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.

 CNS changes can be the direct result of an ingested drug or

may be additive to other underlying CNS processes or medical

conditions.120 Many drug overdoses can produce different clinical manifestations at various times during the intoxication, and

different doses can produce different effects as well.30,68

Drugs with anticholinergic properties can produce disorientation, confusion, delirium, and visual hallucinations early in the

course of the intoxication; coma can become apparent as toxicity progresses. Generally, overdoses with anticholinergic drugs

do not produce true hallucinations, but rather pseudohallucinations. When a patient with an intact baseline mental status presents with psychosis, paranoia, or visual hallucinations,

CNS stimulants such as cocaine or amphetamines should be

considered.30,66

Drug intoxication–induced alterations in CNS function are

initially difficult to distinguish from those caused by underlying

psychiatric disorders, trauma, hypoxia, or metabolic disorders,

such as hepatic encephalopathy or hypoglycemia. However, with

the passage of time, decreased CNS function secondary to drug

toxicity is more likely to wax and wane in severity in contrast to

the more constant CNS depression that occurs with significant

trauma or metabolic disorders. Drug toxicity also rarely produces

focal neurologic findings. Changes in pupil size, reflexes, and vital

signs can provide insights into the pharmacologic class of drug

involved in the intoxication.26,30,31

CNS depression, seizures, disorientation, and other CNS

changes that are commonly associated with drugs likely to be

prescribed by psychiatrists should be evaluated carefully in T.C.

For example, T.C.’s pupil size would most likely be dilated if she

had ingested a TCA because of the anticholinergic effects of these

drugs. TCA intoxications can also cause myoclonic spasms.30

These spasms are often difficult to differentiate from seizure

activity caused by TCA overdoses, although the spasms are often

asymmetric and more persistent.121

CARDIOVASCULAR FUNCTION

Assessment of heart rate, rhythm, conduction, and measurements of hemodynamic function can also be used to help identify

the type of drug ingested. Overdoses of sympathomimetic drugs

usually increase heart rate. Overdoses of cardiac glycosides or

β-blockers can slow the heart rate. Although drugs can increase

or decrease heart rate directly, indirect cardiac effects (e.g., reflex

tachycardia in response to hypotension) also need to be considered. Abnormal heart rates produced by drug overdoses are

usually not treated unless hypotension or severe dysrhythmias

are precipitated.30,43

PULMONARY FUNCTION

Evaluating the rate and depth of respiration and the effectiveness

of gas exchange in an intoxicated patient can also help identify

drugs that might have been ingested. A decrease in respiratory

rate is commonly associated with the ingestion of CNS depressants. An increased respiratory rate and depth is generally associated with CNS stimulant toxicity. An increase in respiratory

rate can also be secondary to respiratory compensation for a

drug-induced metabolic acidosis.30 Aspiration of gastric contents

after vomiting is a common event in drug ingestions. Aspiration pneumonitis is the most common pulmonary abnormality

associated with significant intoxications.46 Noncardiogenic acute

pulmonary edema has been associated with drug overdoses of

salicylates81–84 (especially with chronic intoxications) and the use

of drugs of abuse (e.g., cocaine and heroin).122–129

TEMPERATURE REGULATION

Body temperature is an important and sometimes overlooked

parameter when assessing potential intoxications.30,43 Decreased

mental status is often associated with a loss of thermoregulation,

and this results in a body temperature that falls or increases

toward the ambient temperature. Increased body temperature

(hyperthermia) caused by overdoses of CNS stimulants (e.g.,

cocaine, amphetamines, ecstasy), salicylates, hallucinogens (e.g.,

phencyclidine), or anticholinergic drugs or plants (e.g., jimsonweed) can have serious consequences.30,32,43 Body temperature

should be measured rectally to obtain an accurate representation

of core body temperature.130

Hyperthermia caused by drug overdoses is commonly

encountered in hot, humid environments or when the intoxication is associated with physical exertion, increased muscle tone,

or seizures. In these patients, it is important to obtain renal function tests (e.g., BUN, serum creatinine) and a serum creatine

kinase measurement to determine whether rhabdomyolysis has

occurred secondary to breakdown of muscle tissue.30,43,130

GASTROINTESTINAL FUNCTION

The GI tract should be assessed for decreased motility because

drug absorption can be delayed or prolonged.30,131,132 When

this is the case, decontamination may be beneficial after an oral

ingestion even if a long time has elapsed since the ingestion. The

80 Section 1 General Care

presence of blood in either emesis or stool may signal ingestion

of a GI irritant or caustic substance.133

SKIN AND EXTREMITIES

The physical examination should include a thorough evaluation of the body surfaces. Look for causes of trauma that may

also explain the patient’s condition. Examination of the skin and

extremities can provide evidence of drug intoxication, especially

with IV or subcutaneous drug injection needle marks.30 Drugs

can be hidden in the rectum or vagina.30 Look for drug patches

(e.g., fentanyl) on hidden areas of the body such as the back of

the neck or scrotum. Fluid-filled bullae at gravity-dependent sites

that have been in contact with hard surfaces for a long time suggest prolonged coma.30 Muscle tone also should be assessed.30

Increased tone or myoclonic spasms can be caused by some

drug overdoses (e.g., TCAs) and can produce rhabdomyolysis

or hyperthermia.30,130 Dry, hot, red skin may also be an indication of anticholinergic toxicity.30,43

In summary, an organ system assessment of T.C. can provide useful insights into the identity of drugs that might have

been ingested, the viability of organ function that might have

been adversely affected, and the treatment that should be

instituted.

Laboratory Tests

CASE 4-4, QUESTION 6: What laboratory tests should be

ordered for T.C.?

The laboratory assessment of an intoxicated patient should

be guided by the history of the events surrounding the ingestion,

clinical presentation, and past medical history.25,134 The status of

oxygenation, acid–base balance, and blood glucose concentration

must be determined, especially in patients with altered mental

status such as T.C.43 Oxygenation can be assessed initially by pulse

oximetry, and acid–base status by ABGs and serum electrolyte

concentrations.26,134,135 T.C. was given oxygen and a bolus of

IV fluid on her arrival at the ED. Paramedics administered glucose

during her transportation to the ED.

A medical history of organ dysfunction or medical disorders (e.g., diabetes, hypertension) that can damage organs of

elimination (e.g., kidney, liver) will also guide the need for

laboratory tests. A serum creatinine concentration and liver

function tests (e.g., aspartate aminotransferase [AST], alanine

aminotransferase [ALT]) should be ordered. Other more specific tests reflective of her past medical history can be ordered

subsequent to dialogue with her psychiatrist. A complete blood

cell count, complete chemistry panel, serum osmolality, and

other baseline laboratory tests should be obtained.30 Pregnancy

tests should be considered in female patients of childbearing age because unwanted pregnancies are common causes of

overdose.136,137

A baseline electrocardiogram (ECG) should be obtained when

exposure to a cardiotoxic drug is suspected or whenever the

cardiovascular or hemodynamic status is altered.26,29,43,135 A 12-

lead ECG should be ordered because T.C. is likely to have ingested

a psychotropic agent. Continuous cardiac monitoring should be

instituted because of the significant cardiotoxicity associated with

overdoses of these agents. Patients with severe TCA overdoses

frequently present with symptoms of coma, tachycardia with a

prolonged QRS segment, seizures, hypotension, and respiratory

depression.138–141

A chest radiograph is useful when the potential exists for either

direct pulmonary toxicity or aspiration.26,29 A chest radiograph

is indicated because T.C. had vomitus in her mouth and TCAs

are associated with the development of acute respiratory distress

syndrome and pulmonary edema.138,142,143

Qualitative Screening

CASE 4-4, QUESTION 7: Why should (or should not) T.C.’s

urine and blood be screened to assist in identifying the

ingested substance?

Toxicology laboratory testing can be used to identify the substances involved in a toxic exposure, to exclude substances, or

to measure the concentration of substances in serum or other

biological fluids.27,134,135 The identification and quantification of

compounds should be considered as two distinct types of toxicologic testing.27,144 Qualitative screening, intended to identify

unknown substances, must be able to identify which substance

or class of substances is involved in the toxic exposure. Quantitative testing is similar to therapeutic drug monitoring in that

the presence of the substance usually is known, and the question

being answered is how much is present.27

Screening various biological fluids suspected of having high

concentrations of a parent drug and its metabolites can identify

unknown substances. Urine is screened much more commonly

than blood, whereas gastric fluid is rarely evaluated. A urine drug

screen is preferred to a blood drug screen because urine generally

contains a higher concentration of a drug and its metabolites than

other body fluids.145

When reviewing the results of urine screening panels for drugs

and other substances, one must remember that the presence

of a substance in urine is not necessarily related to a concurrent toxicity. A positive result on a urine screening panel merely

indicates that the patient has ingested or has been exposed

to the substance, but it does not differentiate between toxic

and nontoxic doses. If a drug and its metabolites are eliminated slowly into the urine for a prolonged time, and if the

testing methodology detects small concentrations of the substance, urine drug screening could identify the presence of a

substance days, weeks, or even months after the exposure (e.g.,

marijuana).27,135

It is important to know which drugs or substances are tested

at a given laboratory. Many laboratories restrict the number of

drugs for which they test because 15 drugs account for more

than 90% of all drug overdoses.35 Some urine toxicology screens

only detect common drugs of abuse (e.g., amphetamines, barbiturates, benzodiazepines, cocaine, marijuana, opioids).135 Some

drugs of abuse are not detected on routine drug screening (e.g.,

gamma hydroxybutyrate, ketamine, flunitrazepam).27 Some

analyses detect only antibodies to drug metabolites. For example,

a benzodiazepine screen detects oxazepam, a common benzodiazepine metabolite. However, alprazolam and lorazepam are

not metabolized to oxazepam and will not be detected in a urine

screen. Likewise, an opioid screen may not detect the synthetic

opioids such as fentanyl and methadone.135

Results of qualitative toxicology screening tests are difficult

to interpret. False negatives, false positives, cross-reactivity with

related drugs, chronicity of exposure, and length of time since

last exposure all complicate results.113,114,135 Urine toxicology

screen results rarely change clinical management of the patient.

Monitoring mental, cardiovascular, and respiratory status and

other laboratory parameters provide better clues than the results

of a urine toxicology screen.26,27,134,135,144

Toxicology screening can be appropriate when the history

of a suspected toxic exposure is unavailable, inaccurate, or

81Managing Drug Overdoses and Poisonings Chapter 4

inconsistent with the clinical findings.27 However, it is important to know which drugs are detected on a given toxicology

screen.135 A comprehensive qualitative urine drug screen can be

considered for T.C. because information about the substance(s)

she ingested is not yet known.

Quantitative Testing

CASE 4-4, QUESTION 8: Why should a quantitative toxicology laboratory test be ordered (or not ordered) for T.C. as

well?

After a qualitative urine analysis for drugs, a quantitative analysis of drug concentration in blood can help determine the severity of toxicity and the need for aggressive interventions (e.g.,

hemodialysis).27,36,135,144 Quantitative tests are especially useful

when assessing the potential toxicity of drugs with delayed clinical toxicity or when the toxicity primarily is caused by metabolites (e.g., ethylene glycol, methanol). The concentration of a

drug in serum is sometimes much more predictive of end-organ

damage than clinical findings (e.g., acetaminophen effect on the

liver).

Quantifying the amount of drug in serum is useful when (a)

the concentration of the substance correlates with toxic effects,

(b) the turnaround time for results is rapid, and (c) treatment

can be guided by the serum concentration.35,134,144 To aid in

the care of poisoned patients, stat quantitative serum concentrations of acetaminophen, carbamazepine, carboxyhemoglobin,

digoxin, ethanol, ethylene glycol, iron, lithium, methanol, methemoglobin, phenobarbital, salicylates, and theophylline should be

available at laboratories of large health care facilities.26,27,36,134,144

When blood samples are collected to quantitate potentially

intoxicating substances, as much information as possible should

be obtained about the time course of events to determine

whether absorption and distribution of the substance is complete.

Serial samples may be needed to determine whether significant

absorption is still occurring.32,33 In contrast to the interpretation

of therapeutic serum concentrations of chronically administered

drugs, the serum concentration of a substance ingested in an

overdose is not likely to be at steady state.

Quantitative toxicologic testing will not benefit T.C. at this

point in time because the identity of the ingested substance is

unknown. Nevertheless, a serum ethanol concentration could

be useful in this case because alcohol is often ingested concurrently in overdose situations.134 Most poison centers also recommend obtaining a quantitative acetaminophen level on all

intentional ingestions because serious hepatotoxicity can occur

if acetaminophen ingestion is missed.27,134,135

Assessment

CASE 4-4, QUESTION 9: T.C.’s clinical status has not

changed in the past 10 minutes. A urine toxicology screen,

blood acetaminophen, blood alcohol, and ABGs have been

ordered. The 12-lead ECG shows a prolonged QRS interval of 0.14 seconds (normal, <0.1 seconds). No antidotes

have been administered. T.C.’s physical examination did not

detect any evidence of trauma to her head. Her pupils

were dilated and slowly responsive to light, and her bowel

sounds were hypoactive. What conclusions can be made

at this time with regard to the likely substance ingested

by T.C.?

 not been seen in patients who received more than 6 g every

24 hours.100,110

Deferoxamine should be initially administered to R.F. at a

lower rate of about 8 mg/kg/hour, and his clinical status should

be monitored closely. If the dose is tolerated, the rate can be

increased every 5 minutes until the desired dose of 15 mg/kg/hour

is achieved.98

MONITORING AND DISCONTINUATION

CASE 4-3, QUESTION 14: R.F. is admitted to the pediatric

ICU 1 hour after the initiation of a deferoxamine infusion at

8 mg/kg/hour. How should deferoxamine therapy be monitored, and when should it be discontinued?

The rate of deferoxamine infusion should be increased if

symptoms of severe iron toxicity develop, and the dosage should

be decreased if adverse effects develop.98,99,101,110 The infusion of

deferoxamine should be continued until the serum iron concentration is less than 100 mcg/dL and symptoms of iron toxicity are

no longer present.110 Patients will require chelation therapy for

about 1 to 2 days, depending on the severity of symptoms.98–100

Chelation therapy that continues longer than necessary should be

avoided because deferoxamine infusion for more than 24 hours

has been associated with the development of acute respiratory

distress syndrome.98–100

The urine color change to vin rose indicates ferrioxamine in

the urine.97,101 The disappearance of the vin rose color should

not be used as a reliable marker of adequacy of deferoxamine

therapy because not all patients experience vin rose urine.97,101

There is also no correlation between amount of iron ingested,

serum iron concentration, and the urine color change.97

Deferoxamine can interfere with some laboratory methods

used to measure serum iron concentrations and cause falsely low

values.97,98,108,111 To monitor serum iron concentrations when

deferoxamine has been started, using atomic absorptive spectroscopy is recommended.110 When deferoxamine is initiated,

the clinical laboratory should be contacted to clarify whether

deferoxamine will interfere with their serum iron analysis.

Outcome of Patient R.F.

R.F. was admitted to the pediatric ICU overnight and treated

with a constant infusion of deferoxamine at 15 mg/kg/hour for

13 hours. His GI symptoms were no longer apparent, he became

more alert, and his vitals signs were stable. An analysis of a blood

78 Section 1 General Care

sample for free iron the next morning revealed a serum iron level

of 67 mcg/dL. He was discharged home that afternoon.

ASSESSMENT OF CENTRAL NERVOUS

SYSTEM DEPRESSANT VERSUS

ANTIDEPRESSANT INGESTION

Validation of Ingestion

CASE 4-4

QUESTION 1: T.C., a 34-year-old unconscious woman, was

found lying on the couch with a suicide note. The note

stated that she had ingested 25 of her pills. On discovering T.C. unresponsive, T.C.’s 15-year-old daughter called

paramedics. When the paramedics arrived, T.C.’s heart rate

was 145 beats/minute, BP was 105/65 mm Hg, and respirations were 12 breaths/minute and shallow. T.C. was found in

a pool of vomitus. T.C. responded only to painful stimuli. The

paramedics immediately started an IV line after completing

their assessment of her ABCs. Why should the drug overdose information from this suicidal patient be validated?

Assessing the accuracy of historical information in adult

drug exposures is difficult, and many health care professionals question the validity of information, especially from suicidal patients.25–28,30 The ingestion history could be inaccurate because the patient’s altered mental status might prevent

accurate recollection of what occurred. She may also try to

intentionally mislead health care providers to minimize appropriate care. The supposition that the drug overdose history

from a patient is unreliable is based on studies demonstrating poor correlation between stated drug ingestions and urine

drug test results.26–28,30,35,36,112 There are also numerous falsepositive results that can be misleading because of drug interference.113,114

Urine drug screens generally detect all recent drug and substance use, rather than just an overdosed drug. Urine drug screen

results, therefore, are not reliable indicators of acute exposures.

Every effort should be made to validate the history with information from other sources. In suicidal patients, one should consider

all drugs that may have been available to the patient, as well as

the patient’s presenting symptoms, laboratory tests, and information obtained from family members, police, paramedics, and

other individuals who know the patient.25–28,30

Interventions by Protocol

CASE 4-4, QUESTION 2: In addition to managing the ABCs,

what pharmacologic interventions should be authorized for

the paramedics to administer to T.C. in addition to the initiation of an IV solution?

GLUCOSE AND THIAMINE

Emergency medical service personnel often have protocols

directing them to treat patients who are unconscious from an

unknown cause. These protocols generally include administration of glucose, thiamine, and naloxone.26,30,64,115 If paramedics

cannot measure a blood glucose concentration immediately,

T.C. should be given 50 mL of 50% dextrose to treat possible

hypoglycemia. The risks of hyperglycemia from this dose of

glucose are negligible relative to the significant benefits if the

patient is hypoglycemic. Thiamine should be administered concurrently with glucose because glucose can precipitate WernickeKorsakoff complex in thiamine-deficient patients116 (see Chapter 87, Alcohol Use Disorders). Wernicke encephalopathy is

a reversible neurologic disturbance consisting of generalized

confusion, ataxia, and ophthalmoplegia. Korsakoff psychosis is

believed to be irreversible and is associated with a more prolonged deficiency of thiamine.116,117 This unconscious patient

should also be evaluated for blood loss, sepsis, hypoxia, and evidence of head trauma.25

NALOXONE

The pure opioid antagonist, naloxone, is indicated for the

treatment of respiratory depression induced by opioids,115,118

but many emergency medical service protocols authorize

paramedics to routinely administer naloxone to all patients with

any decreased mental status.118 Naloxone reportedly has reversed

coma and acute respiratory depression in intoxicated patients

who have no evidence of opioid use.64,117 The response of these

patients to naloxone might have been secondary to opioids that

were not detected by the urine toxicology screens (e.g., oxycodone, methadone, fentanyl). Drug-induced CNS depression

usually waxes and wanes, and reports of naloxone success in

patients who have not used opioids could also have been the

result of responses to needle sticks, movement, or other stimuli

rather than a response to naloxone.

Administering naloxone to an opioid-addicted patient can

precipitate withdrawal symptoms (e.g., agitation, combativeness, vomiting, diarrhea, lacrimation, rhinorrhea) that can further complicate the intoxication picture.64 Small doses of naloxone should be administered initially to determine the patient’s

response to this medication. Violent and aggressive behavior

can result when sudden increased consciousness is induced by

naloxone.30 This can complicate emergency care in an emergency transport vehicle and put caregivers and patients at risk

for trauma.64

Initial Treatment

CASE 4-4, QUESTION 3: The paramedics arrive at the ED

with T.C. 30 minutes after her daughter called them. T.C.’s

heart rate in the ED is 148 beats/minute, BP is 90/55 mm Hg,

and respirations have decreased from 12 breaths/minute,

spontaneous and shallow, to 7 breaths/minute, with assisted

ventilation from a bag-valve mask. T.C. remains unresponsive. The paramedics were unable to find any prescriptions

or other medications in the house. The daughter believed

that her mother was taking medication for depression, but

she could not be more specific. The police will notify T.C.’s

husband and try to obtain additional information about the

ingested substance. What initial treatment should be provided for T.C. in the ED?

T.C. should be intubated and mechanically ventilated with

100% oxygen because of her shallow, slow respirations and the

likelihood that vomitus could have been aspirated into her lungs.

The BP taken by the paramedics was 105/65 mm Hg and now

is 90/55 mm Hg. A bolus of IV fluid should be administered to

T.C. to determine whether an increase in her intravascular fluid

volume will increase her BP and improve her mental status.25,43

Antidotes

CASE 4-4, QUESTION 4: T.C.’s husband reports that T.C.

is under the care of a psychiatrist for depression and two

79Managing Drug Overdoses and Poisonings Chapter 4

prior suicide attempts. He does not know the identity of

her medication, but attempts are underway to contact T.C.’s

psychiatrist. What antidotes can be administered in the ED

for diagnostic purposes? Should flumazenil (Romazicon) be

administered?

Theoretically, antidotes such as naloxone, flumazenil, deferoxamine, and digoxin-specific antibody-FAB fragments could be

administered in a hospitalized setting to identify an unknown

toxin.25,29,30,118–120 However, the cost and time required for

administration, and increased risks from these antidotes, preclude their use for diagnostic purposes without some plausible suspicion of a specific drug ingestion. Although naloxone

and flumazenil can reverse CNS depression caused by opioids

and benzodiazepines, respectively, their use is not appropriate

without historical, clinical, or toxicologic laboratory findings

that suggest that one of these drugs is a cause of T.C.’s intoxication.118,119

Organ System Evaluations

CASE 4-4, QUESTION 5: How can the initial physical assessment, using an organ systems approach, help in identifying

the drugs ingested by T.C.?

The patient’s ABCs and CNS and cardiopulmonary functions

should be assessed with special attention to clinical manifestations that suggest ingestion of a specific class of drugs.30,43 T.C.’s

history of depression suggests that antidepressants, antipsychotics, lithium, or benzodiazepines are candidates for ingestion

in her case. An organ system evaluation will help determine

whether these (or other) drugs might have been ingested. Nonprescription medications such as aspirin, acetaminophen, decongestants, and antihistamines, which are commonly available in

most households, should also be considered because adult drug

ingestions usually involve more than one drug.

CENTRAL NERVOUS SYSTEM FUNCTION

Changes in CNS function are probably the single most common finding associated with drug intoxication.30 CNS depression

or stimulation, seizures, delirium, hallucinations, coma, or any

combination of these can be manifested in intoxicated patients.