Toxic doses of salicylate directly stimulate the medullary respiratory center leading
to nausea, vomiting, tinnitus, delirium, tachypnea, seizures, and coma and influence
several key metabolic pathways.
68,73–77 Direct stimulation of the respiratory drive
increases the rate and depth of ventilation, which can result in primary respiratory
alkalosis. The respiratory alkalosis causes increased renal excretion of bicarbonate,
buffering capacity. The patient usually presents with a partially compensated
68,74,75,77 Hypokalemia can result from increased GI and renal
losses of potassium, as well as from systemic alkalosis.
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.
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.
Salicylates have toxic effects on several biochemical pathways that contribute to
metabolic acidosis and other symptoms.
68,75,77 Mitochondrial oxidative
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.
The patient may become severely volume depleted through several
68,75,77 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
Blood glucose concentration is usually normal or slightly elevated, although
hypoglycemia may accompany chronic salicylism (e.g., as illustrated by A.S.) 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
A.S. 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
7.14; serum bicarbonate, 9 mEq/L; respiratory rate, 38 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 A.S., 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, being elderly and taking a lethal amount of aspirin bodes ill for this
CASE 5-2, QUESTION 4: What objective evaluations should be assessed in a patient with presumed
A.S.’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.
73,74 Urine should be tested for
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.
74,75 Physical examination should include an
evaluation of chest radiograph, cardiopulmonary and neurologic function, and
A salicylate blood concentration should be obtained immediately and every 2
24,64,73,75 Serum salicylate concentrations should be reassessed every
2 hours to verify that the original concentration represented a peak level and that the
salicylate level is decreasing rather than increasing.
24,68,73,76,78 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.
Manifestations of severe acute salicylism include a variety of neurologic signs and
symptoms: disorientation, irritability, hallucinations, lethargy, stupor, coma, and
69,73 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.
Pulmonary edema and acute renal failure also can occur, but the former occurs more
commonly after chronic intoxication.
Chronic salicylism symptoms are similar to acute intoxications. However, patients
with chronic exposures may have fewer GI symptoms, but they generally appear more
ill and have more CNS symptoms.
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.
CNS manifestations is related to the cerebrospinal fluid (CSF) salicylate
74,75 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.
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,
24,75,79 Delay in diagnosis has been associated with increased
24,68,75,79 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
71 Death in patients with salicylism, whether acute or
chronic, results from CNS or cardiac dysfunction, or pulmonary edema.
CASE 5-2, QUESTION 5: What would be a reasonable management plan for A.S.?
Management of salicylate intoxication depends on the degree of acid–base and
68,73,75 Activated charcoal is not indicated for A.S. because
approximately 10 hours ago and she has a somewhat altered mental status.
risk of aspiration is greater than the value of possibly adsorbing any remaining
aspirin from the GI tract. In addition, A.S. already has symptoms of salicylate
poisoning, indicating that the aspirin has already been absorbed. Others might argue
that if she ingested 95 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. The benefit
versus risk of giving activated charcoal must be assessed. A.S.’s hypokalemia,
acidosis, and hypoglycemia must be corrected, and it 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.
should be taken to avoid overzealous fluid therapy, which can predispose the patient
to cerebral or pulmonary edema.
73,77 Administration of an IV dextrose bolus is also
indicated because A.S. is hypoglycemic (60 mg/dL).
It is important to correct A.S.’s acidosis because acidosis will increase CSF
74,75 Correction of acidosis can be accomplished by adding
sodium bicarbonate to her IV fluids.
68,73–76 A.S.’s serum sodium and potassium
concentrations should be monitored closely as adding potassium to IV fluids will
82 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.
Seizures are not evident in A.S. 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.
73 Other treatable causes of seizures
(e.g., marked alkalosis, hypoglycemia, hyponatremia) can be present in individuals
such as A.S. and should be ruled out. If seizures occur, benzodiazepines are the drugs
Coagulopathy generally responds to vitamin K1
, which should be given if the PT or
73 GI bleeding or other hemorrhage can occur, but it is not
73,75,76 Mild hyperthermia usually does not require therapy, but cooling fans
and mist may be required for extremely elevated temperatures.
Noncardiogenic pulmonary edema commonly occurs in salicylate intoxications,
especially when the overdose is attributable to chronic ingestions.
edema is associated with a high incidence of neurologic symptoms in patients and
can occur even without fluid overload.
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.
CASE 5-2, QUESTION 6: What measures will enhance salicylate elimination? Which of these may be
Alkalinization of the urine and hemodialysis can enhance the excretion of
salicylate in overdose situations.
68,74 Hemodialysis is preferred because it can also
correct fluid and electrolyte imbalances.
75,78,79 Sodium bicarbonate is recommended
for alkalinization to increase the arterial pH with the goal of minimizing salicylate
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.
76,78,79,81 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.
Potassium replacement in patients receiving alkalinization is essential.
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
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.
68,75,76,78,80 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.
75,80 Because A.S. has many of
the risk factors, she is a candidate for emergent hemodialysis.
CLINICAL OUTCOME OF PATIENT A.S.
A repeat salicylate level 6 hours later (18 hours after ingestion) had increased to 95
mg/dL. Her chemistry panel revealed serum sodium, 143 mEq/L; potassium, 2.2
mEq/L; chloride, 99 mEq/L; bicarbonate, 8mEq/L; glucose, 77 mg/dL; creatinine, 4.9
mg/dL; and BUN, 43mg/dL. Her hemoglobin was now 8.4 g/dL with a hematocrit of
23% and a PT of 16.6 seconds. A.S.’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 5.7. A.S. became fluid overloaded and exhibited dyspnea. She
was placed on a ventilator with worsening of her symptoms. A chest radiograph
showed pulmonary edema. A.S. 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. She had another tonic–clonic seizure, went into respiratory arrest,
coded, and could not be resuscitated.
Gathering History and Communications
more difficult than the consultation in Case 5-1, Question 1?
In cases of unintentional pediatric ingestions, phone calls to a health care provider,
a health care facility, or a poison control center made by individuals other than the
parent are usually more difficult to manage as the caller is often unable 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. Nonparent callers also tend to be more upset about an unintentional ingestion
and may have more difficulty than a parent in taking decisive action.
With this history, the practitioner should consider whether the information
presented by K.M.’s babysitter is consistent with a drug ingestion and whether this
the amount of substance actually ingested is usually small.
substances (e.g., methanol, ethylene glycol, nicotine, caustic substances, camphor,
chloroquine, clonidine, diphenoxylate-atropine, theophylline, oral hypoglycemic
agents, calcium-channel blockers, TCAs, opioids) can produce significant toxicity
even when small amounts are ingested.
Although the history of drug ingestion in K.M. is somewhat vague, the description
of green tablets and green-colored vomitus suggest possible ingestion of iron tablets.
Because this is a possible exposure with a realistic potential for severe toxicity,
K.M. should be brought to the ED for evaluation. Depending on the distance to the
hospital and the anxiety level of the babysitter, the practitioner might want to instruct
the babysitter to call for an ambulance. She should be instructed to bring the green
tablets to the ED along with the child so the tablets can be identified. Other
medications in the house should also be brought to the ED, and the mother should be
house are her iron supplements. The babysitter was instructed to bring K.M. to the nearest Emergency
K.M.’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 case of iron intoxication, the identity of the tablets still has not been
verified. Therefore, K.M. must be carefully assessed, and the ingestion history
All solid dosage prescription drugs are required by the US Food and Drug
Administration (FDA) to have identification markings. Reference books (e.g., Facts
86 Physicians’ Desk Reference),
87 computerized databases (e.g.,
88 and the product manufacturers can assist in identifying solid dosage
forms. Websites such as http://www.pharmer.org
can also be useful in obtaining drug identification information.
The imprint code markings on the green tablet brought to the ED with K.M. and the
mother’s assistance should be sufficient to correctly identify the medication. Once the
tablet has been identified, the maximal number of tablets ingested should be
In K.M.’s case, the bottle containing the green tablets was unlabeled. In most
cases, the label on the 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.
K.M’s vital signs and symptoms should be monitored closely to evaluate whether
her clinical status is consistent with expectations based on the suspected ingestion.
Nausea, vomiting, diarrhea, and abdominal pain are common early signs of iron
91–96 The absence of symptoms, especially within a short time after the
presumed ingestion, should not be interpreted as an indication that a poisoning has
Evaluating Severity of Toxicity
The potential severity of toxicity can be estimated for commonly ingested drugs
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