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ACETAMINOPHEN
POISONING:
A COMPREHENSIVE
REVIEW
DANA BARTLETT, BSN, MSN, MA, CSPI
Dana Bartlett is a professional nurse and author.
His clinical experience includes 16 years of ICU
and ER experience and over 20 years of as a
poison control center information specialist. Dana
has published numerous CE and journal articles,
written
NCLEX
material,
written
textbook
chapters, and done editing and reviewing for
publishers such as Elsevire, Lippincott, and Thieme. He has written widely about
toxicology and was recently named a contributing editor, toxicology section, for
Critical Care Nurse journal. He is currently employed at the Connecticut Poison
Control Center and is actively involved in lecturing and mentoring nurses, emergency
medical residents and pharmacy students.
ABSTRACT
Acetaminophen toxicity is the most common cause of acute liver
failure in the United States, Europe, and Australia. Liver damage after
acetaminophen overdose is common but liver failure and death are
rare. There is a highly effective antidote available, N-acetylcysteine,
and if treated promptly, patient recovery and survival from
acetaminophen toxic overdose is almost assured.
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Policy Statement
This activity has been planned and implemented in accordance with
the policies of NurseCe4Less.com and the continuing nursing education
requirements of the American Nurses Credentialing Center's
Commission on Accreditation for registered nurses. It is the policy of
NurseCe4Less.com to ensure objectivity, transparency, and best
practice in clinical education for all continuing nursing education (CNE)
activities.
Continuing Education Credit Designation
This educational activity is credited for 3.5 hours. Nurses may only
claim credit commensurate with the credit awarded for completion of
this course activity. Pharmacology content is 1 hour.
Statement of Learning Need
In toxic overdosing, acetaminophen can cause liver damage and
failure, and can lead to costly medical treatment and transplantation.
Health teams need to understand the basis for diagnosis and
treatment of acetaminophen overdose, which includes clinical
manifestations of toxicity and use of the Rumack-Matthew nomogram
to interpret acetaminophen plasma concentrations.
Course Purpose
To help clinicians identify patients at risk of liver damage and failure
due to acetaminophen toxic overdose and to know the appropriate
treatment to support full recovery and survival.
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Target Audience
Advanced Practice Registered Nurses and Registered Nurses
(Interdisciplinary Health Team Members, including Vocational Nurses
and Medical Assistants may obtain a Certificate of Completion)
Course Author & Planning Team Conflict of Interest Disclosures
Dana Bartlett, BSN, MSN, MA, CSPI, William S. Cook, PhD,
Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC
all have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Please take time to complete a self-assessment of knowledge,
on page 4, sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge
learned will be provided at the end of the course.
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1. Most acetaminophen is changed to harmless metabolites by
a.
b.
c.
d.
conjugation.
metabolism by cytochrome P-450 enzymes.
elimination in the urine.
elimination in the stool.
2. Acetaminophen is converted to a toxic metabolite by
a.
b.
c.
d.
conjugation.
metabolism by cytochrome P-450 enzymes.
elimination in the urine.
elimination in the stool.
3. The toxic dose of acetaminophen is:
a.
b.
c.
d.
≥
≥
≥
≥
10 grams or 200 mg/kg.
7.5 grams or 150 mg/kg.
15 grams or 150 mg/kg.
20 grams 04 300 mg/kg.
4. The basis of acetaminophen poisoning is
a. rate/amount of NAPQI formation greater than glutathione
availability.
b. rate/formation of conjugation is greater than glutathione
availability.
c. decrease in glutathione effectiveness.
d. increased sensitivity of the liver to the drug.
5. One organ, other than the liver, that is affected by an
overdose of acetaminophen is
a.
b.
c.
d.
the
the
the
the
lungs.
small bowel.
kidneys.
thyroid.
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Introduction
The American Association of Poison Control Centers (AAPCC) publishes
annual reports documenting the number and nature of drug
overdoses. The AAPCC data from 2014 (the latest available data) was
similar to the data from almost every previous year. Acetaminophen
was one of the most common drugs taken in an overdose with intent
to cause self-harm, accounting for almost 17% of the fatalities,1 and
therapeutic errors with acetaminophen that caused liver damage were
quite common.1 Acetaminophen (the drug is called paracetamol in
Europe) overdose is now the most common cause of acute liver failure
in the United States, Europe, and Australia.2
Most patients who have taken an overdose of acetaminophen and who
are treated correctly and promptly will survive with no permanent
damage; in more than 90% of these cases, the patients will recover
completely. However, there are hundreds of deaths every year in the
United States caused by acetaminophen poisoning, and the mortality
rates for patients with acute liver failure caused by acetaminophen
overdose can be as high as 28%.3
Acetaminophen: Pharmacology
Acetaminophen is an over-thecounter analgesic used for mild to
moderate pain and as antipyretic; it
appears to have minimal antiinflammatory action. Although it is
!
The name acetaminophen,
and the brand name
Tylenol®, are both derived
from combinations of the
letters of the chemical
term for acetaminophen,
N-acetyl-p-aminophenol.!
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not completely understood how acetaminophen works, it is thought to
produce its analgesic/antipyretic effects by the following mechanisms
of action.4,5
•
It inhibits synthesis of prostaglandins in the central nervous
system; prostaglandins are hormone-like substances involved in
sensitizing some neurons to pain and mediating many
physiological functions, i.e., the inflammatory response.
•
It blocks pain impulse generation peripherally.
•
It acts as an antipyretic by inhibiting the heat-regulating center
of the hypothalamus.
In therapeutic doses, the drug is rapidly and completely absorbed from
the gastrointestinal tract. The serum concentration of an oral dose
peaks within 10 to 60 minutes, the onset of action is within one hour,
and the therapeutic concentration is 10 to 20 mcg/ml.4,5 First pass
metabolism removes approximately 25% of a therapeutic dose.
After absorption, approximately 90% of
acetaminophen undergoes hepatic
glucuronide and sulfate conjugation; the
acetaminophen/sulfate and
Conjugation is a
process by which the
acetaminophen is
bound to glucuronic
acid and sulfate
acetaminophen/glucuronic acid complexes
are harmless and are eliminated in the urine.
A very small amount of the drug is excreted unchanged in the urine,
and the remainder (approximately 2% or less) is metabolized by
several enzymes of the cytochrome P450 enzyme system to N-acetylbenzoquinoneimine (NAPQI). This metabolite is toxic to the liver and
the kidneys.
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However, if acetaminophen is ingested
in therapeutic doses, NAPQI is
combined with glutathione (also
known as GSH) and the NAPQIglutathione complex is converted to
Glutathione is a tripeptide
synthesized in the liver and
in other organs, which acts
as an antioxidant and is a
very important part of the
body’s defense system
against free radicals and
oxidative stress.
non-toxic mercaptine or cysteine, both of which are excreted in the
urine and bile.4,5
Dosing, Available Forms, Contraindications, Side Effects, and
Drug-Drug Interactions
Currently the adult dose of acetaminophen is 325 mg to 650 mg, every
4 to 6 hours, and the total amount for 24 hours should not exceed 4
grams. The dose for children and adolescents > 12 years of age is the
same as the adult dose. Children < 12 years of age, the dose is 10-15
mg/kg, every 4-6 hours, and the 24-hour total should not exceed 2.6
grams.
Acetaminophen is available in oral tablets, caplets, capsules, and gel
tabs, oral suspensions and solutions, rectal suppositories, and in an
intravenous (IV) formulation. Acetaminophen is frequently added to
over-the-counter cold and cough and allergy relief products,
Triaminic), over-the-counter medications used for sleep, and over-thecounter analgesics. Opioid analgesics and acetaminophen are
frequently combined, as well. Acetaminophen is contraindicated if the
patient has hypersensitivity to the drug or if the patient has severe
hepatic impairment or severe active liver disease. It should be used
cautiously if the patient has G6PD deficiency, consumes ≥ three
alcoholic drinks a day, or has renal impairment. The oral form of
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acetaminophen is considered safe to use during pregnancy.
Acetaminophen does enter breast milk, and the drug should be used
cautiously by nursing mothers.
The side effects of acetaminophen are minimal. Common side effects
are mild and temporary gastrointestinal distress and rash. Rash is
more common in children.
Drug interactions between acetaminophen and commonly used
medications include:
•
Aripiprazole: The serum concentration of aripiprazole may be
increased.
•
Barbiturates: The metabolism of acetaminophen may be
increased, decreasing the effectiveness of acetaminophen and
increasing the risk of liver damage.
•
Carbamazepine: The metabolism of acetaminophen may be
increased, decreasing the effectiveness of acetaminophen.
•
Isoniazid: May enhance the toxic effects of acetaminophen.
•
Peginterferon Alfa-2b: May decrease the serum concentration of
CYP2D6 substrates.
•
Prilocaine: Acetaminophen and prilocaine used together increase
the risk of developing methemoglobinemia.
•
Probenecid: The serum concentration of acetaminophen may be
increased.
•
Warfarin: Acetaminophen may enhance the anticoagulant effect
of warfarin if the daily dose of acetaminophen is >1.3 grams for
>1 week.
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Acetaminophen Toxicity
The toxic dose of acetaminophen was for many years considered to be
≥150 mg/kg or ≥7.5 grams, whichever was lower.5 These figures are
almost certainly very conservative and the toxic dose may be 10 to 12
grams or more for an adult and >250 mg/kg for children.5 The
American Association of Poison Control Centers (AAPCC), in an
evidence-based consensus, decided that the toxic dose of
acetaminophen for adults is ≥10 grams or 200 mg/kg, whichever is
lower, and >200 mg/kg for children.6
The Rumack-Matthew nomogram was developed to ascertain whether
a patient who ingested acetaminophen would have liver toxicity.
Serum concentration levels of acetaminophen are plotted on a graph
against the time that has elapsed since the drug was ingestion.
In recent years, concern has been raised that the maximum 24-hour
therapeutic amount of acetaminophen and the amount considered to
be potentially toxic are both too low. Poison control centers in the
United Kingdom (UK) now use ≥75 mg/kg as the toxic dose, and it
was decided in the UK that the treatment line on the Rumack-Matthew
nomogram (the nomogram will be discussed in more depth later)
should be lowered from 200 mcg/mL to 100 mcg/mL.7 The benefits of
this approach are uncertain,7,8 and, in the United States the dose that
is considered to be toxic and the treatment line on the RumackMatthew nomogram have not been changed.
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Is the Therapeutic Dose Toxic?
There has been long-term concern that the 4-gram maximum
recommended daily dose of acetaminophen may be too high and
potentially harmful. In 2011, the Food and Drug Administration (FDA)
asked manufacturers to limit the amount of acetaminophen to 325 mg
in prescription combination drugs by January 2014, but no request was
made to lower the 4-gram limit. In April 2014, the FDA recommended
that a pharmacist who receives a prescription for a combination
product with more than acetaminophen 325 mg per dosage unit should
contact the prescriber to determine if a product with a lower dose of
acetaminophen would be acceptable.
McNeil Pharmaceuticals, the manufacturer of the Tylenol® brand, has
decreased the 24-hour maximum recommended dose of its
acetaminophen-containing products to 3000 mg of the 500 mg
preparations and 3250 mg of the 325 mg preparations. However,
other manufacturers of acetaminophen products continue to use 4
grams as the limit and this is the maximum dose that will be found in
pharmaceutical references.
There is evidence that 4 grams of acetaminophen can elevate the
serum transaminases in both healthy individuals and in people who
might be at risk for liver damage.9-19 These systematic reviews, metaanalyses, and prospective studies have shown that a daily 4 gram dose
of acetaminophen can cause abnormally high serum transaminases,
however: 1) The transaminase levels were not excessively high;
2) The transaminase levels were not excessively high; 3) The
transaminase levels returned to normal in almost every case; 4) There
was no association between elevation of transaminase levels in these
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cases and not associated with death, liver failure, or permanent liver
damage; 5) These findings were derived from studies that in some
cases examined over 30,000 patients, 6) Some patients in the case
reports had risk factors which have been associated with an increased
susceptibility to liver damage from acetaminophen; and, 7) Many
people who received a 4 gram daily dose or daily doses of 8 to 12
grams did not develop elevated transaminases.
The studies are not conclusive, and there could certainly be outliers of
individuals that could be harmed by ingesting 4 grams of
acetaminophen in a 24-hour period. But available evidence suggests
that 4 grams of acetaminophen ingested over a 24-hour period will not
cause serious or permanent harm to the liver and in most cases, will
cause no damage at all.5 It should be noted, however, that an
elevation of serum transaminases that is temporally related to
ingestion of acetaminophen is concerning. But serum transaminase
levels are influenced by age, body mass index, gender, race, and the
time of day at which they are measured. It has also been shown that
serum transaminase levels of both healthy individuals and people with
stable liver disease can vary by 10-30% from day to day.16 Someone
whose serum transaminase is typically near the top level of normal
may have periods in which the level is abnormally high.
The Toxic Process Of Acetaminophen Poisoning
And Liver Damage
When acetaminophen is taken in therapeutic amounts, the pathways of
glucuronidation and sulfation effectively metabolize 90% of the dose
and there are sufficient stores of glutathione available in the liver to
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effectively bind and neutralize the NAPQI. But when acetaminophen is
taken in toxic amounts, the conjugation pathways become saturated,
and a larger proportion of the ingested dose is metabolized to NAPQI.
The rate of formation of NAPQI and the amount of NAPQI produced
depletes the liver’s glutathione stores and outstrips the liver’s ability to
make more glutathione. When hepatic glutathione stores have been
depleted to approximately 70% of pre-exposure levels - a process that
takes approximately about 8 hours - NAPQI covalently binds to
hepatocytes and liver damage will occur.3,5
The precise mechanisms by which
NAPQI damages the hepatocytes are
not known. It may cause oxidative
stress, it may cause mitochondrial
dysfunction, or it may be that high
amounts of NAPQI can alter the
The primary effect of
acetaminophen poisoning is
liver damage. But the renal
parenchyma can also from
NAPQI and kidney injury is a
very unusual but well
documented effect of
acetaminophen poisoning.
immune function of the liver, producing
an abnormal immune response with inflammation that can irreversibly
damage hepatocytes.2,5,20
Despite the uncertainty as to exactly how an acetaminophen overdose
and excess NAPQI can cause liver damage, there is no doubt that
acetaminophen poisoning and liver damage occur when the rate of
formation of NAPQI outstrips the liver’s ability to make glutathione and
the amount of NAPQI formed is greater than the amount of available
glutathione stores in the liver. That is the basis of acetaminophen
poisoning.
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Clinical Presentation Of Acetaminophen Overdose
The clinical presentation of acetaminophen poisoning has traditionally
been described as having four phases.5,20,21 There can be individual
variation in the presentation but in most cases, these four phases are
easily identifiable and follow each other predictably.
Phase I
This phase occurs from 0 to 24 hours post-ingestion. Nausea,
vomiting, abdominal pain, and anorexia are commonly observed but
occasionally the patient may be asymptomatic and there are no signs
or symptoms that are specific to acetaminophen poisoning. There is
usually no laboratory evidence of liver damage. However, the serum
transaminases can begin to rise as early as eight hours and as late as
36 hours after ingestion,22-24
Phase II
This phase occurs from 24 hours to 72
hours post-ingestion. The
gastrointestinal signs and symptoms
typically diminish or disappear, but some
patients develop right upper quadrant
pain. Serum aspartate aminotranferase
(AST) and alanine aminotransferase
(ALT) (together, the AST and ALT are
AST and ALT are
enzymes contained in
hepatocytes. If the AST
and ALT are elevated,
that indicates liver
damage. The INR and the
PT are measures of the
liver’s ability to produce
clotting factors; the INR
provides information
about the liver’s
functional ability.
commonly called liver function tests or
LFTs) may begin to rise above normal levels; levels at or above 10,000
IU/L are common. A very high AST level soon after overdose indicates
potential for serious poisoning.5 The international normalized ratio
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(INR), and prothrombin time (PT) may also begin to rise above normal
levels. Occasionally, serum blood urea nitrogen (BUN) and creatinine
will also become elevated.
Phase III
This phase develops from 72 hours to 96 hours after ingestion, and it
is characterized by recovery or progression to liver failure. Most
patients, even those who do not receive treatment, will have a mild to
moderate degree of liver damage but this resolves. Other patients
develop fulminant hepatic failure and either recover or succumb.
Patients with fulminant hepatic failure may develop metabolic acidosis,
acute respiratory distress syndrome (ARDS), coagulopathies, coma,
hypoglycemia, cerebral edema, and renal failure.
Phase IV
Phase IV is from 96 hours after ingestion to approximately two weeks
later, and it is characterized by return of liver function. Patients who
have survived Phase III, hepatic damage and function are completely
healed.
It is important for clinicians to be aware that if the patient has
ingested a massive amount of acetaminophen, he/she may not present
with the normal progression through the phases. These patients will
rapidly become comatose and acidotic and may need a liver
transplant.
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Renal Damage
Acute renal failure happens in <2% of all cases of acetaminophen
poisoning.5,25 Most cases of renal impairment caused by
acetaminophen happen because of repeated excessive dosing5 and the
patients have acute kidney injury, hepatic damage, or fulminant liver
failure,5,25 but renal damage can occur (very infrequently) in the
absence of liver damage.5,25
The onset of renal failure caused by acetaminophen typically begins
after liver damage and liver failure; it does not appear that there is a
reliable way to predict which patients with acetaminophen overdose
will develop renal failure, and the peak serum creatinine levels may
not be seen until two to seven days after the ingestion.5
Other Organ Damage
Coma, hypotension, and metabolic acidosis can occur very rapidly in
patients who ingest massive amounts of acetaminophen, i.e., 75-100
grams or when the acetaminophen level is very high, i.e., >800
mcg/mL.26-30 Cardiac damage and dysrhythmias,31-33 acute
pancreatitis, and elevated serum amylase
34,35
have been reported
after acetaminophen overdose, the last being very common.35 Aside
from elevations of serum amylase these effects are rare and are
unlikely to be directly caused by acetaminophen. They are probably
sequelae of hepatic failure, an idiosyncratic response, unrelated to the
overdose, or due to exacerbation of pre-existing medical problems
from acetaminophen-induced hepatic failure.5
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High Risk Patients For Acetaminophen Poisoning
Acetaminophen poisoning represents a balance between the amount
and rate of NAPQI formation and the amount of available glutathione
and the ability of the liver to produce more; and, the primary toxic
effect of acetaminophen poisoning is liver damage. It may be assumed
then that anything which: 1) increases the amount or rate of NAPQI
formation, 2) decreases the amount and rate of glutathione formation,
or 3) increases the liver’s vulnerability to injury, might increase the
risk of liver damage from an acetaminophen overdose.
Researchers have speculated that there are diseases, medical
conditions, and medications which if present or prescribed will increase
the risk for liver damage after an acetaminophen overdose; these are
listed in Table 1. The prescribing information for acetaminophen states
that acetaminophen is contraindicated in patients who have severe
hepatic impairment or severe active liver disease, chronic daily use
may cause liver damage in some patients, and acetaminophen should
be used cautiously in patients who have alcoholic liver disease and/or
consume ≥three alcoholic drinks a day.
Table 1: Risk Factors for Liver Damage after Acetaminophen Overdose5,20,21
Liver disease, specifically hepatitis C
Chronic alcohol abuse or acute alcohol intoxication
Medications that increase the activity and/or production of cytochrome
p450 enzymes, i.e., antiepileptics or antitubercular drugs
Cigarette smoking
Genetic polymorphisms in drug metabolizing enzymes
Age
Poor nutrition status
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These (possible) risk factors can increase NAPQI formation, decrease
glutathione stores, and increase the vulnerability of the liver to
damage. But there is no definitive evidence that any of them, except
for alcohol, increase susceptibility for liver damage after an
acetaminophen overdose5,21 and the treatment protocol would not be
changed if one or more of these risk factors were present.5,21
Alcohol and Acetaminophen Poisoning
The effect of alcohol as a risk factor in relation to acetaminophen is
complicated, not completely understood, and situational.5,21
Acute Alcohol Ingestion/Acute Overdose
Acute alcohol ingestion does not increase the risk of developing liver
damage from acetaminophen overdose and alcohol may protect in
these situations by competing for the activity of the CYP2E1 enzyme.
Chronic Alcohol Use/Acute Overdose
The combination of chronic alcohol use and acute acetaminophen
overdose may slightly increase risk for liver damage but the risk, if
any, appears to be small and clinically insignificant.
Chronic Alcohol Use/Therapeutic Doses
Chronic alcohol users may develop a slight elevation of transaminases
after therapeutic doses of acetaminophen but there is no evidence that
chronic alcohol use and therapeutic doses of acetaminophen together
will cause liver damage.
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Chronic Alcohol Use/Supra-therapeutic Doses
Chronic alcohol users who take repeated supra-therapeutic doses of
acetaminophen are at risk for liver damage. Chronic use of alcohol unlike acute use – increases the activity of CYP2E1, thus increasing
the amount of NAPQI that is formed. Chronic alcoholic users may also
have decreased glutathione stores caused by malnutrition.
Children and Acetaminophen: Is There Less Risk?
Children appear to be less at risk for acetaminophen-induced liver
damage after an overdose. Significant liver damage or death is almost
unheard of after a single, unintentional, pediatric overdose or
exposure. Some of the reasons why this occurs are obvious. Young
children do not try and cause self-harm. A child will seldom swallow
tablets; he/she chew them and the bitter taste acts as a deterrent.
And parents almost always find the child with the medication, stopping
the child before a toxic dose can be consumed and if a toxic dose is
taken, the child is brought to an emergency department for treatment.
There has been speculation that children are inherently resistant to
acetaminophen because the amount of acetaminophen metabolized to
NAPQI was proportionately less in children, that children had greater
glutathione stores, or that they had another way of detoxifying large
amounts of acetaminophen not evident in adults. None of these
proposed protective mechanisms has been verified, however, and
children are inherently more resistant to acetaminophen toxicity than
adults because they are smaller than adults. The size of the pediatric
liver is proportionately bigger than that of adults, so children have
bigger stores of glutathione and metabolize acetaminophen faster.36,37
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Acute Acetaminophen Overdose And Deciding Treatment
Unlike many drugs and toxins for which supportive care is the basis of
treatment, there is a highly effective antidote that can be used to treat
cases of acetaminophen poisoning: N-acetylcysteine (NAC). Although
administering NAC many hours or even days after an ingestion of an
acetaminophen overdose may be helpful, NAC is most effective if it is
given ≤8-10 hours after the ingestion.5,21,38,39 After 8-10 hours from
the time of ingestion has passed, the effectiveness of NAC begins to
decline so prompt identification of patients at risk is very important.
To identify which patients are at risk and need antidotal treatment, the
health team members need to know 1) the dose that was ingested and
when it was ingested, 2) the serum acetaminophen level, 3) the
results of pertinent laboratory tests, and 4) the signs and symptoms
the patient is having. These important aspects of the patient’s history
are discussed further below.
Acetaminophen Ingestion: Dose and Time
The toxic dose of acetaminophen is ≥10 grams or ≥200 mg/kg.
Unfortunately, many patients do not or cannot recall how much
acetaminophen they ingested or when, or they might give the clinician
inaccurate information. Evaluation of patients who had taken
medications with intent to cause self-harm found that as many as
8.4% who did not self-report ingestion of acetaminophen had a
measurable serum level and up to 2.2% had a level that indicated the
need for antidotal therapy.40-42 Every effort should be made to obtain
this information and it is also critical to determine the pattern of
ingestion. If the amount taken was consumed in eight hours of less
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this is considered an acute ingestion,6 and acute and chronic
ingestions are treated differently. The time of ingestion is used to
interpret the serum level and this factor will be discussed in the next
section.
Acetaminophen Serum Level
A serum acetaminophen level should be obtained four hours or later
after the ingestion. A therapeutic dose of acetaminophen is quickly
absorbed and the peak serum level is reached within two hours, but
after overdose the absorption can be delayed and the level must be
obtained four hours or later after ingestion.
An acetaminophen level measured four hours or later after the
ingestion that is ≥150 mcg/mL indicates the potential for
hepatotoxicity and the need for antidotal therapy. But what if an
acetaminophen level done three hours after ingestion is 31 mcg/mL?
How likely is it that a level measured ≥four hours after the ingestion
will be ≥150 mcg/mL? Hendrickson (2015) notes that if the
acetaminophen level is measured between one and three hours postingestion and the level is undetectable “... significant APAP overdose
can likely be excluded.”5 However, research has shown that
acetaminophen levels measured before the four-hour mark cannot be
used to determine risk and will miss potentially toxic exposures.43-46
The level is then plotted on the Rumack-Matthew nomogram.5,21
The Rumack-Matthew nomogram was developed through examining
acetaminophen levels and AST and ALT results after acute overdose,
and the data revealed a consistent trend. If the patient had ingested a
toxic amount of acetaminophen and the time of ingestion was known
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with certainty, an acetaminophen level that was measured ≥four hours
after ingestion could be used to predict which patients would develop
liver injury. The following case scenario helps to elucidate the value of
the nomogram to help determine the probability of liver damage
following acetaminophen toxic overdose.
Case Example:
A patient reported ingestion of 10 grams of acetaminophen
eight hours prior to arrival to the emergency department,
and a reliable witness confirmed the ingestion time. The
acetaminophen level was reported to be 160 mcg/mL. The
level was placed on the nomogram and clearly above the line
labeled probable hepatotoxicity.
In almost all cases of acetaminophen overdose only one level is
needed to use the nomogram and to determine the need for
treatment. (Exceptions are discussed below). Serial, declining levels
document metabolism of the drug, which is to be expected, and there
is no value in trending the acetaminophen levels. Also, levels that are
within the range of normal values should not be considered nontoxic if
the time of ingestion is not known or if the level is toxic when it is
plotted on the nomogram. A level has clinical value only if the time of
ingestion is known.
The Rumack-Matthew nomogram was developed to identify patients
that would develop hepatoxicity (defined as a transaminase level
>1000 IU/L) after taking an acute overdose of acetaminophen. The
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nomogram cannot be used if the time of ingestion is not known; and,
it cannot be used if the overdose is chronic. Further, the nomogram
does not predict which patients will develop liver failure. Using the
Rumack-Matthew nomogram and a single acetaminophen level
measured at ≥fours post-ingestion has been shown to be a highly
effective way to identify which patients are at risk for liver damage
after an acute acetaminophen overdose. Nomogram failures are rare
and probably represent incorrect use of the nomogram, inaccurate
ingestion histories, or outliers in terms of unidentified risk factors.5
Situations that may require multiple measurements or further
assessment are highlighted below.
Slowed Peristalsis
Antihistamines and opioids can slow gut peristalsis and delay
absorption, and several case reports have documented a delayed peak
acetaminophen level caused by a co-ingestion of diphenhydramine or
an opioid.47-52 Delayed peak serum levels have also been reported after
massive ingestions.53,54
Extended Release Acetaminophen
Extended release (XR) acetaminophen has 325 mg that is immediately
available and 325 mg that is absorbed more slowly. In most cases, the
peak serum level occurs within four hours, but in patients who have
taken an overdose of XR acetaminophen up to 15% of them had a first
acetaminophen level that was non-toxic but subsequent levels were
toxic.55-57
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Elevated Serum Bilirubin
Significant elevations of serum bilirubin can cause a false positive
serum acetaminophen level.58-60
Laboratory Tests
Liver transaminases, BUN, creatinine, INR, and PT should be
measured. Elevations of AST and ALT represent liver damage and
these will occur first. An elevation of INR represents damage to the
liver’s functional ability and will occur after AST and ALT have risen.
Acetaminophen overdose can cause minor prolongations of the PT and
INR in the first 24 hours after ingestion61,62 and N-acetylcysteine can
also increase PT and INR.63-67 The INR in these cases is typically
between 1.5 and 2.0. These effects can occur in patients who do not
have liver damage, and the coagulation prolongations are temporary
and of no clinical significance.5,68
Normal laboratory values may indicate that a toxic ingestion has not
occurred, but may also reflect an ingestion that recently happened. If
the AST, ALT, or INR are above the normal range, if the patient has
(or may have taken) an overdose of acetaminophen, and there is no
other reason for the laboratory abnormalities, this is a strong
indication of a need for treatment.
Signs and Symptoms of Acetaminophen Toxicity
Abdominal pain, nausea, and vomiting are common signs and
symptoms of acetaminophen overdose. But these gastrointestinal
complaints are nonspecific, and they may be absent or greatly
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diminished 24 hours or so after the ingestion, but their presence or
absence could be a factor in determining who has acetaminophen
toxicity.
Making the Decision: Who Should be Treated with NAC
When the serum acetaminophen level and the laboratory test results
are known, and the history and physical examination are completed, a
decision regarding treatment can be made. A patient is at risk and
should receive antidotal therapy for the following findings:
•
The acetaminophen level is above the treatment line on the
Rumack-Matthew nomogram.
•
It has been confirmed that the patient has taken a toxic amount of
acetaminophen.
•
It is suspected or possible that the patient has taken a toxic
amount of acetaminophen and there is a measurable
acetaminophen level.
•
There is a measurable acetaminophen level but the time of
ingestion is not known.
•
There is a measurable level but no reported/witnessed history of
acetaminophen ingestion.
•
It is suspected or possible that the patient has taken a toxic
amount of acetaminophen and there is laboratory or clinical
evidence of liver damage.
If the data, i.e., amount ingested and when, and laboratory results are
definitive then the decision to treat or not to treat is simple. If the
patient has a toxic level and he/she took a toxic amount - treat the
patient. If there is no measurable serum acetaminophen and the
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laboratory studies are normal, do not treat the patient, even if there is
a report of a toxic amount ingested. But in many cases the information
needed to make a treatment decision will be unobtainable, ambiguous,
or difficult to interpret.
Example:
A patient reports that she ingested 10 grams of
acetaminophen but she cannot remember when she did so
and there are no witnesses. There is no measurable serum
acetaminophen. She is complaining of abdominal pain and
nausea and she has vomited three times. The AST and ALT are
slightly elevated (82 IU/L and 105 IU/L, respectively), she
has no history of liver disease, and there are no previous
measurements of her transaminases. Should she receive
antidotal therapy?
The example of the patient above should be treated because of what is
known, even if some of that data is ambiguous and/or unreliable.
There is no measurable serum acetaminophen level but we know this
could simply mean the ingestion could have occurred 24 hours or more
prior to the measurement. We know that the patient reported taking a
toxic dose. That may not be true and it can’t be confirmed but it can’t
be disproved either, and the patient’s report is the only known data
about the amount taken. Further, elevations in the AST and ALT were
found; however, these may be due to a medical problem that has not
yet been diagnosed. The elevated AST and ALT could also indicate the
early stage of liver damage from an acetaminophen overdose. The
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patient reported gastrointestinal complaints. These are nonspecific but
are also a common feature of acetaminophen overdose.
Initial Care For Acetaminophen Overdose
In the initial care for individuals with acetaminophen overdose, the
health team should assess the patient’s airway, breathing, and
circulation (ABCs). If there are significant derangements in the ABCs,
it is possible that the patient has taken an acetaminophen overdose as
a massive amount of acetaminophen can cause coma and metabolic
acidosis shortly after the ingestion. These cases are rare so it would be
prudent to consider other medications as the cause. Nevertheless,
acetaminophen overdoses are common so acetaminophen overdose
should be considered in the differential diagnosis if a patient has taken
an unwitnessed overdose and he/she is acidotic, comatose, and
hypotensive.
Gastric Decontamination
Activated charcoal is the preferred method of gastric decontamination.
Gastric lavage and whole bowel irrigation have no place in the
treatment of acetaminophen overdose. Activated charcoal binds avidly
to acetaminophen and prompt administration of activated charcoal can
prevent acetaminophen from being absorbed and converted to NAPQI
and reduce the need for antidotal therapy.5,69-71
A single dose of activated charcoal should be administered if:5,20,71
1. A toxic amount of acetaminophen has been ingested.
2. The ABCs are normal.
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3. The patient is awake, alert, and has a normal gag reflex.
4. He/she has not taken a co-ingestant that may rapidly cause
depressed consciousness.
5. The patient has a functioning gastrointestinal tract.
6. The patient presents ≤one hour after the ingestion.
The one hour time window is the accepted standard for administration
of activated charcoal.72 However, there is some evidence that activated
charcoal given beyond the one hour window may be beneficial;73
certain co-ingestants can decrease peristalsis and increase the
possibility that there is acetaminophen in the gut that can be adsorbed
by charcoal.
Administration of charcoal up to four hours after an acetaminophen
overdose has been recommended.20,71 Each case should be considered
individually. Charcoal adsorbs oral NAC but this is not clinically
important. The use of oral NAC is increasingly uncommon; it would be
unusual to need to use them at the same time, and the adsorption is
not considered clinically important.5,74
Laboratory Studies or Diagnostic Tests
An acetaminophen level and salicylate level should be measured;
patients occasionally confuse aspirin and acetaminophen and may use
the terms interchangeably. The acetaminophen level should be
measured four hours or later from the time of ingestion and if the time
is unknown, a level should be obtained at time of arrival and four
hours from time of arrival. Coagulation tests, blood urea nitrogen
(BUN), creatinine, serum transaminases should also be measured.
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Other laboratory tests and diagnostic studies can be done as the
situation dictates
Hemodialysis
Hemodialysis can remove acetaminophen, and using hemodialysis can
be considered if the patient’s acetaminophen level is extremely high.
However, the antidote is safe and easy to administer and
extracorporeal removal is rarely needed.
Antidotal Therapy: N-Acetylcysteine
The antidote for acetaminophen poisoning is N-acetylcysteine, which is
highly effective. If NAC is given within eight hours of an overdose,
serious liver damage is very unlikely and death is rare.71 NAC can
prevent liver damage, and it can decrease the severity of liver damage
through the following means.5,20,68,75,76
•
Increasing formation of glutathione.
•
Binding to NAPQI
•
Increasing the amount of acetaminophen that is conjugated to
sulfate.
•
Improving blood flow and oxygen delivery to tissues.
•
Acting as anti-inflammatory.
There are two important functions of NAC: 1) it prevents liver damage
and 2) it treats liver damage after the damage has begun. It is very
effective and if NAC is given within eight hours after the ingestion,
there is almost no risk that a patient will develop hepatic failure.
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N-acetylcysteine is most effective when it is given within eight hours of
an acetaminophen overdose, but NAC given after that point is
beneficial and should be given if patients are late presenters.75,76
The standard recommendation is that NAC is most effective when
given within eight hours of an overdose, as previously mentioned.71
However, the prescribing information notes that Acetadote should be
given 8-10 hours after an overdose,39 and Hendrickson (2015)
recommends that NAC therapy should not be unnecessarily delayed
past 6 hours if it can safely be administered earlier.5 An explanation of
these discrepancies would be very lengthy and would not add
significantly to the understanding of NAC therapy. The most important
points are that early administration of NAC is better than providing it
late, and the effectiveness of the antidote diminishes with time.
N-acetylcysteine can be given orally or intravenously and both routes
are equally effective at preventing and treating liver damage from
acetaminophen overdose.5,68 The oral and intravenous forms have not
been directly compared in controlled studies so this information is
based on case studies, theoretical data, and observation.
Oral NAC
In oral NAC the patient is given a loading dose of 140 mg/kg.
Seventeen doses of 70 mg/kg are then given, one dose every four
hours. If the patient vomits within an hour of administration of the
dose, a repeat dose is given.
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Monitoring of the patient during treatment includes laboratory testing
of the AST, ALT, INR, BUN, and creatinine, which should be checked
every day.
Adverse effects of oral NAC are primarily nausea and vomiting. Oral
NAC smells like rotting eggs and does not taste good so these effects
are very common, 20% and higher).5,71,77 These side effects can be
prevented by diluting oral NAC with juice or soda, serving it cold in a
cup with a lid, and instructing the patient to sip it slowly. If needed
oral NAC can be given through a nasogastric tube. Also, pre-treatment
with an antiemetic may also be helpful; ondansetron or
metoclopramide are more effective than traditional antiemetics such as
prochlorperazine.
Contradictions to using oral NAC include sensitivity to NAC, the
inability to use the gut, or persistent vomiting.
Oral NAC is as effective as intravenous administration but the course
of the therapy is 72 hours versus 21. Oral NAC cannot be given to
patients who do not have a functioning gastrointestinal tract and it
cannot easily (or at times safely) be given to patients who have an
altered mental status. Disruption of treatment because of nausea and
vomiting is common and patients may refuse to drink oral NAC
because it is so noxious. Oral NAC may be more effective than when
given intravenously if a patient presents late, i.e., 16 hours or more,
after an ingestion,78-80 but there is no definitive proof of this.68
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Intravenous NAC
Intravenous NAC can be used for any patient who has acetaminophen
poisoning, but NAC given intravenously should be used if the patient is
pregnant, if he/she has hepatic failure, or the oral form cannot be
used, i.e., intractable vomiting and non-functioning gastrointestinal
tract.5 Intravenous (IV) dosing is as follows:
•
Patients >40 kg are given three doses: 1) 150 mg/kg of
Acetadote diluted in 200 mL of 5% dextrose in water (D5W),
infused in over 60 minutes, followed immediately by 2) 50
mg/kg of Acetadote diluted in 500 mL of D5W, infused in over
four hours, followed immediately by 3) 100 mg/kg of Acetadote,
diluted in 1000 mL of D5W, infused in over 16 hours.
•
The maximum doses of Acetadote are 15,000 mg, 10,000 mg
and 5,000 mg for the three respective infusions and these
correspond to a patient who weighs 100 kg. There are no clinical
studies that have investigated higher doses, but as liver size
does not differ significantly between obese and non-obese
patients, no dosage adjustments are necessary for the patient
who weighs >100 kg.5,68
Monitoring of patients receiving intravenous NAC generally involves:
1) 1-2 hours before the 16 hour infusion will be finished, an
acetaminophen level, AST, ALT, and INR should be measured, 2) if no
acetaminophen is detected and the AST, ALT, and INR are normal, the
infusion can be finished and treatment is complete, and 3) if there is
measurable acetaminophen (and with this the possibility of further
formation of NAPQI) or the AST, ALT, or INR are elevated (evidence of
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hepatotoxicity), the patient may need more NAC.5 This issue will be
discussed later in this section.
Adverse reactions have been identified as anaphylactoid, occurring in
18% (some sources report a slightly higher incidence) of patients who
are given intravenous NAC.81,82 These reactions are mostly mild to
moderate,68,81,82 and the patients have flushing, itching, and rash.
Severe reactions characterized by angioedema, bronchospasm, and
hypotension can happen,68,81,82 but they are rare.39 Anaphylactoid
reactions are more likely to happen with the initial, one hour
infusion,39,83 if a patient has a lower acetaminophen level than a higher
(>300 mcg/mL) level,68,81,84 in women and if the patient has
previously been given NAC,85 and if a patient has asthma.39,86,87
If the patient has a minor anaphylactoid reaction with erythema and
flushing the intravenous NAC infusion can be continued and the patient
closely monitored. Other possibilities are if the patient has urticaria
(administer diphenhydramine), if a severe reaction occurs (stop the
infusion and administer (as needed) standard symptomatic treatment,
i.e., adrenaline, antihistamines, inhaled β2 agonists, and
corticosteroids).68,88,89 If signs or symptoms resolve, NAC can be
restarted. If they do not the patient should be switched to oral NAC.68
Duration of Therapy
If at the end of the 24 hour IV NAC there is measurable
acetaminophen, elevations of AST, ALT, or INR, or clinical evidence of
hepatic encephalopathy the patient needs more IV NAC: begin a fourth
bag, 100 mg/kg in 1000 mL, and infuse over 16 hours. Intravenous
venous NAC should then be continued until there is no measurable
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acetaminophen and laboratory test values and the patient’s clinical
status are improving. The need for IV NAC beyond the standard three
bag protocol is not uncommon, and this approach is universally agreed
upon.68,71,90 The endpoint of extended IV NAC therapy is less clear
(note the previous use of imprecise and undefined term improving)
and there are no consensus protocols for this situation.68,71,91 Many
clinicians feel that if the patient’s clinical condition is normal, the AST
has been steadily declining and is below 1000 IU/L and the INR is
<2.0 it is safe to discontinue the NAC.5,71 Each case should be
considered and treated individually and a clinical toxicologist consulted
if needed.
The IV NAC protocol has been in place for over 40 years and it has
been highly successful. But the protocol is applied to every patient,
without consideration of the acetaminophen level or the amount of
drug ingested, and there is evidence that for some patients 21 hours
of IV NAC is not needed and that patients who have very high
acetaminophen levels or have taken a massive amount of
acetaminophen need higher doses of NAC.92,93 Multiple approaches for
decreasing or increasing the amount of NAC and the duration of
therapy have been tried but there is no conclusive data that supports
changing the standard protocol. Hendrickson,5 Howland68 and Heard, et
al.,71 note that if the patient has taken a massive overdose, increasing
the IV NAC dose can be considered.
Chronic Ingestion Of Excess Acetaminophen
Chronic ingestion of an excess amount of acetaminophen - often called
repeated supra-therapeutic ingestion - is a common and potentially
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serious problem.94-97 The U.S. Acute Liver Failure Multicenter
Prospective Study found that unintentional overdoses accounted for
48% of all cases of acetaminophen-related acute liver failure,98 doses
that are not far above the accepted maximum have caused serious
harm,99 and supra-therapeutic acetaminophen ingestions will often
cause hepatoxicity. 95,100
Assessment of a patient who has taken repeated supra-therapeutic
ingestions is challenging. Most people cannot accurately remember the
pattern of use. The Rumack-Matthew nomogram cannot be used to
determine if the serum acetaminophen level is toxic or non-toxic, and
there may not be a detectable level. The serum transaminases
may/may not be elevated and the patient may be asymptomatic. The
AAPCC has provided a guideline for assessment and treatment of
chronic, supra-therapeutic acetaminophen ingestions.6
1. Patients <6 years of age should be referred to an emergency
department if they have ingested:
•
200 mg/kg or more over a single 24-hour perio.
•
150 mg/kg or more per 24-hour period for the preceding 48
hours
•
100 mg/kg or more per 24-hour period for the preceding 72
hours or longer
2. Patients 6 years of age or older should be referred to an
emergency department if they have ingested:
•
at least 10 g or 200 mg/kg (whichever is less) over a single
24-hour period
•
at least 6 g or 150 mg/kg (whichever is less) per 24-hour
period for the preceding 48 hours or longer
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3. If the patient has risk factors that may make them susceptible
to acetaminophen toxicity (i.e., history of alcohol use,
alcoholism, isoniazid use, prolonged fasting), the dose of
acetaminophen considered potentially toxic should 4 grams or
100 mg/kg (whichever is less) per day.
The acetaminophen level, AST, ALT, INR, BUN, and creatinine should
be checked. If the patient has signs or symptoms of liver damage, has
ingested a toxic amount, has a measurable acetaminophen level, or
has abnormal laboratory values, the patient should be considered at
risk and treated with NAC. If the patient reportedly ingested a toxic
amount of acetaminophen, but the physical exam is unremarkable, the
acetaminophen level is zero, and the laboratory values are normal, the
patient would not be considered at risk.
Pregnancy and Acetaminophen Overdose
Acetaminophen does cross the placenta to the fetus,5 and there is
evidence that the fetal liver can synthesize a toxic metabolite and the
fetal liver can be injured.5,20 Assessment and treatment of women who
are pregnant and have taken an overdose of acetaminophen should be
done using standard protocols.5,20,71
Intravenous NAC is preferred to avoid vomiting and interruptions in
treatment and to (possibly) increase the amount of NAC that crosses
the placenta, and IV NAC appears to be safe for the fetus. In most
cases the pregnancy and delivery are uneventful,5,71 but overdose with
acetaminophen by pregnant women has been associated with
spontaneous abortion and fetal death.5,71
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Liver Failure and Transplantation
Liver transplantation can be the only effective therapy in certain cases
of acetaminophen overdose, and the King’s College Hospital Criteria
have traditionally been used to identify patients who need
transplantation.5 These criteria are highlighted below.
•
Serum pH is < 7.30 despite fluid resuscitation
•
The prothrombin time is > 100 seconds
•
The serum creatinine is >3.3 mg/dL
•
Grade III-IV encephalopathy
The APACHE II (Acute Physiologic and Chronic Health Evaluation),
MELD (Model for End-stage Liver Disease), SOFA (Sequential Organ
Failure Assessment) assessment tools and measurement of serum
lactate have also been used in these clinical situations.5 Each of these
and the Kings College Criteria offer differing levels of sensitivity and
specificity.5
Summary
Acetaminophen is the drug most commonly taken with intent to cause
self-harm. Therapeutic errors with acetaminophen are very common as
well, and intentional or accidental acetaminophen overdose is the most
common cause of acute liver failure. Acetaminophen overdose can also
cause renal damage but this is rare, and damage to other organ
systems has been reported but it is unclear if these case reports are
describing an effect of acetaminophen. If acetaminophen is ingested in
massive amounts a rapid onset of acidosis, coma, and hypotension is
possible.
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In order to determine if a patient has taken a toxic dose of
acetaminophen the health team needs to know: 1) how much
acetaminophen has been ingested, and the time taken, 2) the serum
acetaminophen level, 3) the LFTs, BUN, creatinine, and coagulation
studies, and 4) the patient’s health history and the physical
assessment. The toxic dose of acetaminophen after an acute ingestion
is ≥10 grams or ≥200 mg/kg. After chronic overdose, the toxic dose of
acetaminophen depends on how long the patient has been taking the
drug and the presence of risk factors. The serum level must be done at
four hours or later after ingestion and it is plotted on the RumackMatthew nomogram and will be toxic or non-toxic. If the laboratory
studies were abnormally high this would indicate a possible
acetaminophen overdose, but laboratory evidence of liver damage
typically is not evident for 24 hours after ingestion.
The same basic assessment should be used for chronic ingestions of
acetaminophen. However, the Rumack-Matthew nomogram was
designed to evaluate serum acetaminophen levels from acute
ingestions and cannot be used to determine if a serum acetaminophen
level is toxic or non-toxic if the ingestion was chronic. An
acetaminophen level should be measured in these cases and if
acetaminophen is detected then this would be an indication for
treatment, but the nomogram cannot be used.
The treatment for acetaminophen overdose is N-acetylcysteine. Nacetylcysteine is highly effective if it is given within 8-10 hours of the
ingestion. The antidote can and should be given if patients present
after that time but its efficacy is reduced. N-acetylcysteine can be
given orally or intravenously. No direct comparisons between the two
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forms have been done, but the evidence suggests that they are
equally effective. If patients are treated promptly and correctly,
survival is virtually assured and the liver will completely recover.
There are certain conditions that may or may not increase a patient’s
susceptibility to liver damage from excess acetaminophen, but even if
these potential risk factors are present, the standard treatment
protocol should be used. Patients who present late or have taken a
massive ingestion lead to poor outcomes, liver failure, and death.
Antidotal therapy should still be used but liver transplantation may be
the only hope.
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1. Most acetaminophen is changed to harmless metabolites by
a.
b.
c.
d.
conjugation.
metabolism by cytochrome P-450 enzymes.
elimination in the urine.
elimination in the stool.
2. Acetaminophen is converted to a toxic metabolite by
a.
b.
c.
d.
conjugation.
metabolism by cytochrome P-450 enzymes.
elimination in the urine.
elimination in the stool.
3. The toxic dose of acetaminophen is:
a.
b.
c.
d.
≥10 grams or 200 mg/kg.
≥7.5 grams or 150 mg/kg.
≥15 grams or 150 mg/kg.
≥20 grams 04 300 mg/kg.
4. The basis of acetaminophen poisoning is
a. rate/amount of NAPQI formation greater than glutathione
availability.
b. rate/formation of conjugation is greater than glutathione
availability.
c. decrease in glutathione effectiveness.
d. increased sensitivity of the liver to the drug.
5. One organ, other than the liver, that is affected by an
overdose of acetaminophen is
a.
b.
c.
d.
the
the
the
the
lungs.
small bowel.
kidneys.
thyroid.
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6. A massive overdose of acetaminophen can cause a rapid
onset of
a.
b.
c.
d.
metabolic acidosis and coma.
arrhythmias and ARDS.
pancreatitis and congestive heart failure.
coma and myocardial infarction.
7. The serum acetaminophen level must be measured
________________ after an ingestion.
a.
b.
c.
d.
8 hours or more
4 hours or more
2 hours or more
10 hours or more
8. True or False: Organ damage other than hepatic or renal is
common after acetaminophen overdose.
a. True
b. False
9. Laboratory tests used to evaluate cases of acetaminophen
poisoning are
a.
b.
c.
d.
LFTs, BUN, creatinine, INR.
AST, CBC, and creatinine.
ALT, INR, and TSH.
AST, CK, and creatinine.
10. The antidotal therapy for acetaminophen poisoning is
a.
b.
c.
d.
glucagon.
methylene blue.
sodium thiosulfate.
N-acetylcysteine (NAC).
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11. The American Association of Poison Control Centers
(AAPCC), in an evidence-based consensus, decided that the
toxic dose of acetaminophen for children is:
a.
b.
c.
d.
>100
>150
>200
>250
mg/kg.
mg/kg.
mg/kg.
mg/kg.
12. After 24 hour IV NAC, if there is measurable
acetaminophen, elevations of AST, ALT, or INR, or clinical
evidence of hepatic encephalopathy the patient
a.
b.
c.
d.
needs more IV NAC.
should not be administered more NAC.
begin a 2nd bad, 50 mg/kg in 1000 mL.
infuse a 3rd bag, 100 mg/kg over 4 hours.
13. Drug interaction between acetaminophen and
Carbamazepine result in metabolism of acetaminophen
that may be
a.
b.
c.
d.
increased
decreased.
minimally affected, depending on the patient’s genotype.
None of the above: the effectiveness of acetaminophen in not
affected.
14. The clinical presentation of acetaminophen poisoning has
traditionally been described as having ______ phases.
a.
b.
c.
d.
Two
Three
Four
Five
15. Administration of activated charcoal up to _______ hours
after an acetaminophen overdose has been recommended.
a.
b.
c.
d.
Three
Four
Five
Six
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16. True or False: Acetaminophen is available in oral and rectal
forms but NOT in an intramuscular or intravenous
formulation.
a. True
b. False
17. The side effects of acetaminophen are minimal. Common
side effects are
a.
b.
c.
d.
mild and temporary gastrointestinal distress.
rash.
blurry vision.
Answers a., and b., are correct
18. Rash as a side effect of acetaminophen ingestion is more
common in
a.
b.
c.
d.
children.
women.
elderly.
people with preexisting skin disorders.
19. Unintentional overdoses accounted for ____% of all cases
of acetaminophen-related acute liver failure.
a.
b.
c.
d.
25
33
48
55
20. Phase IV of acetaminophen poisoning is
a.
b.
c.
d.
12 hours after ingestion.
96 hours after ingestion to approximately two weeks later.
characterized by return of liver function.
Answers a., and b., are correct
21. True or False: Acetaminophen is the drug most commonly
taken with intent to cause self-harm.
a. True
b. False
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22. A patient reports that she ingested 10 grams of
acetaminophen but she cannot remember when she did so
and there are no witnesses. There is no measurable serum
acetaminophen. She is complaining of abdominal pain and
nausea and she has vomited three times. The AST and ALT
are slightly elevated (82 IU/L and 105 IU/L, respectively),
she has no history of liver disease, and there are no
previous measurements of her transaminases. Should she
receive antidotal therapy?
a. No, she is not at risk of toxic overdose.
b. Yes, because of what is known, even if some of that data is
ambiguous and/or unreliable.
c. No, because the data is ambiguous or unreliable.
d. No, because the patient’s report cannot be confirmed.
23. The ________ has provided a guideline for assessment and
treatment of chronic, supra-therapeutic acetaminophen
ingestions.
a.
b.
c.
d.
APA
AMA
AAPCC
ALF
24. A woman arrived to the emergency department with a
known gastrointestinal surgical resection of a portion of
small bowel. She would benefit most from
a.
b.
c.
d.
a liquid form of NAC.
intravenous NAC.
oral NAC, crushed.
sublingual NAC.
25. NAC side effects of nausea and vomiting can be prevented
by
a.
b.
c.
d.
diluting oral NAC with juice or soda.
giving NAC through a nasogastric tube.
pre-treatment with an antiemetic.
All of the above
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26. True or False: Prochlorperaize is more effective than
ondansetron or metoclopramide.
a. True
b. False
27. A patient who has taken repeated supra-therapeutic
ingestions
a. is said to have acute ingestion of excess acetaminophen.
b. must use the Rumack-Matthew nomogram to determine if the
serum acetaminophen level is toxic or non-toxic.
c. will often cause hepatoxicity.
d. will always have detectible levels of serum acetaminophen.
28. Which of the following statements is true regarding oral
administration of NAC?
a. the course of therapy of oral administration is shorter than IV.
b. disruption of administration due to nausea and vomiting is
uncommon.
c. it is less effective than IV administration of NAC.
d. patients may refuse to drink oral NAC because it is so noxious.
29. When a pregnant woman takes acetaminophen, the drug
a.
b.
c.
d.
does not cross the placenta to the fetus.
the fetal liver can synthesize a toxic metabolite.
can injure the fetal liver.
administration of NAC is contraindicated.
30. True or False: Intravenous administration of NAC to a
pregnant woman who has overdosed on acetaminophen
appears to be safe for the fetus.
a. True
b. False
31. Hemodialysis can remove acetaminophen and using
hemodialysis to remove acetaminophen may be considered
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a.
b.
c.
d.
even in mild cases of acetaminophen poisoning.
if the patient’s acetaminophen level is extremely high.
if a patient refuses to drink oral NAC.
in cases of elevated salicylate toxicity.
32. ____________ is the preferred method of gastric
decontamination of acetaminophen overdose.
a.
b.
c.
d.
Whole bowel irrigation.
Induced vomiting.
Activated charcoal
Gastric lavage
33. The IV NAC protocol is applied to every patient
a. on a case-by-case basis.
b. without regard to acetaminophen levels or amount of drug
ingested.
c. based on the amount of drug ingested.
d. based on the acetaminophen levels.
34. True or False: Significant elevations of serum bilirubin can
cause a false positive serum acetaminophen level.
a. True
b. False
35. Activated charcoal binds avidly to acetaminophen and
prompt administration of activated charcoal can prevent
acetaminophen from being absorbed and converted to
a.
b.
c.
d.
NAPQI.
cytochrome P450.
N-acetylcysteine (NAC).
serum acetaminophen.
36. _________________ can slow gut peristalsis and delay
absorption of acetaminophen.
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a.
b.
c.
d.
Activated charcoal.
Salicylate
N-acetylcysteine (NAC)
Antihistamines and opioids
37. Liver transplantation may be the only effective therapy in
certain cases of acetaminophen overdose, such as
a.
b.
c.
d.
with a non-functioning gastrointestinal tract.
disruption of administration due to nausea and vomiting.
Grade III-IV encephalopathy.
with significant elevations of serum bilirubin.
38. If the patient has _______________ with erythema,
flushing the intravenous NAC infusion can be continued
and the patient closely monitored.
a.
b.
c.
d.
a severe anaphylactoid reaction
nausea
a minor anaphylactoid reaction
slowed gut peristalsis
39. Extended release (XR) acetaminophen has 325 mg that is
immediately available and 325 mg that is absorbed more
slowly such that
a.
b.
c.
d.
with the delayed release, levels do not become toxic.
opioids are the first line of defense to slow gut peristalsis.
activated charcoal is not effective.
first acetaminophen levels may be non-toxic but subsequent
levels may be toxic.
40. True or False: Charcoal adsorbs oral NAC but this is not
clinically important. The use of oral NAC is increasingly
uncommon; it would be unusual to need to use them at the
same time.
a. True
b. False
CORRECT ANSWERS:
1. Most acetaminophen is changed to harmless metabolites by
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a. conjugation.
“After absorption, approximately 90% of acetaminophen
undergoes hepatic glucuronide and sulfate conjugation; the
acetaminophen/sulfate and acetaminophen/glucuronic acid
complexes are harmless and are eliminated in the urine.”
2. Acetaminophen is converted to a toxic metabolite by
b. metabolism by cytochrome P-450 enzymes.
“A very small amount of the drug is excreted unchanged in
the urine, and the remainder (approximately 2% or less) is
metabolized by several enzymes of the cytochrome P450
enzyme system to N-acetyl-benzoquinoneimine (NAPQI). This
metabolite is toxic to the liver and the kidneys.”
3. The toxic dose of acetaminophen is:
a. ≥ 10 grams or 200 mg/kg.
“The toxic dose of acetaminophen is ≥10 grams or ≥200
mg/kg.”
4. The basis of acetaminophen poisoning is
a. rate/amount of NAPQI formation greater than glutathione
availability.
“The rate of formation of NAPQI and the amount of NAPQI
produced depletes the liver’s glutathione stores and outstrips
the liver’s ability to make more glutathione. When hepatic
glutathione stores have been depleted to approximately 70%
of pre-exposure levels - a process that takes approximately
about 8 hours - NAPQI covalently binds to hepatocytes and
liver damage will occur.”
5. One organ other than the liver that is affected by an
overdose of acetaminophen is
c. the kidneys.
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“A very small amount of the drug is excreted unchanged in
the urine, and the remainder (approximately 2% or less) is
metabolized by several enzymes of the cytochrome P450
enzyme system to N-acetyl-benzoquinoneimine (NAPQI). This
metabolite is toxic to the liver and the kidneys.”
6. A massive overdose of acetaminophen can cause a rapid
onset of
a. metabolic acidosis and coma.
“If there are significant derangements in the ABCs, it is
possible that the patient has taken an acetaminophen
overdose as a massive amount of acetaminophen can cause
coma and metabolic acidosis shortly after the ingestion.”
7. The serum acetaminophen level must be measured
________________ after an ingestion.
b. 4 hours or more
“A serum acetaminophen level should be obtained four hours
or later after the ingestion.”
8. True or False: Organ damage other than hepatic or renal is
common after acetaminophen overdose.
b. False
“A very small amount of the drug is excreted unchanged in
the urine, and the remainder (approximately 2% or less) is
metabolized by several enzymes of the cytochrome P450
enzyme system to N-acetyl-benzoquinoneimine (NAPQI). This
metabolite is toxic to the liver and the kidneys.”
9. Laboratory tests used to evaluate cases of acetaminophen
poisoning are
a. LFTs, BUN, creatinine, INR.
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“Laboratory Tests: Liver transaminases, BUN, creatinine, INR,
and PT should be measured.”
10. The antidotal therapy for acetaminophen poisoning is
d. N-acetylcysteine (NAC)
“Unlike many drugs and toxins for which supportive care is
the basis of treatment, there is a highly effective antidote that
can be used to treat cases of acetaminophen poisoning: Nacetylcysteine (NAC).”
11. The American Association of Poison Control Centers
(AAPCC), in an evidence-based consensus, decided that the
toxic dose of acetaminophen for children is:
c. >200 mg/kg.
“The American Association of Poison Control Centers (AAPCC),
in an evidence-based consensus, decided that the toxic dose
of acetaminophen for adults is ≥10 grams or 200 mg/kg,
whichever is lower, and >200 mg/kg for children.”
12. After 24 hour IV NAC, if there is measurable
acetaminophen, elevations of AST, ALT, or INR, or clinical
evidence of hepatic encephalopathy the patient
a. needs more IV NAC.
“If at the end of the 24 hour IV NAC there is measurable
acetaminophen, elevations of AST, ALT, or INR, or clinical
evidence of hepatic encephalopathy the patient needs more
IV NAC: begin a fourth bag, 100 mg/kg in 1000 mL, and
infuse over 16 hours.”
13. Drug interaction between acetaminophen and
Carbamazepine result in metabolism of acetaminophen
that may be
a. increased.
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“Drug interactions between acetaminophen and commonly
used medications include…Carbamazepine: The metabolism of
acetaminophen may be increased, decreasing the
effectiveness of acetaminophen.”
14. The clinical presentation of acetaminophen poisoning has
traditionally been described as having ______ phases.
c. Four
“The clinical presentation of acetaminophen poisoning has
traditionally been described as having four phases.”
15. Administration of activated charcoal up to _______ hours
after an acetaminophen overdose has been recommended.
b. Four
“Administration of charcoal up to four hours after an
acetaminophen overdose has been recommended.”
16. True or False: Acetaminophen is available in oral and rectal
forms but NOT in an intramuscular or intravenous
formulation.
b. False
“Acetaminophen is available in oral tablets, caplets, capsules,
and gel tabs, oral suspensions and solutions, rectal
suppositories, and in an intravenous (IV) formulation.”
17. The side effects of acetaminophen are minimal. Common
side effects are
a. mild and temporary gastrointestinal distress.
b. rash.
c. blurry vision.
d. Answers a., and be are correct [correct answer]
“The side effects of acetaminophen are minimal. Common
side effects are mild and temporary gastrointestinal distress
and rash.”
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18. Rash as a side effect of acetaminophen ingestion is more
common in
a. children.
“The side effects of acetaminophen are minimal. Common
side effects are mild and temporary gastrointestinal distress
and rash. Rash is more common in children.”
19. Unintentional overdoses accounted for ____% of all cases
of acetaminophen-related acute liver failure.
c. 48
“The U.S. Acute Liver Failure Multicenter Prospective Study
found that unintentional overdoses accounted for 48% of all
cases of acetaminophen-related acute liver failure …”
20. Phase IV of acetaminophen poisoning is
a. 12 hours after ingestion
b. 96 hours after ingestion to approximately two weeks later
c. characterized by return of liver function.
d. Answers a., and be are correct [correct answer]
“Phase IV is from 96 hours after ingestion to approximately
two weeks later, and it is characterized by return of liver
function.”
21. True or False: Acetaminophen is the drug most commonly
taken with intent to cause self-harm.
a. True
“Acetaminophen is the drug most commonly taken with intent
to cause self-harm.”
22. A patient reports that she ingested 10 grams of
acetaminophen but she cannot remember when she did so
and there are no witnesses. There is no measurable serum
acetaminophen. She is complaining of abdominal pain and
nausea and she has vomited three times. The AST and ALT
are slightly elevated (82 IU/L and 105 IU/L, respectively),
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she has no history of liver disease, and there are no
previous measurements of her transaminases. Should she
receive antidotal therapy?
b. Yes, because of what is known, even if some of that data is
ambiguous and/or unreliable.
“The example of the patient above should be treated because
of what is known, even if some of that data is ambiguous
and/or unreliable.”
23. The __________ has provided a guideline for assessment
and treatment of chronic, supra-therapeutic
acetaminophen ingestions.
c. AAPCC
“The AAPCC has provided a guideline for assessment and
treatment of chronic, supra-therapeutic acetaminophen
ingestions.”
24. A woman arrived to the emergency department with a
known gastrointestinal surgical resection of a portion of
small bowel. She would benefit most from
b. intravenous NAC
“Oral NAC cannot be given to patients who do not have a
functioning gastrointestinal tract ...”
25. NAC side effects of nausea and vomiting can be prevented
by
a. diluting oral NAC with juice or soda.
b. giving NAC through a nasogastric tube.
c. pre-treatment with an antiemetic.
d. All of the above [correct answer]
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“Adverse effects of oral NAC are primarily nausea and
vomiting… pre-treatment with an antiemetic may also be
helpful … These side effects can be prevented by diluting oral
NAC with juice or soda, serving it cold in a cup with a lid, and
instructing the patient to sip it slowly. If needed oral NAC can
be given through a nasogastric tube.”
26. True or False: Prochlorperaize is more effective than
ondansetron or metoclopramide.
b. False
“Ondansetron or metoclopramide are more effective than
traditional antiemetics such as prochlorperazine.”
27. A patient who has taken repeated supra-therapeutic
ingestions
c. will often cause hepatoxicity.
“Chronic ingestion of an excess amount of acetaminophen often called repeated supra-therapeutic ingestion … and supratherapeutic acetaminophen ingestions will often cause
hepatoxicity…. Most people cannot accurately remember the
pattern of use. The Rumack-Matthew nomogram cannot be
used to determine if the serum acetaminophen level is toxic or
non-toxic, and there may not be a detectable level. The serum
transaminases may/may not be elevated and the patient may
be asymptomatic.”
28. Which of the following statements is true regarding oral
administration of NAC?
d. patients may refuse to drink oral NAC because it is so
noxious.
“Oral NAC is as effective as intravenous administration but the
course of the therapy is 72 hours versus 21…. Disruption of
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treatment because of nausea and vomiting is common and
patients may refuse to drink oral NAC because it is so
noxious.”
29. When a pregnant woman takes acetaminophen, the drug
c. can injure the fetal liver.
“Acetaminophen does cross the placenta to the fetus, and
there is evidence that the fetal liver can synthesize a toxic
metabolite and the fetal liver can be injured.”
30. True or False: Intravenous administration of NAC to a
pregnant woman who has overdosed on acetaminophen
appears to be safe for the fetus.
a. True
“Intravenous NAC is preferred to avoid vomiting and
interruptions in treatment and to (possibly) increase the
amount of NAC that crosses the placenta, and IV NAC appears
to be safe for the fetus. In most cases the pregnancy and
delivery are uneventful, but overdose with acetaminophen by
pregnant women has been associated with spontaneous
abortion and fetal death.”
31. Hemodialysis can remove acetaminophen and using
hemodialysis to remove acetaminophen may be considered
b. if the patient’s acetaminophen level is extremely high.
“Hemodialysis can remove acetaminophen, and using
hemodialysis can be considered if the patient’s acetaminophen
level is extremely high. However, the antidote is safe and easy
to administer and extracorporeal removal is rarely needed.”
32. ____________ is the preferred method of gastric
decontamination of acetaminophen overdose.
c. Activated charcoal
“Activated charcoal is the preferred method of gastric
decontamination. Gastric lavage and whole bowel irrigation
have no place in the treatment of acetaminophen overdose.”
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33. The IV NAC protocol is applied to every patient
b. without regard to acetaminophen levels or amount of drug
ingested.
“The IV NAC protocol has been in place for over 40 years and it
has been highly successful. But the protocol is applied to every
patient, without consideration of the acetaminophen level or
the amount of drug ingested,…”
34. True or False: Significant elevations of serum bilirubin can
cause a false positive serum acetaminophen level.
a. True
“Significant elevations of serum bilirubin can cause a false
positive serum acetaminophen level.”
35. Activated charcoal binds avidly to acetaminophen and
prompt administration of activated charcoal can prevent
acetaminophen from being absorbed and converted to
a. NAPQI.
“Activated charcoal binds avidly to acetaminophen and prompt
administration of activated charcoal can prevent
acetaminophen from being absorbed and converted to NAPQI
and reduce the need for antidotal therapy.”
36. _________________ can slow gut peristalsis and delay
absorption of acetaminophen.
d. Antihistamines and opioids
“Antihistamines and opioids can slow gut peristalsis and delay
absorption, and several case reports have documented a
delayed peak acetaminophen level caused by a co-ingestion of
diphenhydramine or an opioid.”
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37. Liver transplantation may be the only effective therapy in
certain cases of acetaminophen overdose, such as
c. Grade III-IV encephalopathy.
“Liver transplantation can be the only effective therapy in
certain cases of acetaminophen overdose, and the King’s
College Hospital Criteria have traditionally been used to
identify patients who need transplantation. These criteria are:
… Grade III-IV encephalopathy.”
38. If the patient has _______________ with erythema,
flushing the intravenous NAC infusion can be continued
and the patient closely monitored.
c. a minor anaphylactoid reaction
“If the patient has a minor anaphylactoid reaction with
erythema and flushing the intravenous NAC infusion can be
continued and the patient closely monitored…. if a severe
reaction occurs (stop the infusion and administer (as needed)
standard symptomatic treatment,….”
39. Extended release (XR) acetaminophen has 325 mg that is
immediately available and 325 mg that is absorbed more
slowly such that
d. first acetaminophen levels may be non-toxic but subsequent
levels may be toxic.
“Extended release (XR) acetaminophen has 325 mg that is
immediately available and 325 mg that is absorbed more
slowly. In most cases, the peak serum level occurs within four
hours, but in patients who have taken an overdose of XR
acetaminophen up to 15% of them had a first acetaminophen
level that was non-toxic but subsequent levels were toxic.”
40. True or False: Charcoal adsorbs oral NAC but this is not
clinically important. The use of oral NAC is increasingly
uncommon; it would be unusual to need to use them at the
same time.
a. True
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“Charcoal adsorbs oral NAC but this is not clinically important.
The use of oral NAC is increasingly uncommon; it would be
unusual to need to use them at the same time, and the
adsorption is not considered clinically important.”
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