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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2593_Библиотеки_им_академика_М_И_Перельмана
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CASE 5-5, QUESTION 11: Once she is able to tolerate oral NAC treatment, what
dosing regimen would be appropriate for B.W.?
The standard oral NAC protocol is based on the original clinical
studies.
163
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 1330
mg/kg NAC during 72 hours.
170
Because oral NAC contains a
sulfhydryl group, the substance has a very disagreeable taste and
smell (similar to that of rotten eggs) that commonly results in nausea
and vomiting in the patient. To mask the unpleasant taste and odor,
NAC is diluted to a concentration of 5% using a carbonated
beverage or fruit juice.
163
Because the entire dose of oral NAC
passes through the liver, high concentrations are produced, which is
seen as an advantage of oral therapy.
164
Shorter oral NAC regimens are currently being used based on the
efficacy of IV therapy.
171,172
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.
172
Efficacy of N-Acetylcysteine
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CASE 5-5, 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.
161,164,173–175
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 of 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 hepatotoxicity.
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 of 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 does 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 (>10
hours after ingestion) with signs and symptoms of hepatotoxicity
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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) of 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
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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 (ie, 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 test or coagulation study results are abnormal, or if the 20hour 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 of
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
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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 of her oral NAC dose, the
dose should be repeated. If she experiences protracted vomiting,
administration of antiemetic drugs (eg, 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.
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 via IV infusion.
Most reactions can be avoided by infusing the NAC loading dose
slowly for 60 minutes.
149,160,164
Patient Outcome
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 fetus. Once B.W. saw the child’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 pregnancy when
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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 6.06-pound (2.75 kg)
newborn female.
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 1800-222-1222, 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/AT12e. Given here 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
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for gastrointestinal decontamination. Clin Toxicol (Phila). 2013;51:140–146.
(42)
Boyle JS, Bechtel LK, Holstege CP. Management of the critically poisoned patient.
Scand J Trauma Resusc Emerg Med. 2009;17:29. (26)
Chyka PA, Erdman AR, Christianson G, et al. Salicylate poisoning: an evidence-
based consensus guideline for out-of-hospital management. Clin Toxicol
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(Phila). 2007;45:95–131. (71)
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;43:61–87. (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. In: Forging a Poison
Prevention and Control System. The National Academies Press; 2004: chap 5.
(19)
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Gummin DD, Mowry JB, Spyker DA, et al. 2018 Annual report of the American
Association of Poison Control Centers’ National Poison Data System (NPDS):
36th Annual Report. Clin Toxicol (Phila). 2019;57(12):1220–1413. (3)
Höjer J, Troutman WG, Hoppu K, et al. Position paper update: ipecac syrup for
gastrointestinal decontamination. Clin Toxicol (Phila). 2013;51:134–139. (41)
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American Association of Poison Control Centers. www.aapcc.org
Centers for Diseases Control and Prevention, Injury Prevention and Control: Data
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United States Department of Health and Human Services. Substance Abuse and
Mental Health Services Administration Center for Behavorial Health Statistics
and Quality Drug Abuse Warning Network (DAWN).
https://doi.org/10/3886/ICPSR34565.v3
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Benson BE, Hoppu K, Troutman WG, et al. Position paper update: gastric
lavage for gastrointestinal decontamination. Clin Toxicol. 2013;51:140–146.
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;43:61–87.
[No authors listed]. Position paper: cathartics [published correction appears
in J Toxicol Clin Toxicol. 2004;42:1000]. J Toxicol Clin Toxicol. 2004;42:243–
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