AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Salicylates are ubiquitous agents found in hundreds of over-the-counter (OTC) medications and in numerous prescription drugs. Salicylic acid and its derivatives are active ingredients in a wide variety of readily available topical preparations used for the treatment of pain, warts, and acne. Pepto-Bismol, a common antidiarrheal agent, contains 131 mg of salicylate per tablespoon.

Salicylate ingestion continues to be a common cause of poisoning in children and adolescents. The prevalence of aspirin-containing analgesic products makes these agents, found in virtually every household, common sources of both accidental and suicidal ingestion.

Salicylate ingestion is one of the most common methods of drug exposure; however, the incidence of salicylate poisoning in children has declined because of reliance on alternative analgesics and the use of child-resistant containers. Repackaging has decreased children's accessibility to lethal amounts, and salicylate's association with Reye syndrome has significantly decreased its use.

Still, more than 10,000 tons of aspirin are consumed in the United States each year. Salicylate intoxication persists as an important cause of morbidity and mortality. Aspirin or aspirin-equivalent preparations (in milligrams) include children's aspirin (80-mg tablets with 36 tablets per bottle), adult aspirin (325-mg tablets), methyl salicylate (eg, oil of wintergreen) (98% salicylate), and Pepto-Bismol (236 mg of nonaspirin salicylate per 15 mL). Ingestion of topical products containing salicylates, such as Ben-Gay, salicylic acid (keratolytic), and oil of wintergreen or methyl salicylate, can cause severe salicylate toxicity. One teaspoon of 98% methyl salicylate contains 7000 mg of salicylate, the equivalent of nearly 90 baby aspirin and more than 4 times the potentially toxic dose for a child who weighs 10 kg. A comprehensive review of the existing medical literature on methyl salicylate poisoning has determined that it is a relatively common source of pediatric exposures.¹

The prevalence of alternative medicines and popularity of herbs and traditional medicine formulae are increasing in North America. Many of these medicines may contain salicylate. Therefore, consider salicylate poisoning when topical herbal medicinal oil is involved.

Percy Medicine contains bismuth subsalicylate as the active ingredient and is used as a constipation reliever. A case of neonatal salicylate poisoning due to administration of this medicine as a colic reliever has been reported.² It is available OTC, and parents should be educated that salicylate-containing products are not routinely recommended for children aged 1 year or younger.

Pathophysiology

After ingestion, acetylsalicylic acid is rapidly converted to salicylic acid, its active moiety. Salicylic acid is readily absorbed in the stomach and small bowel. At therapeutic doses, salicylic acid is metabolized by the liver and eliminated in 2-3 hours. Salicylate poisoning is manifested clinically by disturbances of several organ systems, including the CNS and the cardiovascular, pulmonary, hepatic, renal, and metabolic systems. Salicylates directly or indirectly affect most organ systems in the body by uncoupling oxidative phosphorylation, inhibiting Krebs cycle enzymes, and inhibiting amino acid synthesis.

Acid-base status

Salicylates stimulate the respiratory center, leading to hyperventilation and respiratory alkalosis. Salicylates also interfere with the Krebs cycle, limit production of ATP, and increase lactate production, leading to ketosis and a wide anion-gap metabolic acidosis. Adult patients with acute poisoning usually present with a mixed respiratory alkalosis and metabolic acidosis. However, respiratory alkalosis may be transient in children such that metabolic acidosis may occur early in the course. Patients with mixed acid-base disturbances have been found to have normal anion-gap metabolic acidosis; therefore, normal anion-gap acidosis does not exclude salicylate.

Salicylates are weak acids that may produce metabolic acidosis through various mechanisms. In toxic concentrations, salicylates interfere with energy production by uncoupling oxidative phosphorylation and may produce renal insufficiency that causes accumulation of phosphoric and sulfuric acids. The metabolism of fatty acids is likewise increased in patients with salicylate toxicity, generating ketone body formation. These processes all contribute to the development of an elevated anion gap metabolic acidosis in patients with salicylate poisoning.

Respiratory system effects

Salicylates cause both direct and indirect stimulation of respiration. A salicylate level of 35 mg/dL or higher causes increases in both rate (tachypnea) and depth (hyperpnea). Salicylate poisoning may cause noncardiogenic pulmonary edema (NCPE) in a few patients. Although the exact etiology is not known, hypoxia is considered a major factor.

Glucose metabolism

Increased cellular metabolic activity due to uncoupling of oxidative phosphorylation may produce clinical hypoglycemia, although the serum glucose levels are within reference range. As intracellular glucose is depleted, the salicylate may produce discordance between levels of plasma and cerebrospinal fluid (CSF) glucose.

Fluid and electrolyte effects

Salicylate poisoning may result in dehydration because of increased GI tract losses (vomiting) and insensible fluid losses (hyperpnea and hyperthermia). All patients with serious poisoning are more than 5-10% dehydrated. Renal clearance of salicylate is decreased by dehydration. Hypokalemia and hypocalcemia can occur as a result of primary respiratory alkalosis.

CNS effects

Salicylates are neurotoxic, which manifests as tinnitus, and ingestion can lead to hearing loss at doses of 20-45 mg/dL or higher. CNS toxicity is related to the amount of drug bound to CNS tissue. Other signs and symptoms include nausea, vomiting, hyperpnea, and lethargy, which can progress to disorientation, seizures, cerebral edema, hyperthermia, coma, and, eventually, death.

GI tract effects

Nausea and vomiting are the most common effects. Pylorospasm and decreased GI tract motility can occur with large doses.

Hepatic effects

Hepatitis can occur in children ingesting doses at or above 30.9 mg/dL.³ Reye syndrome is another form of pediatric salicylate-induced hepatic disease characterized by nausea, vomiting, hypoglycemia, elevated levels of liver enzymes and ammonia, fatty infiltration of the liver, increased intracranial pressure, and coma.

Hematologic effects

Hypoprothrombinemia and platelet dysfunction are the most common effects. Bleeding may also be promoted either by inhibition of vitamin K–dependent enzymes or by the formation of thromboxane A₂.

Musculoskeletal effects

Rhabdomyolysis can occur because of dissipation of heat and energy resulting from oxidative phosphorylation uncoupling.

Clinical and laboratory manifestations

• Phase 1 of the toxicity is characterized by hyperventilation resulting from direct respiratory center stimulation, leading to respiratory alkalosis and compensatory alkaluria. Both potassium and sodium bicarbonate are excreted in the urine. This phase may last as long as 12 hours.
• In phase 2, paradoxic aciduria in the presence of continued respiratory alkalosis occurs when sufficient potassium has been lost from the kidneys. This phase may begin within hours and may last 12-24 hours.
• Phase 3 includes dehydration, hypokalemia, and progressive metabolic acidosis. This phase may begin 4-6 hours after ingestion in a young infant or 24 hours or more after ingestion in an adolescent.

Nausea, vomiting, diaphoresis, and tinnitus are the earliest signs and symptoms of salicylate toxicity. Other early effects include vertigo, hyperventilation, hyperactivity, agitation, delirium, hallucination, convulsion, lethargy, and stupor. Hyperthermia is an indication of severe toxicity.

Mortality/Morbidity

According to the Toxic Exposures Survey from the American Association of Poison Control Centers, 24% of analgesic-related deaths are due to aspirin alone or aspirin in combination with other drugs. Early identification of salicylate poisoning can be lifesaving.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• When possible, elicit the following information:
• • Type of salicylate
  • Amount
  • Approximate time of ingestion
  • Possibility of long-term ingestion
  • Potential co-ingestants
  • Presence of other medical conditions (eg, cardiac, renal diseases)
• Treatment should not be withheld in symptomatic patients because of pending serum level tests. The presence of tinnitus is a clue for salicylate ingestion. Tachypnea, tachycardia, and elevated temperature can be detected by evaluating vital signs.

Causes

Salicylate toxicity continues to be seen in emergency department as a result of unintentional ingestion or suicide attempt. Prompt recognition of clinical signs and symptoms and a high index of suspicion can prevent organ damage and death.

Oral ingestion of a large amount of acetylsalicylate, given for treatment of ear pain, has resulted in severe metabolic derangements and death. Brain histopathology revealed sparse grey matter changes and acute white matter damage.⁴

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Bedside ferric chloride testing: Qualitative determination for the presence of salicylates can be rapidly performed in the emergency department by adding a few drops of 10% ferric chloride (FeCl₃) to 1 mL of urine. If salicylates are present, the solution changes to a brown-purple color. Positive results with the urine ferric chloride test indicate that obtaining a quantitative serum salicylate level is necessary because even the ingestion of a single aspirin tablet can result in a positive test result.
• ABG: ABG should be obtained to evaluate for the presence of acid-base disturbances. Primary respiratory alkalosis may occur, followed by concomitant primary metabolic acidosis resulting from production of lactic acid, metabolites, and other organic acids. Therefore, the most common abnormality is a mixed acid-base disturbance (a primary respiratory alkalosis plus a primary metabolic acidosis).
• Salicylate concentration: Initial and serial salicylate levels are important in the evaluation of salicylate toxicity. The absolute level should not detract from the importance of careful and repeated clinical evaluation.
• • Therapeutic range of salicylate is 15-30 mg/dL. Patients are often symptomatic at salicylate concentrations higher than 40-50 mg/dL. Patients with salicylate concentrations approaching or exceeding 100 mg/dL usually have serious or life-threatening toxicity.
  • Caution: Always confirm the units of measurement with the laboratory. Traditional units are milligrams per deciliter; however, many laboratories report salicylate concentrations in milligrams per liter or micrograms per milliliter, both of which differ by a factor of 10 from the traditional units. For example, a salicylate concentration of 100 mg/dL is seriously toxic, but a concentration of 100 mg/L is subtherapeutic. A concentration of 100 mg/L is equal to a concentration of 10 mg/dL.
  • In overdoses, the peak serum concentration may not occur for 4-6 hours. Concentrations obtained before that time may not reflect peak levels. Levels from 15-30 mg/dL are considered to be within therapeutic range. Signs and symptoms of toxicity begin to appear at levels higher than 30 mg/dL. A 6-hour salicylate level higher than 100 mg/dL is considered potentially lethal and is an indication for hemodialysis. Chronic ingestion can increase the half-life to longer than 20 hours.
  • In significant ingestions, serum salicylate levels should be monitored at least every 2 hours until a peak has been reached and then every 4-6 hours until the peak falls into the nontoxic range.
  • Toxicity of salicylates correlates poorly with serum levels, and the levels are less helpful in patients with long-term exposure. Patients with long-term salicylate toxicity may have a level within the therapeutic range (10-20 mg/dL). Serum salicylate levels correlate only moderately with clinical manifestations. In acute ingestion, levels may be high without significant clinical signs, while long-term exposure levels in the high therapeutic range may be associated with significant clinical toxicity.
  • The Done nomogram was formulated in 1960 to assist physicians in predicting the severity of salicylate intoxication based on a serum level and a known time of ingestion. The nomogram was based primarily on previously healthy pediatric patients with acute single-salicylate ingestion. However, clinical application of the nomogram has several limitations. The nomogram is used only to evaluate a single acute ingestion. In contrast to the Rumack-Matthew nomogram,⁵ the Done nomogram indicates severity of toxicity based on a 6-hour level of non–enteric-coated aspirin rather than the need for antidotal therapy. Currently, the Done nomogram is regarded as not very useful.
• Other laboratory studies
• • Serum electrolyte renal function studies (BUN and creatinine levels)
  • Serum glucose levels
  • Serum acetaminophen levels
  • Liver function tests
  • Coagulation studies (prothrombin time and activated partial thromboplastin time)
  • Urinalysis

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Principles of treatment include limiting absorption, enhancing elimination, correcting metabolic abnormalities, and providing supportive care. No specific antidote is available for salicylates. Although determination of serial serum salicylate concentrations offers valuable information regarding the effectiveness of the treatment implemented, assessment of these levels is a poor substitute for clinical evaluation of a patient. When considering treatment options, the final decision should be individualized according to the clinical status of the patient and should not depend on a particular salicylate level.

Optimal management of a salicylate poisoning depends on whether the exposure is acute or chronic. Gastric lavage and activated charcoal are useful for acute ingestions but not in cases of chronic salicylism. Patients with chronic rather than acute ingestions of salicylates are more likely to develop toxicity, especially of the CNS, and require intensive care. Salicylate poisoning has been shown to cause metabolic derangements with significant inhibition of Krebs cycle enzymes.⁶ It also uncouples oxidative phosphorylation. Because of impaired glucose homeostasis, CNS glucose supply is sometimes lowered, which results in hypoglycorrhachia and delirium, even when serum glucose concentration is normal. Glucose boluses in euglycemic patients with salicylate-induced delirium have shown a prompt improvement in mental status.

• Triage Care: In one study, authors reviewed US poison center data for 2004 and determined that over 40,000 exposures to salicylate-containing products occurred.⁷ They published guidelines on triage care of these patients which are divided as follows:
• • Immediate emergency department referral by local poison control centers
  • • Patients who state ingestion or in whom a large administration is suspected should immediately be referred to the emergency department. 
    • Typical symptoms of salicylate toxicity warrant referral to the emergency department for evaluation.
  • Further triage care can be given
  • • Determine the dose, time of ingestion, presence of symptoms, history of other medical conditions, and presence of co-ingestants in patients without evidence of self-harm.
    • Do not induce vomiting for salicylate ingestion.
    • Activated charcoal for acute ingestions of a toxic dose can be given if no contraindications are observed.  
  • Asymptomatic dermal exposures to methyl salicylate or salicylic acid: The skin should be thoroughly washed with soap and water and the patient can be observed at home.
  • Ocular exposure of methyl salicylate or salicylic acid: The eye or eyes should be irrigated with room-temperature tap water for 15 minutes. If pain, decreased visual acuity, or persistent irritation is reported after irrigation, referral to an ophthalmologist is recommended.
  • Poison centers should monitor the onset of symptoms at periodic intervals for approximately 12-24 hours after ingestion.
• GI tract decontamination
• • Initial treatment should include the use of oral activated charcoal, especially if the patient presents within one hour of ingestion. Some authorities recommend performing gastric lavage in all symptomatic patients regardless of time of ingestion.
  • Activated charcoal can limit further gut absorption by binding to the available salicylates. The recommended initial dose of activated charcoal is 1-2 g/kg of body weight. Use of cathartics is not indicated with activated charcoal.
  • Repeated doses of charcoal may enhance salicylate elimination and may shorten the serum half-life.⁸ A potential indication for repeated doses of activated charcoal may be a plateau in serum salicylate concentrations, which may suggest a bezoar with ongoing absorption.
  • The passage of stool with charcoal and the resolution of clinical manifestations may be the reasonable criteria for discontinuing multiple doses of activated charcoal.
  • Whole bowel irrigation (WBI) with polyethylene glycol has been compared with single-dose activated charcoal in salicylate absorption in volunteer subjects 4 hours after ingesting enteric-coated aspirin.⁹ WBI was more effective in reducing absorption. When enteric-coated aspirin has been ingested or when salicylate levels do not decrease despite treatment with charcoal, WBI should probably be used in addition to charcoal therapy.
• Urinary alkalization
• • Renal excretion of salicylic acid depends on urinary pH. Increasing the urine pH to 7.5 prevents reabsorption of salicylic acid from the urine.¹⁰ Because acidosis facilitates transfer of salicylate into tissues, especially in the brain, it must be aggressively treated by raising blood pH higher than brain pH, thereby shifting the equilibrium from the tissues to the plasma.
  • Concomitant alkalinization of blood and urine keeps salicylates away from brain tissue and in the blood, in addition to enhancing urinary excretion. When the urine pH increases to 8 from 5, renal clearance of salicylate increases 10-20 times. Raising the urinary pH level from 6.1 to 8.1 results in a more than 18-fold increase in renal clearance by preventing nonionic tubular back-diffusion, which decreases the half-life of salicylates from 20-24 hours to less than 8 hours. Because aspirin is a weak acid, it ionizes when exposed to a basic environment, such as alkaline urine. Ions are poorly reabsorbed in the tubules and are excreted more readily. This phenomenon is called ion trapping and also works well for overdoses of other weak acids, such as phenobarbital.
  • Hypokalemia and dehydration limit the effectiveness of urine alkalization. Hypokalemia prevents excretion of alkaline urine by promoting distal tubular potassium reabsorption in exchange for hydrogen ions. Symptomatic patients typically have low serum potassium concentrations or serum potassium concentrations low in the reference range. Treatment with sodium bicarbonate alone may produce further intracellular shift of potassium ions, which further impairs the ability to excrete alkaline urine. Repletion of potassium is often necessary, even when serum potassium levels are in the low reference range (eg, <4.5 mEq/L).
  • Urinary alkalization should be continued at least until serum salicylate levels decrease into the therapeutic range (<30 mg/dL). Although acetazolamide results in the formation of a bicarbonate-rich alkaline urine, it unfortunately also causes metabolic acidosis that can worsen toxicity and, therefore, should not be used.
• Hemodialysis
• • Indications for hemodialysis include a serum level greater than 120 mg/dL (acutely) or greater than 100 mg/dL (6 h postingestion), refractory acidosis, coma or seizures, noncardiogenic pulmonary edema, volume overload, and renal failure.
  • In chronic overdose, hemodialysis may be required for a symptomatic patient with a serum salicylate level greater than 60 mg/dL.
  • Although hemoperfusion has a slightly higher rate of drug clearance than hemodialysis, dialysis is recommended because of its ability both to correct for fluid and electrolyte disorders and to remove salicylates.
  • Peritoneal dialysis is only 10-25% as efficient as hemoperfusion or hemodialysis and is not even as efficient as renal excretion.

Consultations

Early consultation with a medical toxicologist is prudent.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No specific antidote for salicylate poisoning is available. Therapy is focused on immediate resuscitation, correction of volume depletion and metabolic derangement, GI tract decontamination, and reduction of the body's salicylate burden. Early consultation with a medical toxicologist is prudent.

Drug Category: Decontamination agents

Consider activated charcoal decontamination in any patient who presents within 4 hours of ingestion. Activated charcoal is used for drug absorption and may be all that is required in mild-to-moderate toxicity. Activated charcoal is not absorbed and is excreted entirely through the GI tract.

Drug Category: Alkalinizing agents

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes. It also increases renal clearance of acidic drugs.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• A patient may be discharged following adequate GI tract decontamination with activated charcoal if clinical improvement is progressive, acid-base disturbance is not significant, and serial decrease in serum salicylate levels towards the therapeutic range is documented. If any doubt is noted, the patient should be admitted to an appropriate facility.
• If the ingestion was a suicide attempt, ensure adequate psychiatric and social evaluation before discharge.

Patient Education

• For excellent patient education resources, visit eMedicine's Poisoning Center. Also, see eMedicine's patient education article Aspirin Poisoning.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to confirm units of measurement may lead to confusion. Always confirm the units of measurement. Laboratories vary in reported salicylate concentrations by using milligram per deciliter or milligrams per liter, which differ by a factor of 10.
• Immediately begin therapy in symptomatic patients. Do not wait for the salicylate levels to return from the laboratory.
• Monitor serum electrolytes, calcium, and glucose levels, ABG, urine pH and specific gravity, and coagulation studies.
• Patients with severe salicylate intoxication are usually volume depleted and have acid-base disturbances.
• Dehydration or hypokalemia can limit the effectiveness of urine alkalization. Fluid replacement of volume deficits should be undertaken while preparations are made for other measures. Potassium (40 mEq/L) should be administered after adequate urine output has been established.
• A glucose-containing crystalloid should be used in most patients because hypoglycemia has been implicated in the pathophysiology of salicylate-induced CNS injury.
• Patients with salicylate poisoning may have low glucose concentrations in the CSF and CNS despite serum glucose concentrations within the reference range.
• Failure to administer activated charcoal because the ingestion occurred more than one hour prior to emergency department visit is a potential pitfall.
• Symptomatic patients require alkaline diuresis.
• Critically ill patients who have sustained salicylic poisoning require hemodialysis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Feb 12, 2008