150,161,164,170,174–176

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.

174

IV NAC avoids the problems of

the vomiting patient, but oral NAC is safer. Oral NAC is associated with nausea and

vomiting, whereas IV NAC is associated with bronchospasm, urticaria, and

angioedema during administration.

149,160

In addition, oral therapy is much less

expensive.

176

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.

175,177 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

reevaluated 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.

164,170

Monitoring Efficacy of N-Acetylcysteine

CASE 5-5, QUESTION 13: How should the efficacy of NAC therapy be monitored in B.W.?

The effectiveness of NAC intervention in B.W. 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.

160,174 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.

160

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.

152,178–181

Duration of N-Acetylcysteine Therapy

CASE 5-5, 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.

182 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.

162,171,182 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.

172 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.

173,174

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.

152

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

optimal dosage regimen, or optimal length of therapy.

160,164,182 There is consensus,

however, that for optimal results, NAC therapy must be instituted within 10 hours

after ingestion.

149,160,164,170,173,176 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.

164,171,182

N-Acetylcysteine Toxicity

CASE 5-5, QUESTION 15: How should the toxicity of NAC therapy be monitored in B.W.?

With the exception of vomiting, oral NAC is remarkably safe and has not been

associated with toxicity.

149,161,164 Oral NAC must be retained for a minimum of 1 hour

after ingestion to be successfully absorbed. If B.W. 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.

164,183,184

If the patient cannot

tolerate oral liquids, NAC therapy should continue via IV administration.

p. 81

p. 82

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.

149,160,164,182 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.

149,160,164

Outcome of Patient B.W.

B.W. continued to have nausea and vomiting and had difficulty tolerating liquids. IV

NAC was continued. An obstetrics consultation was requested to evaluate B.W.’s

pregnancy. Fetal monitoring was instituted during her hospital admission. A

sonogram was taken of the baby. Once B.W. 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.

B.W. was seen by a psychiatrist. She was scheduled for counseling and prenatal

classes. B.W. seemed eager to attend the classes, and she talked enthusiastically

about the baby when family members came to visit. Because of B.W.’s pregnancy, the

decision was 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.

CONCLUSION

Unfortunately, there is no set formula to treat all poisoned patients. Each exposure is

unique and patient-specific factors must be considered. 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, where consultation

is available 24 hours a day in the United States.

KEY REFERENCES AND WEBSITES

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

http://thepoint.lww.com/AT11e. 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.

(26)

Mowry JB et al. 2013 Annual report of the American Association of Poison Control Centers’ National Poison

Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014;S2:1032. (3)

Chyka PA et al. Position paper:single-dose activated charcoal. Clin Toxicol (Phila). 2005;43:61. (43)

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.

(19)

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

other causes. Emerg Med J. 2009;26:100. (113)

Kociancic T, Reed MD. Acetaminophen intoxication and length of treatment: how long is long enough.

Pharmacotherapy. 2003;23:1052. (180)

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

Toxicol (Phila). 2005;43:553. (89)

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

2004;42:1000]. J Toxicol Clin Toxicol. 2004;42:243. (44)

Höjer J et al. Position paper update: ipecac syrup for gastrointestinal decontamination. J Clin Toxicol. 2013;51:134.

(3)

Thanacoody R. Position paper update: Whole bowel irrigation for gastrointestinal decontamination of overdose

patients. Clin Toxicol (Phila). 2015;53:5. (45)

Proudfoot AT et al. Position paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42:1. (64)

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

Intern Med. 1981;141(3 Spec No):380. (158)

Shannon M, 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. (143)

Chyka PB et al. Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin

Toxicol (Phila). 2007;45:95 (69)

Benson BE et al. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol (Phila).

2013;51:140. (42)

Key Websites

American Association of Poison Control Centers. www.aapcc.org.

Centers for Diseases Control and Prevention Injury Prevention and Control: Data and Statistics (WISQARS).

www.cdc.gov/injury/wisquars/index.html.

Drug Abuse Warning Network. www.dawninfo.samhsa.gov/data.

COMPLETE REFERENCES CHAPTER 5 MANAGING DRUG

OVERDOSES AND POISONINGS

Woolf AD, Lovejoy FR, Jr. Epidemiology of drug overdose in children. Drug Saf. 1993;9:291.

Madden MA. Pediatric poisonings: recognition, assessment, and management. Crit Care Nurs Clin North Am.