INTRODUCTION — Since its clinical introduction in 1950, acetaminophen (N-acetyl-p-aminophenol; APAP; paracetamol) has become the most widely used analgesic-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, overdose of acetaminophen has been recognized to cause fatal and nonfatal hepatic necrosis since 1966 [1]. In addition, repeated supratherapeutic doses can cause hepatotoxicity in children with certain risk factors, including decreased oral intake [2-4].
The management of acetaminophen intoxication in children and adolescents will be presented here. The clinical manifestations and diagnosis of acetaminophen poisoning in children and the evaluation and management of acetaminophen poisoning in adults is discussed separately. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents" and "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Acetaminophen (paracetamol) poisoning in adults: Treatment".)
APPROACH — The initial management of acetaminophen poisoning in children and adolescents depends upon the type of exposure and the patient’s clinical status:
Exploratory ingestions in young children — These exposures usually involve small amounts of acetaminophen in an otherwise asymptomatic child. Hepatotoxicity is rare. Treatment consists of the following (see 'Management of acute poisoning' below):
●Administering activated charcoal to children who present within four hours of exposure and have ingested a potentially toxic dose (>150 mg/kg); we do not advise charcoal if the ingested dose is unknown because the vast majority of such ingestions will not be significant. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Toxic dose' and 'Gastrointestinal decontamination' below.)
●Plotting a timed serum acetaminophen level that is obtained a minimum of four hours after ingestion on the treatment nomogram for acetaminophen poisoning (figure 1). (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Acetaminophen level'.)
●Administering the antidote, N-acetylcysteine to those children with an acetaminophen level that indicates possible toxicity. (See 'N-acetylcysteine' below.)
Intentional ingestions — The likelihood for significant acetaminophen ingestion and co-ingestants is much higher for these patients. Patients who present less than four hours after ingestion and who are asymptomatic may be managed as described for exploratory ingestions in young children above. Additional therapeutic considerations include:
●Supportive care of airway, breathing, and circulation related to toxicity of co-ingestants may be required. (See "Approach to the child with occult toxic exposure", section on 'Initial evaluation and stabilization'.)
●Time of presentation determines the approach:
•Less than 4 hours – Administration of activated charcoal to patients receiving treatment within four hours of ingestion. Patients who present for care after four hours are unlikely to benefit from activated charcoal unless agents that slow gastric motility, such as anticholinergic agents, or opioids were also ingested. (See 'Gastrointestinal decontamination' below.)
•4 to 24 hours – Patients who present four hours or longer after ingestion should have an acetaminophen level obtained as soon as possible, but should also receive empiric treatment with N-acetylcysteine (NAC), pending these results. (See 'N-acetylcysteine' below.)
•Longer than 24 hours – Patients who present more than 24 hours after acute ingestion may manifest symptoms and signs of hepatic injury or failure, such as nausea, vomiting, jaundice, abdominal pain, renal injury, coagulopathy (eg, gastrointestinal bleeding), hepatic encephalopathy, cerebral edema, or hypotension. These cases may not have detectable serum acetaminophen concentrations.
These patients should be treated as for chronic acetaminophen poisoning. Serum concentrations of acetaminophen in this setting do not correlate with toxicity and the treatment nomogram for acetaminophen poisoning should not be used. However, the presence of unmetabolized acetaminophen in patients with other findings suggestive of liver toxicity is a potential indication for NAC administration. (See 'Management of chronic poisoning' below.)
These patients may also require emergent resuscitation, including airway management, intravenous fluids, vasopressors, hemodialysis, or management of cerebral edema. (See "Acute liver failure in adults: Management and prognosis".)
Inappropriate therapeutic dosing — Significant hepatotoxicity and mortality have been described in children receiving inappropriately high doses of acetaminophen (>90 mg/kg per day) for more than one day. These patients may present with clinical findings including nausea, vomiting, right upper quadrant pain, and hepatotoxicity, which may include fulminant hepatic failure. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Inappropriate dosing by a caregiver'.)
Diagnosis of chronic acetaminophen intoxication (repeated excessive dosing) is often difficult and requires the combination of astute history-taking and recognition of typical clinical and laboratory abnormalities. 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 and the treatment nomogram for acetaminophen poisoning should not be used. Establishing the diagnosis of chronic acetaminophen poisoning frequently involves exclusion of other causes of clinical hepatitis. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Chronic exposures' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Differential diagnosis'.)
There is no consensus regarding the management of these children. Serum acetaminophen level, alanine aminotransferase measurement, and prothrombin time are helpful in determining further treatment. Consultation with a regional poison control center (1-800-222-1222) or medical toxicologist is advised. (See 'Additional resources' below.)
Iatrogenic intravenous overdose — Until further information is available, consultation with a poison control center or medical toxicologist is strongly advised for children who have received an iatrogenic overdose of intravenous acetaminophen. (See 'Additional resources' below.)
The approach to overdose with intravenous acetaminophen is based upon case reports and expert opinion and is controversial [5,6]. Some medical toxicologists recommend treatment of all children who receive an intravenous dose >60 mg/kg [6]. This conservative position is supported by a case of possible hepatotoxicity (elevated liver enzymes and international normalized ratio) with full recovery after a single intravenous dose of 75 mg/kg in a five-month-old child with intussusception [7], as well as the consideration that IV acetaminophen is more likely to be used in children who are postoperative and fasting, which increases the risk for hepatotoxicity due to depleted glutathione stores.
However, other experts point out that the liver abnormalities in the single case report noted above occurred too quickly after the acetaminophen overdose to be attributable to poisoning and were more consistent with hepatic injury from the underlying illness, which was associated with shock and required abdominal surgery [5]. Furthermore, critics of the conservative position note that intravenous acetaminophen administration avoids the first pass effect and is likely to result in less production of the toxic metabolite, n-amino-p-benzoquinoneimine in the liver, despite a higher peak concentration [5]. They recommend that only children who receive >150 mg/kg of acetaminophen (figure 1) and that antidotal therapy only be provided to children with an acetaminophen level above the treatment line.
MANAGEMENT OF ACUTE POISONING — After an appropriate history is obtained, initial treatment of the child with acetaminophen exposure and "possible hepatotoxicity" (figure 1) is similar to that of adults. Management focuses on decontamination with activated charcoal (AC) and administration of the acetaminophen antidote, N-acetylcysteine (NAC) as modified by specific types of exposure. (See 'Approach' above and "Acetaminophen (paracetamol) poisoning in adults: Treatment".)
Gastrointestinal decontamination — Children who present soon after a potentially toxic ingestion of acetaminophen (single dose ≥150 mg/kg or 7.5 g) are likely to benefit from gastrointestinal decontamination. We suggest treatment with activated charcoal (AC), 1 g/kg (maximum dose 50 g) by mouth in all patients who present within four hours of a known or suspected acetaminophen ingestion of >150 mg/kg, unless there are contraindications to its administration, such as gastrointestinal obstruction or altered mental status with an unprotected airway. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Indications' and "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal: Adverse effects'.)
AC should be withheld in patients who are sedated and may not be able to protect their airway, unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving AC. Asymptomatic patients who present more than four hours after reported acetaminophen ingestions are unlikely to benefit from AC, and we do not recommend routine treatment in these patients. However, AC may be useful beyond four hours in the presence of certain coingestants that may delay absorption of acetaminophen (eg, sustained-release preparations or agents that slows gut motility such as anticholinergic agents such as diphenhydramine, or opioids).
A number of studies using simulated overdose models in adults have shown that AC reduces acetaminophen exposure and peak acetaminophen levels maximally when given within one hour of ingestion, and that this reduction in acetaminophen absorption is not significant when AC is given four hours after ingestion [8].
Several observational studies primarily performed in adult and adolescent patients with acute acetaminophen overdose support these findings but also suggest a benefit for AC administration beyond one hour:
●In a retrospective study of 981 consecutive patients with an acute acetaminophen overdose, patients who received AC within two hours of ingestion were less likely to require N-acetylcysteine (NAC) treatment [9].
●In another prospective observational study of 145 patients who presented over four hours after acetaminophen ingestion and had serum levels in the probable toxicity range on the treatment nomogram for acetaminophen poisoning, administration of AC with NAC was significantly associated with fewer patients attaining peak alanine aminotransferase (ALT) concentrations >1000 international units/L when compared with treatment with NAC alone (2 versus 36 percent, respectively). These effects were independent of the time of acetylcysteine administration. While limited, this study suggests that administration of AC up to 16 hours after ingestion may be beneficial in selected patients [10].
●An observational study of 200 patients with reported massive (>40 g) overdose found that charcoal administration within 4 hours was associated with a lower risk of hepatotoxicity [11].
●In a prospective study of 122 patients with acetaminophen overdose, administration of AC prior to NAC was associated with significantly less liver injury (AST >125 international units/L) than treatment with NAC alone (5 versus 25 percent, respectively) [12].
Taken together, these studies suggest that limiting treatment with AC to one hour after acetaminophen ingestion as indicated by volunteer studies and the simulated overdose studies may overly restrict the benefit of AC as demonstrated in observational studies of poisoned patients. However, the studies in poisoned patients have focused on liver enzyme elevation as the primary outcome, which may not be clinically relevant and have evaluated a small number of patients who receive AC more than four hours after acetaminophen overdose. Thus, the true benefit of AC when administered more than four hours after acetaminophen overdose is uncertain.
We recommend that children with a potentially toxic ingestion of acetaminophen not undergo gastric emptying with either gastric lavage or syrup of ipecac. Although these procedures have been shown to lower peak serum acetaminophen levels in adolescents and adults, they are significantly less effective than activated charcoal [13]. Furthermore, gastric lavage can increase the risk of aspiration in poisoned patients and persistent vomiting from syrup of ipecac may delay administration of oral N-acetylcysteine. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Syrup of Ipecac' and "Gastrointestinal decontamination of the poisoned patient", section on 'Gastric lavage'.)
N-acetylcysteine — We recommend that all patients at significant risk for hepatotoxicity following acetaminophen overdose receive N-acetylcysteine (NAC).
There are no trials comparing NAC to supportive treatment alone. However, large cohort studies have shown that, when compared with historical control patients who received supportive care alone, administration of NAC within 8 to 10 hours of acetaminophen overdose has been associated with a significant reduction in hepatotoxicity (58.0 to 1.6 percent) and mortality (5.0 to 0.7 percent) [9,14,15]. Furthermore, when NAC is administered late (ie, more than 24 hours) following acetaminophen ingestion to adults with evidence of hepatic failure, it was associated with decreased development of cerebral edema, improved hepatic function, and decreased mortality [16-18].
The mechanism of action and efficacy of NAC in the treatment of acetaminophen intoxication are discussed in detail separately. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'Antidote: acetylcysteine'.)
Indications — Indications for NAC therapy in children and adolescents include:
●Serum acetaminophen concentration above the "treatment" line of the treatment nomogram for acetaminophen poisoning (figure 1) following acute ingestion of an immediate-release preparation. Some experts use other guidelines. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Acetaminophen level'.)
●A suspected single ingestion of greater than 150 mg/kg (7.5 g total dose regardless of weight) in a patient for whom the serum acetaminophen concentration will not be available until more than eight hours from the time of the ingestion. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Toxic dose'.)
●Patients with an unknown time of ingestion beyond 24 hours and a serum acetaminophen concentration >10 mg/L (66 micromol/L). (See 'Management of chronic poisoning' below.)
●Patients with delayed presentation (>24 hours after ingestion) and laboratory evidence of hepatotoxicity (from mildly elevated aminotransferases to fulminant hepatic failure) and a history of excessive acetaminophen ingestion. Children with delayed presentation and hepatic injury should be managed in consultation with a regional poison control center (1-800-222-1222 in the United States) or a medical toxicologist. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Chronic overdoses' and 'Additional resources' below.)
The use of N-acetylcysteine (NAC) in children with delayed (>24 hours) presentation of acetaminophen intoxication has not been studied. However, in a trial of 50 adults with delayed presentation and acetaminophen-induced fulminant hepatic failure, the use of intravenous NAC reduced mortality (20 versus 48 percent) [16].
Controlled studies evaluating the use of NAC in patients with delayed presentation and hepatotoxicity, but without signs of hepatic failure, have also not been performed. Nonetheless, many medical toxicologists recommend the use of NAC in patients with delayed presentation, unmetabolized acetaminophen in the serum, and/or evidence of hepatic injury [19].
●If it is not possible to estimate a time of ingestion (due to lack of information or multiple ingestions), there is no universally accepted approach to risk stratification.
Our approach is to start treatment with acetylcysteine for any patient with an acetaminophen concentration above 20 mcg/mL. We also treat any patient with elevated serum transaminase activity and a history consistent with acetaminophen exposure regardless of the serum acetaminophen concentration. This will maximize the potential benefit of acetylcysteine. We treat these patients for at least 12 hours and repeat the serum acetaminophen concentration (unless it was already undetectable) and the serum transaminase. Some experts also treat patients with a detectable acetaminophen concentration ≤20 mcg/mL and normal serum transaminases.
We then stop acetylcysteine if the patient fulfills all three of the following conditions:
•Asymptomatic (eg, no right upper quadrant pain)
•Acetaminophen concentration is nondetectable
•The serum transaminase activity is decreasing significantly (has decreased to the normal range or to <50 percent of the peak value),
If these conditions are not met, treatment should be continued until the conditions above are fulfilled (serum acetaminophen undetectable and serum transaminase is normal or <50 percent of peak value).
Although other experts treat for the entire 21 hour infusion (checking the serum acetaminophen and liver transaminase concentrations near the end of the infusion and providing further N-acetylcysteine if the transaminase are elevated or acetaminophen remains detectable), we are not aware of any patients who have experienced a poor outcome using our shortened approach as long as all three endpoints are met.
There are reports of adult patients with massive acetaminophen ingestion (history of ingestion of >30 g, or serum concentration >500 mg/L [3300 micromol/L]) who develop liver injury despite early administration of acetylcysteine [20,21]. These cases often involve co-ingestion of diphenhydramine and the patients had elevated acetaminophen levels despite completion of the 21 hour intravenous NAC protocol. Pharmacokinetic models [22,23] and observational studies [11] have suggested that a higher dose of NAC for a longer period of time may be beneficial in such cases. Patients with these clinical features should be discussed with a poison center or toxicologist familiar with the management of acetaminophen overdose. (See 'Additional resources' below.)
Administration — No trials have compared the 21 hour intravenous (IV) and the 72 hour oral treatment regimens for N-acetylcysteine (NAC). Pooled data from a systematic review demonstrate efficacy for both routes of administration in the treatment of acetaminophen poisoning and minimal differences in efficacy as long as the antidote is given within 10 hours [8].
NAC should be administered intravenously to children with any of the following:
●Intractable vomiting
●Contraindications to oral administration (eg, aspiration risk due to altered mental status, pancreatitis, bowel ileus or obstruction, or bowel injury)
●Hepatic failure
●Patients who refuse oral administration
●Pregnant adolescent females (see "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'Treatment in pregnancy')
The regimens for oral or IV administration of NAC are as follows:
●Oral – The standard oral N-acetylcysteine treatment regimen has been regularly used in the United States for over 30 years. It consists of a 72-hour oral course given as a 140 mg/kg loading dose followed by 17 doses of 70 mg/kg every four hours (total dose 1330 mg/kg) [14]. This regimen has the theoretical advantage of delivering the antidote to the portal circulation in patients with oral ingestions. The noxious odor and taste of the preparation sometimes results in problems with vomiting and inability of children to tolerate the full oral course. (See 'Vomiting' below.)
●Intravenous – The 21 hour intravenous (IV) protocol for acetylcysteine treatment has been used in the United Kingdom since the 1970s [24]. The approved IV dosing regime is complicated and requires special care in children to avoid administration of excess free water. Fluid overload and dosing errors in young children receiving IV NAC have resulted in hyponatremia, seizures, and death. Furthermore, IV NAC may cause anaphylactoid reactions and should only be given with frequent monitoring of vital signs and in a setting where immediate treatment is available. (See 'Anaphylaxis (anaphylactoid reaction)' below.)
A total dose of 300 mg/kg of NAC is given intravenously over 21 hours. IV NAC is compatible with 5 percent dextrose, 0.45 percent normal saline (ie, half normal saline), and water for injection. Detailed prescribing information, post-marketing safety data, and a dosing calculator are available from the manufacturer [25]. Children ≥40 kg may receive IV NAC as recommended for adults. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on '20-hour IV protocol'.)
In the United Kingdom, a protocol administering 300 mg/kg over 12 hours with further treatment based on acetaminophen concentration and transaminase changes has been implemented in some institutions [26]. This approach is not widely used in the United States.
The manufacturer recommends the following weight-based dilution in children who weigh <40 kg:
Patients ≤20 kg:
•Loading dose: 150 mg/kg in 3 mL per kg of diluent given IV over 60 minutes
•Second dose: 50 mg/kg in 7 mL per kg of diluent given IV over 4 hours (12.5 mg/kg NAC per hour)
•Third dose: 100 mg/kg in 14 mL per kg of diluent given IV over 16 hours (6.25 mg/kg NAC per hour)
Patients >20 and <40 kg:
•Loading dose: 150 mg/kg in 100 mL of diluent given IV over 60 minutes
•Second dose: 50 mg/kg in 250 mL of diluent given IV over 4 hours (12.5 mg/kg NAC per hour)
•Third dose: 100 mg/kg in 500 mL of diluent administered over 16 hours (6.25 mg/kg NAC per hour)
More recent studies have suggested that a modified infusion of using 50 mg/kg/hour for 4 hours (200 mg/kg) followed by 6.25 mg/kg/hour for 16 hours (100 mg/kg) may decrease adverse events with no change in efficacy [27].
Adverse reactions — Non-IgE mediated anaphylaxis (previously called anaphylactoid reactions) with intravenous administration and vomiting with oral administration are the most common adverse reactions associated with N-acetylcysteine administration.
Fluid overload and dosing errors in young children receiving IV NAC have rarely resulted in hyponatremia, seizures, and death. These severe effects can be avoided by following the manufacturer’s guidelines for administration in children. (See 'Administration' above.)
Anaphylaxis (anaphylactoid reaction) — Anaphylaxis that is not IgE-mediated (previously called an "anaphylactoid reaction") may occur in up to 20 percent of adults and children receiving intravenous N-acetylcysteine (NAC) [25,28]. Patients with a prior history of asthma appear to be predisposed. Although interruption of the IV NAC infusion is often necessary in these patients, most are able to tolerate resumption of NAC infusion. (See "Anaphylaxis: Acute diagnosis", section on 'Causes and mechanisms'.)
Patients receiving IV NAC warrant close monitoring and immediate availability of oxygen, antihistamine medication (eg, diphenhydramine and famotidine), albuterol, epinephrine 1:1000 for intramuscular use, glucocorticoid medication (eg, methylprednisolone), a resuscitation cart, and appropriately sized airway equipment. Thus, NAC infusion should be initiated in clinical settings where critical care monitoring and management is immediately available. Patients who develop anaphylaxis during NAC infusion and are able to continue the infusion should be monitored in a critical care setting for the entire infusion. Patients who tolerate the initial infusion without reaction do not require critical care monitoring for the remaining doses (but may require monitoring for other conditions).
In addition to stopping the NAC infusion, a rapid overview provides treatment recommendations for NAC-induced anaphylaxis (table 1). Additional tables demonstrate a method for calculating epinephrine infusion in children with hypotension (table 2 and table 3).
Limited observational evidence is available regarding the continuation of intravenous NAC in patients with anaphylaxis, and we encourage consultation with a regional poison control center of medical toxicologist to determine whether NAC infusion should continue after an allergic reaction has occurred. Based upon one small case series, the following approach is suggested [29]:
●Patients who experience flushing without pruritus or urticaria do not require intervention and the infusion can be continued, unless more severe signs develop.
●Patients who develop urticaria should have the infusion stopped and be treated with intramuscular epinephrine, diphenhydramine, and glucocorticoid medication (table 1). The infusion can be restarted at the prior rate once the urticaria resolves.
●Patients with angioedema or respiratory symptoms should have the infusion stopped and be treated with epinephrine, diphenhydramine, glucocorticoid medication and if wheezing, albuterol (table 1). In patients for whom signs and symptoms resolve, the infusion may be started at the prior rate one hour after the administration of epinephrine.
●Patients who develop hypotension or other persistent systemic anaphylaxis symptoms after IV acetylcysteine therapy should have the infusion stopped and receive treatment for anaphylaxis (table 1). IV NAC should not be restarted. Oral NAC therapy should be provided as an alternative. These patients will generally tolerate oral acetylcysteine. If the patient cannot be treated with oral acetylcysteine, the clinician should consult a medical toxicologist or poison control center for guidance. (See 'Additional resources' below.)
Vomiting — Approximately 33 percent of subjects treated with oral N-acetylcysteine (NAC) develop nausea and vomiting [30]. The palatability of NAC can be improved by diluting it to a 5 percent solution in cola or juice, covering the cup, and drinking through a straw. If a patient vomits within 60 minutes of an oral dose of NAC, the dose should be repeated.
Antiemetic therapy (eg, metoclopramide 0.1 to 1 mg/kg every two to four hours or ondansetron 0.15 mg/kg, maximum dose: 16 mg) often facilitates administration.
Persistent vomiting in spite of antiemetic therapy is an indication to administer NAC intravenously. (See 'Administration' above.)
Duration of treatment — While the efficacy of IV and oral administration is similar, controversy persists about the optimal duration of N-acetylcysteine (NAC) therapy. The current commonly used treatment protocols are time-based (21 and 72 hours for IV and oral administration, respectively). While these protocols are adequate for the vast majority of patients, it is clear that the 72 hour protocol is longer than needed for many patients while the 21 hour protocol is not long enough for some others. Suggestions for the tailoring of NAC therapy to clinical endpoints based upon the type of acetaminophen exposure and clinical status of the patient is discussed in detail separately. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'Duration of treatment'.)
Monitoring during treatment — Guidelines disagree regarding monitoring during N-acetylcysteine treatment [31,32]. We suggest that patients receiving N-acetylcysteine (NAC) for acetaminophen overdose be monitored according to their clinical condition and the NAC regimen that they receive as follows (see "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'Monitoring during treatment'):
●IV NAC initiated within 8 hours of exposure – These patients typically are asymptomatic and do not have elevations in liver enzymes prior to initiation of NAC therapy. Prior to stopping NAC, we suggest that clinicians measure a serum acetaminophen level and ALT. If the patient has no symptoms, the acetaminophen concentration is undetectable and the ALT is normal, then NAC can be discontinued. Otherwise, IV NAC treatment should be continued at a rate of 6.25 mg/kg per hour until these conditions are met.
Elevation in ALT warrants additional testing as described below. Therapeutic serum concentrations of NAC and high concentrations of acetaminophen can elevate the INR. Elevations due to NAC are usually mild (INR should not be greater than 1.5), occur between 4 and 20 hours post ingestion, and resolve as treatment is continued [33].
●Oral NAC initiated within 8 hours of exposure – These patients typically are asymptomatic and do not have elevations in liver enzymes prior to initiation of NAC therapy. Serum acetaminophen level should be measured every 12 hours until it is undetectable. ALT should also be obtained at least once prior to the end of the 72 hour course. Elevation in ALT warrants additional testing as described below.
●Elevated ALT or symptomatic – We suggest measuring the ALT and INR every 12 hours for any patient who develops ALT elevation or is significantly symptomatic (table 4). More frequent testing does not allow enough time to detect clinically meaningful trends. If the patient develops an ALT greater than 1000 international units/L, coagulopathy (ie, INR >1.5), or encephalopathy, then the serum bicarbonate, glucose, and creatinine should also be measured every 12 hours. Closer monitoring (eg, ICU admission, cardiac monitor) may be indicated based upon the patient's clinical condition if a significant coingestion is known or suspected or other problems arise.
Other therapies — On the basis of limited evidence in animals and humans, fomepizole, in addition to N-acetylcysteine, may have a role for patients at high risk for liver failure after acetaminophen overdose. However, its use should not be routine pending further study in randomized controlled trials. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'Fomepizole'.)
Although several other therapies such as cimetidine, methionine, cysteamine, and dimercaprol have been evaluated for treatment of acetaminophen poisoning, they have no role in its management. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".)
Extracorporeal removal — Although acetaminophen is cleared by hemodialysis [34,35], the safety and efficacy of N-acetylcysteine (NAC) leaves no role for dialysis in the management of acetaminophen poisoning if NAC is available. Extracorporeal removal may be useful for lowering serum acetaminophen concentrations if NAC is not available, but there are no systematic studies to evaluate the effectiveness of this treatment. Hemodialysis should never be considered an alternative to NAC therapy.
In the rare instance when severe acetaminophen poisoning is complicated by acute kidney injury (acute renal failure), hemodialysis is necessary. Otherwise, in the authors’ experience, hemodialysis is rarely needed even for severe poisoning and should be obtained only when standard indications independent of the poisoning are present. If hemodialysis is employed, the dose of NAC should be increased. The amount of increase should be determined in consultation with a poison control center or medical toxicologist. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Urgent indications'.)
Liver transplantation — Liver transplantation is rarely required in children or adolescents with acetaminophen poisoning and is much less commonly employed when compared with adults with acetaminophen hepatotoxicity. The increased availability of liver transplantation has resulted in significant improvement in survival rates for adolescent and adult patients with fulminant hepatic failure as the result of acetaminophen intoxication [8]. Although there is insufficient experience with this treatment in younger patients to evaluate the impact on survival, liver transplantation should also be considered for children. Grade III or greater hepatic encephalopathy carries an extremely poor prognosis [36]. Because it can be difficult to differentiate grade II and III encephalopathy and because disease progression may be rapid, even subtle changes in mentation (not clearly explained by another condition) should prompt evaluation for liver transplantation. Other markers, such as acute kidney injury or progressive increase in the INR, require close monitoring as they may be early signs of impending hepatic failure. However, the degree of transaminase elevation is not considered a prognostic factor.
Clinical and laboratory criteria have been developed for adults that identify patients with fulminant hepatic failure who are unlikely to survive and should therefore be considered for liver transplantation (table 5) [37]. A retrospective review compared these criteria with clinical and biochemical factors that correlated with significant hepatotoxicity as the result of paracetamol (acetaminophen) overdose in 51 children [36]. The criteria that identified patients who should be considered for liver transplantation were the same for adults and children with the exception of the following:
●Delay in treatment was a significant risk factor for children, but not for adults.
●The serum creatinine level that predicted poor prognosis was lower for children (greater than 200 micromol/L [2.3 mg/dL]) than for adults (greater than 300 micromol/L [3.4 mg/dL]).
MANAGEMENT OF CHRONIC POISONING — Children who have received multiple supratherapeutic doses of acetaminophen (>150 mg/kg per day for more than one to two days) are at risk for hepatotoxicity. There is no consensus regarding the management of these children [38]. Consultation with a regional poison control center or medical toxicologist is advised. (See 'Additional resources' below.)
One approach is to classify children with repeated overdose into one of three treatment groups based upon the results of the initial evaluation (including serum acetaminophen concentration and aminotransferases, which should be monitored for 36 hours after the last ingested dose) [2,39]:
●No hepatic injury and no unmetabolized acetaminophen – These children may be discharged home. Their caregivers should receive instruction to avoid acetaminophen for the remainder of the current illness [2]. The caregivers of these children also may benefit from education regarding future prevention of such exposures. (See 'Prevention' below.)
●No liver injury but with unmetabolized acetaminophen – Children without liver injury, but with unmetabolized acetaminophen, are at risk for hepatic injury because they have the potential to generate more toxic metabolite through the cytochrome oxidase system (figure 2). These patients warrant monitoring of serum alanine aminotransferase, prothrombin time, and supportive care in the hospital. Consultation with a regional poison control center or medical toxicologist should be obtained for recommendations regarding antidotal therapy with N-acetylcysteine (NAC). (See 'Additional resources' below.)
●Liver injury (with or without unmetabolized acetaminophen) – Children with a history of multiple supratherapeutic doses of acetaminophen that is associated with hepatic injury with or without unmetabolized acetaminophen should receive NAC and supportive care in the hospital. The optimal mode of delivery and the duration of NAC therapy in this setting have not been established in controlled trials [2,39]. The end-point of therapy in this setting is either resolution of symptoms or liver transplantation [2]. Those patients with moderate to severe hepatotoxicity at initial evaluation warrant transfer to a liver transplant center [2,17,40-43].
RESUMING ACETAMINOPHEN THERAPY — After an acetaminophen overdose, otherwise healthy children and adolescents may safely resume acetaminophen therapy if the following conditions are met [5]:
●No clinical symptoms
●Serum acetaminophen level <10 mg/L (66 micromol/L)
●Normal serum alanine aminotransferase
●Normal prothrombin time
PREVENTION — Prevention of exploratory acetaminophen intoxication in children involves storage of medications out of the reach of children. Prevention of inappropriate dosing involves education of patients, parents, and caregivers regarding fever management and the safe and judicious use of acetaminophen and other antipyretics.
Explicit instructions should be given regarding [44,45]:
●Strictly adhering to the weight-based dosing schedules on the label, with a maximum of five doses per day and a maximum daily dose of 75 mg/kg [46].
●Avoiding concurrent administration of acetaminophen with acetaminophen-containing over-the-counter medications.
●Caution when administering multiple doses of acetaminophen to a child who has had decreased oral intake.
●Caution when using rectal suppositories of acetaminophen because the absorption characteristics and peak concentration times vary depending upon the preparation [47-49]; in addition, suppository preparations should not be divided, since it is impossible to know with certainty the dose in each portion [50].
●Avoidance of the use of adult acetaminophen preparations (325 mg and 500 mg) in children (table 6).
●The fact that there are no data about the safety or efficacy of combined therapy with acetaminophen and ibuprofen in children, and there are several theoretical risks (especially that of renal injury) [51-54]. Thus, although a common practice, such therapy is not supported by evidence and is not suggested. (See "Fever in infants and children: Pathophysiology and management", section on 'Combining or alternating therapy'.)
The pathophysiology and treatment of fever in infants and children is discussed in detail separately. (See "Fever in infants and children: Pathophysiology and management".)
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: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Acetaminophen poisoning (The Basics)" and "Patient education: Toxic hepatitis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview of management – Patients with acute acetaminophen overdose should undergo measurement of serum acetaminophen levels between 4 and 24 hours of ingestion with plotting of the results on the treatment nomogram for acetaminophen poisoning (figure 1) to determine the poisoning severity. Additional management depends upon the type of exposure and the patient’s clinical status. (See 'Approach' above.)
In patients who seek medical attention more than 24 hours after acute ingestion or have ongoing chronic ingestion of supratherapeutic doses of acetaminophen, serum concentrations of acetaminophen do not correlate with toxicity and the treatment nomogram should not be used. However, serum acetaminophen level, along with alanine aminotransferase measurement, and prothrombin time are helpful in determining further treatment. (See 'Inappropriate therapeutic dosing' above.)
●Gastrointestinal decontamination – In a child or adolescent who present within four hours of a known or suspected acetaminophen ingestion of >150 mg/kg, we suggest treatment with activated charcoal (AC), 1 g/kg (maximum dose 50 g) by mouth (Grade 2C). Contraindications to AC include gastrointestinal obstruction or altered mental status with an unprotected airway. Asymptomatic patients who present more than four hours after reported acetaminophen ingestions are unlikely to benefit from AC unless they have ingested sustained-release acetaminophen preparations or coingested substances that delay gastrointestinal motility (eg, anticholinergic agents, or opioids). (See 'Gastrointestinal decontamination' above.)
We recommend that children with potentially toxic ingestions of acetaminophen not undergo gastric emptying with either gastric lavage or syrup of ipecac (Grade 1B).
●Antidote (N-acetylcysteine) – We recommend that all patients at significant risk for hepatotoxicity following acetaminophen overdose receive N-acetylcysteine (NAC) (Grade 1A). For patients who present <24 hours after acetaminophen overdose, the risk of hepatotoxicity is based upon plotting of a serum acetaminophen level on the treatment nomogram (figure 1). NAC may be given intravenously (IV), or orally. Each regimen and its indications are described in the text. NAC is most effective when given within 10 hours of acetaminophen overdose, but may still be of benefit in patients who present >24 hours later. (See 'Management of acute poisoning' above and 'N-acetylcysteine' above.)
NAC should be administered intravenously to children or adolescents with any of the following (see 'Administration' above):
•Persistent vomiting despite antiemetic therapy (see 'Vomiting' above)
•Contraindications to oral administration (eg, aspiration risk due to altered mental status, pancreatitis, bowel ileus or obstruction, or bowel injury)
•Hepatic failure
•Patients who refuse oral administration
•Pregnant adolescent females (see "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'Treatment in pregnancy')
●N-acetylcysteine side effects – Anaphylaxis that is not IgE-mediated (previously called an "anaphylactoid reaction") may occur in up to 20 percent of patients receiving intravenous (IV) NAC. Patients with asthma appear predisposed. Thus, children and adolescents receiving IV NAC warrant close monitoring and immediate availability of resuscitation drugs and equipment. In addition to stopping the NAC infusion, a rapid overview provides treatment recommendations for NAC-induced anaphylaxis (table 1). Additional tables demonstrate a method for calculating epinephrine infusion in children with hypotension (table 2 and table 3). (See 'Anaphylaxis (anaphylactoid reaction)' above.)
Approximately one-third of patients treated with oral NAC develop nausea and vomiting. Ondansetron and metoclopramide are useful antiemetics. If the patient vomits within 60 minutes of an oral dose of NAC, the dose should be repeated. (See 'Vomiting' above.)
●Monitoring during N-acetylcysteine treatment – We routinely measure the ALT prior to stopping NAC and continue treatment as long as the ALT is abnormal, as some patients will develop liver injury during the treatment period. We also suggest remeasuring the serum acetaminophen concentration prior to stopping NAC to verify that the level is undetectable. (See 'Monitoring during treatment' above.)
●Duration of N-acetylcysteine treatment – While these NAC protocols are adequate for the vast majority of patients, it is clear that the 72 hour protocol is longer than needed for many patients while the 21 hour protocol is not long enough for others. Suggestions for the tailoring of NAC therapy to clinical endpoints based upon the type of acetaminophen exposure and clinical status of the patient is discussed in detail separately. (See 'Duration of treatment' above.)
●Chronic supratherapeutic ingestion – Management of children with chronic acetaminophen overdoses should occur in consultation with a regional poison control center or medical toxicologist (see 'Regional poison control centers' above). Children with multiple supratherapeutic ingestions of acetaminophen who do not have liver injury but do have measurable serum acetaminophen levels warrant monitoring of serum alanine aminotransferase, prothrombin time, and supportive care in the hospital. Children with a history of multiple supratherapeutic doses of acetaminophen that is associated with hepatic injury with or without unmetabolized acetaminophen should receive NAC and supportive care in the hospital. Those patients with moderate to severe hepatotoxicity warrant transfer to a liver transplant center. (See 'Management of chronic poisoning' above.)
●Role of liver transplantation – The increased availability of liver transplantation has resulted in significant improvement in survival rates for adolescent and adult patients with fulminant hepatic failure as the result of acetaminophen intoxication. Although there is insufficient experience with this treatment in younger patients to evaluate the impact on survival, liver transplantation should also be offered to children. Clinical and laboratory criteria have been developed for adults that identify patients with fulminant hepatic failure who are unlikely to survive and should therefore be considered for liver transplantation (table 5). (See 'Liver transplantation' above.)
