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 L.P.’s acetaminophen ingestion occurred 5 hours ago; therefore, the drug is likely to be totally absorbed, and no GI decontamination should be initiated.

Estimating Potential Toxicity

CASE 4-5, QUESTION 4: How should the potential toxicity

of the acetaminophen ingestion be assessed in L.P.?

Acetaminophen toxicity results from ingestions greater than

150 mg/kg or more than 7.5 g total in adults. However, serum

acetaminophen concentrations better predict acetaminopheninduced hepatotoxicity than the dose of acetaminophen acutely

ingested.164,165 The Matthew-Rumack nomogram (Fig. 4-1) is

used in the United States to assess the potential for hepatotoxicity

from acute overdoses of acetaminophen.165 The treatment line is

defined by a serum acetaminophen concentration of 200 mcg/mL

at 4 hours after acetaminophen ingestion and 30 mcg/mL at

15 hours after ingestion on a semilogarithmic graph.157 Others prefer to be more conservative and use the bottom line of

150 mcg/mL at 4 hours to begin treatment as histories of ingestion are often inaccurate. The serum acetaminophen concentration is plotted on a graph against the time of ingestion.165 The

nomogram predicts the probability that the AST or ALT will be

greater than 1,000 international units/L and can be used to guide

therapy by indicating whether a specific acetaminophen concentration is in the toxic range.166 The nomogram is useful only

for acute ingestions because it underestimates the potential for

toxicity in chronic acetaminophen ingestions. It should be noted

Hours After Acetaminophen Ingestion

Plasma Acetaminophen Concentration

5

10

50

500 Lower limit for high-risk group

Lower limit for probable-risk group

Treatment nomogram line

400

300

200

150

100

50

30

100

500

1,000

1,300

2,000

3,000

4,000

mcg/mL mol/L 4 8 12 16 20 24

FIGURE 4-1 Nomogram for interpretation of severity of

acetaminophen poisoning. Adapted with permission from

Smilkstein MJ et al. Efficacy of oral N-acetylcysteine in the treatment

of acetaminophen overdose: analysis of national multicenter study

(1976–1985). N Engl J Med. 1988;319:1557.

that although the nomogram is used to plot acetaminophen concentrations for all patients, it has been validated only in healthy

nonalcoholic adult patients.157

Acetaminophen Treatment Nomogram

CASE 4-5, QUESTION 5: When is the preferred time to measure a serum acetaminophen concentration?

Acetaminophen absorption generally is complete within

1.5 to 2.5 hours after ingestion of solid or liquid dosage forms.165

The Matthews-Rumack nomogram is not applicable before

4 hours after ingestion because it is based on complete drug

absorption.165 Most clinical laboratories can complete their

assays and report acetaminophen serum concentration results

within 2 hours.

Stages of Acetaminophen Toxicity

CASE 4-5, QUESTION 6: What are the clinical signs and

symptoms of acetaminophen toxicity?

Early detection of an acetaminophen overdose is difficult

because there are no characteristic early diagnostic findings.

Toxicity appears in stages that may overlap and are not clearcut. About 30 minutes to 24 hours after ingestion, the patient

may exhibit anorexia, nausea, vomiting, malaise, and diaphoresis that can easily be attributed to other causes. The second

stage of acetaminophen toxicity occurs about 24 to 48 hours

after ingestion and is the stage in which hepatotoxicity develops. Hepatotoxicity is universal by 36 hours after ingestion. An

AST measurement is the most sensitive measure of hepatotoxicity as AST abnormalities always precede evidence of actual liver

impairment.157,167,168

In the third stage, 72 to 96 hours after ingestion, maximal

liver dysfunction is evident with the return of anorexia, nausea,

vomiting, and malaise. Symptoms can range from mild to fulminant liver failure with hepatic encephalopathy, coma, and hemorrhage. AST and ALT serum concentrations can be greater than

10,000 international units/L. There are also increases in bilirubin

and INR measurements, as well as abnormalities in glucose and

pH readings. Death, if it occurs, is usually a result of multiorgan

failure or hemorrhage caused by hepatic failure. Most deaths

occur 3 to 5 days after exposure. Patients who survive this stage

go into recovery.157,167,168

Antidotes

CASE 4-5, QUESTION 7: What antidote for acetaminophen

ingestion should be considered in L.P.? How does the antidote work, and when is it most effective?

Toxicity is determined by the results of a serum

acetaminophen concentration measured at least 4 hours after

ingestion.165 NAC is the antidote for acetaminophen toxicity.

NAC is a sulfhydryl donor that converts to cysteine, which is

subsequently converted to glutathione.154,166–168 NAC acts as

a glutathione substitute and directly combines with the toxic

acetaminophen metabolite, NAPQI, reducing it to a nontoxic cysteine conjugate.167 NAC can also substitute for sulfation, which

increases the nontoxic metabolism through that route as well.

NAC increases intrahepatic microcirculation and is believed to

possess hepatoprotective properties, showing some value even

after liver damage has already occurred.154,168

85Managing Drug Overdoses and Poisonings Chapter 4

Instituting therapy early with NAC is essential. When NAC

is started within 8 to 10 hours of the ingestion, hepatotoxicity

resulted in only 1.6% of cases. In patients who were started on

NAC more than 10 hours after ingestion, 53% developed liver

damage.157,168

Safety of N-Acetylcysteine in Pregnancy

CASE 4-5, QUESTION 8: Is NAC safe to use during pregnancy?

Acetaminophen overdose in pregnant women should be managed in the same manner as in nonpregnant patients.160–163 If

the life of the mother is not saved, the fetus will not survive

(unless the child is near term and is emergently delivered); therefore, attention to the mother must be foremost. NAC therapy

is not contraindicated in pregnant patients and might be helpful

because it crosses the placenta and can protect the fetus from

hepatotoxicity.160,162,163

NAC therapy appears to be protective for both mother and

fetus.154,157,160–163 When used as an antidote for acetaminophen

overdose in pregnancy, NAC did not appear to result in toxic

effects to the fetus.154,157,160,162,163 The probability of fetal death

was increased with the delay in NAC treatment after overdose

and with acetaminophen overdose early in gestation.157,160,168

Route of Administration of

N-Acetylcysteine

CASE 4-5, QUESTION 9: The 6-hour acetaminophen concentration in L.P. was 245 mcg/mL. By what route should

NAC be administered?

This concentration of acetaminophen at 6 hours is above the

treatment line on Figure 4-1. Because there was some delay from

the time of ingestion to presentation at the ED and L.P. was

already vomiting, it will be more difficult for L.P. to tolerate oral

NAC. For this reason, IV NAC is recommended.

An FDA-approved sterile, pyrogen-free formulation of NAC is

available as Acetadote.169–171 The use of IV NAC is not completely

risk-free because of a possible anaphylactoid reaction during the

first dose of the IV NAC. The incidence of adverse reactions

ranges from 14.3% to 23%. Asthmatic patients and patients with

ectopy should receive the drug slowly and carefully, while being

watched for symptoms of a reaction.171

A majority of the adverse reactions include nausea, vomiting,

urticaria, flushing, and pruritus. Bronchospasm, angioedema,

hypotension, and death have rarely occurred and must be carefully monitored when the IV route is being used.169,172,173 Most

reactions occur during or just after the first 15 minutes of the initial antidote infusion and appear to be dose related.173 Because

of the timing issue, the first dose of IV NAC is usually administered for 60 minutes instead of 15 minutes, even though a study

comparing adverse reactions in the two infusion rates did not

show clinically significant differences.171,174

Intravenous N-Acetylcysteine

CASE 4-5, QUESTION 10: How should IV NAC be administered to L.P.?

The FDA-approved IV NAC protocol is the same 20-hour

dosing regimen used in Europe, known as the Prescott protocol.169,170,171 A 150 mg/kg loading dose of NAC in 5% dextrose

is infused IV slowly for 60 minutes while watching for symptoms of a possible anaphylactoid reaction. This is followed by

a maintenance dose of 50 mg/kg infused for 4 hours, and then

followed with a 100 mg/kg dose infused for 16 hours. This regimen provides a total of 300 mg/kg NAC during the 20 hours

after the loading dose.171 As soon as the patient is able to tolerate oral administration, the patient can be switched to oral NAC

therapy.

Oral N-Acetylcysteine

CASE 4-5, QUESTION 11: Once she is able to tolerate oral

NAC treatment, what dosing regimen would be appropriate

for L.P.?

The standard oral NAC protocol is based on the original clinical studies.166 The loading dose of NAC is 140 mg/kg orally using

either the 10% or 20% mucolytic solutions that were formulated

for inhalation therapy. Seventeen additional maintenance doses

of 70 mg/kg of NAC are administered at 4-hour intervals after the

initial dose, for a total of 72 hours of therapy. This provides a total

of 1,330 mg/kg NAC during 72 hours.169,175 Because oral NAC

contains a sulfhydryl group, the substance has a very disagreeable taste and smell (like rotten eggs) that commonly results in

nausea and vomiting for the patient. To mask the unpleasant

taste and odor, NAC is diluted to a concentration of 5% using

a carbonated beverage or fruit juice.166 Because the entire dose

of oral NAC passes through the liver, high concentrations are

produced, which is seen as an advantage of oral therapy.169

Shorter oral NAC regimens are currently being used based

on the efficacy of IV therapy.176,177 Short-course oral NAC follows the same 20-hour time course as IV NAC. Patients receive

the usual 140 mg/kg oral loading dose of NAC, followed by

70 mg/kg every 4 hours for five additional doses (20 hours of

therapy). Serum acetaminophen, liver function tests, and INR

are repeated at 20 hours after the loading dose, which is after the

fifth maintenance dose. If 20-hour liver function tests and coagulation studies are normal and the acetaminophen level is less

than the lower limits of detection, NAC can be stopped. A repeat

set of liver function tests is recommended at 36 hours after ingestion. In other versions of the 20-hour NAC therapy, the dosage

regimen is the same, but the laboratory studies are measured

initially, and then at 16, 36, and 48 hours after ingestion.177

Efficacy of N-Acetylcysteine

CASE 4-5, QUESTION 12: Which route of NAC administration is more effective?

There is no proven evidence that one route of NAC administration is superior to the other.168,169,178–180 Patient outcome

after an acetaminophen overdose depends more on the time

after the ingestion that treatment begins rather than on the

route of administration of NAC. Patients who are started on

NAC within 8 to 10 hours after ingestion, regardless of the

route, rarely develop hepatotoxicity. Patients who present late

or have a delay in the time of NAC treatment have higher rates

of hepatoxicity.154,168,169,175,179–181

In one comparative study of IV NAC to oral NAC therapy,

both were effective in reducing hepatotoxicity when therapy was

initiated within 10 hours after ingestion. Vomiting delayed oral

administration of the drug, but IV administration resulted in significantly longer delays in instituting therapy.179 IV NAC avoids

the problems of the vomiting patient, but oral NAC is safer. Oral

86 Section 1 General Care

NAC is associated with nausea and vomiting, whereas IV NAC is

associated with bronchospasm, urticaria, and angioedema during administration.154,168 In addition, oral therapy is much less

expensive.181

Although the time of initiation of therapy is one of the key factors in reducing hepatotoxicity from acetaminophen ingestions,

length of therapy has become another factor.180,182 Because the

duration of therapy with the IV formulation is 21 hours, patients

with severe toxicity may be undertreated. It is essential that the

patient be re-evaluated at the end of the 21 hours to make sure that

acetaminophen levels are not detectable and that liver enzymes

are trending downward significantly. If there is still measurable

acetaminophen and liver enzymes are still elevated, therapy with

NAC must be continued.

Starting oral NAC may take less time to prepare than IV NAC

therapy and is less expensive. If the patient presents early after an

acetaminophen ingestion and does not have nausea and vomiting, oral therapy would be indicated. If the patient presents late

(more than 10 hours after ingestion) with signs and symptoms

of hepatotoxicity along with intractable nausea and vomiting, IV

NAC should be instituted at once.169,175

Monitoring Efficacy of N-Acetylcysteine

CASE 4-5, QUESTION 13: How should the efficacy of NAC

therapy be monitored in L.P.?

The effectiveness of NAC intervention in L.P. should be monitored by daily assessment of her acetaminophen concentration

(as long as it is still measurable), AST, ALT, total bilirubin,

glucose, and INR. The AST and ALT serum concentrations

typically increase within 36 hours (range, 24–72 hours) after

ingestion.168,179 As the hepatic damage continues, the liver

enzymes may peak at several tens of thousands units, even with

NAC therapy. In most patients, AST and ALT begin to decline

after 3 days and then return to baseline values.168

In a small number of patients, usually those who presented late

after the ingestion, fulminant hepatic failure may develop. Symptoms of severe or persistent acidosis, coagulopathy, a significantly

increased serum creatinine, and grade III to IV encephalopathy

are consistent with fatal outcomes in patients with fulminant

hepatic failure. Liver transplantation might be a consideration

for these patients.157,183–186

Duration of N-Acetylcysteine Therapy

CASE 4-5, QUESTION 14: How long should NAC administration be continued?

The original NAC dosing protocol was based on an assumption that the half-life of acetaminophen was 4 hours. After five

half-lives (20 hours), the acetaminophen should be metabolized

and NAC could be discontinued. An NAC dose of 6 mg/kg/hour

was determined to be necessary based on the rate of glutathione

turnover relative to NAPQI production. To ensure that patients

received an adequate NAC dose, the FDA recommended that

this dose be changed to 18 mg/kg/hour for 72 hours.187 This recommendation serves as the basis for the traditional 72-hour oral

course of NAC therapy.

When using the traditional 72-hour oral course of NAC, therapy can be discontinued if the liver function tests are trending toward normal, other laboratory tests (i.e., coagulation

studies, glucose, pH, bilirubin) are within normal ranges, and

acetaminophen is no longer present in the serum. As long as

acetaminophen is present, it can be metabolized to NAPQI and

cause further toxicity.168,176,187 Continued NAC will not be harmful to the patient and can be beneficial.

When using the shorter 20-hour course of oral NAC, if

liver function tests and coagulation studies are normal and the

20-hour acetaminophen concentration can no longer be measured in the serum, NAC therapy can be stopped.177 However, if

20-hour liver function tests or coagulation studies are abnormal,

or if the 20-hour acetaminophen concentration measurement

reveals acetaminophen still present in the serum, NAC therapy

should be continued for at least another 24 hours.178,179 Laboratory tests should be repeated every 24 hours, and the patient’s

progress must be monitored closely. If the patient is not improving, NAC should be continued until the patient recovers, receives

a liver transplant, or dies.157

At this time, there is no consensus as to the best route of

NAC administration, optimal dosage regimen, or optimal length

of therapy.168,169,187 There is consensus, however, that for optimal results, NAC therapy must be instituted within 10 hours

after ingestion.154,168,169,175,179,181 For patients who do not exhibit

any signs of hepatotoxicity, shorter-course NAC therapy reduces

the amount of NAC administered to the patient, decreases the

quantity of laboratory tests, shortens hospital stay, and is less

costly.169,176,187

N-Acetylcysteine Toxicity

CASE 4-5, QUESTION 15: How should the toxicity of NAC

therapy be monitored in L.P.?

With the exception of vomiting, oral NAC is remarkably safe

and has not been associated with toxicity.154,168,169 Oral NAC

must be retained for a minimum of 1 hour after ingestion to

be successfully absorbed. If L.P. vomits within an hour after

her oral NAC dose, the dose should be repeated. If she experiences protracted vomiting, administration of antiemetic drugs

(e.g., ondansetron, metoclopramide) or placement of a duodenal feeding tube can improve GI tolerance.169,188,189 If the patient

cannot tolerate oral liquids, NAC therapy should continue via IV

administration.

IV NAC therapy has been associated with anaphylactoid reactions in up to 14% of the patients. Although most reactions are

not severe, bronchospasm, angioedema, and respiratory arrest

have been reported.154,168,169,187 Patients should be monitored for

allergic and anaphylactoid reactions when NAC is administered

IV. Most reactions can be avoided by infusing the NAC loading

dose slowly for 60 minutes.154,168,169

Outcome of Patient L.P.

L.P. continued to have nausea and vomiting and had difficulty

tolerating liquids. IV NAC was continued. An obstetrics consultation was requested to evaluate L.P.’s pregnancy. Fetal monitoring was instituted during her hospital admission. A sonogram

was taken of the baby. Once L.P. saw her baby’s image from the

sonogram, her depressed mood seemed to lift. Approximately

36 hours after ingestion, her acetaminophen level was no longer

detectable, and her liver function tests showed a mild elevation

of her AST at 274 units/L and an ALT of 188 units/L. Her INR and

total bilirubin values were normal at 0.7 seconds and 0.8 mg/dL,

respectively.

L.P. was seen by a psychiatrist. She was scheduled for counseling and prenatal classes. L.P. seemed eager to attend the classes,

and she talked enthusiastically about the baby when family members came to visit. Because of L.P.’s pregnancy, the decision was

87Managing Drug Overdoses and Poisonings Chapter 4

made to continue NAC for a full 72-hour course with the goal

of protecting the fetal liver as much as possible. Six weeks later,

she had a normal delivery of a healthy 6-pound, 1-ounce baby

girl.

SUMMARY

Unfortunately, there is no cookbook method to treat all poisoned

patients. Each exposure is unique: the patients, substances, symptoms, time of exposure, and circumstances differ in each case.

Treatment of the poisoned patient often involves controversy

because solid, evidence-based science to support a given decision is frequently lacking. When challenged with a poisoning

exposure, consult with a poison control center. By calling 1-800-

222-1222, the call will be connected to the poison center where

consultation is available 24 hours a day nationwide.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT10e. Below are the key references

and websites for this chapter, with the corresponding reference number in this chapter found in parentheses after the

reference.

Key References

Boyle JS et al. Management of the critically poisoned patient.

Scand J Trauma Resusc Emerg Med. 2009;17:29. (29)

Bronstein AC et al. 2009 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 27th Annual Report. Clin Toxicol (Phila). 2010;48:

979. (3)

Chyka PA et al. Position paper: single-dose activated charcoal.

Clin Toxicol (Phila). 2005;43:61. (46)

Committee on Poison Prevention and Control, Board on Health

Promotion and Disease Prevention, Institute of Medicine of the

National Academies. Poison control center activities, personnel,

and quality assurance. Forging a Poison Prevention and Control System. Chapter 5. Washington, DC: The National Academies Press;

2004. (22)

Forsberg S et al. Coma and impaired consciousness in the emergency room: characteristics of poisoning versus other causes.

Emerg Med J. 2009;26:100. (120)

Kociancic T, Reed MD. Acetaminophen intoxication and length

of treatment: how long is long enough. Pharmacotherapy. 2003;23:

1052. (187)

Manoguerra AS et al. Iron ingestion: an evidence-based consensus guideline for out-of-hospital management.Clin Toxicol (Phila).

2005;43:553. (96)

[No authors listed]. Position paper: cathartics [published correction appears in J Toxicol Clin Toxicol. 2004;42:1000]. J Toxicol Clin

Toxicol. 2004;42:243. (47)

[No authors listed]. Position paper: ipecac syrup [published correction appears in J Toxicol Clin Toxicol. 2004;42:1000]. J Toxicol

Clin Toxicol. 2004;42:133. (44)

[No authors listed]. Position paper: whole bowel irrigation [published correction appears in J Toxicol Clin Toxicol.

2004;42:1000; dosage error in article text]. J Toxicol Clin Toxicol.

2004;42:843. (48)

Proudfoot AT et al. Position paper on urine alkalinization.

J Toxicol Clin Toxicol. 2004;42:1. (70)

Rumack BH et al. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;

141(3 Spec No):380. (166)

Liebelt EL. Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal

role for alkalinization and sodium loading. Pediatr Emerg Care.

1998;14:293. (150)

Temple AR. Pathophysiology of aspirin overdosage toxicity, with

implications for management. Pediatrics. 1978;62(5 Pt 2 Suppl):

873. (81)

Vale JA et al. Position paper: gastric lavage. J Toxicol Clin Toxicol.

2004;42:933. (45)

Key Websites

CDC Injury Prevention and Control: Data and Statistics.

http://www.cdc.gov/injury/wisqars/index.html.

Drug Abuse Warning Network. https://dawninfo.samhsa.

gov/data.

5 End-of-Life Care