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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e >

Chapter 190: AcetaminophenOliver L. Hung; Lewis S. Nelson

INTRODUCTION AND EPIDEMIOLOGY

Acetaminophen (N-acetyl-p-aminophenol or paracetamol) is the most popular over-the-counter analgesicand is one of the most common toxic exposures reported to poison centers. Acetaminophen is available as asole agent or combined with a variety of other medications prepared in many di�erent forms, such as tablets,capsules, gels, and liquids. Poisonings o�en occur because of the erroneous belief that this medication isbenign or because the victim was unaware that acetaminophen was an ingredient in the ingested

preparation.1 The U.S. Acute Liver Failure Study Group found that acetaminophen poisoning was the cause of

acute liver failure in 18% of cases initially judged to be of unknown cause.2 Acetaminophen–opioidcombination products have been implicated in chronic overuse, likely due to an increasing opioidrequirement leading to concomitantly increasing acetaminophen exposure. In response to these safetyconcerns, the U.S. Food and Drug Administration recently limited the prescription acetaminophen–opioidcombination preparation strength to 325 milligrams per dosage unit and now requires a boxed warning to

notify consumers of the potential risk for serious liver toxicity.3

During 2010, the American Association of Poison Control Centers received reports of 66,473 exposures to

acetaminophen–opioid combinations and 73,307 exposures to acetaminophen alone.4 There were 65 deathsattributed to isolated ingestions of acetaminophen combinations and 60 deaths attributed to isolated

acetaminophen ingestions.4 Combining ED, hospital, and poisoning databases, an estimated 450 deathsoccur each year in the United States due to acetaminophen overdose, and approximately 100 of them are

unintentional, primarily due to supratherapeutic dosing of child preparations.5

PHARMACOLOGY AND DOSING

ORAL ACETAMINOPHEN

The recommended maximum total daily dose is 3900 milligrams in adults using 325-milligramacetaminophen (regular strength) and 3000 milligrams when using the 500-milligram acetaminophen (extrastrength) preparation. Adults should not use acetaminophen for more than 10 consecutive days unlessdirected by their physician. For children, the recommended acetaminophen dose is 10 to 15 milligrams/kgevery 4 to 6 hours as needed, with a maximum daily dose of 75 milligrams/kg or five doses in a 24-hour

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period. In 2011, the infant acetaminophen formulation (80 milligrams/0.8 mL concentration) wasdiscontinued to minimize the risk for medication error. All pediatric, both infant and child, acetaminophenliquid preparations are now standardized to a concentration of 160 milligrams/5 mL.

Patients with insu�icient glutathione stores (e.g., alcoholics and acquired immunodeficiency syndromepatients) and patients with induced cytochrome P-450 enzymatic activity (e.g., alcoholics and those takingconcurrent anticonvulsant or antituberculous medications) may be at greater risk for developingacetaminophen-induced hepatotoxicity following overdose (as opposed to therapeutic dosing describedearlier). Although the evidence supporting this risk is not definitive, it may be prudent to reduceacetaminophen dosage for this population. In contrast, children, because of their greater ability tometabolize acetaminophen through hepatic sulfation, may be at decreased risk for developing hepatotoxicity

following a moderate overdose.6,7

A�er ingestion of therapeutic doses, acetaminophen is rapidly absorbed from the GI tract, and peak serumconcentrations are usually achieved within 30 minutes to 2 hours. In an overdose, peak serum concentrationsare usually achieved within 2 hours, but delayed absorption of acetaminophen occurs following overdoses ofpreparations in which acetaminophen is combined with propoxyphene or diphenhydramine, as well as those

with altered-release kinetics such as extended-release preparations.8,9,10,11 In therapeutic amounts,acetaminophen has nearly 100% bioavailability, is approximately 20% bound to serum proteins, has avolume of distribution of around 0.85 L/kg, and has an elimination half-life of approximately 2.5 hours. Thetherapeutic concentration for the antipyretic e�ect of acetaminophen is between 10 and 20 micrograms/mL(66 to 132 micromoles/L), but therapeutic concentrations for analgesia are not established.

Oral acetaminophen appears to be nontoxic when administered following therapeutic dosing guidelines.Both retrospective and prospective studies have yielded inconsistent results concerning the risk of acute liver

injury with repeated use of therapeutic acetaminophen doses.12 The prospective studies, which are bettercontrolled than the retrospective ones, find a slight increase in liver injury but no evidence of increased

hepatic failure or death when using therapeutic acetaminophen doses for sustained periods.13 For alcoholicpatients, no evidence of liver injury was seen when treated with the recommended maximal daily dose of

acetaminophen for 3 consecutive days.14,15

IV ACETAMINOPHEN

An IV acetaminophen formulation was approved by the U.S. Food and Drug Administration in 2010 for adultsand children 2 years of age or older. The recommended dosing of IV acetaminophen for adults or childrenweighing more than 50 kg is 650 milligrams every 4 hours or 1000 milligrams every 6 hours, with a maximumtotal daily dose of 4 grams. For adults or children weighing less than 50 kg, the recommended dosing is 12.5milligrams/kg every 4 hours or 15 milligrams/kg every 6 hours (maximum individual dose of 750 milligrams),with a maximum total daily dose of 75 milligrams/kg or 3750 milligrams. Peak concentrations following IV

administration occur at the end of the 15-minute infusion period.16 Compared to a similar dose of oral

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acetaminophen, IV acetaminophen achieves a 70% greater maximum concentration but provides a similar

total drug exposure.16

ACETAMINOPHEN METABOLISM

In therapeutic amounts, acetaminophen is primarily metabolized by the liver through sulfation (20% to 46%)and glucuronidation (40% to 67%), with <5% undergoing direct renal elimination. Normally, a smallpercentage is also oxidized by the cytochrome P-450 system to a reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). This is quickly detoxified by hepatic glutathione to a nontoxic acetaminophen-mercapturate compound that is renally eliminated (Figure 190-1). A�er acetaminophen overdose, hepaticmetabolism through glucuronidation and sulfation may be saturated, and a larger proportion ofacetaminophen is therefore metabolized by cytochrome P-450 to NAPQI, depleting intracellular glutathione.When hepatic stores of glutathione decrease to <30% of normal, NAPQI binds to other hepaticmacromolecules, and hepatic necrosis ensues. Although the clinical manifestations of acetaminophentoxicity are classically delayed, hepatic injury actually occurs early, within 12 hours of exposure.

FIGURE 190-1.

Acetaminophen metabolism. A. A�er ingestion of therapeutic amounts, predominant metabolism is viaglucuronidation and sulfation. The small amount of N-acetyl-p-benzoquinoneimine (NAPQI) generated isconjugated with glutathione to a nontoxic compound. B. A�er ingestion of large amounts, glucuronidationand sulfation are saturated, and an increased amount of NAPQI is generated. Detoxification of NAPQI to anontoxic compound soon depletes glutathione stores, leaving excess NAPQI to bind to intracellular proteins,causing cell death. APAP = N-acetyl-p-aminophenol (acetaminophen).

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Within the hepatic lobule, cytochrome P-450 is concentrated within hepatocytes surrounding the terminalhepatic vein and is least concentrated within hepatocytes surrounding the portal triad. As a result,acetaminophen-induced hepatic injury develops in the characteristic pattern of centrilobular necrosis.Hepatic injury can be identified by microscopic evidence as well as immunofluorescent staining of NAPQI-hepatic protein adducts within hepatocytes. Observed hepatocyte damage typically progresses with cell lysison the second day a�er an acute toxic exposure, releasing hepatic enzymes, such as transaminases, and

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NAPQI-hepatic protein adducts into the circulation where they are detecTable in the serum. This correspondsgenerally to the development of overt clinical toxicity.

CLINICAL FEATURES OF ACETAMINOPHEN TOXICITY

The initial clinical findings of acetaminophen toxicity are nonspecific and delayed in onset.

FOUR STAGES OF ACETAMINOPHEN TOXICITY

The clinical presentation of human acetaminophen poisoning can be roughly divided into four stages (Table190-1). During the first 24 hours a�er exposure (stage 1), patients o�en have minimal and nonspecificsymptoms of toxicity, such as anorexia, nausea, vomiting, and malaise. Hypokalemia and metabolic acidosismay be seen during the first 24 hours and correlate with a high 4-hour acetaminophen

concentration.17,18,19,20 By days 2 to 3 (stage 2), symptoms seen in stage 1 o�en improve, but clinical signs ofhepatotoxicity may occur, including right upper quadrant abdominal pain and tenderness, with elevatedserum transaminases. Even without treatment, most patients with mild to moderate hepatotoxicity recoverwithout sequelae. However, by days 3 to 4 (stage 3), some patients will progress to fulminant hepatic

failure.21,22 Characteristic stage 3 findings include metabolic acidosis, coagulopathy, renal failure,encephalopathy, and recurrent GI symptoms. Patients who survive the complications of fulminant hepaticfailure begin to recover over the next 2 weeks (stage 4), with complete resolution of hepatic dysfunction insurvivors a�er 1 to 3 months.

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TABLE 190-1

Clinical Stages of Acute Acetaminophen Toxicity

Stage 1 Stage 2 Stage 3 Stage 4

Timing First 24 h Days 2–3 Days 3–4 A�er day 5

Clinical

manifestations

Anorexia

Nausea

Vomiting

Malaise

Improvement in anorexia,

nausea, and vomiting

Abdominal pain

Hepatic tenderness

Recurrence of

anorexia, nausea,

and vomiting

Encephalopathy

Anuria

Jaundice

Clinical

improvement and

recovery (7–8 d)

or

Deterioration to

multi-organ failure

and death

Laboratory

abnormalities

Hypokalemia Elevated serum

transaminases

Elevated bilirubin and

prolonged prothrombin

time if severe

Hepatic failure

Metabolic acidosis

Coagulopathy

Renal failure

Pancreatitis

Improvement and

resolution

or

Continued

deterioration

Acetaminophen may also cause acute, extrahepatic toxic e�ects, presumably because of the presence ofcytochrome P-450 or similar enzymes (e.g., prostaglandin H synthase) in other organs. Ingestion of massivedoses of acetaminophen (e.g., 4-hour acetaminophen concentrations >800 micrograms/mL or >5300micromoles/L) is associated with the altered sensorium and a metabolic acidosis with an elevated lactate

that can occur in the absence of either liver failure or hypotension.23 Renal insu�iciency occurs in 1% to 2%

of patients following acetaminophen overdose, usually a�er hepatic failure is evident.24,25,26 In rare cases,

isolated renal injury, cardiac toxicity, and pancreatitis may occur.27,28

DIAGNOSIS

Acute acetaminophen poisoning is diagnosed by the serum acetaminophen concentration and estimatingthe time since ingestion.

A toxic exposure to acetaminophen is suggested when a patient ≥6 years old ingests (1) >10 grams or 200milligrams/kg as a single ingestion, (2) >10 grams or 200 milligrams/kg over a 24-hour period, or (3) >6 gramsor 150 milligrams/kg per 24-hour period for at least 2 consecutive days. For children <6 years old, ingestion of200 milligrams/kg or more of acetaminophen as a single ingestion or over an 8-hour period, or of 150milligrams/kg per 24-hour period for the preceding 48 hours is considered a toxic exposure. These values are

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empiric and not validated in human trials, but they are widely used as recommendations for emergencyevaluation. Even though a patient's history of the amount ingested may be unreliable, a patient report of >10to 12 grams ingested was associated with a 4-hour acetaminophen concentration above 150 micrograms/mL

(1000 micromoles/L) in 40% to 70% of toxic exposures.29,30

Due to the widespread availability of acetaminophen-containing products, the delayed clinicalmanifestations a�er overdose, and the serious complications of acute toxicity without antidotal therapy,measurement of a serum acetaminophen concentration is recommended for all patients presenting to the ED

with an intentional overdose.31,32 Potentially toxic acetaminophen levels have been seen in ED overdose

patients who denied ingesting acetaminophen.33,34 Empirical testing of all patients with intentionaloverdoses may be cost-e�ective, as the estimated cost of treating a single patient for complications ofacetaminophen-induced hepatotoxicity is judged to outweigh the cost of routine laboratory testing allintentional overdose patients. A qualitative acetaminophen urine screen can also be used to identify

potential acetaminophen overdose patients.35

THE RUMACK-MATTHEW NOMOGRAM

The implication of a measured acetaminophen concentration is determined by plotting the value on the

Rumack-Matthew nomogram (Figure 190-2).36 This nomogram was derived from a retrospective analysis oforal acetaminophen overdose patients and their clinical outcomes. The original nomogram line separatingpossible toxicity from unlikely toxicity was based on a 4-hour acetaminophen concentration of 200micrograms/mL (1300 micromoles/L), but was subsequently modified by moving the line to a 4-houracetaminophen concentration of 150 micrograms/mL (1000 micromoles/L) to increase the safety margin fortreatment decisions. The nomogram only directly applies to an acetaminophen concentration obtained a�era single oral exposure and during the window between 4 hours and 24 hours postingestion. Outcomeprediction using this nomogram cannot be applied to acetaminophen concentrations obtained outside this20-hour window or with chronic or recurrent exposures. Obtaining multiple acetaminophen concentrations

following acute overdose is rarely indicated in the absence of hepatotoxicity.37,38 An initial concentrationbelow the nomogram line may rarely "cross the line" in patients who ingest acetaminophen preparations

known to have prolonged absorption kinetics.11 However, the clinical significance of "crossing the line" inthis fashion is unknown. Similarly, because the nomogram was constructed and verified by using only asingle serum concentration, the clinical implications of a concentration above the line that falls below it onrepeat analysis are unknown.

FIGURE 190-2.

Rumack-Matthew nomogram.

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Based on data obtained before the widespread use of antidotal therapy, patients with serum acetaminophenconcentrations above the original line (4-hour postingestion concentration >200 micrograms/mL or >1300micromoles/L) were observed to have a 60% risk of developing hepatotoxicity (defined as alanine

aminotransferase >1000 IU/mL), a 1% risk of renal failure, and a 5% risk of mortality.39 In addition, patientswith extremely high serum acetaminophen concentrations (above a parallel line coinciding with a 4-hour

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postingestion concentration of 300 micrograms/mL or 2000 micromoles/L) were observed to have a 90% riskof developing hepatotoxicity. The prediction of a safe outcome below the nomogram line corresponding to a4-hour postingestion concentration of 150 micrograms/mL (1000 micromoles/L) was confirmed in patientswho did not receive antidotal therapy; the incidence of hepatotoxicity in patients with acetaminophen

concentrations below this nomogram line was 1%, and all patients recovered without complications.38

A method to determine potential toxicity from IV acetaminophen overdose has not been established.Fortunately, the European experience with IV acetaminophen suggests that these overdoses appear to berare in-hospital occurrences that are likely to occur following an error in calculating the acetaminophen dose

in pediatric patients.40,41,42 However, the available clinical data for evaluating IV acetaminophen overdose

remain limited to several published case reports.42 Because the Rumack-Matthew nomogram was solelyderived from oral acetaminophen overdose patients, strictly applying the nomogram to determine toxicityfollowing IV acetaminophen overdose may not be appropriate at this time.

TREATMENT

GI DECONTAMINATION

Treatment of acetaminophen poisoning consists primarily of the timely use of the antidote acetylcysteine

and supportive care.1,36,37 For most cases of acetaminophen poisoning, adequate GI decontamination

consists of the early administration of activated charcoal orally or through a nasogastric tube.1,43,44 Inducingemesis by administering ipecac syrup is undesirable because it delays the administration of the oral antidote.In addition, more aggressive forms of decontamination, such as gastric lavage or whole-bowel irrigation, areunnecessary because of the rapid GI absorption of acetaminophen and the great success of treatingacetaminophen poisoning with acetylcysteine.

ACETYLCYSTEINE

The mainstay for the prevention or treatment of acetaminophen toxicity is the administration of

acetylcysteine.1,45,46,47 The current "standard" acetylcysteine protocols were developed from primarily

observational trials, and it is not clear if they represent the most e�ective regimens.48

Although its mechanisms of action are not fully understood, acetylcysteine is thought to have two important

beneficial e�ects.47,48 In early acetaminophen poisoning (<8 hours a�er ingestion), acetylcysteine avertstoxicity by preventing the binding of NAPQI to hepatic macromolecules. Acetylcysteine may do this by actingas a glutathione precursor or substitute, or a sulfate precursor, or it may directly reduce NAPQI back toacetaminophen. In established acetaminophen toxicity or >24 hours a�er acetaminophen ingestion,acetylcysteine diminishes hepatic necrosis by acting as an antioxidant, decreasing neutrophil infiltration,improving microcirculatory blood flow, or increasing tissue oxygen delivery and extraction.

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If acetylcysteine is given within 8 hours of an acute acetaminophen ingestion, it is nearly 100% e�ective in

preventing the development of hepatotoxicity.39 The longer the initiation of acetylcysteine therapy is

delayed beyond 8 hours a�er ingestion, the greater the risk of developing hepatotoxicity.49 Even up to 24hours following acetaminophen ingestion, however, acetylcysteine treatment is associated with a lower risk

of hepatotoxicity than historical controls.39

Clinical experience suggests that patients with poor glutathione reserves, such as alcoholics and thechronically ill, have similar excellent clinical outcomes when the standard treatment guidelines are appliedto their care. As such, there is no need to alter the use of the acetaminophen treatment nomogram or modifythe dosing of acetylcysteine for these patients.

The weight of evidence suggests that acetylcysteine therapy is both safe and e�icacious during pregnancyand that the approach to treating a pregnant patient following an acetaminophen overdose should remainthe same. Although an ovine model demonstrated that acetylcysteine is unable to cross the placenta, there

are data in humans establishing that it does.50 Acetylcysteine treatment has never been associated with fetalmalformations in humans, but fetal demise and malformations have been described following delayed

acetylcysteine treatment a�er acetaminophen overdose in first-trimester pregnant women.51

IV Acetylcysteine

IV acetylcysteine has been used to supplant oral administration due to its greater ease of administration,greater patient acceptance, equivalent e�icacy, and shorter duration of treatment for many cases of

acetaminophen poisoning.52,53,54,55 The major limitation of IV acetylcysteine is the occurrence of drug-related anaphylactoid reactions (occurring during the first 2 hours of administration), which in mild cases istreated with diphenhydramine and in severe cases is treated by temporarily slowing/stopping the

acetylcysteine infusion.56 The risk of anaphylactoid reaction from IV acetylcysteine ranges from 4% to

17%.57,58,59,60 Asthmatics appear to have a greater risk of anaphylactoid reactions during IV acetylcysteinetherapy, whereas overdose patients with high acetaminophen concentrations appear to have a lower risk of

developing anaphylactoid reactions.59,60,61,62 Approximately 13% of patients treated with IV acetylcysteine

develop nausea and vomiting.63 Rare complications, including status epilepticus, hemolytic uremicsyndrome, cerebral edema, and death, have been reported following massive overdose of IV

acetylcysteine.64,65,66,67

The standard regimen for IV acetylcysteine utilizes a 20-hour protocol with a loading dose of 150milligrams/kg over 15 minutes to 1 hour, followed by a first maintenance dose of 50 milligrams/kg infusedover 4 hours, and then followed by a second maintenance dose of 100 milligrams/kg infused over 16 hours(Table 190-2). Administering the initial dose over an hour appears to minimize the incidence of drug-relatedadverse e�ects, particularly anaphylactoid responses, although this belief has not been substantiated when

prospectively studied.58 Because the three-phase dosing regimen for IV acetylcysteine may result in dosing

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errors and produce side e�ects due to the initial high infusion rate, alternative dosing regimens are being

explored.68,69,70

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TABLE 190-2

Acetylcysteine Dosing Regimens

Oral IV Adult IV Pediatric (<40 kg)

Preparation Available as

10% and 20%

solutions.

Dilute to 5%

solution for oral

administration.

Available as 20% solution. Available as 20% solution.

Dilute to 2% solution by mixing 50

mL in 450 mL 5% dextrose in water.

Loading

dose

140

milligrams/kg.

150 milligrams/kg in 200 mL 5%

dextrose in water infused over

15–60 min.

150 milligrams/kg (7.5 mL/kg)

infused over 15–60 min.

Maintenance

dose

70

milligrams/kg

every 4 h for 17

doses.

50 milligrams/kg in 500 mL 5%

dextrose in water infused over 4

h (12.5 milligrams/kg per hour).

followed by

100 milligrams/kg in 1000 mL

5% dextrose in water infused

over 16 h (6.25 milligrams/kg per

hour).

50 milligrams/kg (2.5 mL/kg) infused

over 4 h (12.5 milligrams/kg per

hour).

followed by

100 milligrams/kg (5 mL/kg) infused

over 16 h (6.25 milligrams/kg per

hour).

Duration of

therapy

72 h. 20 h. 20 h.

Comments Dilute with

powdered drink

mix, juice, or

soda.

Serve chilled.

Drink through a

straw to reduce

disagreeable

smell.

Monitor for drug-related adverse

e�ects and anaphylactoid

reactions.

Monitor for drug-related adverse

e�ects and anaphylactoid reactions.

500 mL of the 2% solution prepared

as described above is enough to

treat a 33-kg child for the full 20-h

course.

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IV acetylcysteine is commercially available as a 20% solution and requires dilution to a 2% solution for

infusion into a peripheral vein. Both 5% dextrose in water and half-normal saline can be used as diluents.71

Given the volume and hypotonicity of fluid required, children and small adults should be carefully monitored

to avoid fluid overload and hyponatremia during treatment.52

Despite the lack of randomized direct comparisons, IV acetylcysteine is as e�ective and safe as oral therapyfor patients with early acetaminophen poisoning, as compared with retrospective cohorts and historical

controls.54,72,73,74,75 IV acetylcysteine is the route of choice for patients with acetaminophen-induced

fulminant hepatic failure, because oral acetylcysteine has not been adequately studied in this setting.76

There is the potential for delayed hepatic toxicity a�er the completion of acetylcysteine therapy, especially

the 20-hour IV protocol.77

Oral Acetylcysteine

The standard 72-hour oral acetylcysteine regimen used in the United States consists of a loading dose of 140milligrams/kg followed by maintenance doses of 70 milligrams/kg every 4 hours for 17 additional doses(Table 190-2). It may still be appropriate in certain patients, such as those at high risk for anaphylactoidresponses to the IV formulation and asthmatics. The taste is disagreeable, and some patients with persistentnausea and vomiting may require concomitant antiemetics such as ondansetron.

EXTRACORPOREAL ELIMINATION

Case reports describe the use of extracorporeal detoxification in patients presenting late a�er a serious

acetaminophen overdose to both remove the drug and treat the hepatic encephalopathy.78,79 The role ofsuch therapy in the overall management of serious acetaminophen toxicity remains to be defined.

TREATMENT GUIDELINES BASED ON TIME TO ED PRESENTATION

Treatment guidelines for oral acetaminophen poisoning are based on the time to presentation to the ED a�eringestion: <4 hours, between 4 hours and 24 hours, and unknown time or >24 hours before presentation

(Figure 190-3).37 In toxic overdoses, the risk of hepatotoxicity increases with the lag time between ingestion

and initiation of acetylcysteine therapy.49 The optimal outcome with acetylcysteine therapy is seen if it isadministered within 8 hours a�er ingestion, so the optimal "decision-time window" for treatment is between

the 4-hour acetaminophen concentration measurement and 8-hour goal to initiate acetylcysteine.39 Nofurther acetaminophen serum measurements are necessary once the need for acetylcysteine therapy hasbeen determined until the completion of the course of therapy.

FIGURE 190-3.

Treatment guidelines for acetaminophen (APAP) ingestion. All times noted are postingestion. AC =acetylcysteine; ALT = alanine aminotransferase; AMS = altered mental status; AST = aspartateaminotransferase; Cr = creatinine; LFTs = liver function tests; PT = prothrombin time; Rx = treatment.

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Presentation Within 4 Hours of Ingestion

For patients who present to the ED within 4 hours and are likely have a significant acetaminophen overdose,treatment begins with GI decontamination (usually activated charcoal) while awaiting the 4-hourpostingestion acetaminophen concentration. If the clinical laboratory can report an acetaminophenconcentration within 8 hours postingestion, wait for the serum acetaminophen concentration and plot theresult on the nomogram to determine whether acetylcysteine therapy is necessary. If the acetaminophenconcentration will not be available by 8 hours postingestion, empirically initiate acetylcysteine therapywithout waiting for the result. Subsequently, when the acetaminophen concentration is determined, theneed for acetylcysteine therapy can be determined with the use of the nomogram.

Presentation >4 and <24 Hours A�er Ingestion

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For patients who present >4 hours but <24 hours following acetaminophen ingestion, determine the serumacetaminophen concentration as soon as possible. GI decontamination may be performed, particularly forsuspected coingestants, but it may have limited e�ectiveness because of the delay in presentation. If thelaboratory can determine the acetaminophen concentration within 8 hours postingestion, await theacetaminophen concentration and plot the result on the nomogram to determine if acetylcysteine therapy isnecessary. Otherwise, empirically administer acetylcysteine.

Presentation >24 Hours A�er Ingestion or Time of Ingestion Unknown

For patients in whom the time of acetaminophen ingestion remains unknown or is >24 hours or for thosewith suggestive clinical findings of acetaminophen poisoning, a serum acetaminophen concentration andserum transaminase, bilirubin, and prothrombin time tests should be determined. Initiate acetylcysteinetherapy as soon as possible while awaiting laboratory results. In this scenario, a detecTable acetaminophenconcentration (>10 micrograms/mL or >66 micromoles/L) suggests that the patient may be at risk fordeveloping hepatotoxicity. Similarly, elevated serum transaminases suggest the possibility of ongoinghepatic toxicity. Therefore, continued acetylcysteine therapy is indicated if the acetaminophen concentrationis measurable or if the serum transaminases are elevated. If serum acetaminophen concentration is <10micrograms/mL (<66 micromoles/L) and the serum transaminases are not elevated, then acetylcysteine canbe discontinued.

DISPOSITION AND FOLLOW-UP

Many experts recommend rechecking serum acetaminophen and transaminase levels at the completion ofacetylcysteine therapy with continuation of acetylcysteine infusion at the rate of 6.25 milligrams/kg per houruntil the serum acetaminophen concentration is not detecTable or is less than 10 micrograms/mL (66

micromoles/L) and transaminase concentrations are normal or rapidly decreasing.48,55

All patients requiring acetylcysteine therapy should be admitted to the hospital until the completion of thetherapy. In general, admission to a hospital floor bed is adequate unless the coingestant is of concern,hepatotoxicity is severe, or the patient is suicidal and 24-hour direct observation cannot be arranged.Patients who are not at risk for developing acetaminophen-induced hepatotoxicity (e.g., acetaminophenconcentration below the nomogram or unmeasurable acetaminophen concentration with normal hepatictransaminase concentrations) should be observed in the ED for 4 to 6 hours to exclude potentially toxiccoingestants before disposition. Psychiatric evaluation should be considered for patients with intentionalacetaminophen overdoses. Cases of acetaminophen ingestion or toxicity should be reported to the regionalpoison control center for both data collection purposes and assistance with management.

SPECIAL CONSIDERATIONS

FULMINANT HEPATIC FAILURE

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Unfortunately, a small percentage of patients who overdose with acetaminophen will develop fulminanthepatic failure. Acetaminophen poisoning is the number one cause of acute liver failure, accounting for 39%

to 46% of cases in the United States.80,81 The mortality rate for patients with acetaminophen-inducedfulminant hepatic failure without acetylcysteine therapy is estimated to be between 5% and 80%. Mostfatalities occur on days 3 to 5 a�er overdose and are attributed to hepatic complications such as cerebraledema, hemorrhage, shock, acute lung injury, sepsis, and multi-organ failure. Patients who eventuallysurvive fulminant hepatic failure generally begin to show evidence of recovery by days 5 to 7. Survivors willeventually develop complete hepatic regeneration without any persistence of hepatic impairment.

Acetylcysteine treatment decreases the incidence of cerebral edema, reduces vasopressor requirements, and

improves survival in acetaminophen-induced fulminant hepatic failure.76,82 Acetylcysteine also appears tobe beneficial in the treatment of other forms of hepatic failure, including viral hepatitis and alcoholic

cirrhosis.83

Prognostic indicators associated with the highest risk of mortality from acetaminophen-induced fulminanthepatic failure include metabolic acidosis (arterial pH <7.30) despite fluid and hemodynamic resuscitation, ora combination of coagulopathy (prothrombin time >100 seconds), renal insu�iciency (serum creatinine >3.3

milligrams/dL or >292 micromoles/L), and grade III or IV hepatic encephalopathy.84 Other predictors of apoor prognosis include an Acute Physiology and Chronic Health Evaluation II score >15, elevated serumlactate (>26 milligrams/dL or >3.0 mmol/L) a�er fluid resuscitation, and elevated serum phosphate (>3.71

milligrams/dL or >1.2 mmol/L) on the second day a�er ingestion.85,86,87 Multifactor scoring systems have

also been developed to predict hepatotoxicity in single and staggered overdoses.88,89,90

Treatment for acetaminophen-induced fulminant hepatic failure includes acetylcysteine therapy, correctionof coagulopathy and acidosis, monitoring for and aggressive treatment of cerebral edema, and early patientreferral to a liver specialty/transplant center. Unlike the treatment of early acetaminophen toxicity, IVacetylcysteine therapy should be continued past the 20-hour standard regimen until the patient recovers,receives a liver transplant, or dies.

MULTIPLE-DOSE AND EXTENDED-RELEASE ACETAMINOPHEN INGESTIONS

Patients with staggered acetaminophen ingestions and liver injury o�en have delayed presentation to the

hospital and a higher rate of adverse outcomes.91 Multiple closely spaced acetaminophen ingestions andextended-release acetaminophen ingestions represent two unique aspects of acetaminophen poisoning forwhich the Rumack-Matthew nomogram cannot be readily applied because a single time of ingestion does notexist. A conservative approach is to assume that a single ingestion occurred at the earliest possible timestated by the patient, with the acetaminophen concentration plotted on the Rumack-Matthew nomogrambased on this artificial time and treatment decisions made accordingly. For example, if the patient ingestsfive doses of 50 milligrams/kg of acetaminophen over a 4-hour period beginning 8 hours ago, a singleacetaminophen ingestion is assumed to have occurred 8 hours ago, and the serum concentration accordinglyis plotted on the nomogram.

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1. 

2. 

3. 

4. 

5. 

6. 

Extended-release acetaminophen formulations consist of a bilayered tablet containing a 325-milligramimmediate-release outer layer and a 325-milligram slow, continuous-release, highly compressed inner layer.Because there are little clinical data concerning overdose with these preparations, treatment guidelinesremain conservative, and the manufacturer recommends obtaining a second acetaminophen concentration 4to 6 hours a�er the first concentration in those situations in which the first measured concentration (4 to 8

hours postingestion) is elevated but below the nomogram line.92,93 A full course of acetylcysteine therapyshould be instituted (or continued if already started) if the second acetaminophen concentration is above thenomogram line. If the initial concentration is above the nomogram line, standard therapy should beadministered, and there is no need to obtain a second concentration.

IV ACETAMINOPHEN OVERDOSE

Accepted guidelines for treatment of IV acetaminophen overdose do not currently exist in the United States.The local poison center should be contacted for guidance following any suspected IV acetaminophenoverdose.

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USEFUL WEB RESOURCES

The American Association of Poison Control Centers (AAPC)—http://www.aapcc.org/DNN

The American Academy of Clinical Toxicology (AACT)—http://www.clintox.org/index.cfm

The European Association of Poisons Centres and Clinical Toxicologists (EAPCCT)—http://www.eapcct.org

The Asia Pacific Association of Medical Toxicology (APAMT)—http://www.asiatox.org

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The South Asian Clinical Toxicology Research Collaboration (SACTRC)—http://www.sactrc.org

TOXBASE: The primary clinical toxicology database of the National Poisons Information Service—http://www.toxbase.org. (Free access for United Kingdom National Health Service hospital departments andgeneral practices, National Health Service Departments of Public Health and Health Protection Agency Units.Available to hospital emergency departments in Ireland by contract. Available to European poison centerswhose sta� are members of the European Association of Poisons Centres and Clinical Toxicologists. Overseasusers may be allowed access on payment of a yearly subscription, subject to approval of the HealthProtection Agency.)

McNeil Consumer & Specialty Pharmaceuticals Acetaminophen Overdose Management—http://www.tylenolprofessional.com/overdose-management.html

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