patient usually presents with a partially compensated respiratory alkalosis.72,78,79,81 Hypokalemia can result from increased

GI and renal losses of potassium, as well as from systemic

alkalosis.72,79,80

Although marked metabolic and neurologic abnormalities

are most commonly observed in young children with advanced

salicylate intoxication, adolescents or adults acutely poisoned

with a large dose of salicylates can exhibit these symptoms as

well.72,78,79 Acute salicylism in a young child often takes a more

severe course than that typically seen in adults. After acute ingestion, children quickly pass through the phase of pure respiratory

alkalosis. Renal bicarbonate loss secondary to respiratory alkalosis reduces the buffering capacity more profoundly in a child

and facilitates the development of metabolic acidosis.72,77,79,81

Salicylates have toxic effects on several biochemical pathways

that contribute to metabolic acidosis and other symptoms.72,79–81

Mitochondrial oxidative phosphorylation is uncoupled and

results in an impaired ability to generate high-energy phosphates, increased oxygen use and carbon dioxide production,

increased heat production and hyperpyrexia, increased tissue glycolysis, and increased peripheral demand for glucose. Salicylates

also inhibit key dehydrogenase enzymes within the Krebs cycle,

resulting in increased levels of pyruvate and lactate. The increased

demand for peripheral glucose causes increased glycogenolysis, gluconeogenesis, lipolysis, and free fatty acid metabolism.

The latter results in enhanced formation of keto acids and

ketoacidosis.77,81

The patient may become severely volume depleted through

several mechanisms.72,79,81 Hyperthermia and hyperventilation

produce increased insensible water loss, vomiting may promote

GI fluid losses, and the solute load caused by altered glucose

metabolism results in an osmotic diuresis. Depending on the

patient’s acid–base balance and net fluid and electrolyte intake

and output, serum sodium and potassium concentrations may be

normal, elevated, or decreased. Hypernatremia and hypokalemia

are most common.77,79

Blood glucose concentration is usually normal or slightly

elevated, although hypoglycemia may accompany chronic salicylism (e.g., as illustrated by V.K.) or occur late in acute intoxication. CNS glucose levels can be markedly reduced in the presence

of normal blood glucose concentrations because increased CNS

glucose utilization to generate high-energy phosphate exceeds

the rate at which glucose can be supplied.72,77,79,81

Other manifestations of severe acute salicylism include a

variety of neurologic signs and symptoms: disorientation, irritability, hallucinations, lethargy, stupor, coma, and seizures.73,77

Hyperthermia may be marked and can result in the inappropriate administration of aspirin as an antipyretic. Coagulopathy

can occur because of impaired platelet function, hypoprothrombinemia, reduced factor VII production, and increased capillary

fragility, especially when aspirin is taken chronically.79–81 Pulmonary edema and acute renal failure also can occur, but the

former occurs more commonly after chronic intoxication.79,81,82

Chronic salicylism symptoms are similar to acute intoxications. However, patients with chronic exposures may have fewer

GI symptoms but generally appear more ill and have more CNS

symptoms.75,83 In both adults and children, the principal signs

of chronic salicylism are a partially compensated metabolic acidosis, increased anion gap, ketosis, dehydration, electrolyte loss,

hyperventilation, tremors, agitation, confusion, stupor, memory deficits, renal failure, and seizures.77,79,80,84 The severity of

CNS manifestations is related to the cerebrospinal fluid (CSF)

salicylate concentration.78,79 CSF concentrations may increase

in the presence of systemic acidosis because a greater fraction

of salicylate is not ionized and can cross the blood–brain barrier. Therefore, metabolic acidosis is especially dangerous in a

salicylate-intoxicated patient.77,79

Unless the history of salicylate intake is specifically sought,

the problem may not be immediately apparent, especially in

the elderly in whom such findings are likely to be attributed to

other causes (e.g., encephalitis, meningitis, diabetic ketoacidosis,

myocardial infarction).27,79,83 Delay in diagnosis has been associated with increased mortality.27,72,79,83 Unfortunately, plasma

salicylate concentrations do not correlate well with the degree of

poisoning in chronically intoxicated patients. It is more important to treat the patient according to the clinical status rather

than his or her salicylate concentration.72 Death in patients with

salicylism, whether acute or chronic, results from CNS or cardiac

dysfunction, or pulmonary edema.77,79,83

ASSESSMENT OF TOXICITY

CASE 4-2, QUESTION 3: What signs, symptoms, and laboratory values in V.K. are consistent with salicylate intoxication?

V.K. demonstrates many of the findings typical of severe

acute salicylism. Hyperventilation has resulted from the direct

respiratory stimulant effects of salicylate and as compensation

for her metabolic acidosis (Pco2, 20 mm Hg; pH, 7.25; serum

bicarbonate, 10 mEq/L; respiratory rate, 36 breaths/minute).

Hypokalemia (2.8 mEq/L) in the presence of metabolic acidosis represents severe potassium depletion because of increased

renal and possibly GI losses. Hyperpyrexia caused by salicylate

is present in V.K., although an infectious cause must also be considered. Her neurologic symptoms of lethargy, disorientation,

and combativeness, as well as tinnitus, nausea, and vomiting,

are commonly seen in severe salicylate intoxication. In addition,

73Managing Drug Overdoses and Poisonings Chapter 4

being elderly and taking a lethal amount of aspirin bodes ill for

this patient’s outcome.

LABORATORY EVALUATION

CASE 4-2, QUESTION 4: What objective evaluations should

be assessed in a patient with presumed salicylate intoxication?

V.K.’s workup illustrates a thorough initial patient evaluation.

Laboratory evaluation should include ABG values, serum electrolytes, BUN, serum creatinine, blood glucose, and a complete

blood cell count.77,79,80 Urine should be tested for specific gravity

and pH.77 In symptomatic patients, a PT or international normalized ratio (INR) and partial thromboplastin times are useful

to assess the presence of salicylate-induced coagulopathy. Vitals

signs should be monitored for an increased respiratory rate and

hyperpyrexia.78,79 Physical examination should include an evaluation of chest radiograph, cardiopulmonary and neurologic function, and measurement of urine output.79

A salicylate blood concentration should be obtained 6 hours

after an acute ingestion at a known time, immediately and

6 hours after an acute ingestion at an unknown time, and immediately and every 2 to 6 hours in symptomatic patients.27,68,77,79,85

Serum salicylate concentrations should be reassessed every 4 to

6 hours to verify that the original concentration represented a

peak level and that the salicylate level is decreasing rather than

increasing.27,72,77,80,82 Obtaining the units of measurement on

salicylate serum concentrations is essential because different laboratories report concentrations in different units (e.g., mg/dL,

mcg/mL, mmol/L). An incorrect interpretation of the salicylate

unit of measurement can result in overestimates or underestimates of the severity.27

Historically, the Done nomogram was used to determine the

degree of toxicity from a known single acute salicylate ingestion by plotting the serum salicylate concentration by time since

the ingestion.86 However, clinical symptoms and laboratory findings are more useful in identifying the degree of acute intoxication, assessing patient prognosis, and guiding therapy.85 In case

of chronic ingestions, the nomogram is not useful, and other

parameters such as acid–base and electrolyte balance should be

used to determine severity of the case.72,77

The Done nomogram is also not useful in certain situations

such as ingestion of enteric-coated or sustained-release salicylate

products, when the time of ingestion is unknown, or when the

patient is acidemic or has renal failure.77,79,80,85–87 The nomogram is also less useful when salicylate serum concentrations

are measured more than 12 hours after ingestion. Serum concentrations obtained less than 6 hours after ingestion in acute

ingestion situations are also difficult to interpret because the

drug level has not yet peaked and can result in an underestimation of the eventual degree of intoxication.72,77,84,87 Salicylate

concentrations can continue to rise for approximately 24 hours

if a large amount has been taken or if enteric-coated tablets have

been ingested. Enteric-coated tablets can clump together, forming a bezoar that slowly releases drug into the gut.79,85 Because

of these difficulties in interpreting salicylate concentrations, the

Done nomogram is no longer used.27

MANAGEMENT

CASE 4-2, QUESTION 5: What would be a reasonable management plan for V.K.?

Management of salicylate intoxication depends on the degree

of acid–base and electrolyte disturbances.72,77,79 Activated charcoal is not indicated for V.K. because the ingestion occurred

approximately 10 hours ago and she has a somewhat altered

mental status.46 The risk of aspiration is greater than the value

of possibly adsorbing any remaining aspirin from the GI tract. In

addition, V.K. already has symptoms of salicylate poisoning, indicating that the aspirin has already been absorbed. Others might

argue that if she ingested 100 tablets, some of the drug may still

be present in the GI tract and giving activated charcoal late may

bind some of the drug still present.

V.K.’s hypokalemia, acidosis, and hypoglycemia must be corrected, and is probably best accomplished through the administration of intravenous (IV) hypotonic saline–dextrose solutions

combined with potassium supplementation. This solution is

administered at a rate that replaces the patient’s deficits and keeps

pace with continued losses.72,77,79–81 Care should be taken to

avoid overzealous fluid therapy, which can predispose the patient

to cerebral or pulmonary edema.79,81 Administration of an IV

dextrose bolus is also indicated because V.K. is hypoglycemic (60

mg/dL).77,79,81

SODIUM BICARBONATE

It is important to correct V.K.’s acidosis because acidosis will

increase CSF salicylate concentrations.78,79 Correction of acidosis

can be accomplished by adding sodium bicarbonate to her IV

fluids.72,77–80 V.K.’s serum sodium and potassium concentrations

should be monitored closely as adding potassium to IV fluids

will mostly likely be required.86 Providing adequate ventilation

to prevent respiratory alkalosis is essential. With a respiratory

rate of 36 breaths/minute, placing the patient on a ventilator

to assist with breathing might be considered. However, forced

mechanical ventilation can interfere with the patient’s need to

compensate to maintain the serum pH. Patients on ventilators

can become severely acidotic, which can result in death because

of an inability to compensate adequately.77,88

SEIZURES

Seizures are not evident in V.K. but can be encountered in cases

of severe salicylate poisoning. Seizures generally carry a poor

prognosis and are indicative of severe salicylate intoxication that

requires hemodialysis.77 Other treatable causes of seizures (e.g.,

marked alkalosis, hypoglycemia, hyponatremia) can be present

in individuals such as V.K. and should be ruled out. If seizures

occur, benzodiazepines are the drugs of choice for treatment.77

COAGULOPATHY AND HYPERTHERMIA

Coagulopathy generally responds to vitamin K1, which should

be given if the PT or INR is prolonged.77 GI bleeding or other

hemorrhage can occur but is not common.77,79,80 Mild hyperthermia usually does not require therapy, but cooling fans and

mist may be required for extremely elevated temperatures.77,81

PULMONARY EDEMA

Noncardiogenic pulmonary edema commonly occurs in salicylate intoxications, especially when the overdose is attributable to

chronic ingestions.77,79,82 Pulmonary edema is associated with a

high incidence of neurologic symptoms in patients and can occur

even without fluid overload.79,82 Increased alveolar capillary

membrane permeability, prostaglandin effects, and a metabolic

interaction with platelets releasing membrane permeability substances are the primary mechanisms for the cause of pulmonary

edema associated with salicylate overdose. Treatment is aimed

at reducing salicylate levels via alkalinization or hemodialysis.82

ALKALINIZATION

CASE 4-2, QUESTION 6: What measures will enhance salicylate elimination? Which of these may be indicated in V.K.?

74 Section 1 General Care

Alkalinization of the urine and hemodialysis can enhance the

excretion of salicylate in overdose situations.72,78 Hemodialysis is preferred because it can also correct fluid and electrolyte

imbalances.79,82,83 Sodium bicarbonate is recommended for alkalinization to increase the arterial pH with the goal of minimizing

salicylate transport into the CNS.78,79,81

Although large doses of sodium bicarbonate can enhance

the renal elimination of the weak acid and shorten its half-life,

this treatment does not favorably influence the morbidity or

mortality of patients with salicylism. Alkalinization with forced

fluid diuresis can also place the patient at risk for sodium and

fluid retention, as well as pulmonary edema if too much fluid

is given too quickly.77,79,80,82 Whether the urine can be adequately alkalinized (pH >7) in severely intoxicated pediatric

patients has been questioned because of the large acid load

that is excreted.72,77,78 Nevertheless, urine alkalinization with

sodium bicarbonate should be attempted in severely salicylateintoxicated adult patients such as V.K.

Potassium replacement in patients receiving alkalinization is

essential.77,79,81 These patients may require large amounts of

potassium supplementation as a result of renal wasting of potassium. The risk for pulmonary edema can be minimized if this is

done without forcing fluids.77,79–81

Hemodialysis should be considered in patients who show progression of severe salicylate intoxication and seizure activity, renal

failure, or plasma salicylate concentrations in the potentially fatal

range.72,79,80,82,84 Patients with a chronic exposure, acidosis, or

CNS symptoms and those who are elderly or ill are high-risk

patients and should be considered for early dialysis.79,84 Because

V.K. has many of the risk factors, she is a candidate for emergent

hemodialysis.

CLINICAL OUTCOME OF PATIENT V.K.

A repeat salicylate level 6 hours later (18 hours after ingestion)

had increased to 93 mg/dL. Her chemistry panel revealed serum

sodium, 144 mEq/L; potassium, 2.1 mEq/L; chloride, 100 mEq/L;

bicarbonate, 9 mEq/L; glucose, 78 mg/dL; creatinine, 4.8 mg/dL;

and BUN, 42 mg/dL. Her hemoglobin was now 8.5 g/dL with a

hematocrit of 23% and a PT of 16.6 seconds. V.K.’s pH on blood

gases remained in the 7.2 to 7.3 range. Urinary alkalinization was

attempted with a high-dose IV sodium bicarbonate infusion in

an attempt to reach a urine pH of 7.5. However, her urine pH

never increased above pH 5.6. V.K. became fluid overloaded and

exhibited dyspnea. She was placed on a ventilator with worsening of her symptoms. A chest radiograph showed pulmonary

edema. V.K. became confused and agitated, pulling at her IV

lines and trying to get out of bed. Nephrology was consulted

to provide emergent hemodialysis to correct the acidosis, electrolyte abnormalities, and fluid overload. As the catheter was

being placed, the patient had a tonic-clonic seizure. Lorazepam

2 mg IV was administered and the seizure stopped. At this time,

the patient was unresponsive. The NG tube revealed the presence of copious amounts of bright red blood. She was rushed to

surgery for an emergency laparotomy. On the way to the operating room, she had another seizure, went into respiratory arrest,

coded, and could not be resuscitated.

ASSESSMENT OF IRON INGESTION

Gathering History and Communications

CASE 4-3

QUESTION 1: The grandmother of R.F., a 20-month-old boy,

calls the ED because her grandson is vomiting and appears

to have been playing with some green tablets. The child

was left alone in his room for about 15 minutes to take a

nap. Why might the consultation with this grandmother be

expected to be more difficult than the consultation in Case

4-1, Question 1?

Phone calls to a health care provider, a health care facility,

or a poison control center from individuals other than the parent are usually more difficult to manage as the caller may not

be able to provide all patient-specific information needed (e.g.,

patient weight, chronic medications) to accurately assess the drug

ingestion. Additional information is often needed from a parent.

Furthermore, nonparent callers tend to be more upset about

an unintentional ingestion and may have more difficulty than a

parent in taking decisive action.

Triage of Call

CASE 4-3, QUESTION 2: Despite additional questioning,

R.F.’s grandmother cannot identify the tablets and cannot

find any labeling or empty medicine containers that could

help in the tablet identification. R.F. is still vomiting, and

some of the vomitus is green-colored like the tablets. There

are three children in the household and two adults who take

medications for various chronic illnesses. According to the

grandmother, R.F. is healthy, and no one else in the household currently has the “flu” or other GI illness. The child’s

mother gave birth 3 weeks ago and is now at her obstetrician’s office for a postnatal visit. What recommendations

could be provided to R.F.’s grandmother at this time?

With this history, the practitioner should consider whether

the information presented by R.F.’s grandmother is consistent

with a drug ingestion and whether this incident is likely to

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