Acute acetaminophen toxicity in adults

Acute

acetaminophen

toxicity

Yurly Golub / Shutterstock

in adults

Abstract: When taken in the recommended dosage, acetaminophen is a safe and effective

analgesic and antipyretic agent. Its wide availability and easy accessibility make accidental

or intentional overdose, leading to hepatotoxicity, a common occurrence. To prevent morbidity

and mortality, prompt recognition of acetaminophen toxicity is essential. This article covers

the stages of acetaminophen toxicity, recommended treatments, and NP considerations,

including patient education recommendations.

By Scott J. Saccomano, PhD, RN, GNP-BC

ne of the most widely used pharmaceutical analgesic and antipyretic agents available today

is acetaminophen, also known as N-acetyl-paminophenol (APAP) and paracetamol. Acetaminophen is a component of hundreds of over-the-counter

(OTC) and prescription medications used worldwide

and is frequently associated with accidental and intentional overdose. Acetaminophen toxicity has medical,

social, and economic negative effects.1,2

Prompt recognition of acetaminophen toxicity is

necessary to decrease morbidity and mortality. Unfortunately, there are only nonspecific clinical findings

associated with early-stage acetaminophen toxicity,

making early recognition and treatment difficult. This

article reviews the stages of acetaminophen toxicity,

O

recommended treatments, and nursing considerations,

including patient education.

�� Background

Acetaminophen is used in many pharmaceutical preparations because of its easy accessibility and low cost.

It is available in both prescription and OTC formulations and is commonly found in three strengths: regular strength, extra strength, and extended release.

Several forms of acetaminophen are available, including tablets, caplets, capsules, oral-disintegrating tablets,

chewable tablets, oral syrup, liquid, solution and suspension, as well as rectal suppositories.3 In 2011, the

FDA approved an acetaminophen I.V. formulation to

be used in an inpatient setting to treat fever and pain

Keywords: acetaminophen, hepatotoxicity, N-acetylcysteine (NAC), N-acetyl-p-aminophenol (APAP), N-acetyl-p-benzoquinone imine (NAPQI),

paracetamol, Rumack-Matthew nomogram

42 The Nurse Practitioner ? Vol. 44, No. 11

Copyright ? 2019 Wolters Kluwer Health, Inc. All rights reserved.



Acute acetaminophen toxicity in adults

in children 2 years of age and older, and adults. It

should be noted that this article concentrates on acute

single oral consumption of acetaminophen; however,

hepatotoxicity has been found as a result of medication

errors with I.V. acetaminophen.2 Additionally, acetaminophen is used in many combination products,

such as combined with an opioid, including codeine

and oxycodone.

When used in the recommended therapeutic doses,

acetaminophen has an excellent safety profile; however,

with misuse and overdose, hepatotoxicity can occur. As

an OTC medication, acetaminophen continues to be

perceived as a benign medication. It should be noted

that acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute liver failure in

the US.2 This misconception helps to explain the high

rate of acetaminophen toxicity.1 (See Acetaminophen

toxicity statistics.) Acetaminophen toxicity is a major

cause of acute liver injury. Perhaps more significantly,

acetaminophen toxicity is the most common cause of

acute liver failure (ALF) and is reported as the primary

reason for emergency liver transplantation in the US.

It is estimated that almost half of the patients with ALF

are related to accidental acetaminophen overdose, with

63% of these involving acetaminophen combination

products.6

�� Pharmacokinetics

An active metabolite of phenacetin and phenazopyridine

HCl, acetaminophen exhibits substantial antipyretic

activity and some analgesic activity. In comparison to

nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen exhibits minimal anti-inflammatory activity.

Acetaminophen is available in both immediate-release

and sustained-release formulations. Historically, the

maximum daily adult dose of acetaminophen was 4 g.

In 2012, the FDA suggested, but did not mandate, a maximum daily dose for adults of 3 g.

When ingested, acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. Thirty

to sixty minutes post ingestion, acetaminophen reaches peak concentration with a half-life of 2 to 3 hours.

Therapeutic levels of extended-release acetaminophen

are maintained at 10 mcg/mL to 20 mcg/mL for approximately 6 to 8 hours. 7 Acetaminophen is not

strongly bound to plasma proteins.8,9

At therapeutic doses, 90% of acetaminophen is metabolized in the liver and is converted into nontoxic

glucuronide and sulfate conjugates that are subsequently



Acetaminophen toxicity statistics

? In 2017, the American Association of Poison Control

Centers reported more than 69,000 individual exposures involving acetaminophen alone, and over 39,000

individual exposures to acetaminophen in combination

with other drugs.4

? In the US, acetaminophen toxicity accounts for approximately 82,000 ED visits annually and almost

30% of these admissions can be attributed to acute

acetaminophen overdose. Additionally, approximately

50% of acute liver failure/injury cases are related to

acetaminophen toxicity.5

excreted by the kidneys. A smaller amount��less than

4%��of acetaminophen is excreted in the urine unchanged. Similar amounts of acetaminophen are also

excreted in urine through a complex conversion process;

the cytochrome P-450 enzyme metabolizes a small

amount of acetaminophen producing a toxic compound, N-acetyl-p-benzoquinone imine (NAPQI).7

NAPQI has a short half-life and conjugates with hepatic

glutathione, which converts it to APAP-cysteine and

APAP-mercapturate, both of which are readily excreted

in urine.

�� Toxicity

Acetaminophen toxicity occurs during a period of up

to 8 hours after ingestion.10 Toxicity in an adult is unlikely to result from a single dose of 7.5 to 10 g. Toxicity

is likely to occur with single ingestions greater than

250 mg/kg or those greater than 12 g over a 24-hour

period. Virtually all patients who ingest doses in excess

of 350 mg/kg develop severe liver toxicity (defined as

peak aspartate aminotransferase [AST] or alanine

aminotransferase [ALT] levels greater than 1,000 IU/L)

unless appropriately treated.7

Ingestion of toxic amounts of acetaminophen overloads the normal glucuronide and sulfate metabolic

pathways. Increased glucuronide rapidly depletes

any available glutathione resulting in unbound

NAPQI binding to hepatocytes and causing cellular

necrosis.10-12 (See Acetaminophen toxicity metabolic

pathways.)

�� Clinical manifestations

Nonspecific signs and symptoms in the early stages of

acetaminophen toxicity make early recognition challenging. This accounts for a possible delay in treatment

and high morbidity and mortality statistics. Most

The Nurse Practitioner ? November 2019

Copyright ? 2019 Wolters Kluwer Health, Inc. All rights reserved.

43

Acute acetaminophen toxicity in adults

patients who overdose on acetaminophen will initially

be asymptomatic, as clinical signs and symptoms of

end-organ toxicity do not usually manifest until 24 to

48 hours after an acute ingestion. As a result, to identify

a patient who may be at risk for hepatotoxicity, NPs

need to determine the time(s) of ingestion, the quantity,

and the formulation of acetaminophen ingested.2

Acetaminophen toxicity is characterized by four

stages, defined in time after ingestion:13

? Stage I: the first 24 hours post ingestion. This is the

most critical stage and is characterized by vague

findings of nausea, malaise, vomiting, pallor, lethargy, anorexia, and diaphoresis.13,14 Some patients

remain asymptomatic during this stage and lab

studies are typically normal.7

? Stage II: 24 to 72 hours post ingestion. Initially, stage

I signs and symptoms resolve and patients appear to

improve clinically while hepatic aminotransferases

(AST, ALT) increase. As stage II progresses, patients

develop right upper quadrant pain, with hepatomegaly and liver tenderness. Elevations of serum

prothrombin time (PT) and total bilirubin levels, and

renal function abnormalities may develop.7

? Stage III: 72 to 96 hours post ingestion. During

this stage, signs and symptoms become more

Acetaminophen toxicity metabolic pathways

The intermediate metabolite NAPQI is responsible for

hepatic injury associated with acetaminophen toxicity;

it is ordinarily detoxified by the addition of sulfhydryl

groups. Glutathione acts as a sulfhydryl group donor,

but in massive overdose, it is not present in sufficient

quantity to protect the liver. N-acetylcysteine acts as a

sulfhydryl group donor to detoxify NAPQI when glutathione is depleted.

Acetaminophen

Acetaminophen sulfate

Acetaminophen glucuronide

Cytochrome P-450

mixed function

oxidase

Toxic intermediate metabolites

(NAPQI)

Glutathione

Overdose

N-acetylcysteine

Mercapturic acid

Hepatocellular damage

Source: Shaffner DH, Nichols DG. Rogers�� Textbook of Pediatric Intensive

Care. Philadelphia, PA: Wolters Kluwer Health; 2015.

pronounced. Systemic findings, including malaise,

nausea, and vomiting, return and can be accompanied by central nervous system involvement, such as

confusion, somnolence, and possible coma. Jaundice

as well as pancreatic, renal, and cardiac damage may

be present.9,15 Peak abnormalities of serum AST,

ALT, bilirubin, and PT are often detected, with AST

levels elevated to 1,000 U/L and may rise as high as

30,000 U/L (normal, 10 to 40 U/L) in severe acetaminophen toxicity. Serum PT levels greater than

2.2 times control (normal, 11.0 to 13.0 seconds), and

total bilirubin levels greater than 4 mg/dL (normal,

0.3 to 1.0 mg/dL) indicate severe hepatotoxicity.16,17

? Stage IV: 4 days to 2 weeks post ingestion (recovery

phase). Stage IV represents the period of hepatic

damage resolution. During this stage, clinical signs,

symptoms, and lab values return to near baseline

or baseline and permanent damage occurs infrequently; this suggests that the patient has received

treatment at some point during Stage II.13

�� Diagnosis

Screening should include the overall doses of acetaminophen per day that are greater than 4 g per dose or 10

g per day. Screening should also include hepatotoxicity

risk factors such as alcoholism; drug therapies such as

isoniazid; fever; hepatitis (viral or toxic); vascular insult;

chronic liver diseases; and reduced glutathione

stores.1,6,18,19 A patient history is very important for diagnosis. The preliminary step in patients with suspected

acetaminophen toxicity is to obtain a history of drug

ingestion and use. Ask questions such as: Is there a history or pattern of acetaminophen use? (single or repeated doses) What was the time of ingestion? What

was the intent of ingestion? (suicide or not) Are there

any coingestants administered with acetaminophen?

Finally, evaluate for any comorbidities such as alcohol

use, Gilbert syndrome, recent fasting, or anticonvulsant

therapy as these can predispose one to hepatic injury.7

In all four stages, key diagnostic studies include:2,13,16,20

? serum acetaminophen concentration

? baseline liver function tests (AST, ALT, total

bilirubin)

? basic chemistry panel (electrolytes, blood urea

nitrogen, creatinine)

? complete blood cell count

? PT/international normalized ratio

? serum amylase

? urinalysis.

44 The Nurse Practitioner ? Vol. 44, No. 11

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Acute acetaminophen toxicity in adults

�� Rumack-Matthew

�� Treatment

nomogram

The goals of treatment include:

When acute acetaminophen ingestion has been con- ? supporting airway, breathing, and circulation as

firmed, the Rumack-Matthew nomogram is the primanecessary

ry treatment guide. (See Rumack-Matthew nomogram ? preventing absorption of ingested acetaminophen

for acetaminophen poisoning.) The Rumack-Matthew

from the gastrointestinal tract

nomogram summarizes the relationship between ? administering the antidote N-acetylcysteine (NAC).

plasma acetaminophen concentration (in microgram/

The treatment of choice for acetaminophen overmL or micromole/L), the time after drug ingestion, dose is the administration of the antidote NAC, which

and the risk of hepatotoxicity. The thick diagonal line is given to all patients at significant risk for hepatotoxof possible hepatotoxicity represents a 25% likeli- icity. NAC prevents the formation of and the buildup

hood of hepatotoxicity. A relatively low level (such as of NAPQI through multiple routes. It prevents binding

10 microgram/mL) is safe soon

after ingestion but associated Rumack-Matthew nomogram for acetaminophen poisoning

with appreciable risk at 24 hours

since it reflects a high initial load Acetaminophen concentration plotted versus time after exposure to predict

potential toxicity and antidote use.

that has now distributed into the

tissues.21

The nomogram should only

be used after a single acute acetaminophen ingestion. The line

indicates the level at which toxicity is possible after acetaminophen overdose. The serum

acetaminophen concentration

is the basis for diagnosis and

treatment. A serum acetaminophen level should be obtained

4 or more hours after an ingestion to ensure that a peak level

has occurred. Patients who

ingest extended-release preparations should have a second

level drawn 4 hours after the

first level to assess for an additional rise in serum concentration. The level should be plotted in relationship to the time

of ingestion to determine the

likelihood of toxicity and the

need for treatment. Use caution in assessing the reliability

of the time of ingestion. This

nomogram cannot be used for

ingestions that occurred more

than 24 hours prior to presentation, repeated supratherapeutic

oral ingestions, or iatrogenic Source: Kline-Tilford AM, Haut C. Lippincott Certification Review: Pediatric Acute Care Nurse Practitioner.

Philadelphia, PA: Wolters Kluwer; 2015.

I.V. overdose.21



The Nurse Practitioner ? November 2019

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45

Acute acetaminophen toxicity in adults

of NAPQI to hepatic macromolecules, acts as a substitute for glutathione, is a precursor for sulfate, and

reduces NAPQI back to acetaminophen. Because of

the conjugation process of NAC and NAPQI, cysteine

and mercapturic acid are produced, which are nontoxic equivalents excreted in the urine.1,16,22

In addition to its effects for acetaminophen toxicity, NAC possesses anti-inflammatory, antioxidant,

and vasodilating properties that will improve microcirculatory blood flow and oxygen delivery to

tissues.23 Because of its vasodilating effects, NAC is

the selected treatment when hepatotoxicity is present, as its actions can potentially decrease morbidity

and mortality. NAC therapy can also be initiated

well past the 8- to 10-hour initial window recommended because the therapy remains effective for a

maximum of 36 hours after ingestion. NAC therapy

is not recommended if acetaminophen levels are not

at the toxic level.13,24

In the US, both oral and I.V. forms of NAC are available. When treated with NAC, approximately 1% of

patients will develop nausea and vomiting. Useful antiemetics are 5-HT3 receptor antagonists, such as ondansetron, that can be administered to relieve nausea and

vomiting. If vomiting occurs within 1 hour of the initial

oral loading dose, the route of administration should be

changed to I.V.25 (See Acetaminophen safety resources.)

Adverse reactions of oral NAC include stomatitis,

nausea, vomiting, fever, rhinorrhea, drowsiness, clamminess, chest tightness, and bronchoconstriction.

Clinically overt acetylcysteine-induced bronchospasm

occurs infrequently and unpredictably even in patients

with asthmatic bronchitis or bronchitis complicating

bronchial asthma.26 The most frequently reported adverse reactions to I.V. acetylcysteine include rash, urticaria, and pruritus, and they most commonly occur

during the initial loading dose of acetylcysteine.27 After

stopping the infusion and administering an antihistamine, the infusion can usually be resumed at a slower

Acetaminophen safety resources

For more information on the use and safe administration

of acetaminophen, visit:

? Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htm.

?

Common-Medicines-with-Acetaminophen-Know-YourDose.pdf.

rate.13,25 Patients treated with I.V. NAC can develop

allergic or anaphylactic reactions. Treatment of these

adverse reactions depends on the severity of the symptoms. Approximately 10% to 20% of patients can develop severe reactions, such as respiratory difficulty;

the infusion should be stopped and the clinician should

contact a medical toxicologist or the poison control

center.21

Other approaches to treatment include gastric

decontamination using activated charcoal (AC).

AC absorbs toxic substances (acetaminophen) on

its surface, rendering it nonabsorbable from the

gastrointestinal tract. AC should be administered

orally within 1 to 2 hours of ingestion, unless contraindicated, as its effectiveness diminishes over

time, especially with a toxic dose.2,16

�� NP considerations

NPs play an important role in preventing morbidity

and mortality caused by acetaminophen toxicity. Obtaining a comprehensive health history with a focus

on medication reconciliation is extremely important.

It is also important to obtain an accurate history of the

time(s) of acetaminophen ingestion, the quantity, and

the formulation of acetaminophen ingested. The history should also include any coingestants, such as salicylates or medications that may delay gastric emptying and acetaminophen absorption (anticholinergic

drugs or opioids).2 Be alert to any medications that

contain acetaminophen, especially in combination

with opioids. The history should also include ethanol

ingestion, tobacco use, and any conditions that reduce

glutathione stores and increase hepatotoxicity risk,

such as older age, alcohol use disorder, underlying

hepatic or renal disease, or compromised nutritional

status.2

Toxic levels of acetaminophen can also impair

renal function; monitor renal function results, as well

as accurate intake and output.2 Acetaminophen effects

can mask infection and can cause drug-induced

antibody-mediated thrombocytopenia; it is essential

to monitor for signs and symptoms of infection as

well as the patient��s platelet count.28,29 Acetaminophen

is known to decrease insulin needs, but it is necessary

to monitor blood glucose because acetaminophen can

falsely elevate glucose monitor readings by a large

margin.2,30

Patient education should include how to read medication labels, including OTC product labels, and follow

46 The Nurse Practitioner ? Vol. 44, No. 11

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