen in young children administered orally or rectally by caregivers or large iatrogenic intravenous dosing errors also can be associated with toxicity. (See 'Unintentional' above.)

Acute intentional ingestions in children older than six years of age and adolescents (ie, suicide attempts) have a higher potential for serious acetaminophen toxicity and may also involve multiple ingestants in addition to acetaminophen when compared with exploratory ingestions in younger children. (See 'Intentional' above.)

●Toxic dose – The toxic dose of acetaminophen depends upon the age of the child and whether the exposure is acute or repeated supratherapeutic dosing. The minimal toxic dose for an acute ingestion is 150 mg/kg, and toxicity is likely to occur with ingestions >250 mg/kg in a 24-hour period. (See 'Toxic dose' above.)

●Indications for emergency department referral – Referral for emergency department evaluation is generally recommended for acute ingestions greater than 200 mg/kg in children younger than six years of age or 10 g, whichever is less; intentional ingestions with a desire for self-harm; patients who are symptomatic; or situations where the ingested dose is unknown. Consultation with a poison control center is helpful in assessing the need for emergency referral, particularly if the ingested product contains other pharmaceuticals, such as opiates (eg, acetaminophen with codeine or oxycodone, antihistamine, etc) or is an extended-release product. (See 'Acute overdoses' above and 'Regional poison control centers' above.)

●Clinical manifestations – The stages of acetaminophen toxicity are described in the table (table 2). Patients who present within 24 hours after an acute acetaminophen overdose are generally asymptomatic with a normal physical examination. Patients with high-risk ingestions (typically >350 mg/kg or >30 grams) can develop altered mental status and a metabolic acidosis with hyperlactemia early (ie, within eight hours) following ingestion. Patients who present more than 24 hours after a potentially toxic acetaminophen overdose are more likely to have manifestations of hepatotoxicity. (See 'Clinical manifestations' above.)

●Evaluation

•Acute overdose – This is defined as any pattern of acetaminophen ingestion as long as the serum concentration can be measured within 24 hours of swallowing the first dose. The likelihood for serious toxicity is determined by plotting a serum acetaminophen concentration obtained between 4 and 24 hours after the initial ingestion on the Revised Rumack-Matthew nomogram (figure 2). (See 'Acute overdoses' above and 'Laboratory evaluation' above.)

•Repeated supratherapeutic ingestion – Toxicity following repeated administration amounting to a supratherapeutic dose of acetaminophen may be difficult to diagnose unless the caregivers are specifically questioned about acetaminophen and over-the-counter medication use (eg, dose, preparation, dosing interval). Patients should be evaluated with a serum acetaminophen concentration, aspartate aminotransferase (AST), alanine aminotransferase (ALT), prothrombin time (PT)/international normalized ratio of PT (INR), and bilirubin. The Revised Rumack-Matthew nomogram should not be used to determine the risk of toxicity. Children with elevated ALT/AST or residual acetaminophen after prolonged acetaminophen overdoses are at risk for hepatotoxicity. Consultation with a poison control center or medical toxicologist is encouraged to guide assessment of poisoning risk and need for specific treatment. (See 'Repeated supratherapeutic ingestion' above and 'Laboratory evaluation' above and 'Regional poison control centers' above.)

●Differential diagnosis – In cases of occult exposure, the differential diagnosis includes other causes of severe liver injury. (See 'Differential diagnosis' above.)