Hospital Medicine

Aspirin toxicity

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Aspirin toxicity

I. What every physician needs to know.

Aspirin is a common over-the-counter medication valued for its anti-inflammatory, analgesic and antipyretic properties. However it can be highly toxic or even fatal with intentional or accidental overdose. Aspirin directly stimulates cerebral respiratory centers and inhibits the citric acid cycle, causing uncoupling of oxidative phosphorylation which ultimately leads to lactic acidosis.

Patients who present with aspirin toxicity may initially appear well before acute decompensation. Serum levels of salicylate may not reflect total body levels, so careful clinical and laboratory observation is important in the care of the patient with aspirin toxicity.

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

Patients or caregivers will usually give a history of aspirin ingestion, though the diagnosis should also be considered in a patient who is suicidal or altered and unable to give a history. Though aspirin ingestion is the most likely cause of salicylate toxicity, the diagnosis should also be considered in patients with ingestions of other salicylates, such as bismuth subsalicylate, certain antiacids, topical salicylic acid preparations and oil of wintergreen.

A. History Part I: Pattern Recognition:

The classic presentation of the aspirin toxic patient is the triad of hyperventilation, tinnitus, and gastrointestinal (GI) irritation. Hyperpnea (deep and rapid breathing) tends to be more common than just tachypnea as the cause of increased minute ventilation. GI symptoms include nausea, vomiting, epigastric pain, and bleeding (usually hematemesis). Fever, sweating, dizziness, or restlessness may be present.

Early in the course of overdose, these symptoms may be mild, and respiratory alkalosis is the main acid-base disturbance. However, metabolic acidosis from build-up of lactic acid becomes the predominant acid-base disorder later in the course of toxicity. Decreased blood pH leads to increased distribution of salicylate into the central nervous system. Acidosis is an ominous sign and may herald the onset of dramatic changes in clinical status, including hemodynamic instability (tachycardia and hypotension), arrhythmias, pulmonary edema, lethargy, hallucinations, seizures, or coma. Patients with chronic toxicity tend to have milder GI symptoms but more prominent neurologic symptoms.

For non-enteric aspirin, acute ingestion of less than 150mg/kg usually causes minimal toxicity whereas doses of more than 500mg/kg are potentially lethal. Ingestions of 150-300mg/kg tend to be mild-moderate in severity while those of 300-500mg/kg are considered serious.

B. History Part 2: Prevalence:

In 2014, over 24,000 cases of salicylate exposure were reported to United States Poison Control Centers. Of these, about 5000 were intentional. Over 200 exposures led to major morbidity, and 15 patients died.

Groups at high risk for aspirin toxicity include children younger than 6 years, the elderly and patients with psychiatric comorbidities.

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

Aspirin toxicity can have a similar clinical presentation to sepsis, and both share the classic acid-base disturbance of concomitant respiratory alkalosis and metabolic acidosis.

Evidence of infection sets sepsis apart. Aspirin toxicity may also look like delirium or a psychiatric disorder. Since psychiatric patients are at higher risk of aspirin overdose (both intentional and accidental), aspirin toxicity should be ruled out in those patients who present with acute change in mental status.

D. Physical Examination Findings.

Deep and rapid respiration (hyperpnea) is the most common finding. Sinus tachycardia is also frequently seen. In more severe cases, there may be crackles on lung exam due to non-cardiogenic pulmonary edema or mental status changes, which range from encephalopathy to lethargy or even coma.

E. What diagnostic tests should be performed:

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

Serum aspirin level should be drawn, though this often does not correlate with the clinical severity of the poisoning. The salicylate concentration must be interpreted in the setting of exposure acuity, product formulation, coingestions (especially of CNS depressants), patient comorbidities, and clinical condition (especially acid-base status). At therapeutic doses the peak concentration is reached 30 minutes to 2 hours after ingestion. However, in overdose the peak may take 6 hours (or even up to 12 hours with enteric coated forms) due to the formation of "concretions" or bezoars by the pills.

Salicylate levels of less than 30mg/dL are generally asymptomatic. Again, levels do not always correlate with clinical severity, but in healthy adults levels between 30-60mg/dL tend to cause mild toxicity, and patients with levels of 60-80mg/dL experience moderate toxicity, whereas levels more than 80mg/dL are associated with severe symptoms and hemodynamic derangement. In children and the elderly, symptoms tend to be more severe at lower levels.

Arterial blood gas is essential to evaluate the degree of metabolic acidosis and respiratory alkalosis. A pH of less than 7.4 in the setting of a low arterial carbon dioxide tension (PaCO2) is an ominous sign. Electrolytes, blood, urea, nitrogen (BUN), creatinine (Cr), calcium (Ca), magnesium, glucose, complete blood count (CBC), liver function tests (LFTs), coagulation factors (coags), acetaminophen and alcohol levels, and a urine toxicology screen should also be ordered.

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

Generally, no imaging studies are required, though chest x-ray should be ordered if there is concern for pulmonary edema, and head computed tomography (CT) might be required to rule out other causes of altered mental status.

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

The dome nomogram was developed in a cohort of pediatric patients with a one-time acute ingestion of aspirin and included patients with polydrug ingestions. As such, it is generally considered not helpful in the management of aspirin toxicity.

III. Default Management.

No antidote exists, so management focuses on decreasing absorption and enhancing elimination of salicylate.

A. Immediate management.

  1. Consider GI decontamination. Activated charcoal has been found to reduce absorption of aspirin though evidence of an impact on morbidity and mortality is limited. Fifty grams is usually given at presentation. Given aspirin's tendency to form pill concretions in the stomach, some experts recommend repeating the dose of charcoal every 3-4 hours if serum aspirin levels are still rising.

    Gastric lavage may be considered early on in a life-threatening overdose (more than 500mg/kg) if the patient presents within 60 minutes of ingestion. Keep in mind that there is a high risk of vomiting and aspiration in aspirin toxicity, so a stable airway is needed for these treatments. Whole-bowel irrigation is not recommended.

  2. Volume resuscitate and alkalinize the urine. The initial goal is to volume replete with normal saline or lactated ringers. Patients are often profoundly dehydrated due to insensate and GI loss and may require up to 4-6 liters of fluid. Once the patient is hydrated, alkalinized fluids should be considered, especially if the patient is symptomatic, has a rising salicylate level, or a level of more than 35mg/dL.

    Alkalinization increases elimination of salicylic acid in the urine; with an increase in the urine pH from 5 to 8, there is at least a 10-fold increase in renal salicylate clearance. One suggested regimen is dextrose 5% in water (D5W) with 3 amps of sodium bicarbonate (NaHCO3) and 40mEq potassium chloride (KCl)/L at a rate of 2-3ml/kg/hr, with a goal urine output of 1-2ml/kg/hour and urine pH of 7.5-8.

  3. Consider hemodialysis. Indications include severe acidosis (pH less than 7.2), hypotension refractory to optimal supportive care, end-organ injury (i.e. seizures, coma, pulmonary edema), renal failure, serum acetylsalicylic acid (ASA) level more than 80-100mg/DL (or more than 40-50mg/dL in chronic toxicity), and intubated patients.

  4. Consult Poison Control. 1-800-222-1222 in the US.

B. Physical Examination Tips to Guide Management.

Watch for the development of signs of severe aspirin toxicity, such as hypotension, altered mental status, seizures, and pulmonary edema. Monitor for volume overload during fluid resuscitation.

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

Recommended lab tests during treatment include:

- Electrolytes, BUN, calcium, magnesium, glucose every 12 hours

- CBC daily (more frequently if evidence of GI bleed)

- ASA level every 2 hours until peak is reached

- Arterial blood gas (ABG) every 2 hours

- During alkalinization, check urine pH every 2 hours (goal = 7.5-8) and serum potassium every 4 hours

D. Long-term management.

The medical management of aspirin overdose usually lasts on the order of 1-2 days, with improvement in most cases. However severe cases may require prolonged supportive care in the intensive care unit dealing with the consequences of metabolic acidosis, arrhythmias, pulmonary edema, and altered mental status.

Once the medical management is complete, psychiatric evaluation is required in cases of intentional overdose. For accidental overdoses, education of patients and caregivers is essential in preventing recurrence. For example, aspirin-containing products should be moved out of the reach of children and patients with dementia. Medisets may be helpful for psychiatric or dementia patients who require therapeutic aspirin.

E. Common Pitfalls and Side-Effects of Management

Aspirin levels may initially be undetectable or low, but in large ingestions, absorption can be unpredictable due to the formation of concretions. Levels may peak suddenly and erratically as the concretion dissolves.

Intubation can be problematic as patients often have significant protective hyperventilation while awake. Most patients who are intubated should be prepared for hemodialysis for this reason. Ventilator settings should attempt to match or exceed the patient's previous estimated minute ventilation with a goal pH that is normal to slightly alkalemic.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Renal insufficiency can greatly prolong elimination of salicylates. Nephrology should be consulted early on for consideration of initiation of hemodialysis.

B. Liver Insufficiency.

Glucose levels should be monitored more frequently (every 4-6 hours) since patients with liver insufficiency are at increased risk for hypoglycemia. As with all patients with ingestions, it is important to rule out coingestion of acetaminophen, which would be more toxic in this population.

C. Systolic and Diastolic Heart Failure

During fluid resuscitation, patients should be monitored more frequently for signs and symptoms of volume overload, with a lower threshold to consult nephrology for hemodialysis.

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)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

Consider increased frequency of monitoring (history, stool guaiac test, hemoglobin level) if there is a history of GI bleed.

J. Hematologic or Coagulation Issues

Consider increased frequency of monitoring for GI bleed (history, stool guaiac test, hemoglobin level).

K. Dementia or Psychiatric Illness/Treatment

Initial management remains as detailed above, but patients will require further evaluation for methods to prevent future overdose (i.e. education of caregivers of demented patients, evaluation of patient safety in the home or other care environment, structured psychiatric evaluation of suicide risk and ability to care for self).

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

- Check ABG and aspirin level every 2 hours; call renal if pH is less than 7.3 or ASA level is more than 80mg/dL

- Check urine pH every 2 hours; change fluid rate or composition to keep pH 7.5-8

B. Anticipated Length of Stay.

Inpatient care will usually last 1-2 days if there is no evidence of severe toxicity and the patient is cleared by psychiatry.

C. When is the Patient Ready for Discharge.

Prior to discharge, the aspirin level should be less than 20mg/dL and trending downward. In addition, the ABG should show resolution of metabolic acidosis and respiratory alkalosis. If there was a significant GI bleed, this should be evaluated prior to discharge and the hematocrit should be stable. If the overdose was intentional, the need for psychiatric admission should be evaluated.

D. Arranging for Clinic Follow-up

N/A

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

Patients should see their primary care provider in 1-2 weeks and their psychiatrist within 1 week (if indicated).

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.

Hemoglobin levels if there is GI bleeding.

E. Placement Considerations.

Inpatient psychiatric treatment may be needed.

F. Prognosis and Patient Counseling.

Acute overdose has 16% morbidity and 1% mortality. Chronic overdose has 30% morbidity and 25% mortality.

Children, the elderly, and patients with chronic kidney disease are at increased risk of adverse outcomes. If the patient survives the acute toxicity, then prognosis is good. However, several patient groups may be at risk for recurrent toxicity (i.e. poorly controlled psychiatric illness, patients with dementia).

Discussions should be held with families and caregivers about ways to limit access to aspirin (for example locking up medications or leaving just a small supply available to the patient, i.e. the use of a mediset).

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None for management of aspirin toxicity.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Prophylaxis for peptic ulcer disease is indicated.

Education about the risks of chronic aspirin toxicity may help prevent readmission.

VII. What's the evidence?

"American College of Medical Toxicology: Guidance document: Management priorities in salicylate toxicity". Journal of Medical Toxicology. vol. 11. 2015. pp. 149-52.

(This is a nice review article that helped me to clarify some of the points in my chapter. Can be replaced by 2014 annual report below.)

Chyka, PA, Erdman, AR, Christianson, G, Wax, PM, Booze, LL, Manoguerra, AS. "Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management". Clinical Toxicology. vol. 45. 2007. pp. 95-131.

Dargan, PI, Wallace, CI, Jones, AL. "An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose". Emergency Medicine Journal. vol. 19. 2002. pp. 206-9.

Herres, J, Ryan, D, Salzman, M. "Delayed salicylate toxicity with undetectable initial levels after large-dose aspirin ingestion". American Journal of Emergency Medicine. vol. 27. 2009. pp. 1173.e1-3.

Mowry, JB, Spyker, DA, Brooks, DE, McMillan, N, Schauben, JL. "2014 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 32nd annual report". Clinical Toxicology. vol. 53. 2015. pp. 962-1147.

(More recent data about prevalence.)

O'Malley, GF. "Emergency Department management of the salicylate-poisoned patient". Emergency Medical Clinics of North America. vol. 25. 2007. pp. 333-46.

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