acetaminophen poisoning: a comprehensive review · acetaminophen poisoning: a comprehensive review...

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1

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.


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.


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.


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


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. 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.


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-the-

counter analgesic used for mild to

moderate pain and as antipyretic; it

appears to have minimal anti-

inflammatory 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.!


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

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 (NAPQI). This metabolite is toxic to the liver and

the kidneys.

Conjugation is a

process by which the acetaminophen is

bound to glucuronic acid and sulfate


However, if acetaminophen is ingested

in therapeutic doses, NAPQI is

combined with glutathione (also

known as GSH) and the NAPQI-

glutathione complex is converted to

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-the-

counter 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

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.


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.


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 Rumack-

Matthew 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.

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, meta-

analyses, 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


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


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

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.

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.


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

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

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.


(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.


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


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


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.


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


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


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 post-

ingestion 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


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


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


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


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


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


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.


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.


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.


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.


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


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


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


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


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


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


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.


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 Rumack-

Matthew 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. N-

acetylcysteine 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


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.

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.


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.




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.


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. 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. arrhythmias 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. 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. 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).


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. >100 mg/kg. b. >150 mg/kg. c. >200 mg/kg. d. >250 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. needs more IV NAC. b. should not be administered more NAC. c. begin a 2nd bad, 50 mg/kg in 1000 mL. d. 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. increased b. decreased. c. minimally affected, depending on the patient’s genotype. d. 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. Two b. Three c. Four d. Five

15. Administration of activated charcoal up to _______ hours

after an acetaminophen overdose has been recommended. a. Three b. Four c. Five d. Six


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. mild and temporary gastrointestinal distress. b. rash. c. blurry vision. d. Answers a., and b., are correct

18. Rash as a side effect of acetaminophen ingestion is more

common in a. children. b. women. c. elderly. d. people with preexisting skin disorders.

19. Unintentional overdoses accounted for ____% of all cases

of acetaminophen-related acute liver failure. a. 25 b. 33 c. 48 d. 55

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 b., are correct

21. True or False: Acetaminophen is the drug most commonly

taken with intent to cause self-harm. a. True b. False


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. APA b. AMA c. AAPCC d. 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. a liquid form of NAC. b. intravenous NAC. c. oral NAC, crushed. d. sublingual NAC.

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


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. does not cross the placenta to the fetus. b. the fetal liver can synthesize a toxic metabolite. c. can injure the fetal liver. d. 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


a. even in mild cases of acetaminophen poisoning. b. if the patient’s acetaminophen level is extremely high. c. if a patient refuses to drink oral NAC. d. in cases of elevated salicylate toxicity.

32. ____________ is the preferred method of gastric

decontamination of acetaminophen overdose.

a. Whole bowel irrigation. b. Induced vomiting. c. Activated charcoal d. 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. NAPQI. b. cytochrome P450. c. N-acetylcysteine (NAC). d. serum acetaminophen.

36. _________________ can slow gut peristalsis and delay

absorption of acetaminophen.


a. Activated charcoal. b. Salicylate c. N-acetylcysteine (NAC) d. Antihistamines and opioids

37. Liver transplantation may be the only effective therapy in

certain cases of acetaminophen overdose, such as

a. with a non-functioning gastrointestinal tract. b. disruption of administration due to nausea and vomiting. c. Grade III-IV encephalopathy. d. 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. a severe anaphylactoid reaction b. nausea c. a minor anaphylactoid reaction d. 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. with the delayed release, levels do not become toxic. b. opioids are the first line of defense to slow gut peristalsis. c. activated charcoal is not effective. d. 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


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.”


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.”


a. ≥ 10 grams or 200 mg/kg. “The toxic dose of acetaminophen is ≥10 grams or ≥200 mg/kg.”


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.


“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.


“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: N-acetylcysteine (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.


“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.”


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),


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]


“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 supra-therapeutic 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


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.”


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.”


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


“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.”

References Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014

Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015;53(10):962-1147.

2. Woolbright BL, Jaeschke H. Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol. 2016 Nov 29. pii: S0168-8278(16)30693-6. doi: 10.1016/j.jhep.2016.11.017. [Epub ahead of print]

3. Bunchorntavakul C, Reddy KR. Acetaminophen-related hepatotoxicity. Clin Liver Dis. 2013;17(4):587-607.

4. Lexicomp®. Acetaminonphen (Lexi-Drugs). November 28, 2016. http://online.lexi.com.online.uchc.edu/lco/action/doc/retrieve/docid/patch_f/6264.

5. Hendrickson RG. Acetaminophen. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank’s Toxicologic Emergencies, 10th ed. McGraw-Hill: New York, NY; 2015. 447-464.

6. Dart RC, Erdman AR, Olson KR, et al., Acetaminophen poisoning: An evidence-based consensus guideline for out-of-hospital management. Clinl Toxicol. 2006;44(1):1-18. Gosselin S, Hoffman RS, Juurlink DN, Whyte I, Yarema M, Caro J. Treating acetaminophen overdose: thresholds, costs, and uncertainties. Clinl Toxicol. 2013; 58(3):130-133.

7. Villeneuve E, Gosselin S, Whyte I. Four-hour acetaminophen concentration after ingested dose based on pharmacokinetic levels. Clin Toxicol. 2014;52(5):556-560.


8. Gelotte CK, Aulier JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day in healthy young adults. Clin Pharmacol Therapeut. 2007;81(6):840-848.

9. Dart RC, Green JL, Kuffner EK, Heard K, Sproule B, Brands B. The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol – a randomized study. Aliment Pharmacol Therapeut. 2010; 32(3):478-486.

10. Rumack B. Heard K, Green JL, et al. The effect of acetaminophen on serum alanine aminotranferase activity in patients who consume ethanol: a systematic review and meta-analysis of published randomized, controlled trials. Pharmacotherapy. 2012; 32(9):784-791.

11. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93.

12. Lavonas EJ, Reynolds KM, Dart RC. Therapeutic acetaminophen is not associated with liver injury in children: a systematic review. Pediatrics. 2010;126(6): e1430-e1444.

13. Heard KJ, Green JL, Dart RC. Serum alanine aminotransferase elevations during10 days of acetaminophen use in non-drinkers. Pharmacotherapy. 2010;30(8):818-822.

14. Kuffner EK, Temple AR, Cooper KM, Baggish JS, Parenti DL. Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials. Curr Med Res Opin. 2006;22(11):2137-2148.

15. Dart RC, Bailey E. Does therapeutic use of acetaminophen cause liver failure? Pharmacotherapy. 2007;27(9):1291-1230.

16. Savino F, Lupica MM, Tarasco V, Locatelli E, Garazzino S, Tovo PA. Fulminant hepatitis after 10 days of acetaminophen treatment at recommended dosage in an infant. Pediatrics. 2011;127(2); e494-e497.

17. Forget P, Wittebole X, Laterre PF. Therapeutic dose of acetaminophen may induce fulminant hepatitis in the presence of risk factors: a report of two cases. Br Journal of Anaesth. 2009;103(60:899-900.

18. Alhelail MA, Hoppe JA, Rhyee SH, Heard KJ. Clinical course of repeated supra-therapeutic ingestion of acetaminophen. Clin Toxicol. 2011;49(2):108-112.

19. Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-induced hepatotoxicity: a comprehensive update. J Clin Transl Hepatol. 2016;4(2):131-142.

20. Burns, MJ, Friedman, SL, Larson AM. Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation,


and diagnosis. UpToDate. October 6, 2015. Retrieved online at http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults-pathophysiology-presentation-and-diagnosis.

21. Singer AJ, Carracio TR, Mofenson HC. The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction. Ann Emer Med. 1995;26(1):49-53.

22. Green TJ, Silvioti ML, Langman C, et al. When do the aminotransferases rise after acute acetaminophen overdose? Clin Toxicol. 2010;48(8):787-792.

23. Al-Hourani K, Mansi R, Pettie J, Dow M, Bateman DN, Dear JW. The predictive value of hospital admission serum alanine transaminase activity in patients treated for paracetamol overdose. QJM. 2013;106(6):541-546.

24. Chen YG, Lin CL, Dai MS, et al. Risk of acute kidney injury and long-term outcome in patients with acetaminophen intoxication: A nationwide population-based retrospective cohort study. Medicine (Baltimore). 2015 Nov;94(46): e2040. doi: 10.1097/MD.0000000000002040.

25. Kanji HD, Mithani S, Boucher P, Dia VC, Yarema MC. Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity. J Popul Ther Clin Pharmacol. 2013;20(3): e207-e211.

26. Zell-Kanter M, Coleman P, Whiteley PM, Leikin JB. A gargantuan acetaminophen level in an acidemic patient treated solely with intravenous N-acetylcysteine. Am J Ther. 2013;20(1):104-106.

27. Sivilotti ML, Juurlink DN, Garland JS, et al. Antidote removal during haemodialysis for massive acetaminophen overdose. Clin Toxicol (Phila). 2013;51(9):855-863.

28. Gosselin S, Juurlink DN, Kielstein JT, et al. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol (Phila). 2014;52(8):856-867.

29. Ghannoum M, Kazim S, Grunbaum AM, Villeneuve E, Gosselin S. Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics. Clin Toxicol (Phila). 2016;54(6):519-522.

30. Lip GY Vale JA. Does acetaminophen damage the heart? J Toxicol Clin Toxicol. 1996;34(2):145-147.

31. Armour A, Slater SD. Paracetamol cardiotoxicity. Postgrad Med J. 1993;69(807):52-54.

32. Ralapanawa U, Jayawickreme KP, Ekanayake EM, Dissanayake AM. A study on paracetamol cardiotoxicity. BMC Pharmacol Toxicol Jul 2016:14;17(1):30. doi: 10.1186/s40360-016-0073-x.

33. Cavanaugh Z, Naut R. Acetaminophen-induced pancreatic pseudocyst: first case report. Conn Med. 2014;78(1):37-39.


34. Igarashi H, Ito T, Yoshinaga M, Oono T, Sakai H, Takayanagi R. Acetaminophen-induced pancreatitis. A case report. JOP. 2009;10(5):550-553.

35. Schmidt LE, Dalhoff K. Hyperamylasaemia and acute pancreatitis in paracetamol poisoning. Aliment Pharmacol Ther. 2004; 20(2):173-179.

36. Tenebein M. Acetaminophen: the 150mg/kg myth. J Toxicol Clin Toxicol. 2004;42(2):145-148.

37. Bond GR. Reduced toxicity of acetaminophen in children: It’s the liver. J Toxicol Clin Toxicol. 2004;42(2):149-152.

38. Heard K, Rumack BH, Green JL, et al. A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning. Clin Toxicol. 2014;52(5):518-525.

39. Acetadote [package insert]. Nashville, TN: Cumberland Pharmaceuticals; 2004.

40. Ashbourne JF, Olson KR, Khayam-Bashi H. Value of rapid screening for acetaminophen in all patients with intentional drug overdose. Ann Emerg Med. 1989;18(10):1035-1038.

41. Sporer KA, Khayam-Bashi H. Acetaminophen and salicylate serum levels in patients with suicidal ingestion or altered mental status. Am J Emerg Med. 1996;14(5):443-446.

42. Lucanie R, Chiang WK, Reilly R. Utility of acetaminophen screening in unsuspected suicidal ingestions. Vet Hum Toxicol. 2002;44(3):171-173.

43. Yarema MC, Green JP, Sivilotti ML, et al. Can a serum acetaminophen concentration obtained less than 4 hours post-ingestion determine which patients do not require treatment with acetylcysteine? Clin Toxicol (Phila). 2016 Oct 28:1-7. [Epub ahead of print]

44. Seifert SA, Kirschner RI, Martin TG, Schrader RM, Karowski K, Anaradian PC. Acetaminophen concentrations prior to 4 hours of ingestion: impact on diagnostic decision-making and treatment. Clin Toxicol (Phila). 2015;53(7):618-623.

45. Froberg BA, King KJ, Kurera TD, et al. Negative predictive value of acetaminophen concentrations within four hours of ingestion. Academ Emerg Med. 2013;20(10):1072-1075.

46. Rhyee SH. Early serum acetaminophen levels: How soon is too soon? Academ Emerg Med. 2013;20(10):1070-1071.

47. Hendrickson RG, McKeown NJ, West PL, Burke CR. Bactrian (“Double hump”) acetaminophen pharmacokinetics: A case series and review of the literature. J Medical Toxicol. 2010;6(3):337-344.

48. Ferguson KL, Chan GM, Lee C, Greller HA, Su M. Delayed hepatotoxicity from combined acetaminophen and


diphenhydramine despite 21-hour intravenous acetylcysteine. Clin Toxicol. (Abstract) 2007;45(6):615.

49. Ho S, Arellano M, Zolkowski-Wynne J. Delayed increase in acetaminophen concentration after Tylenol PM overdose. Am J Emerg Med. 1999;17(3):315-317.

50. Schwartz EA, Hayes BD, Sarmiento KF. Development of hepatic failure despite use of intravenous acetylcysteine after a massive ingestion of acetaminophen and diphenhydramine. Ann Emerg Med. 2009;54(3):421-423.

51. Chan BS, Graudins A, Chiew A. Acetaminophen poisoning with a difference. (Abstract) Clin Toxicol. 2008;46(7):601-602.

52. Kirschner R, Rozier CM, Smith LM, Jacobitz KL. Nomogram line crossing after acetaminophen combination product overdose. Clin Toxicol (Phila). 2016;54(1):40-46.

53. Bihari S, Verghese S, Bersten AD. Delayed and prolonged elevated serum paracetamol level after an overdose – possible causes and implications. Crit Care and Resusc. 2011;13(4):275-277.

54. Smith SW, Howland MA, Hoffman RS, Nelson LS. Acetaminophen overdose with altered acetaminophen pharmacokinetics and hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy. Ann Pharmacother. 2008;42(9):1333-1339.

55. Graudins A. Overdose with modified-release paracetamol (Panadol Osteo®) presenting to a metropolitan emergency medicine network: a case series. Emerg Med Australas. 2014;26(4):398-402.

56. Dougherty PP, Klein-Schwartz W. Unexpected late rise in plasma acetaminophen concentrations with change in risk stratification in acute acetaminophen overdoses. J Emergency Med. 2012;43(1):58-63.

57. Graudins A, Chiew A, Chan B. Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol. Intern Med J. 2010;40(1):72-76.

58. Polson J, Wians FH Jr, Orsulak P, et al. False positive acetaminophen concentrations in patients with liver injury. Clin Chim Acta. 2008; 391(1-2):24-30.

59. Beuhler MC, Curry SC. False positive acetaminophen levels associated with hyperbilirubinemia. Clin Toxicol (Phila). 2005;43(3):167-170.

60. Bertholf RL, Johannsen LM, Bazooband A, Mansouri V. False-positive acetaminophen results in a hyperbilirubinemic patient. Clin Chem. 2003 Apr;49(4):695-698.


61. Thijssen HH, Soute BA, Vervoort LM, Claessens JG. Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle. Thromb Haemost. 2004;92(4):797-802.

62. Whyte IM, Buckley NA, Reith DM, Goodhew I, Seldon M, Dawson AH. Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit. 2000;22(6):742-748.

63. Jepsen S, Hansen AB. The influence of N-acetylcysteine on the measurement of prothrombin time and activated partial thromboplastin time in healthy subjects. Scand J Clin Lab Invest. 1994;54(7):543-547.

64. Mullins ME, Schmidt RU Jr, Jang TB. What is the rate of adverse events with intravenous versus oral N-acetylcysteine in pediatric patients? Ann Emerg Med. 2004;44(5):547-548; author reply 548-549.

65. Pizon AF, Jang DH, Wang HE. The in vitro effect of N-acetylcysteine on prothrombin time in plasma samples from healthy subjects. Acad Emerg Med. 2011;18(4):351-354.

66. Jang DH, Weaver MD, Pizon AF. In vitro study of N-acetylcysteine on coagulation factors in plasma samples from healthy subjects. J Med Toxicol. 2013;9(1):49-53.

67. Thorsen S, Teisner A, Jensen SA, Philips M, Dalhoff K, Bendtsen F. Effect of N-acetylcysteine on the accuracy of the prothrombin time assay of plasma coagulation factor II+VII+X activity in subjects infused with the drug. Influence of time and temperature. Scand J Clin Lab Invest. 2009;69(6):643-650.

68. Howland MA. N-Acetylcysteine. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank’s Toxicologic Emergencies, 10th ed. McGraw-Hill: New York, NY; 2015. 465-472.

69. Buckley NA, Whyte IM, O’Connell DL. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. J Toxicol Clin Toxicol. 1999;37(6):753-757.

70. Duffull SB Isbister GK. Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported doses. Clin Toxicol. 2013;51(8):772-776.

71. Heard K, Dart R. Acetaminophen (paracetamol) poisoning in adults: Treatment. UpToDate. August 30, 2016 https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults-treatment?source=search_result&search=acetaminophen%20toxicity&selectedTitle=1~124.


72. Chyka PA, Seger D, Krenzelok EP, Vale JA; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005;43(2):61-87.

73. Spiller HA, Winter ML, Klein-Schwartz W, Bangh SA. Efficacy of activated charcoal administered more than four hours after acetaminophen overdose. J Emerg Med. 2006;30(1):1-5.

74. Olson KR. Acetaminophen. In: Olson KR, Anderson IB, Benowitz, NL, et al, eds. Poisoning & Drug Overdose, 6th ed. New York, NY: McGraw-Hill;2011.

75. Klein-Schwartz W, Doyon S. Intravenous acetylcysteine for the treatment of acetaminophen poisoning. Expert Opin Pharmacother. 2011;12(1):119-130.

76. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol (Phila). 2012;50(2):91–98.

77. Bebarta VS, Kao L, Froberg B, et al. A multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose. Clin Toxicol (Phila). 2010;48(5):424-430.

78. Yarema MC, Johnson DW, Nettel-Aguirre A, et al. IV versus oral N-acetylcysteine. Ann Emerg Med. 2010;55(4):394-395.

79. Yarema MC, Johnson DW, Berlin RJ, et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med. 2009;54(4):606-614.

80. Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med. 2005;45(4):409-413.

81. Schmidt LE. Identification of patients at risk of anaphylactoid reactions to N-acetylcysteine in the treatment of paracetamol overdose. Clin Toxicol (Phila). 2013;51(6):467-472.

82. Kerr F, Dawson A, Whyte I, et al. The Australasian Clinical Toxicology Intervention Collaboration randomized trial of different loading infusion rates of doses N-acetylcysteine. Ann Emerg Med. 2005;45(4):402-408.

83. Sandilands EA and Bateman DN. Adverse reactions associated with acetylcysteine. Clin Toxicol (Phila). 2009;47(2):81-88.

84. Waring WS, Stephen AF, Robinson OD, et al. Lower incidence of anaphylactoid reactions to N-acetylcysteine in patients with high acetaminophen concentrations after overdose. Clin Toxicol (Phila).2008;46(6):496-500.

85. Pakravan N, Waring WS, Sharma S, Ludlam C, Megson I, Bateman DN. Risk factors and mechanisms of anaphylactoid


reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol (Phila. 2008;46(8):697–702.

86. Prescott LF, Critchley JA. Asthma associated with N-acetylcysteine infusion and paracetamol poisoning. Br Med J (Clin Res Ed). 1984;288(6411):151.

87. Ho SW, Beilin LJ. Asthma associated with N-acetylcysteine infusion and paracetamol poisoning: report of two cases. BMJ. 1983;287:876–877.

88. Yamamoto T, Spencer T, Dargan PI, Wood DM. Incidence and management of N-acetylcysteine-related anaphylactoid reactions during the management of acute paracetamol overdose. Eur J Emerg Med. 2014 Feb;21(1):57-60.

89. Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med. 1998;31(6):710-715.

90. American College of Medical Toxicology. ACMT Position Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose. J Med Toxicol. 2016 Mar 8. [Epub ahead of print]

91. McGovern AJ, Vitkovitsky IV, Jones DL, Mullins ME. Can AST/ALT ratio indicate recovery after acute paracetamol poisoning? Clin Toxicol (Phila). 2015;53(3):164-167.

92. Lucyk SN, Yarema MC, Sivilotti ML, et al. Outcomes of patients with premature discontinuation of the 21-h intravenous N-acetylcysteine protocol after acute acetaminophen overdose. J Emerg Med. 2016;50(4):629-637.

93. Wong A, Graudins A. N-acetylcysteine regimens for paracetamol overdose: Time for a change? Emerg Med Australas. 2016;28(6):749-751.

94. Acheampong P, Thomas SH. Determinants of hepatotoxicity after repeated supra-therapeutic paracetamol ingestion: systematic review of reported cases. Br J Clin Pharmacol. 2016;82(4):923-931.

95. Alhelail MA, Hoppe JA, Rhyee SH, Heard KJ. Clinical course of repeated supra-therapeutic ingestion of acetaminophen. Clin Toxicol (Phila). 2011;49(2):108-112.

96. Wolf MS, King J, Jacobson K, et al. Risk of unintentional overdose with non-prescription acetaminophen products. J Gen Intern Med. 2012;27(12):1587-1593.

97. Bond GR, Ho M, Woodward RW. Trends in hepatic injury associated with unintentional overdose of paracetamol (acetaminophen) in products with and without opioid: an analysis using the National Poison Data System of the American


Association of Poison Control Centers, 2000-7. Drug Saf. 2012;35(2):149-157.

98. Larson M, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364–1372.

99. Bronstein AC, Spyker DA, Cantilena LR Jr., Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). 2008;46(10):927-1057.

100. Lexicomp®. Acetylcysteine (Briggs Drugs in Pregnancy and Lactation). June 6, 2016. http://online.lexi.com.online.uchc.edu/lco/action/doc/retrieve/docid/1090/5711016.

The information presented in this course is intended solely for the use of healthcare professionals taking this course, for credit, from NurseCe4Less.com. The information is designed to assist healthcare professionals, including nurses, in addressing issues associated with healthcare. The information provided in this course is general in nature, and is not designed to address any specific situation. This publication in no way absolves facilities of their responsibility for the appropriate orientation of healthcare professionals. Hospitals or other organizations using this publication as a part of their own orientation processes should review the contents of this publication to ensure accuracy and compliance before using this publication. Hospitals and facilities that use this publication agree to defend and indemnify, and shall hold NurseCe4Less.com, including its parent(s), subsidiaries, affiliates, officers/directors, and employees from liability resulting from the use of this publication. The contents of this publication may not be reproduced without written permission from NurseCe4Less.com.

acetaminophen poisoning: a comprehensive review · acetaminophen poisoning: a comprehensive review...

Documents