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.?

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