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.
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.
In addition, oral therapy is much less
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
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
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
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
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.
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.
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
182 This recommendation serves as the basis for the traditional 72-hour oral
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.
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.
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.
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.
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
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
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
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.
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.
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.
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,
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.
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.
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
Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014;S2:1032. (3)
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)
Toxicol (Phila). 2005;43:553. (89)
2004;42:1000]. J Toxicol Clin Toxicol. 2004;42:243. (44)
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)
Intern Med. 1981;141(3 Spec No):380. (158)
Toxicol (Phila). 2007;45:95 (69)
American Association of Poison Control Centers. www.aapcc.org.
www.cdc.gov/injury/wisquars/index.html.
Drug Abuse Warning Network. www.dawninfo.samhsa.gov/data.
COMPLETE REFERENCES CHAPTER 5 MANAGING DRUG
Woolf AD, Lovejoy FR, Jr. Epidemiology of drug overdose in children. Drug Saf. 1993;9:291.
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