Although the ingested substance still has not been specifically

identified, the available data provide some clues as to the likely

pharmacologic class of drug that was ingested. The presence

of CNS depression (T.C. is unresponsive), slowed ventricular

conduction (prolonged QRS on ECG), tachycardia (heart rate,

148 beats/minute), hypotension (BP, 90/55 mm Hg), and

decreased GI motility (hypoactive bowel sounds), and the history

of a possible depressive illness (history from husband and daughter) are all consistent with a TCA drug overdose. The antidepressant could have been ingested alone or with other agents.

Antidepressant Toxicities

CASE 4-4, QUESTION 10: How would the different toxicities

of the various available antidepressants affect the treatment

of T.C.?

The major pharmacologic effects and toxicities of the antidepressants are similar for all drugs within the same class. When

a specific drug within a therapeutic class has not yet been identified, the overdose should be managed as if the ingested drug

can produce the most severe toxicity of any drug in the class. In

this light, T.C.’s presumed antidepressant drug overdose should

be evaluated and managed initially as TCA (e.g., amitriptyline)

ingestion.140,146 Antidepressants with different structures and

actions (e.g., trazodone [Desyrel], fluoxetine [Prozac], sertraline

[Zoloft]) generally do not produce toxicity as severe as that of

the TCAs.140,146,147

Gastrointestinal Decontamination

CASE 4-4, QUESTION 11: If a TCA ingestion is presumed,

why might GI decontamination be appropriate at this time?

The longer GI decontamination is delayed relative to the

time of ingestion, the less effective it is likely to be because

drug absorption will already have occurred. Because the time

of ingestion is unknown and T.C. is unresponsive, she probably already has absorbed significant amounts of the drug, making her more vulnerable to aspiration. Additionally, T.C. might

already have aspirated because she was found in a pool of vomitus.

TCA overdoses can also cause seizures, which would be a relative contraindication to GI decontamination. In consideration of

these concerns, many would not support GI decontamination for

T.C.44–47,55–58

Others might support GI decontamination because TCAs

have strong central and peripheral anticholinergic properties that

slow GI emptying, which could result in erratic absorption and

delayed toxicity, but T.C. would first need to be intubated to

protect her airway. Furthermore, TCAs have a large volume

of distribution (10–50 L/kg), and both the parent drug and its

metabolite undergo enterohepatic recirculation. The half-life of

TCAs in overdose situations is 37 to 60 hours. For those reasons,

activated charcoal could be reasonably administered in an effort

to adsorb any drug that may not yet be absorbed from the GI

tract.53

Repeated doses of activated charcoal have been used to

increase the elimination of TCAs because of the long half-life

of TCAs and the enterohepatic recirculation. In clinical studies,

multiple-dose activated charcoal has increased the elimination of

amitriptyline, but the data are insufficient to support or exclude

the use of this therapy.50

82 Section 1 General Care

MONITORING EFFICACY

CASE 4-4, QUESTION 12: How should the effectiveness of

GI decontamination be monitored in T.C.?

If activated charcoal is administered, T.C. must first be intubated to protect her airway, and the charcoal must be administered via NG tube because she is unconscious. The insertion of

the NG tube could stimulate the gag reflex, causing vomiting

and possible aspiration. T.C.’s lung sounds should be monitored

closely to determine whether aspiration pneumonitis is developing, particularly because T.C. was found unconscious and had

already vomited.

Activated charcoal, especially in multiple doses, can produce

ileus, GI obstruction, or intestinal perforation, especially when

administered to patients who have ingested drugs that slow GI

motility.50,53,106 Bowel sounds must be monitored frequently to

determine that an ileus is not developing. Once the patient passes

a charcoal-laden stool, the activated charcoal can be considered

to have successfully passed through the GI tract.

Sodium Bicarbonate and

Hyperventilation

CASE 4-4, QUESTION 13: According to T.C.’s psychiatrist,

he prescribed amitriptyline 100 mg at bedtime for her

severe depression. How does this new information alter

T.C.’s treatment plan?

This information confirms the assumptions that a TCA was

ingested. It also specifically identifies the drug ingested. In TCA

ingestions, severe toxicity has been associated with doses of

15 to 25 mg/kg.103 T.C. ingested a total of 2,500 mg based on

her suicide note that said she took 25 tablets. If she weighs about

60 kg and was truthful about the amount taken, she ingested a

significantly toxic dose (about 42 mg/kg).

On the ECG, TCA toxicity will manifest as tachycardia

with prolongation of the PR, QTc, and QRS intervals, ST and

T-wave changes, and abnormalities of the terminal 40-millisecond vector.103,121,138,141,148–151 TCAs have anticholinergic,

adrenergic, and quinidinelike membrane effects on the

heart.121,138,140,146,149 It is believed that the anticholinergic effect

causes the tachycardia and the quinidinelike effect causes the

ECG changes.

In addition, TCAs are sodium-channel blockers.152 Sodiumchannel blockade slows the maximum uptake stroke of phase

0 of the action potential and decreases automaticity. Blockade decreases conduction velocity in the Purkinje fibers, which

increases the QRS interval.149 Myocardial depression, ventricular tachycardia, and ventricular fibrillation are the most common

causes of death from TCAs.141 Therefore, admission to the ICU

with continuous cardiac monitoring is essential for T.C.148

The primary therapy for reversing ventricular arrhythmias and conduction delays is alkalinization of the serum

and sodium loading by administrating IV hypertonic sodium

bicarbonate.121,138,140,141,149,150,153 Indications for sodium bicarbonate include hypotension, prolonged QRS segment (longer

than 100 milliseconds), right bundle branch block, and wide

complex tachycardia.140,150 Alkalinization increases serum protein binding of the TCAs and thereby reduces the amount of

free active drug (probably a minor consideration).121,138,141,150

Correction of the serum pH is beneficial because underlying acidosis increases TCA cardiotoxic effects.150 Furthermore, sodium

bicarbonate has been found useful even in patients with a normal pH because sodium bicarbonate purportedly overcomes the

sodium-channel blockade and decreases cardiotoxicity.150,152

On the basis of T.C.’s tachycardia and a widened QRS segment

on ECG, she should be treated with IV sodium bicarbonate with

the goal of achieving an arterial pH of 7.5 to 7.55.141,150 Sodium

bicarbonate could have been administered earlier because the

suspicion of an antidepressant overdose was strong initially, her

ECG demonstrated QRS prolongation and worsening myocardial conduction, and her BP continued to decline from the time

she 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.103,151

An alternative is to hyperventilate the patient to a pH of 7.5 by

adjusting her ventilator setting, thereby decreasing the cardiotoxicity of the TCA.138,141,151 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.138,152

MONITORING EFFICACY

CASE 4-4, QUESTION 14: How should the sodium bicarbonate therapy in T.C. be monitored?

Many patients intoxicated with TCAs 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 evaluated by monitoring acid–base status using ABGs, especially if the patient is also being ventilated

mechanically.138,152,153

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.150 At a minimum, ABGs

should be determined within an hour of starting sodium bicarbonate therapy to determine pH response to the bicarbonate.153

Bolus bicarbonate can be followed by a constant sodium bicarbonate infusion of 150 mEq/L sodium bicarbonate to maintain

an alkaline pH.150 ABGs must be monitored frequently to ensure

a response.138,152,153 Serial ECGs to measure the QRS interval can

evaluate the efficacy of sodium bicarbonate. A prolonged QRS

interval will generally narrow to normal after the systemic pH

has been increased to about 7.5.153

Seizures

CASE 4-4, QUESTION 15: T.C. gradually developed more

severely altered mental status and became comatose, not

responding even to painful stimuli. She suddenly experienced a tonic-clonic seizure, which lasted about 2 minutes

and terminated spontaneously. Should anticonvulsant therapy be initiated for T.C. at this time?

CNS toxicity is common in TCA overdoses. Symptoms include agitation, hallucinations, coma, myoclonus, and

seizures.121,138–141 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 to treat these seizures.138,141

83Managing Drug Overdoses and Poisonings Chapter 4

Drug overdose–induced grand mal seizures are most commonly single seizures that terminate before drug therapy can

be administered.140 Seizure activity is not expected to persist,

so instituting long-term anticonvulsant therapy is not indicated.

However, if her seizure did not stop within 1 to 2 minutes, a

benzodiazepine would have been indicated.121,138,140 The onset

of action of phenobarbital is too delayed for managing acute

seizures, and phenytoin is usually ineffective in treating drug

toxicity–related seizures.121 After a seizure, the patient may

become more acidotic and hypotensive.141 Blood gases, creatine kinase, and ECG changes should be monitored immediately

after a seizure.

Interpretation of Urine Screens

CASE 4-4, QUESTION 16: T.C.’s BP fell to 88/42 mm Hg, and

dopamine was started. Her pH on repeat ABGs was 7.26.

T.C.’s ECG normalized after the administration of 150 mL

of sodium bicarbonate by IV bolus. After dopamine, her BP

increased to 102/68 mm Hg, and seizure activity ceased.

The urine drug screen results were positive for amitriptyline and nortriptyline. Acetaminophen and alcohol were not

detected in her blood. Does the presence of nortriptyline

indicate that T.C. has ingested other drugs in addition to

her 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.135

Duration of Hospitalization

CASE 4-4, QUESTION 17: How long should T.C. be monitored?

T.C. should be admitted to the ICU and monitored until all

evidence of CNS and cardiovascular toxicity has been reversed.121

There is some controversy over how long symptomatic patients

should be observed. Some believe symptomatic patients need cardiac monitoring for 24 hours after ingestion.140 Others believe

TCA overdose patients need to be monitored until they are symptomfree for 24 hours because of a few reports of late development of symptoms.141 However, 98% of signs of cardiotoxicity and arrhythmias are seen within the first 24 hours after

TCA ingestion.121,139 Because the incidence of late-occurring

symptoms is rare, most patients are discharged after they are

fully awake.138 After the toxicity has completely resolved, T.C.

should be evaluated by a psychiatrist to determine whether

she should be admitted for inpatient treatment of her suicidal

ideation.138–140

Outcome of Patient T.C.

T.C. had no further seizure activity. She remained on a dopamine

infusion for 8 hours and required several more boluses of IV

sodium bicarbonate. The next afternoon, she started to awaken

with her family at the bedside. She was tearful and expressed

regret that her suicide attempt was not successful. She repeatedly

told her family that they would be better off without her. Her

psychiatrist saw her, and arrangements were made to transfer

her to an in-patient psychiatric hospital once she was medically

cleared.

ASSESSMENT OF ACETAMINOPHEN

INGESTION

Mechanism of Hepatotoxicity

CASE 4-5

QUESTION 1: L.P., a 23-year-old woman who is about

32 weeks pregnant, presents to the ED 5 hours after ingesting 50 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. L.P. has vomited spontaneously four times

since the ingestion and is complaining of abdominal pain;

her heart rate is 100 beats/minute, BP is 100/70 mm Hg,

and temperature is 97.5◦F. L.P. 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.154–157

For a diagram that shows the mechanism of

acetaminophen poisoning and treatment, go

to http://thepoint.lww.com/AT10e.

Complication of Pregnancy

CASE 4-5, QUESTION 2: How does L.P.’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 mother.158,159 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.136,137,158,159 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 mother overdoses on

acetaminophen because acetaminophen crosses the placenta.

The fetal liver can oxidize acetaminophen to its hepatotoxic

metabolite by 14 weeks of gestation.154 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.160,161

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 the overdoses.160,162,163 Acetaminophen overdoses

during pregnancy did not appear to increase the risk for birth

84 Section 1 General Care

defects or adverse pregnancy outcome unless the mother suffered severe toxicity, emphasizing the need to treat the mother

promptly.154,160,163

Gastrointestinal Decontamination

CASE 4-5, QUESTION 3: What GI decontamination should

be initiated for L.P.?

L.P.’s acetaminophen ingestion occurred 5 hours ago; therefore, the drug is likely to be totally absorbed, and no GI decontamination should be initiated.

Estimating Potential Toxicity

CASE 4-5, QUESTION 4: How should the potential toxicity

of the acetaminophen ingestion be assessed in L.P.?

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 acetaminopheninduced hepatotoxicity than the dose of acetaminophen acutely

ingested.164,165 The Matthew-Rumack nomogram (Fig. 4-1) is

used in the United States to assess the potential for hepatotoxicity

from acute overdoses of acetaminophen.165 The treatment line is

defined by a serum acetaminophen concentration of 200 mcg/mL

at 4 hours after acetaminophen ingestion and 30 mcg/mL at

15 hours after ingestion on a semilogarithmic graph.157 Others 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 time of ingestion.165 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.166 The nomogram is useful only

for acute ingestions because it underestimates the potential for

toxicity in chronic acetaminophen ingestions. It should be noted

Hours After Acetaminophen Ingestion

Plasma Acetaminophen Concentration

5

10

50

500 Lower limit for high-risk group

Lower limit for probable-risk group

Treatment nomogram line

400

300

200

150

100

50

30

100

500

1,000

1,300

2,000

3,000

4,000

mcg/mL mol/L 4 8 12 16 20 24

FIGURE 4-1 Nomogram for interpretation of severity of

acetaminophen poisoning. Adapted with permission from

Smilkstein MJ et al. Efficacy of oral N-acetylcysteine in the treatment

of acetaminophen overdose: analysis of national multicenter study

(1976–1985). N Engl J Med. 1988;319:1557.

that although the nomogram is used to plot acetaminophen concentrations for all patients, it has been validated only in healthy

nonalcoholic adult patients.157

Acetaminophen Treatment Nomogram

CASE 4-5, 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.165

The Matthews-Rumack nomogram is not applicable before

4 hours after ingestion because it is based on complete drug

absorption.165 Most clinical laboratories can complete their

assays and report acetaminophen serum concentration results

within 2 hours.

Stages of Acetaminophen Toxicity

CASE 4-5, 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 clearcut. 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 most sensitive measure of hepatotoxicity as AST abnormalities always precede evidence of actual liver

impairment.157,167,168

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 recovery.157,167,168

Antidotes

CASE 4-5, QUESTION 7: What antidote for acetaminophen

ingestion should be considered in L.P.? 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.165 NAC is the antidote for acetaminophen toxicity.

NAC is a sulfhydryl donor that converts to cysteine, which is

subsequently converted to glutathione.154,166–168 NAC acts as

a glutathione substitute and directly combines with the toxic

acetaminophen metabolite, NAPQI, reducing it to a nontoxic cysteine conjugate.167 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.154,168

85Managing Drug Overdoses and Poisonings Chapter 4

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

damage.157,168

Safety of N-Acetylcysteine in Pregnancy

CASE 4-5, 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.160–163 If

the life of the mother is not saved, the fetus will not survive

(unless the child is near term and is emergently delivered); therefore, attention to the mother must be foremost. NAC therapy

is not contraindicated in pregnant patients and might be helpful

because it crosses the placenta and can protect the fetus from

hepatotoxicity.160,162,163

NAC therapy appears to be protective for both mother and

fetus.154,157,160–163 When used as an antidote for acetaminophen

overdose in pregnancy, NAC did not appear to result in toxic

effects to the fetus.154,157,160,162,163 The probability of fetal death

was increased with the delay in NAC treatment after overdose

and with acetaminophen overdose early in gestation.157,160,168

Route of Administration of

N-Acetylcysteine

CASE 4-5, QUESTION 9: The 6-hour acetaminophen concentration in L.P. was 245 mcg/mL. By what route should

NAC be administered?

This concentration of acetaminophen at 6 hours is above the

treatment line on Figure 4-1. Because there was some delay from

the time of ingestion to presentation at the ED and L.P. was

already vomiting, it will be more difficult for L.P. to tolerate oral

NAC. For this reason, IV NAC is recommended.

An FDA-approved sterile, pyrogen-free formulation of NAC is

available as Acetadote.169–171 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 reaction.171

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.169,172,173 Most

reactions occur during or just after the first 15 minutes of the initial antidote infusion and appear to be dose related.173 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.171,174

Intravenous N-Acetylcysteine

CASE 4-5, QUESTION 10: How should IV NAC be administered to L.P.?

The FDA-approved IV NAC protocol is the same 20-hour

dosing regimen used in Europe, known as the Prescott protocol.169,170,171 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.171 As soon as the patient is able to tolerate oral administration, the patient can be switched to oral NAC

therapy.

Oral N-Acetylcysteine

CASE 4-5, QUESTION 11: Once she is able to tolerate oral

NAC treatment, what dosing regimen would be appropriate

for L.P.?

The standard oral NAC protocol is based on the original clinical studies.166 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 1,330 mg/kg NAC during 72 hours.169,175 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.166 Because the entire dose

of oral NAC passes through the liver, high concentrations are

produced, which is seen as an advantage of oral therapy.169

Shorter oral NAC regimens are currently being used based

on the efficacy of IV therapy.176,177 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.177

Efficacy of N-Acetylcysteine

CASE 4-5, 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.168,169,178–180 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 hepatoxicity.154,168,169,175,179–181

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.179 IV NAC avoids

the problems of the vomiting patient, but oral NAC is safer. Oral

86 Section 1 General Care

NAC is associated with nausea and vomiting, whereas IV NAC is

associated with bronchospasm, urticaria, and angioedema during administration.154,168 In addition, oral therapy is much less

expensive.181

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.180,182 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 re-evaluated 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.169,175

Monitoring Efficacy of N-Acetylcysteine

CASE 4-5, QUESTION 13: How should the efficacy of NAC

therapy be monitored in L.P.?

The effectiveness of NAC intervention in L.P. 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.168,179 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.168

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.157,183–186

Duration of N-Acetylcysteine Therapy

CASE 4-5, 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.187 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.168,176,187 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.177 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.178,179 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.157

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

NAC administration, optimal dosage regimen, or optimal length

of therapy.168,169,187 There is consensus, however, that for optimal results, NAC therapy must be instituted within 10 hours

after ingestion.154,168,169,175,179,181 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.169,176,187

N-Acetylcysteine Toxicity

CASE 4-5, QUESTION 15: How should the toxicity of NAC

therapy be monitored in L.P.?

With the exception of vomiting, oral NAC is remarkably safe

and has not been associated with toxicity.154,168,169 Oral NAC

must be retained for a minimum of 1 hour after ingestion to

be successfully absorbed. If L.P. 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.169,188,189 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.154,168,169,187 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.154,168,169

Outcome of Patient L.P.

L.P. continued to have nausea and vomiting and had difficulty

tolerating liquids. IV NAC was continued. An obstetrics consultation was requested to evaluate L.P.’s pregnancy. Fetal monitoring was instituted during her hospital admission. A sonogram

was taken of the baby. Once L.P. 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.