be associated with a significant adverse outcome. Most 2-yearold children experience limited toxicity with unintentional drug

ingestions because only a relatively small amount of substance is usually ingested.6,7 Nevertheless, some substances

(e.g., methanol, ethylene glycol, nicotine, caustic substances,

camphor, chloroquine, clonidine, diphenoxylate-atropine, theophylline, oral hypoglycemic agents, calcium-channel blockers,

TCAs) can produce significant toxicity when only small amounts

are ingested.7,89,90

Although the history of drug ingestion in R.F. is somewhat

vague, the description of a green tablet, the vomiting of green

material, and the recent pregnancy of his mother suggest possible ingestion of prenatal iron tablets. Because this exposure

would be categorized as an unknown toxicity with a realistic

potential for severe toxicity if iron tablets were ingested, R.F.

should be brought to the ED for evaluation. Depending on the

distance to the hospital and the anxiety level of the grandmother,

the practitioner might want to instruct the grandmother to call

for emergency medical services transportation. She should be

instructed to take the green tablets to the ED along with the

child so the tablets can be identified. Other medications that are

in the house should also be taken to the ED, and the mother

should be contacted at the obstetrician’s office.

Substance Identification

CASE 4-3, QUESTION 3: R.F.’s mother has been contacted

and has confirmed that the only green tablets in the house

are her prenatal iron supplements. She is close to the

75Managing Drug Overdoses and Poisonings Chapter 4

hospital and will await the arrival of her son. R.F. arrived

20 minutes later along with one green tablet and an

empty prescription container that was found by his older

brother. R.F. is still vomiting but is awake and alert with

a heart rate of 125 beats/minute, a respiratory rate of

28 breaths/minute, a temperature of 99.1◦F, and pulse

oximetry of 99%. How can the maximal potential severity

of this ingestion be estimated at this time?

R.F.’s vital signs, when corrected for age, are normal. Attention should now focus on identifying the ingested substance and

the maximal potential severity of the ingestion. Although this

case involves an unknown ingestion, with a possibility of being

a severe iron intoxication, the identity of the tablets still has not

been verified. Therefore, R.F. must be carefully assessed, and the

ingestion history reaffirmed.

All solid dosage prescription drugs are required by the US Food

and Drug Administration (FDA) to have identification markings. Reference books (e.g., Facts and Comparisons,91Physicians’

Desk Reference),92 computerized databases (e.g., IDENTIDEX),93

and the product manufacturers can assist in identifying solid

dosage forms. Websites such as http://www.pharmer.org94 and

http://www.drugs.com95 can also be useful in obtaining drug

identification information.

The imprint code markings on the green tablet brought to the

ED with R.F., the empty medication container, and the mother’s

assistance should be sufficient to correctly identify the tablet.

The identification of this green tablet will most likely establish the toxicity potential because most childhood ingestions

usually involve only one substance. Once the tablet has been

identified, the maximal number of tablets ingested should be

estimated.

The label on the empty medication container can provide

information on the identity and number of tablets dispensed.

The date the prescription was obtained, the number of estimated

doses taken, and the number currently remaining in the medication container can be used to approximate the maximal number

of tablets ingested.

R.F.’s vital signs and symptoms should be monitored at frequent intervals to evaluate whether his clinical status is consistent with expectations based on the suspected ingestion. Nausea, vomiting, diarrhea, and abdominal pain are commonly

encountered early in the course of iron intoxication.96–101 The

absence of symptoms, however, should not be interpreted as an

indication that a poisoning has not occurred, especially if the

patient is being evaluated within a short time after the presumed

ingestion.96,98–101

Evaluating Severity of Toxicity

CASE 4-3, QUESTION 4: R.F. weighs 22 pounds, appears

to be in no apparent distress, and has stopped vomiting.

About 30 mL of dark-colored vomitus was recovered, but

no tablets are seen, and testing demonstrates that no blood

is present in the vomitus. A maximum of 11 tablets was

ingested based on the bottle label and the mother’s recall.

What degree of toxicity should be expected in R.F.?

The potential severity of ingestion can be estimated for commonly ingested drugs such as acetaminophen,102 salicylates,75

iron,96 and TCAs103 because of well-established dose–toxicity

relationships. Acute elemental iron ingestions of less than

20 mg/kg are usually nontoxic, doses of 20 to 60 mg/kg result

in mild to moderate toxicity, and doses of more than 60 mg/kg

are severe and potentially fatal.97,99,101

The label on the prescription medication container, as well

as independent verification of the tablet by R.F.’s mother and

the tablet imprint, indicates that each tablet contained 300 mg

of ferrous sulfate in an enteric-coated formulation. Because

the dose–toxicity relationship of iron is based on the amount

of elemental iron ingested, knowledge of the specific iron salt

is important in calculating the ingested dose. Ferrous sulfate

contains 20% elemental iron, ferrous gluconate contains 12%,

and ferrous fumarate contains 33%.96,97,99,100 Therefore, each

300-mg ferrous sulfate tablet contains 60 mg of elemental iron.

R.F. ingested a maximum of 11 enteric-coated ferrous sulfate

300-mg tablets and he weighs 22 pounds (10 kg). His ingestion

of approximately 66 mg/kg (60 mg per tablet × 11 tablets =

660 mg total divided by 10-kg patient weight) of iron places him

at risk of severe toxicity. Although R.F.’s only symptom is vomiting at this time, absorption could be delayed because he ingested

an enteric-coated formulation.

Abdominal Radiographs

CASE 4-3, QUESTION 5: R.F. is expected to experience

potentially severe toxicity from his ingestion of iron. Why

would an abdominal radiograph be useful to verify the number of iron tablets that were actually ingested?

Radio-opaque substances (e.g., iron, enteric-coated tablets,

chloral hydrate, phenothiazines, heavy metals), theoretically, can

be visualized in the GI tract by an abdominal radiograph.104 The

ability of a radiograph to demonstrate the presence of a radiodense substance depends on the dosage form, concentration, and

molecular weight of the substance. The intact dosage form can

often be detected if the tablet has not already disintegrated or

dissolved.104

To see X-rays of iron in the GI tract, go to

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

Less than one-third of pediatric abdominal radiographs show

positive evidence of tablets or granules after iron poisoning.105

Children are more likely than adults to chew tablets rather than

swallow them whole, and false-negative results can occur even

when whole tablets have not already started to disintegrate. If the

tablets were chewed, an abdominal radiograph to verify the number of ingested iron tablets is not likely to be useful. However,

an abdominal radiograph after the completion of GI decontamination can help assess whether additional decontamination is

needed.104

Gastrointestinal Decontamination

CASE 4-3, QUESTION 6: Why would gastric lavage or activated charcoal not be indicated for the management of

R.F.’s iron ingestion?

When selecting a method of GI decontamination, consider the

substance ingested, maximal potential toxicity expected from the

drug dosage form, potential time course of toxicity, time elapsed

between ingestion and the initiation of treatment, symptoms,

and physical examination findings. Decontamination with activated charcoal is not indicated because R.F. has ingested iron

tablets, which are not adsorbed by activated charcoal.53,96,104

Gastric lavage would also not be effective because the removal

of large undissolved iron tablets from the stomach is limited by

76 Section 1 General Care

the small internal diameter of the gastric lavage tube, especially

in pediatric patients.104,105

Whole Bowel Irrigation

CASE 4-3, QUESTION 7: What other method of GI decontamination should be considered for R.F.?

Whole bowel irrigation with a polyethylene glycol electrolyte

solution can be considered in this case. WBI fluid can be administered orally or infused by NG tube at a rate of 1.5 to 2 L/hour for

adults and at a rate of 500 mL/hour for children.63,106 Although

the large volume of fluid to be ingested during a period of several

hours and the frequent association of nausea and vomiting often

result in poor patient compliance, R.F. is hospitalized and the

fluid can be infused by NG tube. WBI should be continued until

the rectal effluent is clear, which may take many hours.63,106,107

MONITORING EFFECTIVENESS OF TREATMENT

CASE 4-3, QUESTION 8: How should the effectiveness of

GI decontamination be assessed in the ED?

The simplest method of assessing GI decontamination is to

visually inspect the return fluid from the WBI for tablets or

tablet fragments. Increasing serum iron concentrations, deteriorating clinical status, or evidence of radiodense tablets in the GI

tract on abdominal radiograph would warrant more aggressive

treatment.97–99,105,107

Serum Iron Concentrations

CASE 4-3, QUESTION 9: At this time, R.F. has no evidence of

CNS or cardiovascular symptoms that can occur with toxic

iron ingestions. He did have one large dark-colored diarrheal stool that tested negative for blood. A serum iron concentration, obtained about 3 hours after the ingestion, was

470 mcg/dL (normal, 60–160 mcg/dL). What conclusions as

to severity or likely clinical outcome can be derived from

this serum iron concentration?

The serum iron concentration provides an indication as to

whether more aggressive therapy is needed.101,105,108 The higher

than normal serum iron concentration confirms the suspicion

that R.F. has ingested iron tablets despite both his current lack

of serious symptoms and the absence of tablet evidence in the

rectal effluent or by abdominal radiograph.

The time course of absorption is probably the most difficult

pharmacokinetic parameter to evaluate with toxic ingestions.

For example, drug concentrations can continue to rise after an

overdose despite GI decontamination.98,100,101,108 This prolongation of absorption time is further complicated when sustainedrelease or enteric-coated dosage formulations have been ingested

because the onset of symptoms is unpredictable.99

R.F.’s serum iron concentration of 470 mcg/dL suggests

a serious ingestion because peak serum iron concentrations

greater than 500 mcg/dL are usually predictive of significant

toxicity.98–101,105,108 This single serum iron concentration does

not provide information as to whether the serum concentration is rising or declining or when the serum iron concentration

will peak as a result of his iron ingestion.109 Iron tablets may

also clump together and form a bezoar. Bezoar formation can

result in prolonged absorption and delay the onset of toxicity.98,101

Samples for peak serum iron concentration should be obtained

4 to 6 hours after ingestion.99–101,108 Although R.F.’s serum iron

concentration was measured approximately 3 hours after ingestion, another serum iron measurement in 2 to 4 hours is needed

because he ingested an enteric-coated formulation.

Blood Glucose, White Blood Cell Count,

and Total Iron Binding Capacity

CASE 4-3, QUESTION 10: R.F. had WBI administered

through the NG tube for 4 hours until the rectal effluent was

clear. At this time, R.F. began to vomit numerous times and

became drowsy and fussy. A second serum iron concentration was ordered (i.e., 6 hours after ingestion). What other

laboratory tests could be helpful in assessing the potential

toxicity of iron in R.F.?

Blood glucose concentrations and white blood cell counts usually are increased when serum iron concentrations are greater

than 300 mcg/dL. A white blood cell count greater than 15,000/μL

and a blood glucose concentration greater than 150 mg/dL within

6 hours of ingestion generally suggest a greater likelihood of

severe iron intoxication.98 These tests provide supplemental confirmation of iron intoxication and may be useful in medical facilities in which serum iron concentrations cannot be obtained.

These laboratory tests are not routinely monitored in iron poisoning because of the poor sensitivity (about 50%).99 Treatment

should not be based on a white blood cell and glucose concentration alone.98–100,105 If a patient with severe iron toxicity presents

to a health care facility that cannot perform timely serum iron

levels, either the blood iron sample must be sent to a laboratory

that can do the testing quickly or the patient must be transferred

to a health care facility that can do serum iron testing for patient

monitoring.

It was once believed that if the serum iron concentration

exceeded the total iron binding capacity concentration, it would

indicate substantial iron toxicity. The correlation between the

total iron binding capacity concentration and iron toxicity, however, has not held up, and the total iron binding capacity test is

no longer used to monitor iron toxicity.101

Stages of Iron Toxicity

CASE 4-3, QUESTION 11: It is now 6 hours since R.F.

ingested the iron tablets. His second serum iron concentration is not yet available. He continues to be fussy and

drowsy but has missed his usual afternoon nap. He has several more episodes of vomiting. Why is R.F.’s relatively mild

course at this time not particularly reassuring?

The time between the ingestion of an overdose of drugs and

the development of severe toxicity can be delayed. It is unclear

why there may be an asymptomatic period, but it may be secondary to delayed absorption of the ingested drug, the time

required for the drug distribution, or the time needed to form

a toxic metabolite. Consequently, R.F. may still exhibit further

symptoms of severe toxicity. Four distinct stages of symptoms

can be encountered with iron toxicity.96–101

STAGE I

Stage I symptoms usually occur within 6 hours of ingestion.

During this time, nausea, vomiting, diarrhea, and abdominal pain

are encountered and are probably secondary to the erosive effects

of iron on the GI mucosa. The caustic effects of free iron can

cause bleeding as evidenced by blood in the vomitus and stool.

77Managing Drug Overdoses and Poisonings Chapter 4

In more severe intoxications, CNS and cardiovascular toxicity can

be present during stage I.98–101

STAGE II

The second stage of iron toxicity has been suggested as a period

of decreasing symptoms and an apparent improvement in the

clinical condition. This stage can last for up to 12 to 24 hours after

the ingestion and could be misinterpreted as resolving toxicity.

This stage may represent the time needed for the absorbed iron

to distribute throughout the body before systemic symptoms

develop.96 Alternatively, this stage might merely reflect patients

who did not receive treatment early in the course of intoxication

and appeared to be well before systemic effects developed. In

most severe cases, stage II is not encountered and the patient’s

condition continues to progressively deteriorate.98–101

STAGE III

Stage III generally occurs 12 to 48 hours after iron ingestion and is characterized by CNS toxicity (e.g., lethargy, coma,

seizures) and cardiovascular toxicity (e.g., hypotension, shock,

pulmonary edema). Metabolic acidosis, hypoglycemia, hepatic

necrosis, renal damage, and coagulopathy can be experienced at

this stage.98–101

STAGE IV

The final stage is apparent 4 to 6 weeks after acute iron ingestion

and consists of late-appearing GI tract sequelae that are secondary to the initial local toxicity. In this stage, prior tissue damage

can progress to gastric scarring and strictures at the pylorus,

resulting in permanent abnormalities of GI function.98–101

Patients can present to the health care facility in any stage of

iron toxicity and can have a fatal outcome in any stage. Assigning

a stage of toxicity should not be based on time since ingestion,

but instead should be based on clinical symptoms.100

Deferoxamine Chelation

CASE 4-3, QUESTION 12: The clinical laboratory has

reported that the second serum iron concentration that was

obtained 6 hours after ingestion from R.F. has increased

from 470 to 553 mcg/dL. The child has continued to vomit.

R.F.’s mother states that the child looks “pale” to her. What

criteria are most important in determining whether the antidote deferoxamine should be administered to R.F.?

Deferoxamine (Desferal) chelates iron by binding ferric ions

in plasma to form the iron complex ferrioxamine.99 Deferoxamine prevents iron toxicity at a cellular level by removing iron

from mitochondria.97 Unfortunately, deferoxamine is not a very

effective antidote as a relatively small amount of iron is bound

(approximately 9 mg of iron to 100 mg of deferoxamine).109,110

The iron–deferoxamine complex primarily is excreted renally as

ferrioxamine.97,99,100 Renal elimination of the ferrioxamine usually results in a pinkish-orange urine, often described as “vin

rose.”97,99,100 Deferoxamine therapy should be initiated when

serum iron concentrations exceed 500 mcg/dL and when symptoms of iron toxicity (e.g., GI symptoms, hemorrhage, coma,

shock, seizures) are present.97–100 R.F. is experiencing symptoms,

he presumably ingested up to 66 mg/kg of elemental iron, and

iron absorption appears to be ongoing based on the increase in

his serum iron concentration. Therefore, R.F. should be treated

with deferoxamine.

DEFEROXAMINE DOSE

CASE 4-3, QUESTION 13: What dose of deferoxamine

should be prescribed for R.F., and how should it be administered?

Deferoxamine is most effective when administered intravenously as a constant infusion owing to its short half-life

(76 ± 10 minutes).98,100,109 Clinically, a slow IV infusion is

preferred instead of intramuscular administration because the

IV dose can be better controlled, is less painful, and is better absorbed than an intramuscularly administered dose.100–101

Deferoxamine at a dose of 15 mg/kg/hour is usually administered

in a continuous IV infusion. However, doses up to 45 mg/kg/hour

have been used in patients with severe iron poisoning.98–101,109

Hypotension can result from administering IV boluses of deferoxamine too rapidly.97,99,101,109,110 According to the manufacturer,

the total deferoxamine dose should not exceed 6 g every 24 hours

when administered to adults or children, but adverse effects have

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