Acetaminophen Toxicity Treatment & Management

In addition to antidote therapy, supportive care is essential in acetaminophen toxicity. Immediate assessment of the patient's airway, breathing, and hemodynamic status (ie, ABCs) is critical, while considering and initiating treatment for suspected acetaminophen overdose. As with any ingestion, assessing for other potential life-threatening co-ingestants is very important.

Guidelines from the American Association for the Study of Liver Diseases (AASLD) recommend gastric lavage and administration of activated charcoal (AC) for all patients presenting within 4 hours of ingestion. ^[27] Measure a 4-hour serum acetaminophen concentration to assess the potential risk for hepatotoxicity, using the Rumack-Matthew nomogram.

Patients with acetaminophen concentrations below the “possible” line for hepatotoxicity on the Rumack-Matthew nomogram may be discharged home after they are medically cleared. If the ingestion occurred with intent to do self-harm, a thorough psychosocial, psychological, and/or psychiatric evaluation is indicated before the patient can be discharged safely from the medical care facility.

Admit patients with acetaminophen concentrations above the "possible" line on the Rumack-Matthew nomogram for treatment with N-acetylcysteine (NAC). Treat patients with evidence of liver failure, metabolic acidosis, coagulopathy, and/or encephalopathy in an intensive care unit (ICU). Transfer patients with evidence of clinically significant hepatotoxicity to a medical facility with intensive care support and liver transplant services.

Early administration of NAC after suspected acetaminophen overdose is most essential. ^[35] NAC is nearly 100% hepatoprotective when it is given within 8 hours after an acute acetaminophen ingestion. Guidelines from the American College of Emergency Physicians recommend the use of NAC to treat acute acetaminophen overdose in patients with either possible or probable risk for hepatotoxicity, according to the Rumack-Matthew nomogram, and ideally within 8-10 hours post ingestion. ^[36] AASLD guidelines note that IV or oral NAC nearly completely prevents liver injury if given within 12 hours of ingestion, and recommend administration for patients presenting later as well. ^[27]

Because of the relatively benign nature of NAC, and the risk of adverse effects from acetaminophen toxicity, NAC should be given even if the history is unclear but a potentially toxic acetaminophen ingestion is suspected. NAC should be administered while awaiting an acetaminophen concentration if the patient presents close to, or later than, 8 hours after an acute ingestion, or if the patient is pregnant.

A late presentation should not preclude NAC administration if the history or presentation suggests potential toxicity. ^[37] Failure to administer NAC because of late presentation is considered medically and legally inappropriate.

A common error is to discontinue acetylcysteine after 20-21 hours without reassessing the patient. Recommended criteria for stopping acetylcysteine are as follows ^[3] :

• Acetaminophen concentration < 10 μg/mL
• International normalized ratio < 2.0
• Alanine transaminase and aspartate transaminase levels are normal for the patient or, if elevated, have decreased 25-50% from peak
• The patient is clinically well

Investigational agents for the treatment of acetaminophen toxicity include fomepizole, an alcohol dehydrogenase inhbitor that is approved for use in methanol and ethylene glycol poisoning. Fomepizole inhibits the formation of toxic APAP metabolites and may prevent or reverse mitochondrial toxicity. ^[38] Fomepizole is gaining increased off-label use as an adjunct to NAC in patients with high-risk acetaminophen overdose. ^[39]

Surgical evaluation for possible liver transplantation is indicated for patients who have severe hepatotoxicity and potential to progress to liver failure. Criteria for liver transplantation include the following:

• Metabolic acidosis unresponsive to resuscitaton
• Kidney failure
• Coagulopathy
• Encephalopathy

Oral activated charcoal (AC) avidly adsorbs acetaminophen and may be administered if the patient presents within 1 hour after ingesting a potentially toxic dose. AC should not be administered if the patient is mentally compromised and does not have an intact or protected airway. ^[40]

Oral AC may be of potential benefit longer than 1 hour after the ingestion if the ingestion involves an agent that delays gastric emptying or slows gastrointestinal (GI) motility. In one case series, oral AC administered with NAC 4 hours after ingestion was shown to be effective in reducing the incidence of transaminitis after toxic APAP ingestion. ^[37] However, it is well documented that the effectiveness of oral AC diminishes over time, especially beyond 60 minutes after a toxic ingestion. Administration of NAC is of highest priority in this case.

Oral NAC is the drug of choice for the treatment of acetaminophen overdose. GI decontamination with activated charcoal prior to starting NAC therapy does not change the recommended NAC administration schedule. The FDA-approved dosage regimen for oral NAC starts with a loading dose of 140 mg/kg, followed by 17 doses, each at 70 mg/kg, given every 4 hours. The total duration of the treatment course is 72 hours. ^[26]

A national multicenter study found that oral NAC is safe and effective for as long as 24 hours after a toxic ingestion. ^[41] Treatment with oral NAC effectively prevented hepatotoxicity, regardless of the initial serum acetaminophen level, if it was started within 8 hours of the ingestion. NAC's treatment effectiveness did not depend on whether it was started 0-4 or 4-8 hours after ingestion. ^[41]

Effervescent acetylcysteine tablets for oral use (Cetylev) have been discontinued. However,  the 20% intravenous solution can be adapted for oral administration by diluting it to a 5% solution (50 mg/mL) with fruit juice or carbonated beverage. Unfortunately, the solution has a foul sulfur odor. If the patient vomits within 60 min of administration, repeat the dose.

In 2004, the FDA approved an intravenous (IV) formulation of NAC (Acetadote) for use in adults. In 2006, this FDA approval was modified to include children (patients < 40 kg). IV NAC is the therapeutic formulation used in many hospitals. Additional indications for IV administration of NAC include the following:

• Altered mental status
• GI bleeding and/or obstruction
• A history of caustic ingestion
• Potential acetaminophen toxicity in a pregnant woman
• Inability to tolerate oral NAC because of emesis refractory to proper use of antiemetics

Pharmaceutical guidelines for IV NAC administration depend on the patient's body weight and/or on whether the ingestion is acute or chronic. Continuous IV infusion is recommended for acute ingestion, as follows:

• Loading dose: 150 mg/kg IV; mix in 200 mL of 5% dextrose in water (D5W) and infuse over 1 h
• Dose 2: 50 mg/kg IV in 500 mL D5W over 4 h
• Dose 3: 100 mg/kg IV in 1000 mL D5W over 16 h

In patients who weigh more than 100 kg, limited data suggest a loading dose of 15,000 mg infused IV over 1 hours, then a first maintenance dose of 5,000 mg IV over 4 hours and a second maintenance dose of 10,000 mg over 16 hours.

To reduce the risk of reconstitution and administration errors, simpler IV NAC regimens have been developed. ^[42] One such off-label regimen consists of a loading dose of 150 mg/kg, given over 60 minutes, followed by a maintenance infusion of 15 mg/kg/hr, which is continued until the serum acetaminophen concentration measures less than 10 mg/L and the liver enzyme concentrations remain normal or are trending downward. ^[43]

In a retrospective study in 59 pediatric patients, age 2 months to 18 years, the above-described regimen appeared effective and well tolerated. Treatment durations ranged from 4.25 to 89 hours. Two patients developed hepatoxicity, but none experienced liver failure. The only documented adverse reactions to NAC were minor anaphylactoid reactions, including flushing, facial redness, and itching. These reactions occurred at the end of the loading dose infusion of IV NAC, and responded to IV diphenhydramine or slowing of the infusion rate. ^[43]

A randomized, controlled trial by Bateman et al reported less vomiting, retching, or need for rescue antiemetic treatment at 2 hours with a modified regimen in which IV NAC was given in a dose of 100 mg/kg over 2 hours followed by 200 mg/kg over 10 hours. The study was not powered to detect non-inferiority of the shorter protocol versus the standard approach, but the proportion of patients with a 50% increase in alanine aminotransferase concentrations did not differ between the standard and shorter modified regimen. ^[44]

Intermittent IV infusion may be considered for late-presenting or chronic ingestion. A loading dose of 140 mg/kg IV (diluted in 500 mL D5W) is infused over 1 h. Maintenance doses of 70 mg/kg IV are given every 4 hours for at least 12 doses (dilute each dose in 250 mL of D5W and infuse over a minimum of 1 hour).

Adverse side effects associated with IV administration include flushing, pruritus, and rash (seen in about 15% of patients). Stopping the infusion, administering an antihistamine, and restarting NAC at a slower infusion rate remedy those adverse effects. Bronchospasm and hypotension can occur, but those adverse effects are rare (< 2% of patients). ^[45]

In cases of acetaminophen overdose, early administration of NAC takes priority over GI decontamination with oral activated charcoal (AC). Although AC does bind to NAC, AC adsorbs APAP more avidly. Therefore, any decrease in the bioavailability of oral NAC that may result from the administration of AC is clinically inconsequential. Importantly, AC administration may prevent significant APAP absorption from the GI tract and obviate the need for NAC if AC is administered within 60 minutes of an acute ingestion. ^[46]

Oral NAC administration may be staggered with AC administration in the rare cases where the patient needs multiple doses of AC for the treatment of a co-ingestant. ^[47] Treatment with intravenous NAC is preferable in this situation.

Consider and evaluate for possible co-ingestants and consider the possible effects of decreased GI motility on the absorption of APAP, because the predictive value of the treatment nomogram may be less reliable in these situations. Therefore, in the absence of good data on multidrug ingestions or co-ingestions involving APAP, administer NAC as early as possible and consult the regional poison control center for guidance on a treatment regimen.

If a patient presents 8-24 hours or later after an acute ingestion, initiate NAC therapy immediately and evaluate for laboratory evidence of hepatotoxicity. If evidence of hepatotoxicity exists, continue NAC therapy and consult a regional poison control center for guidance on a treatment regimen.

NAC administration in cases of liver failure has been associated with a decreased incidence of cerebral edema and improved survival. Therefore, NAC therapy should be initiated if concern exists for potential toxicity while awaiting confirmatory laboratory studies.

Because NAC can be beneficial for acetaminophen-induced liver failure when patients present more than 24 hours after a single ingestion, medical toxicologists recommend initiating treatment with NAC in patients who present after 24 hours if an acetaminophen concentration is detected and if hepatic injury is evident from liver function studies.

The beneficial effect of NAC in late treatment, when liver damage has already occurred, suggests that additional local hepatic repair mechanisms may be result from NAC administration. Proposed mechanisms of NAC in this setting include an antioxidant effect, decreased neutrophil accumulation, and improved microcirculatory blood flow supporting increased oxygen delivery to hepatic tissue.

Continuation of NAC therapy is based on the patient's clinical status, detectable serum acetaminophen, and liver function test results. The Rumack-Matthew nomogram is not valid in cases of late presentation and should not be used to guide medical management in these cases.

If a patient presents after multiple ingestions or chronic ingestion of supratherapeutic doses of acetaminophen over hours or days, evaluate for the presence of a persistent serum APAP concentration and laboratory indicators of hepatotoxicity. Begin NAC therapy if the patient has elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels or a measurable serum APAP concentration. Consult a regional poison control center for guidance on a treatment regimen.

Extended-release acetaminophen (Tylenol ER) consists of acetaminophen 325 mg in immediate release (IR) form surrounding a matrix of acetaminophen 325 mg formulated for slow release. Some alteration of the elimination kinetics of this preparation may affect the reliability of the Rumack-Matthew nomogram to predict potential hepatotoxicity and subsequent treatment based on serum APAP concentrations.

Several studies show that the elimination of ER and IR APAP preparations is nearly identical after 4 hours. However, some case reports have documented APAP levels above the potential toxicity and treatment line on the nomogram as late as 11-14 hours after the ingestion of the ER preparation.

Given these findings, recommended management for overdose of ER preparations includes the measurement of 4-, 6-, and 8-hour APAP concentrations. Begin NAC therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin NAC therapy. More prolonged monitoring of APAP levels may be necessary in patients who have food in their stomach or have taken co-ingestants that delay gastric emptying.

Consult a regional poison control center for guidance in the evaluation and optimal treatment regimen for these cases.

Investigational agents for the treatment of acetaminophen toxicity, which have the potential to be used together with NAC or even instead of NAC, include fomepizole, an alcohol dehydrogenase inhbitor that is approved for use in methanol and ethylene glycol poisoning. Fomepizole inhibits the formation of toxic APAP metabolites and may prevent or reverse mitochondrial toxicity. ^[38]

A consensus statement from four clinical toxicology societies (US and Canadian) concluded that the available data on the use of fomepizole for acetaminophen toxicity did not support a standard recommendation. ^[3] Nevertheless, growing numbers of case series describe fomepizole as safe and possibly effective in this setting, and some of these authors recommend considering off-label adjunctive use of fomepizole by experienced clinicians in high-risk APAP overdose. ^{[38, 39, 48]}

Other investigational agents for acetaminophen toxicity include 4-methylpyrazole (a c-jun N-terminal kinase inhibitor) ^[49] and calmangafodipir (a superoxide dismutase mimetic). ^[50] Calmangafodipir is a successor to mangafodipir, a magnetic resonance imaging (MRI) contrast agent that was discovered to have therapeutic properties. ^[51] A Scottish study concluded that the combination of NAC and calmangafodipir is safe and tolerated in patients with acetaminophen overdose, and found evidence that the combination may reduce liver injury biomarkers more than NAC alone. ^[52]

Consultation with a medical toxicologist is recommended for patients who have a complicated or late presentation, liver or kidney dysfunction, or a history of potentially toxic co-ingestants. Medical toxicologists are available through consultation with a regional poison control center. For ingestions seen as a "cry for help" or as an intent to self-harm, psychosocial, psychological and/or psychiatric evaluations are required.

A hepatologist who is directly affiliated with a transplantation medical center should be consulted in the setting of hepatic dysfunction and liver failure. Concurrently, consult a transplantation surgeon in the setting of clinical and laboratory indicators that are highly predictive of death unless urgent transplantation is undertaken (see Prognosis). The United Kingdom King's College Hospital criteria for the determination of the urgent need for transplantation after acetaminophen-induced fulminant liver failure include any one of the following:

• Arterial pH less than 7.3 after fluid resuscitation
• Grade III or IV encephalopathy
• Prothrombin time (PT) greater than 100 seconds
• Serum creatinine level greater than 3.4 mg/dL