Acetaminophen (paracetamol) poisoning: Management in adults and children

INTRODUCTION — Acetaminophen poisoning is among the most common causes of medication-related poisoning and death. It may occur following an acute ingestion or through repeated ingestions of supratherapeutic amounts. The management of the acetaminophen-poisoned patient may include stabilization, decontamination, and administration of acetylcysteine, a specific antidote. Indications for acetylcysteine and/or gastrointestinal decontamination depend on the patient's presenting symptoms, time since and duration of exposure, and serum acetaminophen and aminotransferase concentrations.

The management of acetaminophen poisoning in adults and children is reviewed here and summarized in the table (table 1). The following related content is discussed separately:

●Evaluation and diagnosis of acetaminophen poisoning, use of the Revised Rumack-Matthew nomogram, and determination of risk of liver injury (see "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents")

●Evaluation and management of liver injury or failure (see "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis" and "Acute liver failure in adults: Management and prognosis" and "Acute liver failure in children: Etiology and evaluation" and "Acute liver failure in children: Management, complications, and outcomes" and "Drug-induced liver injury")

●General approach to the poisoned patient (see "General approach to drug poisoning in adults" and "Approach to the child with occult toxic exposure" and "Initial management of the critically ill adult with an unknown overdose")

PATIENT WITH RELIABLE HISTORY AND ACUTE INGESTION — An acute ingestion 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 [1]. Interpreting acetaminophen concentrations following an acute ingestion is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation after acute overdose' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Laboratory evaluation'.)

Patient presenting within eight hours of ingestion — If the patient can provide a reliable history regarding the time of an acute ingestion and there is no liver injury on presentation, then the risk of developing liver injury needs to be determined using the Revised Rumack-Matthew nomogram (figure 1) as early symptoms do not reliably predict or exclude acetaminophen toxicity.

Liver injury is defined biochemically by an elevation of the alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentration. If the aminotransferases are elevated (or above baseline if chronically abnormal), then the history should be considered unreliable, and the patient should receive antidotal therapy with acetylcysteine regardless of the acetaminophen concentration since liver injury would not be expected to develop this rapidly. (See 'Patient with unreliable history' below.)

Serious hepatotoxicity is uncommon and death extremely rare if acetylcysteine is administered within eight hours following acetaminophen overdose and before the onset of liver injury [2-4]. (See 'Efficacy and mechanism' below.)

The patient may need supportive care with intravenous (IV) fluids and antiemetics. (See "Approach to the adult with nausea and vomiting", section on 'Drug therapy'.)

Rarely, a patient with a high-risk ingestion (typically >30 grams) can develop altered mental status and a metabolic acidosis with hyperlactemia early (typically within eight hours) following ingestion [5]. Management is discussed below. (See 'Patient with high-risk ingestion' below.)

Patient presenting within four hours of ingestion

Gastrointestinal decontamination — In a patient presenting within four hours of a known or suspected potentially toxic (single dose ≥150 mg/kg or 7.5 g) acetaminophen ingestion, we suggest administering a single dose of activated charcoal (AC). The dose is 1 g/kg (maximum dose 50 g) orally. Contraindications to AC administration include gastrointestinal obstruction or altered mental status with an unprotected airway. Tracheal intubation should not be performed solely for the purpose of giving AC. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

The traditional recommendation of limiting treatment with AC to one hour after acetaminophen ingestion may overly restrict the benefit of AC as demonstrated in observational studies and a trial of poisoned patients. In patients with acetaminophen ingestion, studies have shown that AC administration within four hours limits acetaminophen absorption, reduces need for acetylcysteine treatment, and reduces risk of developing liver injury [6-9]. In a small trial of intentional acetaminophen ingestions, AC decreased mean acetaminophen concentration by 52 percent (but the placebo arm was stopped early for ethical reasons) [7]. In a large observational study, patients who had ingested more than 10 grams of acetaminophen were less likely to develop concentrations above the Revised Rumack-Matthew nomogram treatment line after receiving AC (with and without gastric lavage) as compared with no decontamination (25 versus 41 percent, odds ratio [OR] 0.50, 95% CI 0.33-0.75) [9].

We recommend that patients with a potentially toxic ingestion of acetaminophen not routinely undergo gastric emptying with either gastric lavage or induced emesis (eg, syrup of ipecac). Although these procedures have been shown to limit the absorption of acetaminophen after simulated overdose and in clinical trials, they are significantly less effective than AC [7,9-13]. In one trial, AC decreased mean serum acetaminophen concentrations by 52 percent as compared with 39 and 41 percent for gastric lavage and syrup of ipecac, respectively [7]. In a large observational study, gastric lavage in addition to AC provided no additional benefit over AC alone in decreasing the number of patients who developed concentrations above the Revised Rumack-Matthew nomogram treatment line after having ingested more than 10 grams of acetaminophen (23 versus 28 percent) [9]. Furthermore, gastric lavage can increase the risk of aspiration in poisoned patients and persistent vomiting from syrup of ipecac may delay administration of oral acetylcysteine. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Syrup of Ipecac' and "Gastrointestinal decontamination of the poisoned patient", section on 'Gastric lavage'.)

Obtain four-hour acetaminophen concentration — Unless the patient is developing parent-compound toxicity (altered mental status, metabolic acidosis) due to a high-risk ingestion (see 'Patient with high-risk ingestion' below), we decide if acetylcysteine is needed based on a serum acetaminophen concentration obtained four hours after the ingestion or as soon as possible thereafter. The benefit of acetylcysteine does not appear to be time dependent within the first four hours following non-high-risk ingestion. (See 'Administer acetylcysteine if risk of liver injury' below.)

Serum concentrations drawn before four hours have limited utility. Additionally, AC may limit absorption of a potentially toxic ingestion and obviate the need for acetylcysteine as determined by the four-hour concentration. The interpretation of concentrations measured before four hours is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Ingestion of immediate-release acetaminophen' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Acetaminophen concentration'.)

Patient presenting four to eight hours after ingestion

Administer acetylcysteine if risk of liver injury — Poisoning severity (ie, risk of developing liver injury) following an acute ingestion is quantified by plotting a timed serum acetaminophen concentration on the Revised Rumack-Matthew nomogram (figure 1). (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Ingestion of immediate-release acetaminophen' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Acetaminophen concentration'.)

In a patient with a serum acetaminophen concentration that falls above the Revised Rumack-Matthew nomogram treatment line (figure 1) following an acute ingestion, we recommend acetylcysteine. Details regarding acetylcysteine administration, including route, dose, adverse effects, monitoring, and deciding when to stop, are discussed below. (See 'Acetylcysteine administration and monitoring' below.)

A patient with an ingestion of an extended-release formulation (labeled for use on an eight-hour basis) or a co-ingestion with an anticholinergic agent or opioid may need a repeat acetaminophen concentration to exclude delayed absorption. If any concentration falls above the treatment line (figure 1), we recommend acetylcysteine. The circumstances and timing of obtaining a repeat concentration are discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Ingestion of extended-release formulation or anticholinergic/opioid co-ingestion' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Acetaminophen concentration'.)

Role of gastrointestinal decontamination — Since acetaminophen absorption is typically complete by four hours after ingestion, administering AC is unlikely to benefit most patients who presents more than four hours after a reported ingestion.

However, AC may be useful beyond four hours in a patient with a reliable history of a very large ingestion (>30 grams), following an ingestion of an extend-release formulation (table 2), or with co-ingestion of certain agents that slow gut motility and delay absorption (eg, anticholinergic agents, opioids), especially if there is evidence of ongoing absorption such as an increasing acetaminophen concentration [1].

An observational study found that administration of AC to patients who presented more than four hours after acetaminophen ingestion was associated with lower peak ALT concentrations independent of the time of acetylcysteine administration [14]. While limited, this study suggests that administration of AC more than four hours after ingestion may be beneficial, although it included a small number of patients and focused on liver enzyme elevation as the primary outcome, which may not be clinically relevant. Thus, the true benefit of AC when administered more than four hours after acetaminophen overdose is uncertain.

Patient presenting beyond eight hours after ingestion — In a patient with a suspected acute ingestion of greater than 150 mg/kg (7.5 g total dose regardless of weight) for whom the serum acetaminophen concentration will not be available until more than eight hours from the time of the ingestion, we recommend administering acetylcysteine before the serum acetaminophen concentration results. Beyond eight hours following ingestion, the risk of developing liver injury increases as the time to administration of acetylcysteine increases [3].

If the concentration results below the Revised Rumack-Matthew nomogram treatment line (figure 1), the aminotransferases are normal (or at baseline if chronically abnormal), and the patient does not have signs or symptoms of liver injury, the acetylcysteine can be stopped, and no further treatment is needed. Otherwise, continue the acetylcysteine until stopping criteria are met. Details regarding acetylcysteine administrations, including route, dose, adverse effects, monitoring, and deciding when to stop, are discussed below. (See 'Acetylcysteine administration and monitoring' below.)

PATIENT WITH RELIABLE HISTORY AND REPEATED SUPRATHERAPEUTIC INGESTION — Repeated supratherapeutic ingestion is defined as multiple ingestions during a period greater than 24 hours [1]. The Revised Rumack-Matthew nomogram cannot be used for risk stratification. The dose and duration criteria that define a repeated supratherapeutic ingestion and thus warrant obtaining a serum acetaminophen concentration are the following and discussed in detail separately (see "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation after repeated supratherapeutic ingestion' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Repeated supratherapeutic ingestion'):

●If ingestion period was 24 to 48 hours – Ingestion of greater than 6 g/day (150 mg/kg/day) of acetaminophen.

●If ingestion period >48 hours – Ingestion of greater than 4 g/day (100 mg/kg/day) of acetaminophen.

In a patient with a repeated supratherapeutic ingestion (based on the above criteria) and a serum acetaminophen concentration ≥20 mcg/mL (132 micromol/L) or with elevated aminotransferases (unless they are at baseline if chronically abnormal), we recommend acetylcysteine [1,15-17]. The acetylcysteine should be continued until stopping criteria are met. Details regarding acetylcysteine administration, including route, dose, adverse effects, monitoring, and deciding when to stop, are discussed below. (See 'Acetylcysteine administration and monitoring' below.)

A patient with a history of repeated supratherapeutic ingestion of acetaminophen and elevated aminotransferases should be presumed to have acetaminophen-induced liver injury regardless of the measured serum acetaminophen concentration.

PATIENT WITH UNRELIABLE HISTORY — In the setting of an unreliable or inaccurate history (unable to establish the time of ingestion; conflicting statements; or symptoms, signs, or laboratory values inconsistent with the history such as elevated aminotransferases within eight hours of ingestion), the Revised Rumack-Matthew nomogram cannot be used for risk stratification [1]. We recommend the following approach:

●Acetaminophen ≤10 mcg/mL (66 micromol/L) and aminotransferases are normal (or at baseline if chronically abnormal) – We do not administer acetylcysteine.

●Acetaminophen >10 mcg/mL (66 micromol/L) or aminotransferases are elevated (unless the elevation is patient's baseline value) – Given the unknown risks, we suggest a conservative approach of starting treatment with acetylcysteine. This approach maximizes the potential benefit of acetylcysteine. (See 'Acetylcysteine administration and monitoring' below.)

We administer acetylcysteine for 12 hours and then repeat the serum acetaminophen concentration and the aminotransferases. We stop acetylcysteine if the patient fulfills all the stopping criteria discussed below. (See 'Duration of treatment (stopping criteria)' below.)

If these conditions are not met, treatment should be continued until all the conditions are fulfilled.

Although other experts treat for the entire 21-hour infusion (checking the serum acetaminophen and aminotransferases near the end of the infusion and providing further acetylcysteine if the aminotransferases 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 endpoints are met.

●"Last known time prior to acute ingestion" – If the history suggests an ingestion over any period in the 24 hours preceding presentation and it is possible to narrow the initial ingestion to a specific time window (eg, 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-case scenario and plot the measured serum concentration using the "last known time prior to ingestion" as the "time of ingestion." Acetylcysteine would be given if the acetaminophen concentration falls above the Revised Rumack-Matthew nomogram treatment line (figure 1) based on this scenario.

PATIENT WITH LIVER INJURY (INCLUDING DELAYED PRESENTATION)

Acetylcysteine regardless of acetaminophen concentration — In a patient with symptoms and signs of liver injury (eg, nausea, vomiting, abdominal pain, elevated aminotransferases, jaundice, kidney injury, coagulopathy, hepatic encephalopathy, cerebral edema) (table 3) and a history of acetaminophen ingestion, we recommend acetylcysteine. Do not use the Revised Rumack-Matthew nomogram for risk stratification in these circumstances. Details regarding acetylcysteine administrations, including route, dose, adverse effects, monitoring, and deciding when to stop, are discussed below. (See 'Acetylcysteine administration and monitoring' below.)

This situation typically occurs when presentation for care is delayed (ie, 12 to 24 hours) following ingestion. Acetylcysteine therapy is associated with a benefit, even if started more than 24 hours after ingestion or no acetaminophen is still detectable in the serum. For example, in patients with fulminant hepatic failure from acetaminophen, acetylcysteine decreases mortality and need for liver transplantation [18]. (See 'Efficacy and mechanism' below.)

A patient with a delayed presentation and liver injury should be managed in consultation with a regional poison control center or a medical toxicologist. (See 'Regional poison control centers' below.)

Monitoring — We measure the alanine aminotransferase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), and serum acetaminophen concentration every 12 hours. More frequent testing does not allow enough time to detect clinically meaningful trends. If the patient develops an ALT or AST >1000 international unit/L, coagulopathy (ie, INR >1.5), or encephalopathy, then the serum bicarbonate, glucose, and creatinine should also be measured every 12 hours. The ALT and AST are used to monitor the degree of liver injury, and the other tests are used to determine possible need for liver transplant [19]. (See "Acute liver failure in adults: Management and prognosis", section on 'Laboratory testing' and "Acute liver failure in children: Management, complications, and outcomes", section on 'Laboratory monitoring'.)

Intensive monitoring (eg, intensive care unit [ICU] admission, cardiac monitor) may be indicated based upon the patient's clinical condition, if a significant co-ingestion is known, or other problems arise. A patient with a mild liver injury can often be managed in a non-ICU setting.

Fulminant hepatic failure — In a patient who develops fulminant hepatic failure (hepatic failure is differentiated from liver injury by the onset of impaired synthetic function and/or encephalopathy), we suggest acetylcysteine be administered intravenously (IV) instead of orally. There are no studies of oral acetylcysteine dosing in hepatic failure. The dosing protocol is the same as the 21-hour regimen (see '21-hour intravenous protocol' below), except the final infusion rate (6.25 mg/kg/hour) is continued until stopping criteria are met or the patient receives a liver transplantation (and the serum acetaminophen concentration is nondetectable) [7,10,18,20].

In a patient with fulminant hepatic failure and persistently elevated acetaminophen concentrations, hemodialysis may be an option to increase clearance. (See 'Role of extracorporeal removal' below.)

The increased availability of liver transplantation has resulted in significant improvement in survival rates for patients with fulminant hepatic failure from acetaminophen toxicity [6]. Supportive therapies for the management of acute liver failure and its complications (including encephalopathy, coagulopathy, and acute kidney injury) are described elsewhere. (See "Acute liver failure in adults: Management and prognosis" and "Acute liver failure in children: Management, complications, and outcomes".)

Indications for consultation with liver transplant team — We recommend consultation with a liver transplant team in a patient with any of the following despite acetylcysteine treatment [1]:

●Progressive increase in aminotransferases and worsening coagulation abnormalities

●Encephalopathy

●Multisystem failure

Modified King's College Criteria — In patients with fulminant hepatic failure from acetaminophen, the modified King's College Criteria are helpful to determine prognosis and thus which patients should be managed in a center that offers liver transplantation [21]. Recovery is often observed even in patients who have evidence of severe hepatocellular necrosis and synthetic dysfunction, so not all patients with fulminant hepatic failure will require a liver transplant. Notably, the degree of aminotransferase elevation is not part of these criteria, nor is it considered a prognostic factor. The criteria are below and presented in the algorithm (algorithm 1):

●Arterial lactate >3.5 mmol/L after early fluid resuscitation (ie, at least 1 L) or

●Arterial lactate >3.0 mmol/L after adequate fluid resuscitation (ie, tissue perfusion restored) or

●Arterial pH <7.3 (irrespective of grade of encephalopathy) or

●Grade III or IV encephalopathy with both a prothrombin time (PT) greater than 100 seconds and a serum creatinine greater than 3.4 mg/dL (300 micromol/L)

The original King's College Criteria (table 4) are discussed elsewhere; they did not include an early serum lactate, which improved upon their predictive accuracy [21,22]. The sensitivity and specificity of the modified King's College Criteria for predicting individuals likely to die without transplantation are 95 and 91 percent, respectively. (See "Acute liver failure in adults: Management and prognosis", section on 'King's College Criteria'.)

Acute kidney injury — In the rare instance when severe acetaminophen poisoning is complicated by acute kidney injury, hemodialysis may be necessary based on standard indications (eg, refractory fluid overload, severe hyperkalemia, severe metabolic acidosis, uremia). (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Acute kidney injury (acute renal failure)' and "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Urgent indications'.)

PATIENT WITH IATROGENIC INTRAVENOUS OVERDOSE — In a patient who receives a single intravenous (IV) acetaminophen dose ≥90 mg/kg actual total body weight (TBW), receives a cumulative dose ≥150 mg/kg TBW during 24 hours, or has a serum acetaminophen concentration drawn four hours after the infusion was started that falls above the Revised Rumack-Matthew nomogram treatment line (figure 1), we recommend acetylcysteine [1,23].

Consultation with a poison control center or medical toxicologist is advised for patients who have received an iatrogenic overdose of IV acetaminophen. (See 'Regional poison control centers' below.)

Most iatrogenic dosing errors have involved a 10-fold overdose in small children caused by calculating the dosage in milligrams but then administering the solution in milliliters [23].

The approach to treatment of IV acetaminophen overdose is controversial as clinical experience is limited [23,24]. Some medical toxicologists recommend treatment of all patients who receive an IV dose greater than 60 mg/kg [24]. This conservative position is based on case reports and the concern that IV acetaminophen carries increased risk for hepatotoxicity since it is commonly used in the postoperative and fasting settings, which predispose to depleted glutathione stores [25]. However, we question the conclusions drawn from these case reports and note that IV acetaminophen avoids the first-pass effect and is therefore likely to have less hepatic production of the toxic metabolite n-amino-p-benzoquinoneimine despite a higher peak serum concentration.

PATIENT WITH HIGH-RISK INGESTION

Supportive care — A patient with a high-risk ingestion (>30 grams) may be critically ill early following the overdose and before hepatic failure develops due to parent-compound toxicity [5]. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Parent compound toxicity (high-risk ingestion)'.)

The following supportive measures may be required:

●Airway management for altered mental status (see "The decision to intubate")

●Intravenous (IV) fluids and/or vasopressors for shock (see "Use of vasopressors and inotropes")

●Bicarbonate therapy for severe metabolic acidosis (see "Bicarbonate therapy in lactic acidosis")

We recommend consultation with a poison center or medical toxicologist given the management complexities and risk of developing liver injury despite acetylcysteine treatment in these patients. (See 'Regional poison control centers' below.)

Gastrointestinal decontamination — We administer a single dose of activated charcoal (AC) even if beyond four hours after ingestion, especially if there is evidence of ongoing absorption such as an increasing acetaminophen concentration [1]. Dosing and contraindications are discussed above and separately. (See 'Gastrointestinal decontamination' above and "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

Administer acetylcysteine early — In a patient with a history of high-risk acetaminophen ingestion (>30 grams) or signs of parent-compound toxicity (eg, hemodynamic instability, altered mental status, metabolic acidosis), we administer acetylcysteine as rapidly as possible instead of waiting for the serum acetaminophen concentration to result. Dosing is discussed below. (See 'High-risk patients' below.)

Role of extracorporeal removal — In a patient with a serum acetaminophen concentration ≥900 mcg/mL (5960 micromol/L) and altered mental status or metabolic acidosis, we suggest hemodialysis in addition to acetylcysteine [1,26]. These recommendations are based on expert opinion and the observation that hemodialysis can clear acetaminophen and toxic metabolites from serum. Hemodialysis can also correct a metabolic acidosis. However, there are many reported cases of recovery with acetylcysteine therapy alone, and in the authors' experience, hemodialysis is rarely needed even for severe poisoning.

Dosing of acetylcysteine during hemodialysis is discussed below. (See 'During hemodialysis' below.)

The safety and efficacy of acetylcysteine generally leaves no role for dialysis in the standard management of acetaminophen poisoning even though acetaminophen is cleared by hemodialysis [27,28]. Hemodialysis is not an alternative to acetylcysteine therapy if acetylcysteine is available. However, hemodialysis should be performed when standard indications are present independent of the poisoning. (See 'Acute kidney injury' above and "Enhanced elimination of poisons".)

ACETYLCYSTEINE ADMINISTRATION AND MONITORING

Choice of protocol — We agree with an expert consensus statement that whichever regimen is chosen, it should deliver at least 300 mg/kg acetylcysteine orally or intravenously (IV) during the first 20 to 24 hours of treatment [1]. Many acetylcysteine protocols have been described, and some debate continues about the appropriate route and duration following acute ingestion.

The 21-hour IV protocol is used most often, and a 20-hour simplified (two-bag) protocol is a reasonable alternative. An oral dosing protocol is also a reasonable alternative in certain patients, discussed immediately below.

We administer acetylcysteine until stopping criteria are met. We do not adhere to a predefined duration (eg, 21 hours) and do not stop acetylcysteine without reassessing the patient [1]. Shorter (eg, 12-hour) protocols have been described but also rely on stopping criteria and are not solely time based. (See 'Duration of treatment (stopping criteria)' below.)

Choice of intravenous versus oral — There are no head-to-head trials comparing IV and oral acetylcysteine protocols in patients treated early after ingestion. In most patients, either the oral or IV route is acceptable. Available data suggest that both routes are effective and differences are minimal [29,30]. For example, a meta-analysis of observational studies included 5164 patients who received acetylcysteine and found a similar rate of liver injury for the IV and oral routes (13.2 versus 12.6 percent) [29]. IV administration is favored for patients with any of the following:

●Intractable vomiting

●Contraindications to oral administration (eg, aspiration risk due to altered mental status, pancreatitis, bowel ileus or obstruction, bowel injury)

●Hepatic failure (see 'Fulminant hepatic failure' above)

●Refusing oral administration

●Pregnancy (see 'Pregnant patients' below)

Nonallergic anaphylactic reactions (NAARs) can occur in 10 to 20 percent of patients treated with IV acetylcysteine, most commonly during the first hour of infusion and almost exclusively within the first five hours [31]. Patients who receive IV acetylcysteine should be closely monitored in a setting where personnel, medications, and equipment necessary to manage anaphylaxis are readily available. (See 'Nonallergic anaphylactic reactions to intravenous route' below and 'Setting for intravenous acetylcysteine infusion' below.)

21-hour intravenous protocol — The 21-hour IV protocol for acetylcysteine is approved by the US Food and Drug Administration and has been in use in the United Kingdom since the 1970s. This dosing regimen is complicated and is performed as follows:

●Administer an initial loading dose of 150 mg/kg IV over 60 minutes.

●Next, administer a dose of 50 mg/kg over four hours (ie, infusion at 12.5 mg/kg per hour IV for four hours).

●Finally, administer a dose of 100 mg/kg over 16 hours (ie, infusion at 6.25 mg/kg per hour IV for 16 hours).

This treatment protocol provides a total of 300 mg/kg over 21 hours [32]. The treatment period is often extended when patients have large ingestions or elevated serum aminotransferases. (See 'Duration of treatment (stopping criteria)' below.)

In children less than 40 kg, the dose is the same, but the dilution strategy is modified. (See 'Intravenous acetylcysteine dilution in children' below.)

Simplified 20-hour (two-bag) intravenous protocol — The two-bag regimen simplifies dosing by combing the first two steps of the 21-hour protocol and is given in the following manner:

●First, administer a four-hour infusion at 50 mg/kg per hour IV (ie, total of 200 mg/kg over four hours).

●Next, administer a 16-hour infusion at 6.25 mg/kg per hour IV (ie, total of 100 mg/kg over 16 hours).

The results of a large retrospective study and experience in Europe, Australia, and the United States indicate that NAARs during treatment with IV acetylcysteine can be reduced by using a two-bag regimen instead of the traditional three-bag regimen. In the study, NAARs occurred twice as often in patients treated with the three-bag regimen as compared with the modified two-bag regimen (10 versus 4.3 percent, OR 2.5, 95% CI 1.1-5.8) [33]. Similar studies show comparable results [34-38]. While further trials are needed to confirm the improved safety of the two-bag regimen, we believe it is a reasonable treatment approach in adults and adolescents (ie, patients weighing >40 kg).

Oral protocol — The oral acetylcysteine protocol consists of the following:

●A loading dose of 140 mg/kg orally, followed by

●A dose of 70 mg/kg orally every four hours until stopping criteria are met (see 'Duration of treatment (stopping criteria)' below)

The dose does not need to be adjusted if the patient has been treated with activated charcoal (AC).

The noxious odor and taste of the oral acetylcysteine preparation sometimes results in problems with vomiting and inability of patients, especially children, to tolerate multiple doses. (See 'Vomiting with oral route' below.)

A 72-hour acetylcysteine oral dosing protocol (time based for total of 18 doses) was used in the United States for more than 30 years with excellent outcomes. The incidence of hepatotoxicity for patients treated within eight hours of ingestion is less than 10 percent but increases to approximately 40 percent if treatment is delayed beyond 16 hours. In the largest study of oral acetylcysteine, no deaths occurred among patients treated before the onset of aminotransferase elevation [3]. Truncated oral protocols have been described, and even though many of these are time based, we treat to the same stopping criteria used for IV administration [39-41].

The oral regimen has the theoretical advantage of delivering the antidote directly to the portal circulation.

Dosing in special populations

Weight >100 kg — In a patient weighing >100 kg, we provide a maximum acetylcysteine dose (either IV or oral) based on a 100 kg weight [1]. The basis for recommending a maximum dose is not clear, but evidence is scant regarding added benefit of acetylcysteine doses calculated with weights above these maximum amounts [42]. However, in a large observational study, clinicians often based dosing on total body weight (TBW) with a low rate of adverse events [43].

High-risk patients — We initiate treatment with acetylcysteine as rapidly as possible using standard dosing for (see '21-hour intravenous protocol' above):

●Patients who present with very high serum acetaminophen concentrations (concentration above the high-risk line on the Revised Rumack-Matthew nomogram) (figure 1)

●Patients with a reliable history of high-risk ingestion (>30 g)

●Patients with signs of parent-compound toxicity (altered mental status, metabolic acidosis early following ingestion)

Some authors suggest that a higher dose of acetylcysteine may be required for high-risk overdoses [44]. Clinicians should contact a poison center or medical toxicologist immediately to determine whether it is appropriate to modify standard treatment. (See 'Additional resources' below.)

If guidance from a poison center or medical toxicologist cannot be obtained and the initial serum acetaminophen concentration is above 300 mcg/mL, a reasonable treatment approach is to double the final infusion rate of the 21-hour IV protocol to 12.5 mg/kg/hour and continue the infusion at this rate until acetylcysteine stopping criteria are met. (See 'Duration of treatment (stopping criteria)' below.)

Several reports have described patients with a high-risk acetaminophen ingestion (>50 g or serum concentration >500 mg/L [3300 micromol/L]) who developed liver injury despite early treatment with IV acetylcysteine using the standard 21-hour protocol [45-47]. Several of these cases involved co-ingestion of diphenhydramine, and patients had elevated acetaminophen concentrations at the completion of the 21-hour IV acetylcysteine protocol. The results of a large prospective study and a retrospective study of patients hospitalized for treatment of acute acetaminophen overdose both suggest that a significant number of patients with high-risk ingestion will develop liver injury if treated with standard protocols, even when treatment with acetylcysteine is initiated within eight hours [5,48]. Computerized simulation of overdose supports an increased acetylcysteine dose in this circumstance [49]. However, there are no controlled studies demonstrating that increasing the dose of acetylcysteine prevents liver injury following high-risk overdose.

During hemodialysis — In a patient receiving IV acetylcysteine, we administer a dose of at least 12.5 mg/kg/hour during hemodialysis [1]. We do not adjust the acetylcysteine dose if administered orally during hemodialysis.

The higher dose is recommended because hemodialysis removes acetylcysteine [50,51]. However, it is not clear that the amount of acetylcysteine removed affects clinical outcomes.

Adverse reactions to acetylcysteine — While IV acetylcysteine administration is prone to dosing errors, significant adverse events stemming from such miscalculations are rare [52].

Nonallergic anaphylactic reactions to intravenous route — Between 10 and 20 percent of patients treated with IV acetylcysteine develop a non-IgE mediated NAAR, previously called an anaphylactoid reaction [15,53]. Patients with a prior history of asthma appear to be predisposed. Reactions vary in severity and are tolerable to most patients. Nevertheless, patients receiving IV acetylcysteine warrant close monitoring, and all essential medications and equipment necessary to manage anaphylaxis should be readily available when the initial infusion is administered (table 5 and table 6). (See "Anaphylaxis: Emergency treatment".)

In a patient who develops an NAAR, we suggest the following approach [54]:

●Flushing without pruritus or urticaria – Stop the acetylcysteine infusion for 15 to 30 minutes, then restart at the prior rate unless more severe signs develop.

●Urticaria – Stop the acetylcysteine infusion and administer intramuscular epinephrine, diphenhydramine, and a glucocorticoid. The infusion can be restarted at the prior rate once the urticaria resolves.

●Angioedema or respiratory symptoms – Stop the acetylcysteine infusion and administer epinephrine, diphenhydramine, a glucocorticoid, and albuterol (if wheezing). If signs and symptoms resolve, the infusion may be restarted at the prior rate one hour after the administration of epinephrine.

●Hypotension or other persistent systemic anaphylaxis symptoms – Stop the acetylcysteine infusion and administer epinephrine, diphenhydramine, a glucocorticoid, and albuterol (if wheezing) followed by further anaphylaxis treatment (table 5 and table 6). Additional tables demonstrate a method for calculating epinephrine infusion in children with hypotension (table 7 and table 8). IV acetylcysteine should not be restarted. Oral acetylcysteine therapy should be provided as an alternative since these patients will generally not have an NAAR to oral acetylcysteine. If the patient cannot be treated with oral acetylcysteine, or the clinician is considering continuing IV acetylcysteine in patients with anaphylaxis, we encourage consultation with a medical toxicologist or regional poison control center for guidance. (See 'Regional poison control centers' below.)

Vomiting with oral route — Approximately 33 percent of patients treated with oral acetylcysteine develop nausea and vomiting [55]. The palatability of acetylcysteine can be improved by diluting it to a 5% solution in cola or juice, covering the cup, and drinking through a straw.

It is reasonable to administer an antiemetic to nauseated patients or patients who have vomited prior to receiving oral acetylcysteine. Serotonin 5-HT3 receptor antagonists (eg, ondansetron) are effective antiemetics that are widely used in this setting [56].

If a patient vomits within 60 minutes of an oral dose of acetylcysteine, the dose should be repeated. Persistent vomiting in spite of antiemetic therapy is an indication to administer acetylcysteine IV.

Setting for intravenous acetylcysteine infusion — The initial infusion of IV acetylcysteine should be administered in a setting where oxygen, antihistamine medication (eg, diphenhydramine and famotidine), albuterol, epinephrine, a glucocorticoid (eg, methylprednisolone), a resuscitation cart, and appropriately-sized airway management equipment is readily available. This is typically the emergency department or critical care setting.

A patient who tolerates the initial infusion without developing an NAAR does not require critical care monitoring for the remaining doses (but may require monitoring for other conditions). A patient who develops anaphylaxis during acetylcysteine infusion and is able to continue the infusion (as discussed above) should be monitored in a critical care setting for the remainder of the entire infusion.

A patient without liver injury or with minimal liver injury who is tolerating acetylcysteine can typically be managed in a non-critical care setting.

Early international normalized ratio elevation — INR elevation within the first 20 hours following exposure does not reflect developing synthetic dysfunction or fulminant hepatic failure and does not carry prognostic value. Both therapeutic acetylcysteine serum concentrations and high concentrations of acetaminophen can elevate the INR. These elevations are usually mild (INR not greater than 1.7), occur between 4 and 20 hours after ingestion, and resolve as treatment is continued [57].

Duration of treatment (stopping criteria) — We use clinical endpoints rather than a predetermined time to determine duration of acetylcysteine treatment [1,45,47,58,59]. We stop acetylcysteine treatment after a minimum of 300 mg/kg over 20 to 24 hours has been administered and all of the following criteria are met [1]:

●Serum acetaminophen concentration <10 mcg/mL (66 micromol/L)

●INR <2.0

●ALT and AST are normal (or at baseline if chronically abnormal) or, if elevated, these have decreased 25 to 50 percent from the peak

●Patient is clinically well (eg, no nausea/vomiting, no abdominal pain)

If all of these criteria are not met:

●We continue acetylcysteine at a rate of at least 6.25 mg/kg/hour (or 70 mg/kg every four hours orally).

●Every 12 hours, we re-evaluate the patient and repeat the ALT, AST, INR, and acetaminophen concentration until all of the stopping criteria are met.

While the efficacy of IV and oral administration is similar, controversy persists about the optimal duration of acetylcysteine therapy, and various approaches to determine duration of therapy have been described [60-62]. The current treatment protocols approved by the US Food and Drug Administration are time based (21 and 72 hours). While these protocols are adequate for the vast majority of patients, it is clear that the 72-hour protocol is longer than needed for most patients while the 21-hour protocol is not long enough for others. There are case reports of patients with toxic acetaminophen concentrations or liver injury at the end of the 21-hour treatment period [45,47,58]. Therefore, we prefer to check laboratory studies prior to stopping treatment.

Shorter protocols have been described, but these are essentially tailored to the individual patient and not time based. For example, the Scottish and Newcastle Antiemetic Pretreatment for Paracetamol Poisoning (SNAP) protocol has been adopted into routine practice in various hospitals in the United Kingdom. The SNAP protocol provides a total 300 mg/kg acetylcysteine dose but over 12 hours (acetylcysteine IV loading dose of 50 mg/kg per hour for two hours followed by an infusion of 20 mg/kg per hour for 10 hours). However, the infusion is continued if stopping criteria are not met (these criteria are slightly different than described above). Trial and observational data suggest that, compared with the standard 21-hour IV protocol, the SNAP protocol is associated with similar rates of liver injury and fewer adverse effects [34,63].

Efficacy and mechanism — Acetylcysteine is the accepted antidote for acetaminophen poisoning. Acetylcysteine is most effective at preventing liver injury if started within eight hours of an acute ingestion; however, acetylcysteine provides benefit at any time after ingestion, even if there is no acetaminophen still present in serum.

There are no trials comparing acetylcysteine versus supportive treatment alone. However, large cohort studies have shown that, when compared with historical control patients who received supportive care alone, administration of acetylcysteine within 8 to 10 hours of acetaminophen overdose has been associated with a significant reduction in hepatotoxicity (1.6 versus 58.0 percent) and mortality (0.7 versus greater than 5.0 percent) [3,4,64,65]. Multiple studies have confirmed an extremely low incidence of hepatotoxicity following early acetylcysteine administration [2,32,66,67]. Furthermore, in patients with evidence of fulminant hepatic failure following acetaminophen ingestion, even when acetylcysteine was administered late (ie, more than 24 hours), there was decreased development of cerebral edema, improved hepatic function, and decreased mortality [18,68,69].

No deaths have been reported in any of the large studies of acetaminophen overdose provided acetylcysteine was given within 10 hours of ingestion, regardless of the initial serum acetaminophen concentration [2,3,70]. When fulminant hepatic failure and death occur from acetaminophen poisoning, they typically result from delays in seeking medical attention, recognition of poisoning, or institution of appropriate therapy.

Although some controversy persists regarding mechanism, most toxicologists believe acetylcysteine prevents acetaminophen-induced liver injury by restoring hepatic glutathione stores, which are depleted by acetaminophen metabolism to its toxic metabolite n-amino-p-benzoquinoneimine (NAPQI). Sufficient hepatic glutathione stores protect from liver injury by conjugating with NAPQI (figure 2). Other purported benefits include improved hepatic microcirculatory function and oxygen utilization, scavenging of free radicals, and decreased cerebral edema, especially in patients with acetaminophen-induced liver injury [16].

INVESTIGATIONAL

Biomarkers — Biomarkers for early identification of patients at greatest risk for acute liver injury following acetaminophen overdose are being developed and studied [71-74]. Further study of such approaches is needed before any can be recommended for clinical use.

Fomepizole — We recommend against routine use of fomepizole as an adjunct for treatment of acetaminophen poisoning in the absence of clear evidence of efficacy. However, preliminary evidence suggests that fomepizole may have a role as an adjunct to acetylcysteine in patients at high risk for hepatic failure following acetaminophen poisoning. For example, animal studies report that early administration of fomepizole prevents acetaminophen oxidation and limits liver injury [75-77]. Fomepizole may also inhibit Jun-N-terminal kinase (JNK), an important enzyme involved in hepatotoxicity [78]. A human volunteer study demonstrated decreased formation of oxidative metabolites following administration of fomepizole after supratherapeutic doses of acetaminophen [79]. Several case reports have described patients at high risk for significant toxicity who did well following treatment with fomepizole and acetylcysteine [80-82].

Fomepizole is approved by the US Food and Drug Administration for the treatment of toxic alcohol poisoning (ie, methanol and ethylene glycol) [83]. It is a potent inhibitor of alcohol dehydrogenase and CYP2E1 and has an excellent safety profile in this setting.

SPECIAL POPULATIONS

Pregnant patients — The essential elements of treating acetaminophen overdose do not differ significantly in the pregnant patient. [84,85].

●Intravenous (IV) acetylcysteine preferred over oral formulation – Many toxicologists prefer to give IV acetylcysteine to pregnant patients to reduce the risk of vomiting and ensure more rapid delivery to the fetus. Systemic acetylcysteine concentrations are higher with IV administration, and this may increase the amount of acetylcysteine that crosses the placenta. Nonetheless, both IV and oral routes have been used successfully to treat pregnant patients with acetaminophen overdose, and oral formulations may be used when IV acetylcysteine is not available. Data do not exist to demonstrate that the oral route is less effective in the pregnant patient [1]. Oral administration produces therapeutic acetylcysteine concentrations in cord blood [86].

●Acetylcysteine dosing, duration, and monitoring – Acetylcysteine dosing and the duration of treatment do not differ in the pregnant patient. Standard laboratory studies and monitoring should be performed in pregnant patients with acetaminophen overdose. The need for fetal monitoring is determined by standard clinical criteria. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'General approach and laboratory evaluation' and "Overview of antepartum fetal assessment".)

●Risk of adverse fetal outcomes – The most important intervention to prevent pregnancy loss is early treatment with acetylcysteine. In a prospective observational study of 60 pregnant patients with acetaminophen overdose, increasing time to acetylcysteine administration was associated with an increased risk of miscarriage and fetal death [84]. Multiple case reports describe similar findings [86-88].

Since acetaminophen crosses the placenta, maternal overdose causes fetal exposure, and case reports have described fetal and neonatal death from liver necrosis [84,89]. While there are several reports of good outcomes among mothers with liver injury following acetaminophen overdose [90-92], it is likely that maternal toxicity increases the risk for adverse pregnancy outcomes. The rate of fetal malformations does not appear to be increased following acetaminophen overdose, but data are limited [85,93].

●Maternal risk assessment for liver injury – The Revised Rumack-Matthew nomogram is used to determine the need for treatment in acute ingestions in pregnant patients as there are no studies suggesting that the risk of maternal hepatotoxicity from acetaminophen overdose is altered by pregnancy [66]. Use of the Revised Rumack-Matthew nomogram is described separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation after acute overdose'.)

In pregnant patients with repeat or chronic ingestions, serum acetaminophen and aminotransferase concentrations should be measured. Treatment with acetylcysteine is indicated if the serum acetaminophen concentration is greater than 20 mcg/mL or a serum aminotransferase concentration is elevated (>50 international units/L) [94].

●Newborn toxicity – There are rare case reports of patients delivering while poisoned with acetaminophen. In several of these cases, the neonate also had toxic acetaminophen concentrations [87,95]. In such circumstances, the neonate should be treated with acetylcysteine using standard dosing. (See 'Intravenous acetylcysteine dilution in children' below and 'Acetylcysteine administration and monitoring' above.)

Children — The use of acetaminophen among children increased when concerns were raised about an association between aspirin and Reye syndrome. Small children are particularly vulnerable to iatrogenic dosing errors, especially with IV formulations. Repeated supratherapeutic acetaminophen doses can cause hepatotoxicity in children with risk factors such as decreased oral intake [96-98]. (See "Fever in infants and children: Pathophysiology and management", section on 'Combining or alternating therapy' and 'Patient with Iatrogenic intravenous overdose' above.)

Exploratory ingestions in young children — Liver injury is rare among exploratory ingestions (ie, as a result of exploratory behavior) since they usually involve small amounts of acetaminophen in an otherwise asymptomatic child. Approach to treatment consists of the following:

●Administer activated charcoal (AC) to a child who presents within four hours of exposure and has ingested a potentially toxic dose (>150 mg/kg); we advise not administering 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' above.)

●Plot a timed serum acetaminophen concentration obtained a minimum of four hours after ingestion on the Revised Rumack-Matthew nomogram (figure 1). (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Acetaminophen concentration'.)

●Administer acetylcysteine to a child with an acetaminophen concentration that is above the treatment line on the Revised Rumack-Matthew nomogram.

Inappropriate therapeutic dosing — Our approach is to children with inappropriate therapeutic dosing is similar to management of adults and is based on whether the history of dose and time of ingestion are reliable and the results of the initial evaluation (including serum acetaminophen concentration and aminotransferases) [1]:

●Unreliable history of duration of exposure or dose ingested – Management is based on the serum acetaminophen concentration and the aminotransferases. (See 'Patient with unreliable history' above.)

●Reliable history of duration and dose

•Exposure has occurred during <24 hours and the serum concentration can be measured within 24 hours of swallowing the first dose – Management is similar to an acute ingestion, and the Revised Rumack-Matthew nomogram is used to determine risk of liver injury. (See 'Patient with reliable history and acute ingestion' above.)

•Dosing has occurred over a period >24 hours – Management is based on the daily dose ingested, the serum acetaminophen concentration, and the aminotransferases. (See 'Patient with reliable history and repeated supratherapeutic ingestion' above.)

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. The dose and duration criteria that raise concern for developing liver injury are discussed separately. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Repeated supratherapeutic ingestion'.)

In general, children with no liver injury and no unmetabolized acetaminophen measured in serum may be discharged home [96]. Their caregivers should receive instruction to avoid acetaminophen for the remainder of the current illness. The caregivers also may benefit from education regarding future prevention of such exposures. (See 'Prevention of recurrent ingestion' below.)

Children with a history of multiple supratherapeutic doses of acetaminophen that is associated with liver injury with or without unmetabolized acetaminophen should receive acetylcysteine and supportive care in the hospital. We use the same end-points of acetylcysteine therapy as in adults, although the optimal mode of delivery and the duration of therapy in this setting have not been established in trials [1,96,99]. Consultation with a regional poison control center or medical toxicologist is advised. (See 'Duration of treatment (stopping criteria)' above and 'Regional poison control centers' below.)

Diagnosing chronic acetaminophen toxicity (ie, repeated excessive dosing over a period >24 hours) is often difficult in children 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 (eg, nausea, vomiting, abdominal pain), and easily confused with alternative diagnoses (eg, viral syndrome). Serum concentrations of acetaminophen in this setting do not correlate with toxicity, and the Revised Rumack-Matthew nomogram 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 'Repeated supratherapeutic ingestion' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Differential diagnosis'.)

Intravenous acetylcysteine dilution in children — We follow the manufacturer's weight-based dilution protocol for children who weigh less than 40 kg to prevent fluid overload and administering excess free water, which has resulted in hyponatremia, seizures, and death.

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 four hours (12.5 mg/kg acetylcysteine per hour)

●Third dose: 100 mg/kg in 14 mL per kg of diluent given IV over 16 hours (6.25 mg/kg acetylcysteine 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 four hours (12.5 mg/kg acetylcysteine per hour)

●Third dose: 100 mg/kg in 500 mL of diluent given IV over 16 hours (6.25 mg/kg acetylcysteine per hour)

Fulminant hepatic failure and liver transplantation — In a child with hepatic failure from acetaminophen, the indications for consultation with a liver transplant team are the same as for adults [1]. (See 'Indications for consultation with liver transplant team' above.)

In a young child, even subtle changes in mentation (not clearly explained by another condition) should prompt consultation with a liver transplantation team [100]. Differentiating grade II and III hepatic encephalopathy in a young child can be difficult (table 9), disease progression may be rapid, and grade III or IV encephalopathy carries an extremely poor prognosis. (See "Acute liver failure in children: Etiology and evaluation", section on 'Physical examination'.)

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. A retrospective review included 51 children with acetaminophen overdose and found that children had the same clinical and biochemical risk factors for poor outcomes as adults, although the serum creatinine threshold for poor prognosis was lower for children (>200 micromol/L [2.3 mg/dL] versus >300 micromol/L [3.4 mg/dL] for adults) [100]. Similar to adults, the degree of transaminase elevation is not considered a prognostic factor.

In a child with progressive hepatic failure from acetaminophen, liver transplantation should be considered as it interrupts the natural course and may be lifesaving (figure 3). 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 [6]. However, liver transplantation is rarely required in children with acetaminophen poisoning and is much less commonly employed compared with adults; thus, experience with outcomes in younger patients is limited. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Liver transplant'.)

WHEN CAN PATIENT RESUME TAKING ACETAMINOPHEN? — After an acetaminophen overdose, patients may safely resume acetaminophen therapy if all of the following conditions are met [23]:

●No clinical symptoms

●Serum acetaminophen level <10 mg/L (66 micromol/L)

●Normal serum alanine aminotransferase (ALT)

●Normal prothrombin time (PT) and international normalized ratio (INR)

PREVENTION OF RECURRENT INGESTION — In the setting of accidental acetaminophen ingestion, prevention of recurrence involves education of patients, parents, and caregivers regarding the safe and judicious use of acetaminophen and other antipyretics.

Depending on the circumstance that resulted in ingestion or toxicity, explicit instructions should be given regarding the following [101,102]:

●Strictly adhering to the weight-based dosing schedules on the label, with a maximum daily dose of 4 grams in adults and 75 mg/kg in children [103].

●Avoiding concurrent administration of acetaminophen with acetaminophen-containing over-the-counter medications or combination acetaminophen-opioid 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 [104-106]; in addition, suppository preparations should not be divided since it is impossible to know with certainty the dose in each portion [107].

●Avoidance of adult acetaminophen preparations (325 mg and 500 mg) in young children (table 2).

●Storing medications out of the reach of children to prevent exploratory acetaminophen ingestions. (See "Prevention of poisoning in children".)

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 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 5^th to 6^th 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 10^th to 12^th 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 topic (see "Patient education: Acetaminophen poisoning (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Evaluating risk for liver injury – The risk of developing liver injury following an acute ingestion (ie, any pattern of acetaminophen ingestion as long as the serum concentration can be measured within 24 hours of swallowing the first dose) is determined by plotting a timed serum acetaminophen concentration on the Revised Rumack-Matthew nomogram (figure 1). (See 'Patient with reliable history and acute ingestion' above.)

The Revised Rumack-Matthew nomogram cannot be applied to a patient with an unreliable history or a repeated supratherapeutic ingestion (ie, multiple ingestions during a period greater than 24 hours). (See 'Patient with reliable history and repeated supratherapeutic ingestion' above and 'Patient with unreliable history' above.)

A table is provided that summarizes the management (table 1). The evaluation of acetaminophen poisoning, use of the Revised Rumack-Matthew nomogram, and determination of risk of liver injury are discussed in detail separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents".)

●Gastrointestinal decontamination – In a patient who presents within four hours of a potentially toxic ingestion of acetaminophen (single dose ≥150 mg/kg or 7.5 g), we suggest administering activated charcoal (AC) (Grade 2C). The dose is 1 g/kg (maximum dose 50 g) orally. Contraindications to charcoal include gastrointestinal obstruction or altered mental status with an unprotected airway; tracheal intubation should not be performed solely for the purpose of giving AC. (See 'Gastrointestinal decontamination' above.)

●Antidote (acetylcysteine)

•Indications – In a patient with acetaminophen poisoning at risk for hepatotoxicity (concentration above treatment line on Revised Rumack-Matthew nomogram (figure 1)) and in a patient with liver injury with exposure to acetaminophen, we recommend treatment with acetylcysteine (Grade 1A). Acetylcysteine is most effective at preventing liver injury if started within eight hours of an acute ingestion but can still decrease need for liver transplant and mortality even in the presence of liver injury without detectable acetaminophen in serum. Patients who should receive acetylcysteine include the following:

-Acute ingestion with serum acetaminophen concentration drawn at four hours or more that is above the treatment line on the Revised Rumack-Matthew nomogram (figure 1). (See 'Patient presenting within eight hours of ingestion' above.)

-Suspected single ingestion of greater than 150 mg/kg (7.5 g total dose regardless of weight) when the serum acetaminophen concentration will not be available until more than eight hours from the time of the ingestion. (See 'Patient presenting beyond eight hours after ingestion' above.)

-Reliable history with repeated supratherapeutic ingestion and a serum acetaminophen concentration ≥20 mcg/mL (132 micromol/L) or aminotransferases are elevated (unless the elevation is patient's baseline value). (See 'Patient with reliable history and repeated supratherapeutic ingestion' above.)

-Unreliable history and acetaminophen >10 mcg/mL (66 micromol/L) or aminotransferases are elevated (unless the elevation is patient's baseline value). (See 'Patient with unreliable history' above.)

-History of acetaminophen ingestion and any evidence of liver injury. (See 'Patient with liver injury (including delayed presentation)' above.)

•Dosing protocols – Acetylcysteine may be given intravenously (IV) or orally. IV administration is preferable in patients with vomiting, nonfunctioning bowel, or pregnancy; those refusing oral administration; and those who present with liver injury. (See 'Choice of intravenous versus oral' above.)

The most used acetylcysteine dosing protocols are the 21-hour IV protocol, the 20-hour "two-bag" IV protocol, and the oral protocol. Whichever protocol is chosen, it should deliver at least 300 mg/kg acetylcysteine during the first 20 to 24 hours of treatment. (See 'Choice of protocol' above.)

•Duration (stopping criteria) - We use clinical endpoints rather than time to determine the duration of acetylcysteine therapy. We stop acetylcysteine treatment after a minimum of 300 mg/kg over 20 to 24 hours has been administered and all of the following criteria are met (see 'Duration of treatment (stopping criteria)' above):

-Serum acetaminophen concentration <10 mcg/mL (66 micromol/L)

-International normalized ratio (INR) <2.0

-Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are normal (or at baseline if chronically abnormal) or, if elevated, these have decreased 25 to 50 percent from the peak

-Patient is clinically well (eg, no nausea/vomiting, no abdominal pain)

•Adverse reactions - Between 10 and 20 percent of patients treated with IV acetylcysteine develop a nonallergic anaphylactic reaction (NAAR). In patients who develop only flushing, stop the acetylcysteine infusion for 15 to 30 minutes, then restart at the prior rate unless more severe signs develop. Management of more severe reactions includes administering intramuscular epinephrine, diphenhydramine, and a glucocorticoid. (See 'Nonallergic anaphylactic reactions to intravenous route' above and 'Vomiting with oral route' above.)

●Fulminant hepatic failure – In patients who develop fulminant hepatic failure (differentiated from liver injury by the onset of impaired synthetic function and/or encephalopathy), acetylcysteine decreases mortality and need for liver transplantation. The Modified King's College Criteria (algorithm 1) can help determine prognosis without liver transplantation. (See 'Fulminant hepatic failure' above.)

●Role of extracorporal removal following high-risk ingestion – In a patient with a serum acetaminophen concentration ≥900 mcg/mL (5960 micromol/L) and altered mental status or metabolic acidosis, we suggest hemodialysis in addition to acetylcysteine (Grade 2C). Hemodialysis can clear acetaminophen and toxic metabolites from serum and can also correct a metabolic acidosis. (See 'Role of extracorporeal removal' above.)

●Exploratory ingestions in young children – These exposures typically involve small amounts of acetaminophen in an otherwise asymptomatic child and rarely result in liver injury. They are treated similarly to acute ingestions in adults. (See 'Exploratory ingestions in young children' above.)