CASE 5-4, QUESTION 15: A.G. gradually developed more severely altered mental status and became
CNS toxicity is common in TCA overdoses. Symptoms include agitation,
hallucinations, coma, myoclonus, and seizures.
117,133–136 Seizures can cause significant
increases in acidosis and increase cardiotoxicity. Seizures are often seen
immediately before cardiopulmonary arrest. Because of the severe consequences of
prolonged seizures, aggressive drug treatment with rapid onset of action is indicated,
and benzodiazepines are the drugs of choice.
Drug overdose–induced grand mal seizures are most commonly single seizures that
terminate before drug therapy can be administered.
135 Seizure activity is not expected
to persist, so instituting long-term anticonvulsant therapy is not indicated. However,
if A.G.’s seizure did not stop within 1 to 2 minutes, a benzodiazepine would have
117,133,136 The onset of action of phenobarbital is too slow for acute
seizures, and phenytoin is usually ineffective in treating drug toxicity–related
117 After a seizure, the patient may become more acidotic and hypotensive.
Blood gases, creatine kinase, and ECG changes should be monitored immediately
Interpretation of Urine Screens
CASE 5-4, QUESTION 16: A.G.’s BP fell to 80/42 mm Hg, and dopamine was started. His pH on repeat
Nortriptyline is a metabolite of amitriptyline and, therefore, was identified on the
urine drug screen. Metabolites, as well as the parent compound, are often identified
on comprehensive urine drug screens.
CASE 5-4, QUESTION 17: How long should A.G. be monitored?
A.G. should be admitted to the ICU and monitored until all evidence of CNS and
cardiovascular toxicity has been reversed.
117 There is some controversy over how
long symptomatic patients should be observed. Some believe symptomatic patients
need cardiac monitoring for 24 hours after ingestion.
overdose patients need to be monitored until they are symptom-free for 24 hours
because of a few reports of late development of symptoms.
of cardiotoxicity and arrhythmias are seen within the first 24 hours after TCA
117,134 Because the incidence of late-occurring symptoms is rare, most
patients are discharged after they are fully awake.
133 After the toxicity has completely
resolved, A.G. should be evaluated by a psychiatrist to determine whether he should
be admitted for inpatient treatment of his suicidal ideation.
A.G. had no further seizure activity. He remained on a dopamine infusion for 8 hours
and required several more boluses of IV sodium bicarbonate. The next afternoon, he
started to awaken and expressed regret that his suicide attempt was not successful.
Arrangements were made to transfer him to an inpatient psychiatric hospital once he
ASSESSMENT OF ACETAMINOPHEN INGESTION
acetaminophen. Her pregnancy was unplanned, and she has received no prenatal care. B.W. has vomited
spontaneously 6 times since the ingestion and is complaining of abdominal pain; her heart rate is 95
Acetaminophen is metabolized in the liver by glucuronidation and sulfation. The
mixed-function oxidase system cytochrome P-450 (CYP) 2E1 metabolizes a portion
of the acetaminophen to the highly reactive metabolite N-acetyl-p-benzoquinoneimine
(NAPQI). In therapeutic doses, this metabolite is detoxified in the liver by
glutathione. At toxic serum acetaminophen concentrations, the glucuronidation and
sulfation metabolic pathways become saturated. Usually, NAPQI is detoxified by
conjugation with glutathione, but increased amounts of the toxic metabolite deplete
hepatic glutathione stores. When glutathione stores are decreased to about 30% of
normal, the toxic metabolite binds to liver cells, resulting in the characteristic
centrilobular hepatic necrosis seen in acetaminophen overdoses.
CASE 5-5, QUESTION 2: How does B.W.’s pregnancy change the management of her acetaminophen
Pregnancy does not alter the initial approach to the assessment or treatment of
potentially toxic ingestions, and assessment should focus initially on the mother.
Overdoses during pregnancy are often associated with attempted abortions,
depression, prior loss of a child or children, potential loss of a lover, or economic
Intentional ingestions of analgesics, prenatal vitamins, iron,
psychotropic agents, and antibiotics account for 74% of the overdoses during
The fetus is at risk when the mother overdoses on acetaminophen because
acetaminophen crosses the placenta. The fetal liver can oxidize acetaminophen to its
hepatotoxic metabolite by 14 weeks of gestation.
151 However, the fetal liver has only
about 10% of the capability of the adult liver to metabolize acetaminophen. The fetal
liver can conjugate acetaminophen with both glutathione and sulfate, but
detoxification by glutathione conjugation appears to be decreased.
In studies of maternal acetaminophen toxicity, most of the pregnant women
survived without damage to themselves or their babies. However, there were also
maternal and fetal deaths as a result of overdose.
155,157 Acetaminophen overdoses
during pregnancy did not appear to increase the risk for birth defects or adverse
pregnancy outcomes unless the mother suffered severe toxicity, emphasizing the need
Gastrointestinal Decontamination
CASE 5-5, QUESTION 3: Should GI decontamination be initiated for B.W.? Justify your rationale.
B.W.’s acetaminophen ingestion occurred 8 hours ago; therefore, the drug is likely
to be totally absorbed, and no GI decontamination should be initiated.
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 acetaminophen-induced hepatotoxicity than the dose of acetaminophen acutely
158,159 The Rumack–Matthew nomogram is used in the United States to assess
the potential for hepatotoxicity from acute overdoses of acetaminophen.
treatment line is defined by a serum acetaminophen concentration of 200 mcg/mLat 4
hours after acetaminophen ingestion and 30 mcg/mL at 15 hours after ingestion on a
152 Many 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
159 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.
The nomogram is useful only for acute ingestions because it underestimates the
potential for toxicity in chronic acetaminophen ingestions. It should be noted that
although the nomogram is used to plot acetaminophen concentrations for all patients,
it has been validated only in healthy nonalcoholic adults.
Acetaminophen Treatment Nomogram
CASE 5-5, 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.
159 The Rumack–Matthew nomogram is not
applicable before 4 hours after ingestion because it is based on complete drug
159 Most clinical laboratories can complete their assays and report
acetaminophen serum concentration results within 2 hours.
Stages of Acetaminophen Toxicity
CASE 5-5, QUESTION 6: What are the clinicalsigns 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 clear-cut. 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
measure of hepatotoxicity as AST abnormalities always precede evidence of
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
CASE 5-5, QUESTION 7: What antidote for acetaminophen ingestion should be considered in B.W.? 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.
159 N-acetylcysteine, or NAC, is the antidote
for acetaminophen toxicity. NAC is a sulfhydryl donor that converts to cysteine,
which is subsequently converted to glutathione.
149,160,162,163 NAC acts as a glutathione
substitute and directly combines with the toxic acetaminophen metabolite, NAPQI,
reducing it to a nontoxic cysteine conjugate.
163 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.
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
Safety of N-Acetylcysteine in Pregnancy
CASE 5-5, 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.
If the life of the mother is not saved, the fetus
will not survive (unless the child is near term and is emergently delivered). NAC
therapy is not contraindicated in pregnant patients and might be helpful because it
crosses the placenta and can protect the fetus from hepatotoxicity.
NAC therapy appears to be protective for both mother and fetus.
When used as an antidote for acetaminophen overdose in pregnancy, NAC did not
appear to cause toxic effects to the fetus.
149,152,155,157 The probability of fetal death was
increased with the delay in NAC treatment after acetaminophen overdose.
Route of Administration of N-Acetylcysteine
CASE 5-5, QUESTION 9: The 9-hour acetaminophen concentration in B.W. was 170 mcg/mL. By what
route should NAC be administered?
This concentration of acetaminophen at 6 hours is above the treatment line on the
161 Because there was some delay from the time of
ingestion to presentation at the ED and B.W. was already vomiting, it will be more
difficult for B.W. to tolerate oral NAC. For this reason, IV NAC is recommended.
An FDA-approved sterile, pyrogen-free formulation of NAC is available as
164–166 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
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.
reactions occur during or just after the first 15 minutes of the initial antidote infusion
and appear to be dose related.
168 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
CASE 5-5, QUESTION 10: How should IV NAC be administered to B.W.?
The FDA-approved IV NAC protocol is the same 20-hour dosing regimen used in
Europe, known as the Prescott protocol.
164,165,166 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
CASE 5-5, QUESTION 11: Once she is able to tolerate oral NAC treatment, what dosing regimen would be
The standard oral NAC protocol is based on the original clinical studies.
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
170 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.
Because the entire dose of oral NAC passes through the liver, high concentrations are
produced, which is seen as an advantage of oral therapy.
Shorter oral NAC regimens are currently being used based on the efficacy of IV
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
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
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
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 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
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