Hospital Medicine

Salicylate toxicity

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I. What every physician needs to know.

Salicylate toxicity, or salicylism, can occur from acute ingestion of a single large dose of salicylates, or it can occur from lower doses taken over a longer period of time. Salicylates are contained in many prescription and non-prescription products, from acetylsalicylic acid (aspirin), to methyl salicylate (oil of wintergreen) which is often contained in sports creams and topical products. Because methyl salicylate is so concentrated (a single teaspoon can contain 4,000mg or more) and can be absorbed through the skin, it can be easy for the total dose of salicylates to be unrecognized.

There were more than 29,000 exposures involving salicylates reported to poison centers in the US in 2009, resulting in at least 22 deaths. A review of the guidelines used at many poison centers suggested that ingestions of less than 150mg/kg are often managed at home by observation. Some centers recommend home decontamination at doses between 150 and 300 mg/kg. Ingestions totaling more than 150 to 300mg/kg are generally referred to an emergency department for evaluation. Ingestions of greater than 500mg/kg are considered to be potentially lethal.

Salicylates are generally absorbed quickly through the gastrointestinal tract. The elimination half-life is generally between 3 and 12 hours at therapeutic doses, but this can increase unpredictably up to 30 hours in the setting of an overdose. The serum-free level of salicylates will generally increase in the setting of low serum albumin. Salicylates are excreted renally, but are reabsorbed from the urine more quickly at lower urinary pH.

Unintentional chronic overdoses on salicylates may occur when an individual is unaware of the type and amount of salicylates in various products. This can occur with athletes using multiple sports rubs and creams that contain methyl salicylate, for example. Pediatric patients and elderly patients may also be more at risk for accidental overdoses of salicylates.

II. Diagnostic Confirmation: Are you sure your patient has salicylate toxicity?

In addition to recognizing the clinical syndrome of salicylate toxicity described below, an important consideration is whether or not any clinically significant coingestants are present. Intentional and unintentional overdoses can present with more than one toxidrome simultaneously, and it is important to diagnose and treat each of them.

A. History Part I: Pattern Recognition:

The classic symptoms of acute salicylate toxicity include:

  • Tinnitus

  • Nausea and/or vomiting

  • An initial respiratory alkalosis

  • An increased anion gap metabolic acidosis

Symptoms of chronic toxicity are more variable and can include:

  • Delirium

  • Seizures

  • Metabolic acidosis

  • Pulmonary edema

  • A SIRS (systemic inflammatory response syndrome) like picture with fever, hypotension, tachypnea, and even acute respiratory distress syndrome, disseminated intravascular coagulation

B. History Part 2: Prevalence:

While anyone can be exposed to toxic levels of salicylates, some groups at increased risk include the elderly, children, and people with depression or a history of suicide attempts. Athletes are at a higher risk of both acute and chronic toxicity from topical salicylates.

C. History Part 3: Competing diagnoses that can mimic salicylate toxicity.

Patients with salicylate toxicity, particularly chronic toxicity, may present with vague symptoms (altered mental status, fever, dyspnea) that can make it difficult to arrive at the proper diagnosis. A careful history of prescription and non-prescription medications is important to correctly diagnoses or exclude salicylate toxicity.

D. Physical Examination Findings.

Physical exam findings may be subtle and vary with degree and chronicity of exposure, but classically may include:

  • Hypotension

  • Fever

  • Tinnitus

  • Deafness

  • Delirium

  • Somnolence

  • Dyspnea

  • Tachypnea

  • Noncardiogenic pulmonary edema

E. What diagnostic tests should be performed?

N/A

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The appropriate tests to order will vary based upon the actual presenting symptoms, but commonly may include:

  • A salicylate level should be ordered when the diagnosis is entertained. A therapeutic level is approximately 10 to 25 mg/dL. Symptoms of toxicity may appear at levels of 60 to 70mg/dL in chronic exposure. A salicylate level greater than 100mg/dL is typically considered to be severe poisoning. The salicylate level should be followed serially, as the half-life can vary with exposure amounts. At therapeutic doses, the half-life is generally between 3 and 12 hours, however this may increase up to 30 hours at toxic doses.

  • The Done nomogram has not been shown to be as useful for salicylate toxicity as other nomograms for other ingestions.

  • A basic metabolic panel and arterial blood gas can be useful in defining the patient's acid-base status and assessing for respiratory alkalosis and metabolic acidosis which can be seen in salicylate toxicity.

  • In patients with intentional or unintentional overdoses, it can be useful to rule out common coingestants with a urine drug screen, acetaminophen level, ethanol level, and levels for any other medications that the patient takes on a regular basis or has access to. Measuring serum osmoles to evaluate the osmolar gap can be useful in screening for other ingestants, particularly in the case of a metabolic acidosis with increased anion gap.

  • Salicylate toxicity may lead to a low uric acid level, though it is not necessary to order this routinely.

  • An electrocardiogram is useful in general screening of patients with acute overdoses to look for signs suggestive of specific toxidromes.

  • A complete blood count (CBC) and coagulation studies are useful to rule out hemolysis (which can occur with salicylate toxicity). Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are particularly at risk for this.

  • Since salicylates are reabsorbed from at increased rates with acidic urine, a urinalysis can be helpful.

  • Salicylate toxicity doesn't normally affect the liver directly, but other coingestants can (e.g. acetaminophen). Liver function tests may be useful to screen for hepatic injury, and a low albumin level may indicate increased free levels of salicylate in the blood stream.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

If a patient with salicylate toxicity presents with dyspnea, tachypnea, altered mental status, or any other signs pointing towards pulmonary edema or aspiration, a chest radiograph or potentially a CT scan should be obtained.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Not applicable.

III. Default Management.

N/A

A. Immediate management.

Immediate management of salicylate toxicity should be aimed at cardiopulmonary support, minimizing ongoing organ damage, and maximizing elimination of the salicylate. Patients with altered mental status and cardiopulmonary instability may need emergent or urgent intubation. It is important to ensure adequate ventilation with any intubated patient so as not to compromise a patient's respiratory compensation for a metabolic acidosis.

Patients with hypotension may need aggressive volume resuscitation, and even unstable patients may benefit from intravenous fluids to increase urinary excretion of salicylates. Some physicians recommend alkalinizing the urine and monitoring urine pH to maximize excretion of salicylates, particularly in patients with salicylate-induced pulmonary edema (SIPE). This can be accomplished with 150mmol of sodium bicarbonate in 1 liter of 5% dextrose solution (D5W) running at 1.5 times maintenance fluid rate. An appropriate target urine pH is 7-8.

Patients presenting after an acute ingestion may benefit from activated charcoal. If charcoal is given, and a patient needs acetylcysteine for an acetaminophen coingestion, the dose of acetylcysteine will need to be increased by 50%. Consideration can also be given to gastric lavage.

Patients with a coingestion of narcotics may benefit from naloxone.

Patients with evidence of organ damage, unusually high salicylate levels (> 100mg/dL after an acute ingestion, or > 40mg/dL in chronic ingestions), or severe acidosis may benefit from a nephrology consultation for hemodialysis to assist with salicylate elimination, correction of acid-base status, and avoiding volume overload from intravenous fluids.

Contact the appropriate poison control center for further recommendations and information regarding salicylate toxicity.

Patients presenting with a suicide attempt or depression should be evaluated by a psychiatrist or mental health professional, and the appropriate suicide precautions taken.

B. Physical Examination Tips to Guide Management.

Serial physical examination should include assessment of:

  • Neurologic status to ensure resolution of any delirium

  • Signs of volume overload due to aggressive rehydration

  • Respiratory status and resolution of tachypnea

  • Urine output

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

A salicylate level should be checked several times a day until it has improved to within a therapeutic range or below. A patient with a salicylate level that is not decreasing as expected may need evaluation for hemodialysis to improve elimination. Patients who are receiving intravenous fluids containing bicarbonate in order to increase urinary excretion should have a urinalysis performed two to three times a day to monitor urine pH until salicylate levels have improved.

Patients with significant acid-base disturbances should have an ABG and BMP monitored until these disturbances have resolved. The exact frequency should be based on the severity of the abnormalities, hemodynamic status, and whether the patient is intubated. Patients with an increased anion gap should have this followed until it normalizes. A CBC may be checked daily for the first several days to ensure that the patient does not experience any significant anemia secondary to hemolysis.

D. Long-term management.

Long-term management of salicylate toxicity consists primarily of education about the types of prescription and non-prescription medications that can contain salicylates to help avoid further episodes.

E. Common Pitfalls and Side-Effects of Management

Common pitfalls include:

  • Not remembering to increase the dose of acetylcysteine by 50% if activated charcoal has been given.

  • Giving bicarbonate containing fluids too early in management if a respiratory alkalosis is the predominant acid-base disturbance.

  • Unnecessarily intubating a patient whose hyperventilatory drive may be compensating for an underlying metabolic acidosis.

A less common complication can be the formation of a bezoar in the setting of high concentrations of salicylates. This can slow the absorption from the GI tract and lead to prolonged exposure to elevated levels. In this setting, the administration of charcoal can be helpful beyond the usual two to four hour time window.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Since salicylates are excreted in the urine, patients with renal insufficiency should be assessed for potential hemodialysis. Patients already on hemodialysis or peritoneal dialysis should have this continued as soon as possible.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

Monitor closely for volume overload with aggressive hydration.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

Monitor closely for pulmonary edema due to hydration that may worsen the patient's respiratory status.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

Patients with a history of depression or previous suicide attempts may be at risk for an intentional overdose.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Sign-out for a patient with salicylate toxicity should include:

  • Baseline mental status

  • Last salicylate level and when the next scheduled check should occur

  • Type and rate of intravenous fluids

  • Whether the patient is being dialysed

B. Anticipated Length of Stay.

The length of stay for a patient with salicylate toxicity will depend on the severity and type of symptoms and presence of organ damage, as well as the need for further psychiatric care in cases of intentional overdoses.

C. When is the Patient Ready for Discharge.

A patient will typically be ready for discharge when their salicylate level is non-detectable, acid-base abnormalities have been corrected, and their mental status is at baseline.

D. Arranging for Clinic Follow-up

N/A

1. When should clinic follow up be arranged and with whom.

Most patients can follow-up with their primary care physician in 2 weeks. Patients with intentional overdose may need ongoing inpatient psychiatric care until they are deeded safe for discharge by their treating psyhiatrist.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Basic metabolic panel.

E. Placement Considerations.

Most patients will be able to return home after recovery. Elderly patients admitted for salicylate toxicity should be evaluated for their ability to live independently. They may simply need assistance from family with managing their medications, or may benefit from a home health evaluation.

F. Prognosis and Patient Counseling.

Patients should be provided with counseling about the proper dosing of salicylate containing prescription and non-prescription medications.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

None.

What's the evidence?

Bronstein, AC, Spyker, DA, Cantilena, LR, Jr Green, JL, Rumack, BH, Giffin, SL. "2009 annual report of the american association of poison control centers' national poison data system (NPDS): 27th annual report". Clin Toxicol (Phila). vol. 48. 2010. pp. 979-1178.

Chyka, PA, Erdman, AR, Christianson, G, Wax, PM, Booze, LL, Manoguerra, AS, Caravati, EM, Nelson, LS, Olson, KR, Cobaugh, DJ, Scharman, EJ, Woolf, AD, Troutman, WG. "Americal Association of Poison Control CentersHealthcare Systems BureauHealth ResourcesSevices AdministrationDepartment of HealthHuman Services: Salicylate poisoning: An evidence-based consensus guideline for out-of-hospital management". Clin Toxicol (Phila). vol. 45. 2007. pp. 95-131.

Glatstein, M, Garcia-Bournissen, F, Scolnik, D, Rosenbloom, E, Koren, G. "Sudden-onset tachypnea and confusion in a previously healthy teenager". Ther Drug Monit. vol. 32. 2010. pp. 700-703.

Glisson, JK, Vesa, TS, Bowling, MR. "Current management of salicylate-induced pulmonary edema". South Med J. vol. 104. 2011. pp. 225-232.

Lund, B, Seifert, SA, Mayersohn, M. "Efficacy of sustained low-efficiency dialysis in the treatment of salicylate toxicity". Nephrol Dial Transplant. vol. 20. 2005. pp. 1483-1484.

O'Malley, P. "Sports cream and arthritic rubs: The hidden dangers of unrecognized salicylate toxicity". Clin Nurse Spec. vol. 22. 2008. pp. 6-8.

Shahidi, NT, & Westring, DW. "Acetylsalicylic acid--induced hemolysis and its mechanism". J Clin Invest. vol. 49. 1970. pp. 1334-1340.

Spinello, IM, Dellinger, RP. "Management of Poisoning and Overdose in the Intensive Care Unit". Clin Pulm Med. vol. 9. 2002. pp. 213-220.

Varela, N, Bognar, M, Agudelo, C, Jurado, R. "Salicylate toxicity in the older patient". J Clin Rheumatol. vol. 4. 1998. pp. 1-5.

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. vol. 22. 2005. pp. 401-403.

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