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