INTRODUCTION — Acetaminophen poisoning is among the most common causes of medication-related poisoning and death. Acetaminophen poisoning may occur following a single acute ingestion or through the repeated ingestion of supratherapeutic amounts. The management of the acetaminophen-poisoned patient may include stabilization, decontamination, and administration of N-acetylcysteine, a specific antidote. The duration of N-acetylcysteine treatment is determined by the type of ingestion and the presence or absence of elevated serum alanine aminotransferase (ALT) concentrations.
The treatment of acetaminophen poisoning is reviewed here. The diagnosis of acetaminophen poisoning, both acute and chronic, and the management of hepatic injury or failure are discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation" and "Acute liver failure in adults: Management and prognosis".)
OVERVIEW OF MANAGEMENT — The initial management of acetaminophen poisoning is determined by the patient's presenting symptoms. Most patients who present early (within 24 hours) after an acute acetaminophen ingestion are asymptomatic, while others may require treatment for symptoms related to coingestants.
As there are no early symptoms that predict acetaminophen toxicity, poisoning severity following an acute ingestion is quantified by plotting a timed serum acetaminophen concentration on the modified Rumack-Matthew nomogram (figure 1). Patients with serum acetaminophen concentrations that fall above the treatment line following an acute overdose are treated with N-acetylcysteine. In addition, N-acetylcysteine is given to all patients at significant risk for hepatotoxicity or who manifest signs of hepatotoxicity following an ingestion of acetaminophen. (See 'Indications' below.)
Use of the nomogram, as well as risk factors for hepatotoxicity and the diagnosis of both acute and chronic acetaminophen poisoning, are discussed separately. A summary table to facilitate emergency management is provided (table 1). (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation".)
In certain clinical scenarios, it can be difficult to determine the risk associated with exposure to acetaminophen and the appropriate management. A number of the most common and challenging circumstances are reviewed below and separately:
●Time of ingestion is unknown (see 'When time of ingestion is unclear or unknown' below)
●Pregnant patient (see 'Treatment in pregnancy' below)
●Ingestion of a sustained release drug formulation (see "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Ingestion of sustained-release acetaminophen')
●Repeated supratherapeutic ingestion (see "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation after repeated supratherapeutic ingestion')
Patients who present later (after 24 hours) 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 patients may require emergency resuscitation, including airway management, intravenous fluids, vasopressors, hemodialysis, or management of cerebral edema. (See "Acute liver failure in adults: Management and prognosis".)
GASTROINTESTINAL DECONTAMINATION — Adult patients who present soon after a potentially toxic ingestion of acetaminophen (single dose ≥7.5 g) are likely to benefit from gastrointestinal (GI) 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, unless there are contraindications to its administration.
Charcoal 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 charcoal. Asymptomatic patients who present more than four hours after a reported ingestion are unlikely to benefit from AC, and we do not recommend routine treatment in these patients. A general approach to decontamination of poisoned patients is discussed separately. (See "Gastrointestinal decontamination of the poisoned patient".)
A number of studies using simulated overdose models have shown that AC reduces acetaminophen exposure [1]. Several clinical trials have confirmed these findings:
●A randomized trial evaluating decontamination following acetaminophen overdose found that patients treated with AC had a larger decrease in serum acetaminophen concentrations than those treated with gastric lavage or an emesis-inducing drug [2].
●A prospective observational study found that patients who received AC prior to N-acetylcysteine were less likely to develop liver injury than those who did not [3].
●A retrospective study of 981 consecutive patients with an acute acetaminophen overdose found that patients who received AC within two hours of ingestion were less likely to require N-acetylcysteine treatment [4].
●A prospective observational study found that administration of AC to patients who presented more than four hours after acetaminophen ingestion was associated with lower peak alanine aminotransferase (ALT) concentrations, and that these effects were independent of the time of N-acetylcysteine administration. While limited, this study suggests that administration of AC more than four hours after ingestion may be beneficial [5].
Studies have shown that induced emesis [6,7] and gastric lavage [8,9] limit the absorption of acetaminophen after simulated overdose and in clinical trials [2,6]. However, these therapies appear to be less effective than activated charcoal, so they are not routinely recommended [2,4].
ANTIDOTE: ACETYLCYSTEINE
Indications — N-acetylcysteine is the accepted antidote for acetaminophen poisoning and is given to all patients at significant risk for hepatotoxicity. Indications for N-acetylcysteine therapy include:
●Serum acetaminophen concentration drawn at four hours or more following acute ingestion of an immediate-release preparation is above the "treatment" line of the treatment nomogram for acetaminophen poisoning (figure 1).
●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.
●Patient with an unknown time of ingestion and a serum acetaminophen concentration >10 mcg/mL (66 micromol/L).
●Patient with a history of acetaminophen ingestion and any evidence of liver injury.
●Patients with delayed presentation (>24 hours after ingestion) consisting of laboratory evidence of liver injury (ranging from mildly elevated aminotransferases to fulminant hepatic failure) and a history of excessive acetaminophen ingestion. Patients with delayed presentation and hepatic injury should be managed in consultation with a regional poison control center or a medical toxicologist. (See 'Regional poison control centers' below.)
Effectiveness — Serious hepatotoxicity is uncommon and death extremely rare if N-acetylcysteine is administered within eight hours following acetaminophen overdose [10-12].
The key to effective treatment is to start therapy before the onset of liver injury, which can be defined biochemically by an elevation of the alanine aminotransferase (ALT) concentration. This is accomplished by initiating treatment within eight hours of an acute ingestion. Determination of the risk for hepatotoxicity following either acute or chronic acetaminophen ingestion is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation and diagnosis'.)
Although some controversy persists regarding mechanism, most toxicologists believe N-acetylcysteine prevents acetaminophen-induced hepatic injury by restoring hepatic glutathione stores.
There are no randomized, placebo-controlled trials evaluating the efficacy of N-acetylcysteine for the prevention of hepatic injury from acetaminophen poisoning, as such trials were considered unethical. However, several studies have described an extremely low incidence of hepatotoxicity following early N-acetylcysteine administration [10-16]. In addition, when N-acetylcysteine is administered late following acetaminophen ingestion to patients with evidence of hepatic failure, it decreases mortality and improves hepatic and cerebral function [17-19].
Some debate continues about the appropriate route and duration of early N-acetylcysteine therapy following acute ingestion. The 20-hour intravenous (IV) protocol is used most often [15]. Prior to the availability of an IV formulation of acetylcysteine, a 72-hour oral protocol was used in the United States with similar outcomes [11]. Subsequently, a shorter (12-hour) protocol was developed for low-risk patients who meet specific treatment endpoints. We review these protocols immediately below. A discussion of how they are modified based upon clinical circumstances is discussed further on. (See 'Duration of treatment' below.)
There are reports of adult patients with massive acetaminophen ingestion (ingestion >30 g, or serum concentration >500 mg/L [3300 micromol/L]) who develop liver injury despite early administration of N-acetylcysteine [20,21]. Several of these cases involved coingestion of diphenhydramine and the patients had elevated acetaminophen concentrations at the completion of the 20-hour IV N-acetylcysteine protocol. Pharmacokinetic models suggest that a higher dose of N-acetylcysteine given for a longer period may be beneficial in such cases [22,23]. Patients with these clinical features should be discussed with a poison center or toxicologist familiar with the management of acetaminophen overdose. Other medications that may worsen the outcome of acetaminophen poisoning are reviewed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Medications and herbal products'.)
20-hour IV protocol — The 20 hour IV protocol for N-acetylcysteine treatment has been used in the United Kingdom since the 1970s.
The approved 20-hour IV dosing regime is complicated and is performed as follows:
●Administer an initial loading dose of 150 mg/kg IV over 15 to 60 minutes (we recommend 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 20 to 21 hours [15]. The treatment period is often extended when patients have large ingestions or elevated serum transaminase activity. This is discussed below. (See 'Duration of treatment' below.)
Simplified 20-hour (two-bag) IV protocol — The results of a large retrospective study and experience in Europe, Australia, and the United States indicate that nonallergic anaphylactic reactions (NAAR) during treatment with IV N-acetylcysteine can be reduced by using a two-bag regimen instead of the traditional three-bag regimen described in the manufacturer's package insert and most dosing references. In the study, NAARs occurred in 10 percent of the 389 patients treated with the standard regimen versus 4.3 percent of the 210 patients treated with a modified two-bag regimen (odds ratio [OR] 2.5; 95% CI 1.1-5.8) [24]. Similar studies show comparable results [25-28]. 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 older adolescents.
The two bag regimen can be 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)
72-hour oral protocol — The 72-hour oral (PO) dosing protocol for N-acetylcysteine treatment has been used successfully in the United States for more than 30 years, and consists of the following:
●A loading dose of 140 mg/kg PO, followed by
●A dose of 70 mg/kg PO every four hours for a total of 17 doses
The dose does not need to be adjusted if the patient has been treated with activated charcoal.
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 N-acetylcysteine, no deaths occurred among patients treated before the onset of transaminase elevation [11].
There are several reports describing truncated oral protocols. The duration of treatment is discussed further below. (See 'Duration of treatment' below.)
12-hour protocol — In a small randomized controlled trial, patients treated with the 12-hour protocol and slower rate of loading dose infusion had significantly fewer adverse effects than those treated with the standard 20-hour protocol [25]. For the 12-hour protocol, the loading dose of N-acetylcysteine is 50 mg/kg per hour for two hours, followed by an infusion of 20 mg/kg per hour for 10 hours. Acetylcysteine is stopped once the international normalized ratio (INR) is less than 1.3, the alanine aminotransferase (ALT) concentration is less than 100 U/L (and not more than twice the admission value), and the serum acetaminophen concentration is less than 20 mg/L (ie, 20 mcg/mL or 132 micromol/L). If these criteria are not met, the final infusion rate is continued. An observational study (reported as an abstract) reported similar treatment outcomes for the 12-hour protocol when compared with standard therapy [29].
IV versus oral — There are no head-to-head trials comparing the 20-hour IV and the 72-hour oral treatment protocols in patients treated early after ingestion. The best available data suggest that both routes are effective and differences are minimal [30,31]. In most patients, either the oral or IV route is acceptable. IV administration is favored for patients with any of the following:
●Vomiting
●Contraindications to oral administration (ie, pancreatitis, bowel ileus or obstruction, bowel injury)
●Hepatic failure
●Patients who refuse oral administration
Patients with evidence of hepatic failure require IV therapy. (See 'Treatment in hepatic failure' below.)
Effect of patient weight on dosing — Current dosing protocols for N-acetylcysteine in the United States are calculated using patient bodyweight. However, the maximum dose is based upon a weight of 100 kg for IV therapy and 110 kg for oral therapy [32,33]. The basis for these recommendations is not clear, but there is no evidence that N-acetylcysteine doses calculated with weights above these maximum amounts provide added benefit [34]. However, in a large observational study, clinicians often based dosing on actual weight with a low rate of adverse events [35]. Dosing based upon either the patient’s actual weight or the maximum recommended weights described here is acceptable.
Adverse reactions — While dosing errors are common during IV N-acetylcysteine administration [36], significant adverse events stemming from such miscalculations are rare. 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.
Anaphylaxis (anaphylactoid reaction) — Prospective studies suggest that between 10 and 20 percent of patients treated with IV N-acetylcysteine develop a hypersensitivity reaction (ie, anaphylaxis that is not IgE-mediated, formerly known as an anaphylactoid reaction) [37,38]. Reactions vary in severity and most of these subjects are able to tolerate the infusion when it is restarted. Nevertheless, patients receiving IV N-acetylcysteine warrant close monitoring and the medications and equipment necessary to manage anaphylaxis should be readily available when the initial infusion is administered (table 2). (See "Anaphylaxis: Emergency treatment".)
Patients receiving IV N-acetylcysteine warrant close monitoring and all essential medications and tools needed to treat anaphylaxis and airway emergencies should be immediately available. These include oxygen, antihistamine medication (eg, diphenhydramine and famotidine), albuterol, epinephrine (1:1000 for intramuscular use), glucocorticoid medication (eg, methylprednisolone), a resuscitation cart, and emergency airway management equipment. Patients who develop anaphylaxis during N-acetylcysteine infusion and are able to continue the infusion should be monitored in a critical care setting for the remainder of the 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).
Limited observational evidence is available regarding the continuation of IV N-acetylcysteine in patients with anaphylaxis, and we encourage consultation with a regional poison control center or medical toxicologist to determine whether the infusion should continue after an allergic reaction has occurred. (See 'Additional resources' below.)
Based upon one small case series, the following approach is suggested [39]:
●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, as well as diphenhydramine and a glucocorticoid. 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. In patients for whom signs and symptoms resolve, the infusion may be restarted at the prior rate one hour after the administration of epinephrine.
●Patients who develop hypotension or other persistent systemic anaphylaxis symptoms after IV N-acetylcysteine therapy should have the infusion stopped and receive treatment for anaphylaxis (table 2). IV N-acetylcysteine should not be restarted. Oral N-acetylcysteine therapy should be provided as an alternative. These patients will generally tolerate oral N-acetylcysteine. If the patient cannot be treated with oral N-acetylcysteine, the clinician should consult a medical toxicologist or poison control center for guidance.
Vomiting — Approximately 33 percent of subjects treated with oral N-acetylcysteine develop nausea and vomiting [40]. The palatability of N-acetylcysteine can be improved by diluting it to a 5 percent 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 N-acetylcysteine. Serotonin 5-HT3 receptor antagonists (eg, ondansetron) are effective antiemetics that are widely used in this setting [41]. Although treatment with ondansetron was associated with higher peak ALT values in one trial, the clinical relevance of these findings remains unclear [25].
If a patient vomits within 60 minutes of an oral dose of N-acetylcysteine, the dose should be repeated. Persistent vomiting in spite of antiemetic therapy is an indication to administer N-acetylcysteine intravenously.
Duration of treatment — While the efficacy of IV and oral administration is similar, controversy persists about the optimal duration of N-acetylcysteine therapy. The current treatment protocols approved by the US Food and Drug Administration (FDA) are time-based (20 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 20-hour protocol is not long enough for some others.
Many authors recommend that therapy be tailored to each patient, using clinical endpoints rather than time to determine duration [20,42-44]. We suggest the following approach for three common clinical scenarios based upon the type of ingestion and the clinical status of the patient:
●Acute ingestion with treatment started when ALT is NOT elevated or within eight hours of ingestion – Administer IV or oral N-acetylcysteine for a minimum of 20 hours (some authors suggest longer treatment when the oral route is used) [45].
Check the serum ALT and acetaminophen concentrations as the patient is approaching the end of the protocol (approximately 18 hours after starting treatment). If the serum ALT is elevated OR if the serum acetaminophen concentration is detectable, continue treatment with N-acetylcysteine at 6.25 mg/kg per hour (for IV protocol) or 70 mg/kg every four hours (for oral protocol) and obtain a serum acetaminophen concentration and ALT measurement every 12 hours thereafter. If the ALT is elevated, also measure the international normalized ratio (INR).
Treatment can be stopped when the serum acetaminophen concentration is undetectable, the ALT is clearly decreasing or in the normal range, and the INR is less than two. There is no uniformly accepted definition of "clearly decreasing." One conservative definition is a decrease of more than 50 percent from the peak measurement or three consecutive decreasing values, all below 1000 international units/L.
●Repeated ingestion with treatment started when ALT is NOT elevated – Administer IV or oral N-acetylcysteine for a minimum of 12 hours [46]. After 11 hours of treatment check the serum ALT activity and acetaminophen concentration. If the serum ALT is elevated OR if the serum acetaminophen concentration is detectable, continue treatment with N-acetylcysteine at 6.25 mg/kg per hour (for IV protocol) or 70 mg/kg every four hours (for oral protocol) and obtain a serum acetaminophen concentration and ALT measurement every 12 hours thereafter. If the ALT is elevated, also measure the patient's INR.
Treatment can be stopped when the serum acetaminophen concentration is undetectable, the ALT is clearly decreasing or in the normal range, and the INR is less than two. There is no uniformly accepted definition of "clearly decreasing." One conservative definition is a decrease of more than 50 percent from the peak measurement or three consecutive decreasing values, all below 1000 international unit/L.
●Evidence of hepatic injury following either acute or repeated ingestion – Administer IV or oral N-acetylcysteine until the ALT is clearly decreasing, the INR is less than two, AND the serum acetaminophen concentration is undetectable. There is no uniformly accepted definition of "clearly decreasing." One conservative definition is a decrease of more than 50 percent from the peak measurement or three consecutive decreasing values, all below 1000 international unit/L. Patients who develop hepatic encephalopathy are treated as described immediately below.
Monitoring during treatment — If N-acetylcysteine therapy is initiated within eight hours of ingestion (ie, before ALT elevation), one major guideline recommends no additional testing at the end of treatment [47]. However, we suggest measuring the ALT prior to stopping N-acetylcysteine and continuing treatment if 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 N-acetylcysteine to verify that the level is undetectable. Our approach is based upon a small number of case reports in which patients had toxic acetaminophen concentrations at the end of the 20-hour IV treatment protocol [20,42,43].
Other guidelines recommend measuring serum acetaminophen, INR, serum bicarbonate, and serum creatinine at the end of treatment and continuing treatment if any value is abnormal [48]. The ALT is used to monitor the degree of hepatic injury and the other tests are used to determine the need for liver transplant [49]. A full discussion of the criteria for liver transplantation is found separately. (See "Acute liver failure in adults: Management and prognosis".)
We suggest measuring the ALT and INR every 12 hours for any patient who develops ALT elevation. More frequent testing does not allow enough time to detect clinically meaningful trends. If the patient develops an ALT greater than 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. Closer monitoring (eg, intensive care unit [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.
Side effects — Both therapeutic serum concentrations of N-acetylcysteine and high concentrations of acetaminophen can elevate the INR. These elevations 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 [50].
ANTIDOTE TREATMENT IN SPECIAL CIRCUMSTANCES
When time of ingestion is unclear or unknown — Measuring a screening serum acetaminophen concentration is recommended for all patients with a history of overdose or altered mental status thought to be caused by overdose (see "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation and diagnosis'). However, in some cases, there is no practical way to ascertain the time of ingestion, making it impossible to use the acetaminophen poisoning nomogram for risk stratification. We recommend the following approach to these patients:
If the history suggests a single ingestion and it is possible to narrow the ingestion time to a specific 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." N-acetylcysteine would be given based upon this scenario.
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. Given the unknown risks, we take a conservative approach. We suggest starting treatment with N-acetylcysteine for any patient with a detectable serum acetaminophen concentration. In addition, we suggest treating any patient with elevated serum transaminase concentrations and a history consistent with acetaminophen exposure regardless of the serum acetaminophen concentration. This approach maximizes the potential benefit of acetylcysteine.
We suggest treating these patients for 12 hours and then repeating the serum acetaminophen concentration (unless it was already undetectable) and the serum transaminase. We stop acetylcysteine treatment if the patient fulfills all three of the following conditions:
●Patient is asymptomatic (eg, no right upper quadrant pain)
●Acetaminophen concentration is non-detectable, AND
●Serum transaminase activity is decreasing significantly (has decreased to normal range or to <50 percent of 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.
Treatment in hepatic failure — If a patient develops hepatic failure (hepatic failure is differentiated from hepatic injury by the onset of encephalopathy), intravenous (IV) N-acetylcysteine decreases mortality and improves hepatic microcirculatory function.
There are no studies of oral N-acetylcysteine in hepatic failure, so all patients should receive IV therapy. The dosing protocol is the same as the 20-hour regimen used for the prevention of hepatic injury, except the final infusion rate (6.25 mg/kg per hour) is continued until the patient receives a liver transplant OR the hepatic encephalopathy resolves [2,6,17] and the international normalized ratio (INR) is less than two [51].
Additional supportive therapies for the management of acute hepatic failure and its complications (including encephalopathy, coagulopathy, and acute renal injury) are started as indicated. Patients with acute liver failure from acetaminophen should be considered for liver transplant and referred to a specialty center. (See "Acute liver failure in adults: Management and prognosis".)
Massive overdose — We recommend that clinicians treating patients who present with high serum acetaminophen concentrations (concentration measured four or more hours after ingestion that is above the nomogram line at 300 mcg/mL, and decreases according to a four-hour half-life), or a reliable history of massive ingestion (>50 g), initiate treatment with N-acetylcysteine as rapidly as possible using standard dosing. They should then contact a poison center or medical toxicologist immediately to determine whether it is appropriate to modify treatment. (See 'Additional resources' below and '20-hour IV protocol' above and 'Simplified 20-hour (two-bag) IV protocol' above.)
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 20-hour IV protocol to 12.5 mg/kg per hour and continue the infusion until the serum acetaminophen concentration is undetectable.
Several reports have described patients with a massive acetaminophen overdose (>50 g) who developed hepatic failure despite early treatment with IV N-acetylcysteine using the standard 20-hour protocol [20,21,43]. 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 massive ingestion will develop liver injury if treated with standard protocols, even when treatment with N-acetylcysteine is initiated within eight hours [52,53]. These observations have led some authors to suggest that a higher dose of N-acetylcysteine may be required for large overdoses [23], and a computerized simulation of overdose supports this concept [22]. However, there are no controlled studies demonstrating that increasing the dose of acetylcysteine prevents liver injury following massive overdose.
Treatment in pregnancy — The essential elements of treating acetaminophen overdose do not differ significantly in the pregnant patient. Many toxicologists prefer to give N-acetylcysteine intravenously to pregnant patients to reduce the risk of vomiting and ensure more rapid delivery to the fetus.
Since acetaminophen crosses the placenta, maternal overdose causes fetal exposure and there are case reports of fetal and neonatal death from hepatic necrosis following maternal overdose [54,55]. Nevertheless, most cases of pregnant women with an acetaminophen overdose are uneventful [54,56].
There are no studies suggesting that the risk of hepatotoxicity from acetaminophen overdose is altered by pregnancy. Therefore, the Rumack-Matthew nomogram is used to determine the need for treatment in acute ingestions [14]. Use of the 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 transaminase concentrations should be measured. Treatment with N-acetylcysteine is indicated if the serum acetaminophen concentration is greater than 20 mcg/mL or a serum transaminase concentration is elevated (>50 international unit/L) [46]. Dosing and the duration of treatment do not differ in the pregnant patient. (See 'Antidote: acetylcysteine' above.)
While there are several reports of good outcomes among mothers with hepatic injury following acetaminophen overdose [57-59], it is likely that maternal toxicity increases the risk for adverse pregnancy outcomes. There does not appear to be an increase in the rate of fetal malformations following acetaminophen overdose, but data are limited [56,60].
The most important intervention to prevent pregnancy loss is early treatment with N-acetylcysteine. In a prospective observational study of 60 pregnant women with acetaminophen overdose, increasing time to N-acetylcysteine administration was associated with an increased risk of miscarriage and fetal death [54]. Multiple case reports describe similar findings [61-63].
Most clinicians use IV N-acetylcysteine in pregnancy, arguing that the IV route is preferable because systemic drug concentrations are higher and this may increase the amount of N-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 N-acetylcysteine is not available. Oral administration produces therapeutic N-acetylcysteine concentrations in cord blood [61].
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 serum acetaminophen concentration' and "Overview of antepartum fetal assessment".)
There are rare case reports of women delivering while poisoned with acetaminophen. In several of these cases, toxic acetaminophen concentrations were measured in the neonate [62,64]. In such circumstances, the neonate should be treated with N-acetylcysteine using standard dosing. The post-partum mother should be treated using standard therapy for acetaminophen overdose as described above. (See "Management of acetaminophen (paracetamol) poisoning in children and adolescents".)
Repeated supratherapeutic ingestion — Evaluation of the patient with possible acetaminophen toxicity from a repeated supratherapeutic ingestion is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation after repeated supratherapeutic ingestion'.)
OTHER TREATMENTS
Cimetidine — Several other treatments have been suggested as possible adjuncts for the prevention of acetaminophen-induced liver injury. The most commonly cited is cimetidine, an inhibitor of acetaminophen metabolism [65-69]. While this treatment was useful in animal models, it had no effect in a clinical trial where patients were treated with N-acetylcysteine [70,71]. Other substances have also been evaluated in animal models, but none is considered standard care in humans [71-75].
Older studies evaluated therapies such as methionine, cysteamine, and dimercaprol [13,76,77], but these treatments were limited by adverse effects and play no role in current management.
Fomepizole — There is interest in using fomepizole as an adjunct for treatment of acetaminophen poisoning. While the preliminary evidence presented below suggests that fomepizole may have a role as an adjunct for patients at high risk for liver failure following acetaminophen poisoning, the authors feel that, in the absence of controlled studies, it cannot yet be recommended for routine use.
Fomepizole is routinely used as in inhibitor of alcohol dehydrogenase for treatment of toxic alcohol poisoning, has an excellent safety profile, and is approved by the US Food and Drug Administration (FDA) [78]. (See "Methanol and ethylene glycol poisoning: Management", section on 'Fomepizole'.)
In addition to inhibiting alcohol dehydrogenase, fomepizole is a potent inhibitor of CYP 2E1. Animal studies report that early administration of fomepizole prevents acetaminophen oxidation and limits hepatic injury [75,79,80]. Fomepizole may also inhibit Jun-N-terminal kinase (JNK), an important enzyme involved in hepatotoxicity [81]. A human volunteer study demonstrated decreased formation of oxidative metabolites following administration of fomepizole after supratherapeutic doses of acetaminophen [82], and several case reports have described patients at high risk for significant toxicity who did well following treatment with fomepizole [83-85].
Extracorporeal removal — Although acetaminophen is cleared by hemodialysis [86,87], the safety and efficacy of N-acetylcysteine leaves no role for dialysis in the standard management of acetaminophen poisoning if N-acetylcysteine is available. Extracorporeal removal may be useful for lowering serum acetaminophen concentrations if N-acetylcysteine is not available, but there are no systematic studies to evaluate the effectiveness of this treatment. Hemodialysis should never be considered an alternative to N-acetylcysteine 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. For patients with a massive overdose and evidence of mitochondrial dysfunction (such as severe lactic acidosis without liver failure), some experts advocate early hemodialysis in addition to acetylcysteine [88]. However, this recommendation is based on expert opinion and there are many reported cases of recovery with acetylcysteine therapy alone. While hemodialysis is a reasonable treatment, it should not be considered a standard therapy for these cases.
Of note, hemodialysis removes N-acetylcysteine as well as acetaminophen, so some toxicologists recommend doubling the standard dose during hemodialysis [89,90]. However, it is not clear that the amount of N-acetylcysteine removed affects clinical outcomes, so increasing the rate is not universally recommended and should not be considered a standard of care. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Urgent indications'.)
PROGNOSIS — The outcome of acetaminophen intoxication is nearly always good if the antidote, N-acetylcysteine (NAC), is administered in a timely fashion. No deaths have been reported in any of the large studies of acetaminophen overdose provided NAC was given within 10 hours of ingestion, regardless of the initial serum acetaminophen concentration [10,11,91]. As an example, one study of 333 consecutive acetaminophen overdose cases found that hepatotoxicity occurred in only 4 percent of patients and mortality was less than 1 percent when NAC was rapidly administered [92]. Thus, when fulminant hepatic failure and death occur from acetaminophen poisoning, they result from a delay in seeking medical attention, recognition of poisoning, or the institution of appropriate therapy.
Studies are underway to discover combinations of biomarkers that can identify early in their presentation those patients at greatest risk for acute liver injury following acetaminophen overdose [93-96]. Further study of such approaches is needed before any can be recommended for clinical use.
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 topic (see "Patient education: Acetaminophen poisoning (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview of management – The management of acetaminophen poisoning is determined by the patient's presenting symptoms, duration of exposure, and serum acetaminophen concentration and aminotransferases (table 1). The risk of developing liver injury in acute ingestions is determined by plotting a timed serum acetaminophen concentration on the modified Rumack-Matthew nomogram (figure 1). The nomogram cannot be applied to patients with chronic supratherapeutic ingestion or when time of ingestion is not known; these patients are typically given antidotal therapy empirically. (See 'Overview of management' above.)
Risk factors for hepatotoxicity following acetaminophen ingestion, the diagnosis of acetaminophen poisoning, and the use of the nomogram are discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation".)
●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 orally administering activated charcoal (1 g/kg, maximum dose 50 g) (Grade 2C). Contraindications to charcoal include gastrointestinal obstruction or altered mental status with an unprotected airway; endotracheal intubation should not be performed solely for the purpose of giving charcoal. (See 'Gastrointestinal decontamination' above.)
●Antidote (N-acetylcysteine) – In a patient with acetaminophen poisoning at significant risk for hepatotoxicity and in a patient with liver injury with exposure to acetaminophen, we recommend treatment with N-acetylcysteine (Grade 1A). The key to effective treatment is to start therapy before the onset of alanine aminotransferase (ALT) elevation. N-acetylcysteine is most effective at preventing hepatic 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 hepatic injury without detectable acetaminophen in serum. (See 'Antidote: acetylcysteine' above.)
•Indications – Patients who should receive N-acetylcysteine include the following (see 'Indications' above):
-Single ingestion with serum acetaminophen concentration drawn at four hours or more that is above the treatment line on the Rumack-Matthews nomogram (figure 1)
-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
-Unknown time of ingestion and a serum acetaminophen concentration >10 mcg/mL (66 micromol/L)
-History of acetaminophen ingestion and any evidence of liver injury
-Presentation for care more than 24 hours after ingestion with liver injury and a history of excessive acetaminophen ingestion or supratherapeutic dosing
•Dosing protocols – N-acetylcysteine may be given intravenously (IV) or orally. IV administration is preferable in patients with vomiting, non-functioning bowel, or pregnancy; those refusing oral administration; and those who present with liver injury. (See 'IV versus oral' above.)
The most commonly used N-acetylcysteine dosing protocols are the 20-hour IV protocol, the simplified 20-hour "two-bag" IV protocol, and the 72-hour oral protocol. Growing evidence suggests the 20-hour "two-bag" IV protocol may have fewer adverse effects. (See '20-hour IV protocol' above and 'Simplified 20-hour (two-bag) IV protocol' above and '72-hour oral protocol' above.)
•Duration of N-acetylcysteine – We tailor N-acetylcysteine therapy to the patient, using clinical endpoints rather than time to determine treatment duration. We routinely measure the ALT prior to stopping N-acetylcysteine and continue treatment if the ALT is abnormal. We repeat the serum acetaminophen concentration prior to stopping N-acetylcysteine to verify that the level is undetectable. (See 'Duration of treatment' above and 'Monitoring during treatment' above.)
•N-acetylcysteine side effects – Between 10 and 20 percent of patients treated with IV N-acetylcysteine develop a nonallergic anaphylactic reaction (NAAR). Management depends upon the severity of the reaction. In a patient who develops only flushing, no intervention is needed and the N-acetylcysteine should be continued. More severe reactions are treated by holding the N-acetylcysteine infusion and administering intramuscular epinephrine, diphenhydramine, and a glucocorticoid. In patients with vomiting from oral N-acetylcysteine treatment, administer ondansetron and repeat the oral dose if vomiting occurred within 60 minutes. (See 'Anaphylaxis (anaphylactoid reaction)' above and 'Vomiting' above.)
●Antidotal treatment in special circumstances – In certain clinical scenarios, it can be difficult to determine the risk associated with exposure to acetaminophen and the appropriate management. An approach to some of the most common and challenging circumstances is provided:
•Time of ingestion is unknown (see 'When time of ingestion is unclear or unknown' above)
•Pregnant patient (see 'Treatment in pregnancy' above)
•Hepatic failure or massive overdose (see 'Treatment in hepatic failure' above and 'Massive overdose' above)
•Ingestion of a sustained-release drug formulation (see "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Ingestion of sustained-release acetaminophen')
•Repeated supratherapeutic ingestion (see "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation after repeated supratherapeutic ingestion')
