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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)