Download (Acetaminophen) in products with and without opioid: an analysis

ACETAMINOPHEN POISONING:
A COMPREHENSIVE REVIEW
DANA BARTLETT, RN, BSN, MSN, MA
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 on the
subject of 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. Decisions made to
treat acetaminophen toxicity are often determined by the age and atrisk presentation of the patient. The Rumack-Matthew nomogram is a
proven highly sensitive tool to determine patients at risk and requiring
treatment. Treatment may include the administration of
acetylcysteine; and, the route of administration includes
considerations of its efficacy, safety and cost. Poor outcomes can
include liver failure and death. If treated promptly, patient recovery
and survival from acetaminophen toxic overdose is almost assured.
1
Continuing Nursing Education Course Planners
William A. Cook, PhD, Director, Douglas Lawrence, MA, Webmaster,
Susan DePasquale, MSN, FPMHNP-BC, Lead Nurse Planner
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 2 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.
2
Course Purpose
This course will help nurses 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.
Continuing Nursing Education (CNE) 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, RN, BSN, MSN, MA, 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.
Activity Review Information
Reviewed by Susan DePasquale, MSN, FPMHNP-BC
Release Date: 1/1/2016
Termination Date: May 13, 2017
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.
3
1) Most acetaminophen is changed to harmless metabolites by:
a. conjugation
b. metabolism by cytochrome P-450 enzymes
c. elimination in the urine
d. elimination in the stool
2) Acetaminophen is converted to a toxic metabolite by:
a. conjugation
b. metabolism by cytochrome P-450 enzymes
c. elimination in the urine
d. elimination in the stool
3) The toxic dose of acetaminophen is:
a. ≥ 10 grams or 200 mg/kg
b. ≥ 7.5 grams or 150 mg/kg
c. ≥ 15 grams or 150 mg/kg
d. ≥ 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) Organ damage other than hepatic or renal is common after
acetaminophen overdose.
a. True
b. False
4
Introduction
The American Association of Poison Control Centers (AAPCC) publishes
annual reports documenting the number and nature of drug
overdoses. The AAPCC data from 2012 (the latest available data) was
similar to the data from almost every previous year. Acetaminophen
was the most common drug taken in an overdose with intent to cause
self-harm, and therapeutic errors with acetaminophen that caused
liver damage are also 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
The majority of 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.3 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%.4
Acetaminophen: Pharmacology
Acetaminophen is an over-the-counter
analgesic used for mild to moderate pain
and as antipyretic; it appears to have
minimal anti-inflammatory action.
The name acetaminophen,
and the brand name
Tylenol®, are both derived
from combinations of the
letters of the chemical
Although it is not completely understood
term for acetaminophen,
how acetaminophen works, it is thought to
N-acetyl-p-aminophenol.
5
produce its analgesic/antipyretic effects by these mechanisms of
action:5,6

It inhibits synthesis of prostaglandins in the central nervous
system;

It blocks pain impulse generation peripherally;

It acts as an antipyretic by inhibiting the heat-regulating center
of the hypothalamus.
Learning Break: Prostaglandins are hormone-like substances that
are involved in sensitizing some neurons to pain and mediating many
physiological functions, i.e., the inflammatory response.
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 μg/ml.3,5,6 First pass
metabolism removes approximately 25% of a therapeutic dose.
After absorption, approximately 90% of
acetaminophen undergoes hepatic
Conjugation is a process
by which the
glucuronide and sulfate conjugation; the
acetaminophen is bound to
acetaminophen/sulfate and
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-acetyl-benzoquinoneimine
6
(NAPQI). This metabolite is toxic to the liver and the kidneys.
However, if acetaminophen is ingested in therapeutic doses, NAPQI is
combined with glutathione and the NAPQI-glutathione complex is
converted to non-toxic mercaptine or cysteine, both of which are
excreted in the urine and bile.3,5.6
Learning Break: Glutathione (also known as GSH) is a tripeptide
synthesized in the liver and in other organs. It acts an antioxidant
and it is a very important part of the body’s defense system against
free radicals and oxidative stress.
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
geltabs; 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 overthe-counter analgesics. Opioid analgesics and acetaminophen are
frequently combined, as well.
7
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 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.
8

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.
Acetaminophen Toxicity
The toxic dose of acetaminophen was for many years considered to be
≥ 150 mg/kg or ≥ 7.5 grams, whichever was lower.7 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.8,9 The
American Association of Poison Control Centers (AAPCC), in an
evidence-based consensus, decided that the toxic dose of
acetaminophen is ≥ 10 grams or 200 mg/kg,10 for an adult or a child
and this appears to be the universally accepted figure.11
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
9
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 later) should be lowered
from 200 mcg/mL to 100 mcg/mL.12 The benefits of this approach are
at this time uncertain,12,13 and, in the United States the dose that is
considered to be toxic and the treatment line on the Rumack-Matthews
nomogram have not been changed.
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.
10
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.14-24 Although these systematic
reviews, meta-analyses, and prospective studies have shown that a
daily 4 gram dose of acetaminophen can cause abnormally high serum
transaminases, these high levels were:
1) not excessively high;
2) returned to normal in almost every case;
3) not associated with death, liver failure, or permanent liver
damage;
4) from the literature reviewed of studies that in some cases
examined over 30,000 patients, and;
5) of some patients in the case reports that had risk factors
which have been associated with an increased susceptibility to
damage from acetaminophen.
In addition, many people who received a 4-gram daily dose or doses of
up to 8 to 12 grams a day did not develop elevated
transmaminases.14,23
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.
11
Learning Break: 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.21 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
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
12
The precise mechanisms by which NAPQI damages the hepatocytes
are not known.3,26 It may cause oxidative stress, it may cause
mitochondrial dysfunction, or it may be that high amounts of NAPQI
can alter the immune function of the liver, producing an abnormal
immune response with inflammation that can irreversibly damage
hepatocytes.27,28 However, 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.
Learning Break: 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.
Signs And Symptoms Of Acetaminophen Overdose
Liver Damage
The clinical presentation of acetaminophen poisoning has traditionally
been described as having four phases of liver damage.29 There can be
some individual variation in the presentation, but in most cases, these
four phases are easily identifiable and follow each other quite
predictably.
13

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, but occasionally the serum transaminases will begin to
rise during the first 24 hours after ingestion.

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
commonly called liver function tests or LFTs) may begin to rise
above normal levels; levels at or above 10,000 IU/L are not
uncommon. The international normalized ratio (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.
Learning Break: 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.
14

Phase III:
This phase develops from 72 hours to 96 hours post-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. These serious cases happen very soon after a
massive ingestion of acetaminophen or if the patient presents
very late after ingestion.

Phase IV:
This phase is from 96 hours post-ingestion to approximately two
weeks post-ingestion, and is characterized by return of liver
function. Patients who have survived Phase III, hepatic damage
and function are completely healed.
Learning Break: 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.
15
Renal Damage
Acute renal failure happens in approximately 1% to 2% of all cases of
acetaminophen poisoning.30-34 The renal parenchyma may form
NAPQI, but it is not clear if this explains renal damage in these cases.
Renal failure following an acetaminophen overdose can occur without
elevates LFTS or evidence of fulminant hepatic failure, but this is even
more unusual.31,32
It does not appear that there is a reliable way to predict which patients
with acetaminophen overdose will develop renal failure. The onset of
renal failure typically begins after evidence of liver damage and liver
failure. The peak serum creatinine levels may not be seen until two to
seven days after the ingestion.30-33
Other Organ Damage
There have been rare instances of other organ systems being injured
by acetaminophen overdose. Cardiac damage and cardiac effects, such
as ECG changes and dysrhythmias, has been reported after
acetaminophen overdose,35,36 and, autopsy reports in some of these
cases did find evidence of myocardial damage. However, given that
reports of cardiac effects after acetaminophen poisoning are very rare
and the confounding factors in these cases, such as concurrent use of
medications that can affect cardiac status, incomplete, the clinical
information needed to confirm a diagnosis and the presence of other
serious clinical effects (i.e., metabolic acidosis), make it seem safe to
assume that if acetaminophen is directly toxic to the heart, cardiac
damage is highly unusual.
16
Acute pancreatitis has occasionally been reported after acetaminophen
overdose,
37-40
and elevated serum amylase is fairly common. One
author found that 246 of 814 patients (28%) who had taken an over
dose of acetaminophen had elevated serum amylase; 18% of these
patients did not have laboratory evidence of liver damage; and 75% of
the patients who developed fulminate hepatic failure had
hyperamylasemia.40 The pathogenesis of this phenomenon is not clear.
It may be an idiosyncratic response, a direct toxic effect of
acetaminophen, or, in some cases, it may be associated with hepatic
or renal damage caused by the overdose.
Risk Factors For Acetaminophen Poisoning
Acetaminophen poisoning essentially represents a balance between the
amount of NAPQI formed and the rate at which it is formed, and the
amount of glutathione available and the ability of the liver to produce
more. The major toxic effect of acetaminophen poisoning is liver
damage and damage to the liver’s functional capacity. It seems
reasonable then to assume 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 risks of liver damage when acetaminophen
is taken in a toxic amount.
A question to ponder is: are there risk factors that may make some
people more susceptible to damage from acetaminophen when it is
taken in overdose? Some researchers have speculated that there are,
and the potential risk factors that have been identified are listed
below:3,29
17

Liver disease, specifically hepatitis C

Chronic alcohol abuse or acute alcohol intoxication Medications
such as antiepileptics or antituberucular drugs that increase the
activity of the cytochrome P450 enzyme that produces NAPQI

Cigarette smoking

Genetic polymorphisms in drug metabolizing enzymes

Age

Poor nutrition status that may cause decreased glutathione
stores.
However, at this point there is no definitive evidence that most of
these purported risk factors would increase an individual’s
susceptibility to liver damage after an acetaminophen overdose.41,42
The strongest evidence for such an effect is for hepatitis C.43,44 The
role of alcohol as a risk factor is not completely understood and is
controversial.3,45 Acute ingestion of alcohol may actually have a
protective effect; ethanol competes for the cytochrome P450 enzyme
that produces NAPQI. Chronic alcohol ingestion decreases glutathione
stores and increases the activity of that specific cytochrome P450
enzyme, but people who chronically ingest alcohol do not seem to
have an increased risk of liver damage and liver failure after
acetaminophen overdose.16 Yet, there is also some evidence that it is
the pattern of use that can make alcohol ingestion risky in these
situations. People who chronically abuse alcohol may not be more
susceptible to liver injury after an acute overdose of acetaminophen,
but may be at a higher risk if they are chronically taking larger than
therapeutic doses.
18
At this time, there is no answer, and the status of these risk factors is
still being investigated. And in some ways, the question is
unimportant. The prescribing information for acetaminophen states
that the drug should be used with caution in people who have alcoholic
liver disease and that people who consume ≥ three drinks a day and
use acetaminophen may be at risk for liver damage. Alcohol use/abuse
and the other risk factors that may increase susceptibility to liver
damage from acetaminophen are common and widely distributed, yet
with prompt and proper treatment survival after an acetaminophen
overdose is virtually assured.
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 harm themselves by taking an overdose. They
seldom swallow tablets; they chew them and the bitter taste acts as a
deterrent. Generally, by the time parents discover that their child has
ingested acetaminophen, the child is stopped from taking the
medication before too much can be ingested and/or is brought to an
emergency department where treatment can be prompt.
There has been speculation that children are inherently resistant to
acetaminophen. Speculation was that 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,
19
however, and the reason why children are inherently more resistant to
acetaminophen toxicity than adults is simply size. The size of the
pediatric liver is proportionately bigger than it is for adults, so children
have greater relative glutathione stores and metabolize
acetaminophen faster.46,47
Acetaminophen Acute Overdose And Patient Treatment
Deciding At-Risk Patients
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.3,48,49 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.
In order to make this assessment and decide which patients are at risk
and need antidotal treatment, the health team members would need
to obtain the following information from the patient and/or family:
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.
Dose:
The toxic dose of acetaminophen is considered to be ≥ 10 grams or
≥ 200 mg/kg. When considering the ingested dose, making the
20
decision as to whether or not treat a patient who has taken an excess
of acetaminophen should be easy; if the amount ingested was ≥ 10
grams or ≥ 200 mg/kg, the patient should receive NAC.
Unfortunately, many patients cannot or do not provide accurate
information about the amount of drug ingestion or when the ingestion
occurred. The health team involved in treating the patient should try
to use all of their resources to determine what the ingested dose and
time was, but, in many cases, such as when ingestion involves an
attempt at self-harm, this can’t be done. The time of ingestion and the
pattern of ingestion are crucially important. If the ingestion was
completed in four hours or less it can be considered acute. The time of
ingestion is used to interpret the serum level and this will be discussed
in the next section.
Acetaminophen serum level:
A serum acetaminophen level should be obtained four hours or later
after the ingestion. Although, in therapeutic doses the absorption and
peak serum level are reached within two hours, in the case of an
overdose absorption can be delayed, thus the level should obtained
four hours or later after ingestion. The level is then plotted on the
Rumack-Matthew nomogram.50 The nomogram is an assessment tool
that has been proven to be very effective.
Rumack-Matthew nomogram:
The Rumack-Matthew nomogram was developed through the
examination of acetaminophen levels and AST and ALT results. The
developers of the nomogram noted a trend that was very consistent.
If the patient had ingested a toxic amount of acetaminophen and the
21
time of ingestion was known with certainty, an acetaminophen level
that was obtained at some point four hours or later after that ingestion
time could be used to predict which patients would develop liver
injury. Below is a case scenario, which illustrates how the RumackMatthew nomogram is used following an overdose of acetaminophen:
A patient reports that he ingested 10 grams of acetaminophen eight
hours prior to arrival to the emergency department. A reliable
witness confirms the ingestion time. The acetaminophen level is
160 μg/mL. The level is placed on the nomogram and it is clearly
above the line labeled probable hepatotoxicity.
The Rumack-Matthew nomogram, proven to be highly sensitive (if not
highly specific) always will accurately identify patients at risk when
used correctly. Only one level is needed to use the nomogram. Serial
levels that are lower than previous ones simply document metabolism
of the drug; there is no need to get them and they are of no clinical
value. Also, levels that are within the range of normal values should
not be considered non-toxic if the time of ingestion is not known or if
the level is toxic according to the nomogram. The level is considered
toxic or non-toxic depending on when, in relation to the ingestion, the
level was obtained; the absolute value in and of itself is of no clinical
importance except to confirm that acetaminophen has been ingested.
The nomogram assumes that an acetaminophen level measured at
four hours post-ingestion represents the peak level. This is almost
always true, but exceptions have been noted.
Antihistamines and opioids can slow gut peristalsis, delay absorption
and several case reports have documented a delayed peak
22
acetaminophen level caused by a co-ingestion of diphenhydramine or
an opioid.
51-55
Delayed peak serum levels have been reported after
massive ingestions
56-58
and after ingestion of extended-release
products, i.e., Tylenol Arthritis®.59-60
In patients that have ingested an extended release acetaminophen
product, an acetaminophen level should be obtained at four hours
after the ingestion. Another acetaminophen level should be repeated
four to six hours later. If either level is above the treatment line the
patient is at risk and should receive antidotal therapy. If neither level
is above the treatment line, the patient doesn’t need antidotal therapy.
This approach should also be considered if the patient ingested a
medication that can slow peristalsis.
Learning Break: What if a patient’s serum acetaminophen level
measured at three hours post-ingestion is 89 μg/mL? Should another
level be measured? It is unlikely that a low serum acetaminophen
level measured before the four hour post-ingestion mark will
subsequently rise to the toxic level of 150 μg/mL at four hours, but it
is not impossible.61,62 Froberg, et al (2013) checked serum
acetaminophen levels between one and four hours post-ingestion in
83 patients who had taken an acute acetaminophen overdose. They
found a level done during this time that was < 100 μg/mL a yielded
false positive rate of 6.5%, so at least five patients with a non-toxic
level subsequently developed a four-hour level that was toxic.
23
Laboratory tests:
Elevations of the AST, ALT, and INR certainly can confirm that the
patient has taken a toxic dose of acetaminophen. AST and ALT
elevations occur first, representing damage to hepatocytes while
elevations of INR occur later (representing damage to liver function).
The elevation of the AST and ALT typically begin at approximately 24
hours after ingestion, but this can occur as early as eight hours postingestion and as late as 36 hours.63-65
Normal laboratory values may indicate that a toxic ingestion has not
occurred, but the goal of treating a patient with an acetaminophen
overdose is to prevent harm to the liver. These laboratory studies
should be obtained and, if they are abnormal, a patient who has taken
an overdose of acetaminophen should be treated. Waiting for evidence
of damage is not optimal therapy.
Signs and symptoms:
There are signs and symptoms of liver damage caused by
acetaminophen that are commonly observed: abdominal pain, nausea,
and vomiting. But these signs and symptoms are to some extent
subjective, non-specific, and they may be absent or greatly diminished
24 hours or so after the ingestion.
Although not common, it is possible for the signs and symptoms to be
absent and there will be no laboratory evidence of liver damage. The
physical exam and the patient’s subjective complaints, signs and
symptoms, should be considered; however, these are often unreliable
or not highly useful in making a treatment decision.
24
Of course, there will be many instances in which the information
needed to make a treatment decision will be unobtainable, ambiguous,
or can’t be interpreted. The case scenario below highlights this:
A patient presents with an undetectable level, however, has
symptoms of nausea and vomiting. The patient reports that she
ingested 15 grams of acetaminophen but she cannot remember
when she did so and the ingestion can’t be confirmed. Lab serum
levels reveal an AST/ALT that are slightly elevated, but there are
no medical records available to support the determination of
whether these abnormal laboratory values are new or old or
caused by a medical problem.
Making the decision as to which patients are at risk and need
therapy with NAC can be tricky. The best course of action is to
realize that cases in which the data is ambiguous or unavailable
are common, consider the situation as a whole, and err on the
side of caution. N-acetylcysteine is highly effective and very safe
and, if the wrong decision is made, the patient could suffer liver
failure and death.
Consider a patient to be at risk and give NAC if:

The acetaminophen level is above the treatment line on the
Rumack-Matthew nomogram;

If it has been confirmed that the patient has taken a toxic
amount of acetaminophen;

If it is suspected or reported that the patient has taken a toxic
amount of acetaminophen and there is a measurable
acetaminophen level;
25

If there is a measurable acetaminophen level but the time of
ingestion is not known;

If it is suspected or reported that the patient has taken a toxic
amount of acetaminophen and there is laboratory evidence of
liver damage;

If the patient has been chronically ingesting toxic or
supratherapeutic amounts of acetaminophen and there is a
measurable acetaminophen level and/or laboratory evidence of
liver damage.
Initial Care: Stabilization and Treatment
Assess the airway, breathing, and circulation (ABCs). If there are
significant derangements in the ABCs, it is possible, but not very likely
that these changes are due to an acetaminophen overdose. As
mentioned previously, a massive amount of acetaminophen can cause
coma and metabolic acidosis shortly after the ingestion, but this rarely
happens.66,67 If the patient with a reported/alleged acetaminophen
overdose is acidotic, hypotensive, and unresponsive, the health team
must act quickly to assess the patient for an acetaminophen overdose.
But, remember that presentations such as this are unusual, so
considering the possibility of a co-ingestion is prudent.
Physical exam
In performing a physical exam its necessary to pay particular attention
to the abdominal area. The patient should be asked how much
acetaminophen was ingested, what dosage form was ingested (i.e.,
extra strength, sustained release), when the drug was ingested and
over what period of time, and a determination should be made
26
whether this was the only ingestion or if the patient had taken any
acetaminophen in the hours and days prior to the current ingestion.
Administer a single dose of activated charcoal if the patient presents
with any of the following:
1) normal, stable ABCs;
2) mentation is awake and alert;
3) normal gag reflex;
4) no co-ingestant that may lead to a rapid depression in
consciousness, and;
5) arrives at the hospital within one hour of the ingestion.
Activated charcoal binds avidly to acetaminophen and if it is given
within one hour after ingestion, it may prevent a toxic amount of
acetaminophen from being absorbed and converted to NAPQI.11
Another consideration is that activated charcoal will bind to oral NAC.
However, it is uncommon to need to administer activated charcoal and
NAC at the same time, and, even if it were required to do so, the
binding of NAC to charcoal is not considered important and there
would be no need to increase the dose of NAC.68 Ipecac (a thick oral
syrup preparation that induces vomiting) is no longer available; and,
gastric lavage (stomach pumping) should not be performed.69-71
Hemodialysis
Acetaminophen can be removed by hemodialysis. Using hemodialyis
could be considered if the patient’s acetaminophen level is extremely
high. However, such a circumstance would be extremely rare, and as
the antidote is safe and easy to administer, extracorporeal removal
should not be done.
27
Serum acetaminophen level
Obtaining a serum acetaminophen level should be done four hours or
later from the time of ingestion, but, if this time is not known, a serum
level should be obtained immediately and then another level in four
hours. Also, a serum salicylate level should be obtained. Patients
occasionally confuse aspirin and acetaminophen and may use the
terms interchangeably.
Additional serum levels that should be obtained include an INR, LFTS,
BUN, and creatinine. Once the acetaminophen level is known, it can be
plotted on the nomogram and if the time of ingestion is known, the
decision to use/not use NAC can be made.
Antidotal Therapy: N-Acetylcysteine (NAC)
Acetaminophen poisoning results from an imbalance between the rate
and the amount of formation of a toxic metabolite and the availability
of the body’s glutathione stores and its capability to make more
glutathione. At the present time, there are no proven ways to limit the
absorption of acetaminophen aside from the timely administration of
activated charcoal.
There are no proven ways to increase the conjugation of
acetaminophen to glucuronide or sulfate, and there are no proven
ways to decrease the metabolism of acetaminophen to NAPQI. The
only proven therapy for acetaminophen poisoning is N-acetylcysteine
(NAC). NAC can prevent liver damage and liver failure caused by an
overdose of acetaminophen by increasing the body’s ability to detoxify
NAPQI.
28
There are several ways in which NAC works. Glutathione is synthesized
in the liver from the amino acids cysteine, glutamate, and glycine.72
There is a limited amount of cysteine available in the liver, and NAC
provides a source of cysteine so more glutathione can be synthesized.
This increased synthesis of glutathione is one of the most important
ways that NAC prevents and treats liver damage.73,74 NAC may also
work by reversing NAPQI back to acetaminophen by: binding directly
to NAQI, increasing the amount of ingested acetaminophen that is
conjugated to sulfate, changing and ameliorating the course of liver
damage (once NAPQI binds to hepatocytes) by increasing hepatic
oxygen delivery, acting as an anti-inflammatory and antioxidant agent,
and, increasing hepatic blood flow.3,73,74
N-Acetylcysteine has two important functions: it prevents liver damage
and treats liver damage after the damage has begun. It is very
effective; and, if given soon after the ingestion, there is almost no risk
that a patient will develop hepatic failure. There may be liver damage,
but this will resolve and the patient will recover. Less than 1% of
patients die who take an overdose of acetaminophen and who are
treated promptly with NAC.
When NAC is given from 0 to 10 hours post-ingestion of
acetaminophen it is equally effective. There is evidence that NAC given
outside of this time period and even several days after an ingestion of
acetaminophen may be helpful, and it is recommended that NAC be
given in these situations.73,74 It can be given orally or IV; the IV form
is Acetadote®. Below are the various NAC administration routes and
dosing regimens, as well as the recommended laboratory studies and
potential side effects.
29

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 dose,
repeat the dose. The AST, ALT, INR, BUN, and creatinine should
be checked every day.
Nausea and vomiting are very common side effects. The NAC
should be diluted with juice or soda, served cold in a cup with a
lid (the odor of NAC is noxious) and sipped slowly. It can also be
given through a nasogastric tube.
Pre-treatment with an anti-emetic may also be helpful:
ondansetron or metoclopramide are more effective than
traditional anti-emetics such as prochlorperazine. Contradictions
to using oral NAC include sensitivity to NAC, the inability to use
the gut, or persistent vomiting.

Intravenous NAC:
The patient (if he/she is > 40 kg in bodyweight) is given a
loading dose of 150 mg/kg of Acetadote® in 200 ml of 5%
dextrose; and, this is given over 60 minutes. This is followed
immediately by a dose of 50 mg/kg in 500 ml of 5% dextrose,
and given over four hours. The third dose is given immediately
after the second, and it is 100 mg/kg in 1000 ml of 5%
dextrose, which is given over 16 hours.
If the patient’s bodyweight is > 100 kg, the maximum dose that
should be given is 15 grams, 5 grams, and 10 grams,
30
respectively, regardless of the bodyweight.75,76 Adverse
reactions to intravenous NAC are common (56% in some
prospective studies) but easily managed.73,77 These reactions
usually occur during the loading dose and are anaphylactoid;
such as, wheezing, urticaria, rash, pruritus, flushing, nausea,
and vomiting.73
Serious reactions such as
bronchospasm, dyspnea, and
hypotension are uncommon.
Diphenhydramine can be given for
cutaneous reactions and the
intravenous infusion can be
continued, but if the patient
develops angioedema,
Note: There is a website
sponsored by the company
that manufactures
Acetadote®,
www.acetadote.net, that
has a dosing calculator and
a lot of useful information
about the drug.
bronchospasm, or hypotension
then the infusion should be stopped;
and, beta agonists, corticosteroids, diphenhydramine,
epinephrine, and intravenous fluids as needed should be given.73
There should be a waiting period until the reaction subsides, and
then the infusion may be cautiously re-started. Two hours prior
to the end of the 16-hour infusion, an acetaminophen level, AST,
ALT, and INR should be obtained. If there is a measurable
acetaminophen level, or abnormal LFTs or INR, it may be
advisable to administer more intravenous NAC.
31
Learning Break: Older references may be found that recommend
infusing the loading dose of Acetadote® over 15 minutes. This was
the original protocol, but it was soon discovered that the incidence of
anaphylactoid reactions was unacceptably high and if the loading dose
was infused within 60 minutes, adverse reactions were far less
common. This difference is why some articles discussing intravenous
NAC will refer to a 20-hour protocol instead of the 21-hour protocol.
No one knows what the optimum treatment is for patients who have
received the entire oral or intravenous course of NAC and have
evidence of liver damage or a measurable acetaminophen serum level.
The accepted standard is to continue the NAC if, at the end of the
course of therapy, there is still measurable acetaminophen and/or
abnormal laboratory values indicating liver damage or dysfunction.74 It
has generally been thought that NAC can be discontinued when there
is evidence that the liver is recovering, but there is no agreed upon
definition of that term.
N-Acetylcysteine: Oral Versus Intravenous
There have been no randomized, controlled trials that have directly
compared the effectiveness of oral versus intravenous NAC, but the
available evidence indicates that when given within 0-10 hours postingestion there is no difference.78-81 The rate of serious adverse effects
is lower for intravenous NAC than it is for oral.73 Therapeutic overdose
with intravenous NAC has been reported to cause bronchospasm,
hypotension, and seizures.73
32
Clinical evidence suggests that intravenous NAC may be more effective
when it is given to patients who present within 12 hours of an
ingestion while the oral form is more effective if a patient presents 18
hours or later after an ingestion.81 At this time, the intravenous form is
preferred due to better tolerability and shorter hospital stay, and the
issue of which preparation is more effective if patients present early or
late has not been resolved.
Chronic Ingestions Of Excess Acetaminophen
Chronic ingestion of an excess amount of acetaminophen is a very
common and potentially very serious problem.82-85 The U.S. Acute
Liver Failure Multicenter Prospective Study found that unintentional
overdoses accounted for 48% of all cases of acetaminophen-related
acute liver failure85 and doses that were not far above the accepted
maximum have caused serious harm.84
Chronic excess ingestion - commonly called supratherapeutic ingestion
- is also a difficult problem to assess. Patients who have taken large
amounts of acetaminophen for several days typically do so because
they have dental and musculoskeletal pain, and they often cannot
remember their pattern of analgesic use. The Rumack-Matthew
nomogram cannot be used to determine if the serum acetaminophen
level is toxic or non-toxic. The serum transaminases may not be
elevated and the patient may be asymptomatic.
The AAPCC has provided a guideline for assessment and treatment of
chronic, supratherapeutic acetaminophen ingestions.10
33
1. Patients < 6 years of age should be referred to an emergency
department if they have ingested:
a) 200 mg/kg or more over a single 24-hour period;
b) 150 mg/kg or more per 24-hour period for the
preceding 48 hours; or
c) 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:
a) at least 10 g or 200 mg/kg (whichever is less) over a
single 24-hour period; or
b) at least 6 g or 150 mg/kg (whichever is less) per 24hour period for the preceding 48 hours or longer.
If the patient has risk factors that may make them susceptible to
acetaminophen toxicity (i.e., history of alcohol abuse,
alcoholism, isoniazid use, prolonged fasting), the dose of
acetaminophen considered potentially toxic should 4 grams or
100 mg/kg (whichever is less) per day.
Check the acetaminophen level, AST, ALT, INR, BUN, and creatinine. If
the patient) has signs/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.
34
It is not uncommon for patients to present many hours or days after
acetaminophen ingestion, and/or after the process of liver damage has
already begun. The optimal time for administering NAC is 0-10 hours
after ingestion, and NAC is essentially given to prevent liver damage.
However, there is evidence that NAC can be effective even if it is given
many hours or days after acetaminophen ingestion, and giving NAC in
these situations is commonly done.
Liver Failure And Transplantation
Acute liver failure can cause sepsis, hypoglycemia, metabolic acidosis,
encephalopathy, coagulopathies, and coma.3 Transplantation can be
the only effective therapy in certain cases of acute liver failure.
However, some patients will recover and transplantation has many
risks, so it is very important to know which patients will and which
patients will not, need a transplant. The King’s College Hospital Criteria
have traditionally been used to identify patients who need
transplantation.86 These criteria are:

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)
criteria have also been used, some researchers feel that serum lactate
is a better predictor for identifying patients who need transplantation,
and other guidelines have been proposed.87-89 These approaches all
have advantages and limitations and at this time the King’s College
Hospital Criteria appear to be the most commonly accepted
approach.90
35
Pregnancy And Acetaminophen Overdose
Overdose with acetaminophen by pregnant women has been
associated with spontaneous abortion and fetal death. Acetaminophen
does cross the placenta and reaches the fetus, and there is evidence
that the fetal liver can synthesize a toxic metabolite and the fetal liver
can be injured. The majority of cases of acetaminophen overdose by
pregnant women have had good outcomes, but if it is known or
suspected that a pregnant woman has taken an overdose of
acetaminophen, she should be treated with NAC.90 If there are signs of
fetal distress and the mother has evidence of severe hepatotoxicity,
emergency delivery is indicated.91
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
actually describing an effect of acetaminophen. If acetaminophen is
ingested in massive amounts a rapid onset of acidosis, coma, and
hypotension is possible.
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;
36
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 seen as 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. Patients may have
non-specific gastrointestinal complaints, but these may be absent or
resolve 24 hours or so 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 IV. No direct comparisons between the two forms have
37
been done, but the evidence suggests that they are equally effective.
The IV form is preferred because it is a 21-hour dosing protocol and
the oral dosing protocol is 72 hours. 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. Poor outcomes, liver failure and death, are
caused by patients who present late or have taken a massive
ingestion. Antidotal therapy should still be used but liver
transplantation may be the only hope.
Please take time to help NurseCe4Less.com course planners
evaluate the nursing knowledge needs met by completing the
self-assessment of Knowledge Questions after reading the
article, and providing feedback in the online course evaluation.
Completing the study questions is optional and is NOT a course
requirement.
38
1) Most acetaminophen is changed to harmless metabolites by:
a. conjugation
b. metabolism by cytochrome P-450 enzymes
c. elimination in the urine
d. elimination in the stool
2) Acetaminophen is converted to a toxic metabolite by:
a. conjugation
b. metabolism by cytochrome P-450 enzymes
c. elimination in the urine
d. elimination in the stool
3) The toxic dose of acetaminophen is:
a. ≥ 10 grams or 200 mg/kg
b. ≥ 7.5 grams or 150 mg/kg
c. ≥ 15 grams or 150 mg/kg
d. ≥ 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
39
5) One organ other than the liver that is affected by an
overdose of acetaminophen is:
a. the lungs
b. the small bowel
c. the kidneys
d. the thyroid
6) A massive overdose of acetaminophen can cause a rapid
onset of:
a. metabolic acidosis and coma
b. arrhthymias and ARDS
c. pancreatitis and congestive heart failure
d. coma and myocardial infarction
7. The serum acetaminophen level must be measured ____
after an ingestion.
a. 8 hours or more
b. 4 hours or more
c. 2 hours or more
d. 10 hours or more
8. Organ damage other than hepatic or renal is common after
acetaminophen overdose
a. True
b. False
40
9. Laboratory tests used to evaluate cases of acetaminophen
poisoning are:
a. LFTs, BUN, creatinine, INR
b. AST, CBC, and creatinine
c. ALT, INR, and TSH
d. AST, CK, and creatinine
10. The antidotal therapy for acetaminophen poisoning is:
a. glucagon
b. methylene blue
c. sodium thiosulfate
d. N-acetylcysteine (NAC)
Correct Answer Key:
1.
A
2.
B
3.
A
4.
A
5.
C
6.
A
7.
B
8.
B
9.
A
10. D
41
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