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

The use of salicylates dates back 2500 years to when Hippocrates recommended the use of willow bark to relieve the pain of childbirth. Salicylic acid is the extract from willow bark that produces the analgesic effect. Today, salicylates are used in many over-the-counter and prescription medications for their analgesic, anti-inflammatory, and antipyretic properties. Aspirin (acetylsalicylic acid)–containing products are the most commonly found salicylates. Sources of salicylate poisoning include aspirin overdose and excessive topical application or ingestion of ointments that contain methyl salicylate (oil of wintergreen). Salicylate ingestion was a common cause of poisoning and death in children in the United States prior to the 1970s, when legislation was passed that required childproof packaging on medications. Despite the reduction of poisonings due to repackaging, salicylate toxicity remains a significant cause of morbidity and mortality.

Pathophysiology

Acid-base disturbances, electrolyte abnormalities, and central nervous system effects characterize salicylate poisoning. The wide range of toxic effects varies depending on the age of the patient and whether the ingestion is chronic or acute.

Metabolic effects

In salicylate toxicity, as salicylate levels increase, the acid-base disturbance progresses from respiratory alkalosis to mixed respiratory alkalosis and metabolic acidosis. In children, the progression to metabolic acidosis occurs more rapidly. Salicylates directly stimulate respiratory centers in the medulla, causing hyperventilation and, subsequently, respiratory alkalosis. Salicylates also cause the uncoupling of oxidative phosphorylation, which leads to decreased adenosine triphosphate production, increased oxygen consumption, increased carbon dioxide production, and increased heat production. Derangement in the Krebs cycle and in carbohydrate metabolism leads to an accumulation of organic acids, including pyruvate, lactate, and acetoacetate, causing metabolic acidosis.

Toxic levels of salicylates also displace large amounts of plasma bicarbonate, worsening the metabolic acidosis. The metabolic acidosis in salicylate poisoning is an anion gap acidosis, Na⁺ - (Cl- +HCO₃-) greater than 14 mEq/L. Other causes of anion gap metabolic acidosis that can be confused with or can coexist with salicylate toxicity include diabetic ketoacidosis, renal failure, lactic acidosis, and volatile alcohol overdose (methanol, ethylene glycol).

Fluid and electrolyte effects

Increased metabolic rate, pyrexia, tachypnea, and vomiting lead to fluid loss and dehydration. Compensation for respiratory alkalosis leads to increased renal excretion of bicarbonate and increased excretion of sodium and potassium. Because of significant water losses, hyponatremia might not be present; however, hypokalemia is prominent.

Central nervous system effects

Toxic effects in the CNS range from mild confusion to coma. The exact mechanism that produces CNS toxicity is not known, but the degree of CNS effects, as well as overall mortality, correlates with the concentration of salicylates in brain tissue. Acidemia increases the nonionized form of salicylates, allowing for movement across the blood-brain barrier and, therefore, increasing CNS toxicity.

Gastrointestinal effects

Salicylate ingestion can cause nausea, vomiting, and abdominal pain. Salicylate stimulation of medullary chemoreceptors and local irritation of the GI tract produce emesis. Upper GI ulceration and bleeding can occur. Gastrointestinal effects are much more prominent in acute ingestion.

Ototoxicity

Salicylate toxicity results in a reversible ototoxicity characterized by tinnitus, deafness, and dizziness.

Pulmonary effects

Noncardiogenic pulmonary edema is the most common cause of major morbidity and might be related to an increase in the permeability of pulmonary vasculature caused by salicylates. Acute respiratory distress syndrome is more prominent in chronic ingestions than in acute ingestions.

Hematological effects

Salicylates inhibit vitamin K–dependent synthesis of factors II, VII, IX, and X, leading to a prolonged prothrombin time. Salicylates prolong bleeding time by inhibiting a prostaglandin-initiated sequence required for platelet aggregation.

Hepatic effects

Dose-dependent hepatotoxicity can occur with salicylate poisoning. A small percentage of patients might develop hepatitis, but most develop an asymptomatic elevation of transaminases.

Renal effects

Acute renal failure has rarely been reported.

Mortality/Morbidity

Mortality rates vary with chronicity of exposure. Compared with acute toxicity, chronic toxicity carries higher morbidity and mortality rates and is more difficult to treat.

• Acute overdose - Mortality rate of less than 2%
• Chronic overdose - Mortality rate as high as 25%

CLINICAL

Section 3 of 10  

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

History

• Acute ingestion is associated with the following factors:
• • History of suicide attempts involving teens and adults and of accidental ingestion by children
  • Possible asymptomatic early presentation
  • Nausea, vomiting, hematemesis
  • Diaphoresis and fever
  • Epigastric pain
  • Tinnitus
  • CNS effects generally presenting later in the toxicity course
• Chronic ingestion is associated with the following factors:
• • Change in mental status in elderly patients, prompting medical evaluation
  • Prominent CNS symptoms, including confusion, disorientation, hallucinations, lethargy, seizures, and coma
  • The long-term treatment of children with inappropriate dosing of salicylates

Physical

• Vital signs
• • Fever
  • Increased respiratory rate
  • Tachycardia
• Pulmonary manifestations
• • Tachypnea
  • Respiratory arrest
• Cardiovascular manifestations
• • Dysrhythmias (premature ventricular contractions; ventricular tachycardia, fibrillation, or both)
  • Hypotension and shock
• Gastrointestinal manifestations (more prominent in acute intoxication)
• • Epigastric tenderness
  • Emesis or hematemesis
• Neurologic manifestations
• • Confusion, disorientation, hallucinations
  • Lethargy
  • Seizures
  • Coma

Causes

• Accidental ingestion
• Suicide attempt
• Inappropriate dosing of salicylates in children and elderly people

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Caffeine overdose
Reye syndrome

WORKUP

Section 5 of 10  

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

Lab Studies

• Monitor electrolytes to test for the following:
• • Hypokalemia
  • Hyponatremia or hypernatremia
  • Anion gap acidosis
  • Hypoglycemia
• Monitor arterial blood gas frequently during treatment to assess response to treatment, with the goal of maintaining a pH level of 7.45-7.55. In addition, use arterial blood gas assessment to test for the following:
• • Respiratory alkalosis
  • Metabolic acidosis
• Monitor BUN and creatinine levels to assess for the following:
• • Dehydration revealed by increased BUN/creatinine ratio
  • Renal failure (rare)
• Monitor CBC count, prothrombin time, activated partial thromboplastin time, and international normalized ratio to test for the following:
• • Coagulopathy with prolonged prothrombin time
  • Leukocytosis
• Use liver function testing to assess for the following:
• • Elevated aspartate aminotransferase
  • Elevated alanine aminotransferase
• Serum salicylate level
• • Treatment and prognosis should not be based on the salicylate level alone.
  • In acute ingestions, an initial 6-hour salicylate level should be obtained. The possibility of prolonged or delayed absorption from sustained-release products or bezoar formation warrants that the salicylate level should be obtained again every 2 hours until the level begins to decrease.
  • The Done nomogram can be used to predict the severity of toxicity following a single acute salicylate ingestion only. The Done nomogram is not valid under the following conditions:¹
    • Chronic salicylate overdoses (level may be within reference or therapeutic range)
    • Enteric-coated aspirin has been ingested
    • Salicylates have been ingested over several hours
    • Salicylates have been ingested in a 24-hour period prior to acute ingestion
    • Renal failure is present
  • Nontoxic salicylate levels drawn 6 hours postingestion do not rule out toxicity.
  • Many toxicologists no longer use the Done nomogram.
  • In chronic ingestions, serum salicylate levels correlate poorly with toxicity.
• Urine pH: Monitor urine every 2 hours during treatment, with a goal of maintaining alkaline urine with a pH level greater than 7.5.
• Ferric chloride test/Ames Phenistix test: These are sensitive but nonspecific tests that detect salicylates in the urine.

Imaging Studies

• Chest radiograph might reveal aspiration pneumonitis or noncardiogenic pulmonary edema.
• A CT scan of the head is necessary to rule out a structural lesion as a cause of change in mental status if the etiology is not clear.

Other Tests

• ECG might reflect hypokalemia (U wave, flattened T wave, QT prolongation) or reveal dysrhythmias (sinus tachycardia, premature ventricular contractions, ventricular tachycardia, ventricular fibrillation).

TREATMENT

Section 6 of 10  

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

Medical Care

• Supportive care stabilizes the airway, breathing, and circulation and provides respiratory and cardiovascular support, as necessary.
• For gastrointestinal decontamination, administer activated charcoal (1 mg/kg) to all patients with suspected toxic ingestions (ie, patients who are symptomatic or who have history of ingestion of >150 mg/kg). Evidence to support multiple dose-activated charcoal administrations is conflicting. Use additional doses (0.5 mg/kg q4h) if evidence of continued absorption is present, as demonstrated by rising serum salicylate levels. Whole bowel irrigation with polyethylene glycol can be useful in reducing absorption in cases of suspected bezoar formation, as well as in cases of enteric-coated aspirin ingestion.
• Hydrate and correct electrolyte abnormalities. Patients are generally dehydrated upon presentation; begin correction of fluid deficits with IV crystalloid solution to maintain urine output at 2 mL/kg/h. Aggressively treat electrolyte abnormalities. To correct hypokalemia, add KCl to intravenous fluid (20-40 mEq/L) once the patient is determined not to be anuric. Correct hypoglycemia by adding dextrose to the intravenous fluid or by a 50% dextrose in water (D50W) bolus followed by dextrose-containing intravenous fluid.
• Urinary alkalinization enhances salicylate elimination by promoting the ionization of salicylates. Ionized salicylates cannot be reabsorbed in renal tubules; this increases urinary elimination. Alkalinization of serum is important in minimizing CNS toxicity. Ionized salicylates are unable to cross the blood-brain barrier; this decreases the salicylate concentration in the CNS. Increased CNS salicylate levels have been shown to correlate with CNS toxicity.
• • Urinary and serum alkalinization is necessary in all symptomatic patients and in patients with acute ingestion who have 6-hour levels greater than 50-60 mg/dL. Alkalinization of urine/serum can be achieved by administration of sodium bicarbonate by boluses of 1-2 mEq/kg, in addition to continuous infusion of 5% dextrose in water (D5W) with 100-150 mEq of sodium bicarbonate at double the maintenance rates.
  • Adequate serum potassium levels are required to maintain alkaline urine. In hypokalemia, potassium reabsorbs with sodium instead of hydrogen ions, making alkalinization of urine difficult. If urinary pH remains acidic despite alkaline serum pH, add additional potassium to the intravenous fluid.
  • Do not use carbonic anhydrase inhibitors (acetazolamides) to produce alkaline urine. While they do alkalinize urine, they also produce an acidic serum and have been associated with increased mortality.
• Use hemodialysis in cases of severe toxicity to enhance elimination of salicylates and to correct fluid and electrolyte abnormalities. Indications for hemodialysis include severe manifestations, such as encephalopathy, coma, seizures, cerebral edema, acute respiratory distress syndrome, and renal failure. In addition, use hemodialysis if the patient's condition deteriorates despite adequate alkalinization of urine and supportive care or if alkalinization of urine cannot be achieved.

Consultations

• Toxicologist
• Nephrologist for patients who meet criteria for hemodialysis
• Psychiatrist for cases of intentional ingestions (ie, suicide attempts)

MEDICATION

Section 7 of 10  

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

The goal of therapy is to remove or neutralize excess amounts of salicylate present in the GI tract.

Drug Category: Antidotes

These agents are used to treat poisoning caused by most drugs and chemicals.

Drug Category: Cathartics

These agents are used to accelerate the passage of poisons through the intestinal tract and prevent their absorption.

Drug Name	Polyethylene glycol (Colovage, Colyte, GoLYTELY)
Description	Laxative with strong electrolyte and osmotic effects that has cathartic actions in GI tract.
Adult Dose	240 mL (8 oz) PO q10min until a total of 4 L is consumed or until rectal effluent is clear
Pediatric Dose	Not established; recommended dose is 25-40 mL/kg/h PO for 4-10 h or until rectal effluent is clear
Contraindications	Documented hypersensitivity; colitis; megacolon; bowel perforation; gastric retention; GI obstruction
Interactions	Reduces effectiveness and absorption of oral medications
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Ulcerative colitis, hot loop polypectomy

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Admit patients with acute ingestions of greater than 300 mg/kg or moderate-to-severe signs of toxicity to ICU. Other indications for ICU admission include abnormal mental status, deranged coagulation parameters, or metabolic acidosis.
• Admit patients with minor symptoms to a monitored floor.
• Patients with enteric-coated aspirin ingestions might have delayed absorption. A history of potentially significant ingestion requires admission for observation and serial salicylate level testing regardless of whether the patient remains asymptomatic or whether initial levels are nontoxic.

Further Outpatient Care

• Patients with acute, single ingestions of non–enteric-coated salicylates of less than 150 mg/kg who remain asymptomatic and have 6-hour postingestion levels in the nontoxic range with a repeat level that indicates a level decrease can be discharged with a follow-up consultation with a primary care physician.
• Patients with intentional ingestions meeting the above criteria can be transferred to the psychiatric service.

Prognosis

• In acute ingestions, toxicity can be predicted by dose ingested.
• • Less than 150 mg/kg, asymptomatic-to-mild toxicity
  • Ingestions of 150-300 mg/kg, mild-to-moderate toxicity
  • Ingestions of 300-500 mg/kg, serious toxicity
  • Greater than 500 mg/kg, potentially lethal

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Aspirin Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Failure to consider the diagnosis in cases of chronic salicylate toxicity is a common pitfall. More than 50% of cases are misdiagnosed at the time of admission.
• Consider salicylate toxicity in any elderly patient with unexpected delirium.

REFERENCES

Section 10 of 10

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

1. Dugandzic RM, Tierney MG, Dickinson GE, Dolan MC, McKnight DR. Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Ann Emerg Med. Nov 1989;18(11):1186-90. [Medline].
2. Danel V, Henry JA, Glucksman E. Activated charcoal, emesis, and gastric lavage in aspirin overdose. Br Med J (Clin Res Ed). May 28 1988;296(6635):1507. [Medline].
3. Dargan PI, Wallace CI, Jones AL. An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose. Emerg Med J. May 2002;19(3):206-9. [Medline].
4. Davis JE. Are one or two dangerous? Methyl salicylate exposure in toddlers. J Emerg Med. Jan 2007;32(1):63-9. [Medline].
5. Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbein M. Does multiple-dose charcoal therapy enhance salicylate excretion?. Arch Intern Med. Jun 1990;150(6):1281-3. [Medline].
6. O'Malley GF. Emergency department management of the salicylate-poisoned patient. Emerg Med Clini North Am. May 2007;25(2):333-46. [Medline].
7. Pierce RP, Gazewood J, Blake RL Jr. Salicylate poisoning from enteric-coated aspirin. Delayed absorption may complicate management. Postgrad Med. Apr 1991;89(5):61-2, 64. [Medline].
8. Proudfoot AT. Toxicity of salicylates. Am J Med. Nov 14 1983;75(5A):99-103. [Medline].
9. Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med. Feb 23 1981;141(3 Spec No):364-9. [Medline].
10. Wood DM, Dargan PI, Jones AL. Measuring plasma salicylate concentrations in all patients with drug overdose or altered consciousness: is it necessary?. Emerg Med J. Jun 2005;22(6):401-3. [Medline].
11. Yip L, Dart RC, Gabow PA. Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am. May 1994;12(2):351-64. [Medline].

Article Last Updated: Nov 8, 2007