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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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(>100 milliseconds), right bundle branch block, and wide complex
tachycardia.
135,145
Alkalinization increases serum protein binding of
the TCAs and reduces the amount of free active drug (likely a minor
consideration).
116,133,136,145
Correction of the serum pH is beneficial
because underlying acidosis worsens TCA-induced cardiotoxicity.
145
Furthermore, sodium bicarbonate has been found useful even in
patients with a normal pH because sodium bicarbonate purportedly
overcomes the sodium channel blockade and reduces
cardiotoxicity.
145,147
On the basis of A.G.’s tachycardia and a widened QRS segment
on ECG, he should be treated with IV sodium bicarbonate with the
goal of achieving an arterial pH of 7.45 to 7.55.
136,145
Sodium
bicarbonate could have been administered earlier because the
suspicion of an antidepressant overdose was strong initially, his ECG
demonstrated QRS widening and worsening myocardial conduction,
and his BP continued to decline from the time he was first seen by
the paramedics. If not monitored closely, the use of IV sodium
bicarbonate could introduce the risk of sodium overload and
subsequent pulmonary edema.
98,146
An alternative is to hyperventilate the patient to a pH of 7.5 by
adjusting his ventilator setting, thereby reducing the cardiotoxicity of
the TCA.
133,136,146
The combination of IV bicarbonate and mechanical
ventilation is more likely to produce severe alkalemia. Careful and
frequent monitoring of the serum pH of patients on dual therapy is
essential.
133,147
MONITORING EFFICACY
CASE 5-4, QUESTION 14: How should the sodium bicarbonate therapy in A.G.
be monitored?
Patients intoxicated with TCAs often present with severe acidosis.
Large doses of sodium bicarbonate may be required to normalize the
arterial pH. The efficacy of sodium bicarbonate administration can be
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evaluated by monitoring acid–base status using ABGs, especially if
the patient is also being ventilated mechanically.
133,147,148
Sodium bicarbonate should be administered IV as a bolus of 1 to 2
mEq/kg for a 1- to 2-minute period. Continuous ECG monitoring is
needed to monitor results of the bolus on cardiac abnormalities.
Repeat bolus doses are administered as needed until the QRS
interval narrows and tachycardia slows. Blood pH should be tested
after several boluses to determine whether a target pH of 7.5 to 7.55
has been obtained.
145
At a minimum, ABGs should be determined
within an hour of starting sodium bicarbonate therapy to determine
pH response.
148
Bicarbonate boluses can be followed by a constant
sodium bicarbonate infusion of 150 mEq/L to maintain an alkaline
pH.
145
ABGs must be monitored frequently to ensure a
response.
133,147,148
Serial ECGs to measure the QRS interval are
useful for evaluating the efficacy of sodium bicarbonate therapy. A
widened QRS interval will generally normalize after the systemic pH
has been increased to about 7.5.
148
Seizures
CASE 5-4, QUESTION 15: A.G. gradually developed more severely altered
mental status and became comatose, not responding even to painful stimuli. He
suddenly experienced a tonic-clonic seizure, which lasted about 1 minute and
terminated spontaneously. Should anticonvulsant therapy be initiated for A.G. at
this time?
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.
133,136
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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 been indicated.
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 seizures.
117
After
a seizure, the patient may become more acidotic and hypotensive.
136
Blood gases, creatine kinase, and ECG changes should be
monitored immediately after a seizure.
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 ABGs was 7.20. A.G.’s ECG normalized after the
administration of 150 mL of sodium bicarbonate by IV bolus. After dopamine,
his BP increased to 100/56 mm Hg, and seizure activity ceased. The urine drug
screen results were positive for amitriptyline and nortriptyline. Acetaminophen,
salicylates, and ethanol were not detected in his blood. Does the presence of
nortriptyline indicate that A.G. has ingested other drugs in addition to his
amitriptyline?
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.
132
Duration of Hospitalization
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
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should be observed. Some believe symptomatic patients need
cardiac monitoring for 24 hours after ingestion.
135
Others believe that
patients with TCA overdose need to be monitored until they are
symptom-free for 24 hours because of a few reports of late
development of symptoms.
139
However, 98% of signs of
cardiotoxicity and arrhythmias are seen within the first 24 hours of
TCA ingestion.
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.
133–135
Patient Outcome
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 was medically cleared.
ASSESSMENT OF ACETAMINOPHEN
INGESTION
Mechanism of Hepatotoxicity
CASE 5-5
QUESTION 1: B.W., an 18-year-old female who is about 30 weeks pregnant,
presents to the ED 8 hours after ingesting 40 acetaminophen 500-mg tablets.
She is depressed and hoped to end her pregnancy by ingesting
acetaminophen. Her pregnancy was unplanned, and she has received no
prenatal care. B.W. has vomited spontaneously six times since the ingestion
and is reporting abdominal pain; her heart rate is 95 beats/minute, BP is 110/74
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mm Hg, and temperature is 98.5 °F (36.94 °C). B.W. does not have any chronic
diseases, and the remainder of her medical history is unremarkable.
How does an overdose of acetaminophen cause toxicity?
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.
149–152
Complication of Pregnancy
CASE 5-5, QUESTION 2: How does B.W.’s pregnancy change the management
of her acetaminophen ingestion?
Pregnancy does not alter the initial approach to the assessment or
treatment of potentially toxic ingestions, and assessment should
focus initially on the pregnant patient.
153,154
Overdoses during
pregnancy are often associated with attempted abortions,
depression, prior loss of a child or children, potential loss of a lover,
or economic reasons.
131,132,153,154
Intentional ingestions of analgesics,
prenatal vitamins, iron, psychotropic agents, and antibiotics account
for 74% of the overdoses during pregnancy.
The fetus is at risk when the pregnant patient 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%
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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.
155,156
In studies of maternal acetaminophen toxicity, most of the
pregnant females 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 of birth defects or
adverse pregnancy outcomes unless the mother suffered severe
toxicity, emphasizing the need to treat the mother promptly.
149,155
Gastrointestinal Decontamination
CASE 5-5, QUESTION 3: Should GI decontamination be initiated for B.W.? What
is 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.
Estimating Potential Toxicity
CASE 5-5, QUESTION 4: How should the potential toxicity of the acetaminophen
ingestion be assessed in B.W.?
Acetaminophen toxicity results from ingestions >150 mg/kg or >7.5
g total in adults. However, serum acetaminophen concentrations
better predict acetaminophen-induced hepatotoxicity than does the
dose of acetaminophen acutely ingested.
158,159
The Rumack–
Matthew nomogram is used in the United States to assess the
potential for hepatotoxicity from acute overdoses of
acetaminophen.
160,161
The treatment line is defined by a serum
acetaminophen concentration of 200 μg/mL at 4 hours after
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acetaminophen ingestion and 30 μg/mL at 15 hours after ingestion
on a semilogarithmic graph.
152
Many prefer to be more conservative
and use the bottom line of 150 μg/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.
159
The nomogram predicts the probability that the AST
or ALT will be >1000 IU/L and can be used to guide therapy by
indicating whether a specific acetaminophen concentration is in the
toxic range.
162
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.
152
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 of 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 absorption.
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 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 clear-cut. About 30 minutes
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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 because AST abnormalities always precede evidence
of actual liver impairment.
152,160,163
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 >10,000 IU/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.
152,160,163
Antidotes
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
NAC is
the antidote for acetaminophen toxicity. It 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
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properties, showing some value even after liver damage has already
occurred.
149,160
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 >10
hours after ingestion, 53% developed liver damage.
152,160
Safety of N-Acetylcysteine in Pregnancy
CASE 5-5, QUESTION 8: Is NAC safe to use during pregnancy?
Acetaminophen overdose in pregnant patients should be managed
in the same manner as in nonpregnant patients.
155–157
If the life of the
pregnant patient 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.
155,157
NAC therapy appears to be protective for both the pregnant
patient and fetus.
152,155,158–160,162,163
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.
152,156,160
Route of Administration of N-Acetylcysteine
CASE 5-5, QUESTION 9: The 9-hour acetaminophen concentration in B.W. was
170 μg/mL. By what route should NAC be administered?
This concentration of acetaminophen at 6 hours is above the
treatment line on the Rumack–Matthew nomogram.
161
Because there
was some delay from the time of ingestion to presentation at the ED
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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 Acetadote®.
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%. Patients with asthma and patients with ectopy should
receive the drug slowly and carefully, while being watched for
symptoms of a reaction.
166
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.
167,168
Most 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 significant
differences.
166,169
Intravenous N-Acetylcysteine
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 loading dose.
166
Oral N-Acetylcysteine
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