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CALL US...TM
The Official Newsletter of the California Poison
Control System
Volume 7, Number 4
Fall 2009
Salicylates
Introduction
Medications containing
salicylic acid and its derivatives have been in use since ancient times. By the 1700’s, extracts of willow bark, rich
in salicylate, were known to have beneficial effects on fever, pain, and
inflammation. Acetylsalicylic acid was
first synthesized by French chemist Charles Gerhardt in 1853, and was patented
under the name “aspirin” by the drug firm Bayer in 1899.
Poisoning with
salicylate-containing products remains a common problem, largely due to their
wide availability and their presence in many over-the-counter cold and fever
preparations. In 2007, over 4800
exposures to aspirin alone were reported to United States poison centers, with
63 deaths; these represent 5% of all fatal poisonings reported. Toxicity may occur with intentional acute
overdose or unintentionally if supratherapeutic doses are taken chronically. Toxicity can occur not only from ingestion of
aspirin-containing medications, but also from the excessive application of
salicylate-containing ointments, keratolytic agents, or liniments, particularly
those containing methyl salicylate (oil of wintergreen).
Case
Presentation
A
57-year-old male was found wandering the streets, confused and
disoriented. He was brought into the ED
by paramedics, where initial vital signs were: temperature 98.6°F (orally),
blood pressure 132/62 mm Hg, heart rate 119 beats per minute, respiratory rate
28/minute, and oxygen saturation 94% on room air. The patient was noted to be confused and
diaphoretic. Pupils were mid-sized and
reactive, his neck was supple, he was tachypneic but lungs were clear, and he was
tachycardic with normal heart tones. Bowel
sounds were normal. Neurologic
examination was remarkable for confusion but was otherwise nonfocal.
Following
initial evaluation, he was placed on supplemental oxygen by nasal cannula,
placed on a cardiac monitor, and an IV line was inserted. Fingerstick blood glucose was normal. Portable chest radiograph revealed diffuse
bilateral patchy infiltrates. Complete
blood count was remarkable for a white blood cell count of 14,000/mm3,
and serum chemistry evaluation revealed: Na 144, K 2.8, Cl 101, HCO3
20, BUN 25, Cr 1.2, Glucose 144.
Urinalysis showed specific gravity 1.023, pH 5.5, 2+ protein, and 3+
ketones. EKG revealed sinus tachycardia
with a rate of 121 beats per minute and a normal QRS duration. The patient was diagnosed with pneumonia, administered
intravenous antibiotics, and admitted to the hospital.
Upon
arrival to the medical ward, an astute intern obtained an ABG on room air,
which revealed a pH of 7.44, pCO2 of 27, and pO2 of 57. A salicylate level was obtained and was 63
mg/dL. A rectal temperature read 100.9°F. Nephrology was consulted and the patient
underwent emergent hemodialysis. The
following morning his mental status had normalized, and chemistry and ABG
analyses were normal. The patient denied
intentional overdose and stated that he had been taking aspirin 650 mg 7-8
times per day for several weeks due to chronic low back pain.
Questions:
1.
What are the primary mechanisms of salicylate toxicity?
2. What laboratory findings in this case
(other than salicylate level) should have prompted the consideration of
salicylate toxicity?
3. What treatments are available for the
treatment of salicylate toxicity?
4. What precautions should clinicians consider
when treating patients with salicylate toxicity?
Epidemiology
Salicylate-containing
medications have been widely used in the U.S. and around the world for more
than 100 years. Use has declined in the
U.S. over recent years, particularly in children, due to the discovery of
aspirin’s association with Reye syndrome and with the increasing use of
nonsteroidal anti-inflammatory drugs (NSAIDs).
However, aspirin continues to be responsible for a significant number of
cases of morbidity and mortality every year; aspirin-containing products account
for 1 in 8 analgesic-related deaths annually.
While
intentional salicylate overdose results in the majority of deaths, mortality
due to unintentional overdose is not uncommon and can be due to multiple
factors. Terminology used on product
labels can be confusing and is commonly misinterpreted. Many over-the-counter cold preparations
contain salicylates, and patients who do not read labels carefully may take
these products and then ingest additional aspirin, not realizing that the
combination product already contains a therapeutic salicylate dose.
Other
substances not widely known to contain salicylate may be the cause of
unintentional exposures. Topical methyl
salicylate-containing compounds, such as oil of wintergreen, are extremely
potent (1 teaspoon of 100% oil of wintergreen contains 7 g of salicylate) and
ingestion of even a small amount can be lethal for a small child. Additionally, bismuth
subsalicylate-containing compounds (such as Pepto-Bismol) contain 8.7 mg of
salicylate per mL, and people using large amounts (200-300 mL) of this
substance are at risk for salicylate toxicity.
Pathophysiology
Salicylates
have many effects on the body. Nausea
and vomiting occur as a result of gastric irritation and additionally due to
stimulation of the chemoreceptor trigger zone.
Tinnitus and other auditory disturbances occur as a result of direct
toxicity of salicylate on the inner ear; the exact mechanism is unclear. Salicylates stimulate the medullary
respiratory center in the brainstem, causing hyperventilation and producing a
primary respiratory alkalosis.
Additionally,
salicylates uncouple oxidative phosphorylation, resulting in decreased ATP
production and increased heat production and manifesting clinically as
hyperthermia. Increased free fatty acid
metabolism occurs in the setting of salicylate toxicity, resulting in the
formation of multiple ketoacids and causing an anion gap metabolic
acidosis. Salicylates inhibit the Krebs
cycle, leading to the accumulation of lactate, pyruvate, and other organic
acids which also contribute to the metabolic acidosis. Salicylate poisoning may result in
noncardiogenic pulmonary edema thought to be a result of increased permeability
of the pulmonary vasculature. This
mechanism may also be responsible for cerebral edema seen in some patients with
severe salicylate poisoning. Some patients may have an elevation in their
prothrombin time due to hypoprothrombinemia from an unclear mechanism. However,
clinically significant bleeding is rare in salicylate overdose.
Clinical
Presentation
It
may be difficult to distinguish between acute and chronic salicylate toxicity
since symptoms are similar between the two groups. Acute toxicity can present initially with
hyperventilation (hyperpnea or tachypnea) due to stimulation of the medullary
respiratory center, although this may not always occur, particularly in
children. Nausea, vomiting, and
diaphoresis are also common. Auditory
disturbances may be present; tinnitus is classically described, but patients
may complain of ringing, hissing, hearing loss, or deafness. Other symptoms and signs can include
delirium, agitation, lethargy, and hallucinations. Seizures may occur and are a sign of
significant CNS toxicity or cerebral edema.
In moderate to severe toxicity, uncoupling of oxidative phosphorylation
may lead to hyperthermia.
Chronic
toxicity usually occurs in elderly patients who have unintentionally overdosed
on salicylates in the treatment of chronic conditions such as arthritis. Patients may present with nausea, vomiting,
auditory symptoms, delirium, confusion, slurred speech, tachycardia,
hyperthermia, or seizures. Older
patients may present with a decline in their ability to perform activities of
daily living with no clear etiology.
Although symptoms are similar to those found in acute overdose, onset of
symptoms in chronic toxicity is usually more insidious and this may lead to a
delay in diagnosis. Patients with
chronic salicylism may be initially diagnosed with sepsis, pneumonia, pulmonary
edema, congestive heart failure, hyperthyroidism, diabetic ketoacidosis,
delirium, psychosis, or dementia.
Diagnosis
Diagnosis
of salicylate toxicity is based upon the presence of an elevated serum
salicylate concentration in conjunction with signs or symptoms of salicylate
toxicity. In general, patients with
chronic toxicity will manifest symptoms at lower levels compared to patients
with acute toxicity. Care must be taken
to note the units in which salicylate concentrations are reported. Although
concentrations are usually reported in mg/dL, some laboratories may report in
mg/L, and confusion between the two can result in a tenfold error in
interpretation. Salicylate toxicity does
not accurately correlate with serum salicylate levels particularly in the chronic
setting. The Done nomogram, which was
first published in 1960, was derived from primarily pediatric patients in
narrowly defined conditions and should not be used to determine the need for
treatment. In establishing the diagnosis
and assessing the severity of salicylate poisoning, it is paramount to consider
clinical manifestations and degree of acidosis in conjunction with the
salicylate concentration. A salicylate concentration should not be used in
isolation to establish or exclude the diagnosis of salicylate toxicity or
determine its severity.
Patients
will typically have a widened anion gap as measured on serum chemistries, and
urinalysis will usually reveal ketonuria as a result of the presence of ketone
bodies such as acetoacetic acid and acetone.
Blood gas analysis should be performed at the same time that serum
salicylate concentration is measured.
Classically, patients will present with a mixed acid-base disorder with
a respiratory alkalosis and a metabolic acidosis. Early in toxicity, patients will be alkalemic
(pH >7.4) due to a primary respiratory alkalosis as a result of medullary
stimulation of respiration. The presence
of acidemia (pH <7.4) is concerning, since a lower serum pH will allow more
salicylate to unbind from serum proteins and enter the CNS resulting in
increased toxicity. Patients with
clinical manifestations of salicylate poisoning will require vigilant clinical
and laboratory monitoring as progression towards severe toxicity may go
unrecognized resulting in preventable morbidity and possibly mortality.
Treatment
Initial
treatment of salicylate poisoning includes airway management, oxygenation, and
intravenous fluid administration.
Aspirin is well bound by activated charcoal, and a starting dose of 1
g/kg body weight should be strongly considered (without sorbitol), particularly
if the patient presents within 1 hour of ingestion. Activated charcoal is preferred to the use of
gastric lavage, and ipecac is no longer recommended. Whole bowel irrigation (WBI) with
polyethylene glycol should be considered in patients with large ingestions,
particularly with enteric-coated aspirin preparations, or in patients with
increasing salicylate levels over time. When this occurs an aggregation or
concretion of pills, known as pharmacobezoars, may be present in the stomach
and may be more rapidly cleared with WBI.
Serum alkalinization with sodium
bicarbonate should also be considered in cases of salicylate poisoning with acidemia. Patients who are able to tolerate the
increased demands of hyperventilation and are already alkalemic may require
less sodium bicarbonate therapy or none at all.
Because aspirin is a weak acid, it is ionized in an alkaline environment
and thus cannot cross the blood-brain barrier.
The goal of alkalinzation of the serum is to prevent protonation of the
salicylate ion to form an uncharged molecule capable of distribution into vital
tissues and organ systems such as the CNS.
Administration of 1-2 ampules (45-90 mEq) of sodium bicarbonate as a
bolus followed by an infusion (ex. 3 ampules mixed with D5W at 1.5-2 times
maintenance fluid rate) will help to “trap” salicylate ions in the blood and
will allow more rapid excretion in the urine.
Alkalinization is most helpful in those patients whose serum pH is not
already elevated (>7.5) and care should be taken not to raise serum pH to
inappropriately high levels (>7.55).
Hypokalemia occurs commonly in salicylate-poisoned patients and prevents
urinary excretion of salicylate unless corrected.
While many textbooks
suggest that the goal of sodium bicarbonate therapy is urinary alkalinization in an effort to enhance excretion of
salicylate, this may be difficult to achieve, especially in the setting of
electrolyte abnormalities, and if administered over-aggressively may place the
patient at risk for severe alkalemia.
There is little scientific evidence to suggest that urinary
alkalinization in salicylate poisoning results in improved outcomes. Older
publications may also recommend the use of carbonic anhydrase inhibitors such
as acetazolamide to alkalinize urine, but this therapy may result in
acidification of the serum thereby increasing the potential for enhancing
distribution of salicylate into tissues and should therefore be avoided.
Hemodialysis
can remove salicylate ion and also correct fluid and electrolyte abnormalities
that are common in salicylate-poisoned patients. Dialysis should be considered in patients
with severe acid-base or electrolyte disturbances despite appropriate therapy,
and in patients with renal insufficiency, pulmonary or cerebral edema,
persistent CNS disturbances, or progressive clinical deterioration. Some textbooks also advocate dialysis in
acute overdoses with serum salicylate levels >90-100 mg/dL or in chronic
overdoses with serum levels >60 mg/dL; these are general guidelines,
however, and patients who appear very ill despite lower levels should be
considered for dialysis.
Discussion of Case Questions
1.
What are the primary mechanisms of salicylate toxicity?
Salicylates
stimulate the medullary respiratory center, causing a respiratory
alkalosis. Additionally, salicylates
uncouple oxidative phosphorylation and inhibit the Krebs cycle, resulting in
the formation of multiple organic acids and the development of a wide anion gap
metabolic acidosis. Ultimately, membrane
permeability increases leading to pulmonary edema and CNS toxicity.
2.
What laboratory findings in this case (other than salicylate level)
should have prompted the consideration of salicylate toxicity?
The
patient has an elevated anion gap of 23, which should have prompted the
consideration of salicylates as a potential etiology. Additionally, the patient has ketonuria,
proteinuria, and hypokalemia, all of which are commonly seen with salicylate
toxicity. Examination of the patient’s
blood gas reveals a mixed acid base disorder with primary respiratory alkalosis
and concomitant metabolic acidosis, which is a classic finding in patients
poisoned by salicylates.
3.
What treatments are available for the treatment of salicylate toxicity?
Alkalinization
of the serum to a pH of 7.45-7.55 can help to “trap” ionized salicylate
molecules in the blood and allows them to be renally excreted more readily;
ensuring that the patient has a normal serum potassium will improve renal
excretion of the salicylate ion. Hemodialysis removes salicylates from the
blood and corrects fluid and electrolyte abnormalities associated with
salicylate toxicity, and is the treatment of choice in severely poisoned
patients.
4. What precautions should clinicians
consider when treating patients with salicylate toxicity?
The
excessive use of sodium bicarbonate therapy may place the patient at risk for
fluid overload, particularly those with renal insufficiency or congestive heart
failure.
Solutions
of sodium bicarbonate for infusion should be formulated with D5W. Mixing sodium
bicarbonate ampules with other sodium containing solutions can result in a
hypertonic sodium solution that could lead to hypernatremia during infusion.
Patients
with salicylate poisoning should be admitted to a monitored setting to closely
observe for clinical deterioration, complications of therapy, or need for
escalation in therapy with dialysis. Under-appreciation of salicylate toxicity
or delays in dialysis have resulted in worsening toxicity and death.
When
considering intubation in a salicylate poisoned patient, the clinician should
carefully assess the patient’s preintubation minute ventilation and make every
effort to match this by adjusting ventilator settings accordingly. This can be
accomplished by measurement of preintubation pH and pCO2 with an arterial blood
gas analysis. Acidemia as discussed above will enhance salicylate distribution
and toxicity and should be avoided.
CONSULTATION ASSISTANCE
Consultation
with a specialist in poison information or with a medical toxicologist can be
obtained free of charge by calling the California Poison Control System at
1-800-222-1222.
This
issue of CALL US... was written by Shaun Carstairs, MD
CALL
US... is published by the California Poison Control System. Editorial Board:
Executive Director, Stuart E. Heard, PharmD; CPCS Medical Directors: Timothy E.
Albertson, MD, Richard F. Clark, MD, Richard Geller, MD, Kent R. Olson, MD;
CPCS Managing Directors: Judith Alsop, PharmD, Thomas E. Kearney, PharmD, Lee
Cantrell, PharmD. Assistant Editors:
Binh Ly, MD, Cyrus Rangan, MD, and Aaron Schneir, MD. Editor: Richard F. Clark,
MD.
The California Poison Control System is operated by
the School of Pharmacy, University of California, San Francisco. (callus@calpoison.org)