Salicylate toxicity – 7 Interesting Facts

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Key Points

  • Salicylate toxicity affects multiple organ systems including:
    • Central nervous system: cerebral edema, coma, agitation, tinnitus, and seizures
    • Pulmonary system: hyperventilation or tachypnea, and acute lung injury
    • Gastrointestinal system: nausea and vomiting
  • Adults: classic acid-base abnormality encountered is a mixed picture of metabolic acidosis and respiratory alkalosis
  • Children: most present with acidemia
  • Toxicity is dose dependent 1
    • Acute ingestion is above 150 mg/kg
    • Mild to moderate toxicity with doses that range from 150 to 300 mg/kg
    • Serious toxicity with doses that range from 300 to 500 mg/kg
    • Doses over 500 mg/kg are often fatal
  • Oil of wintergreen (methyl salicylate) is potent; ingestion of any amount more than a lick or taste in children younger than age 6 years or more than 4 mL in people older than age 6 years is potentially toxic 2
  • Early symptoms of toxicity include the triad of hyperventilation, tinnitus, and gastrointestinal symptoms (eg, nausea, vomiting, abdominal pain); dehydration can develop
  • Later symptoms and symptoms of increasingly severe poisoning include central nervous system changes (eg, progressive alteration in mental status, seizures) and hyperthermia
  • Chronic salicylate toxicity is most common in elderly people and often misdiagnosed initially owing to its insidious onset, lack of history of overdose, and presence of nonspecific clinical findings (eg, general decline in function, altered mental status)
  • Early involvement of local poison center staff and consulting medical toxicologist facilitates appropriate diagnosis and treatment
  • Clinical presentation is the most important measurement of toxicity 3
    • Elevated salicylate concentration confirms the diagnosis and guides therapy
    • Salicylate concentration higher than 30 mg/dL is associated with toxicity
  • Mainstay of treatment includes gastric decontamination with activated charcoal, alkalinization, and volume replacement; hemodialysis is definitive treatment of serious toxicity
  • Close monitoring of clinical status, electrolytes, acid-base status, urinary pH, and serial salicylate concentrations are important to determine necessary adjustments in treatment
  • Death occurs in up to 5% 4 of patients with severe poisoning; mortality is particularly high (up to 25%) in patients with chronic toxicity

Pitfalls

  • Hyperpnea is a common and sometimes subtle finding early in toxicity; failure to appreciate hyperpnea can lead to delayed diagnosis and treatment 7
  • Maintain a high suspicion for chronic toxicity in elderly; delayed diagnosis and missed diagnosis is common in this age group. Frequent misdiagnoses include sepsis and dementia; 1 clue is unexplained metabolic acidosis 1
  • Always confirm concentration units when evaluating salicylate concentration to avoid misinterpreting significance of concentration level; concentration level may be reported as milligrams per deciliter, milligrams per liter, or millimoles per liter 6
  • Avoid screening for acid-base abnormalities solely by assessing anion gap because abnormally high anion gap is not a reliable screen for salicylate toxicity; arterial blood gas is the best way to monitor acid-base status in salicylate poisoning 6
  • Initiate definitive treatment of chronic exposure at a lower threshold salicylate concentration; significant toxicity with chronic salicylate exposure occurs at relatively low concentrations when compared with acute exposures 6
  • Do not wait until confirmation of drug concentration level to initiate gastrointestinal decontamination or alkalinization when clinical presentation is suggestive of possible significant acute salicylate poisoning; delay in treatment can result in increased toxicity 8
  • Do not base treatment decisions solely on declining salicylate concentration in the face of clinical deterioration 6
  • Failure to add potassium to dextrose-water-bicarbonate IV solution can result in inability to alkalinize urine; goal is to maintain serum potassium in high normal range to optimize urinary alkalinization process 8
  • Failure to recognize impending end-organ toxicity and promptly initiate hemodialysis can lead to increased toxicity and end-organ damage; early consultation with nephrology can help avoid delay in initiation of definitive care 8
  • Intubation and mechanical ventilation is a high-risk procedure in salicylate-poisoned patients 6 7
    • Strictly adhere to indications for intubation and mechanical ventilation
    • If intubation is absolutely indicated, initiate preventative measures (eg, hyperventilation, bicarbonate bolus, hemodialysis) to avoid exacerbation of acidosis and resultant increase in central nervous system toxicity associated with the procedure
  • Failure to appreciate continued or delayed absorption of salicylate or total body salicylate burden can occur when relying on only 1 or 2 drug concentration levels; establish a clear trend in salicylate concentration before concluding absorption is complete or total body burden is decreasing 8

Terminology

Clinical Clarification

  • Salicylate toxicity results from ingestion of products containing salicylic acid in doses higher than therapeutic; toxicity can be acute or chronic
  • Salicylate toxicity affects multiple organ systems, including: 6
    • Central nervous system: cerebral edema, coma, agitation, tinnitus, and seizures
    • Pulmonary system: hyperventilation/tachypnea and acute lung injury
    • Gastrointestinal system: nausea and vomiting
  • Clinical presentation is the most important measurement of toxicity; elevated salicylate concentration confirms diagnosis and guides therapy 3
    • Salicylate concentrations higher than 30 mg/dL are usually associated with toxicity
    • Presents differently in adults and children
      • Adults: classic acid-base abnormality encountered is a mixed picture of metabolic acidosis and respiratory alkalosis
      • Children: most present with acidemia

Classification

  • Based on timing
    • Acute: a single overdose
    • Chronic: multiple ingestions of salicylate over time that are higher than therapeutic
  • Based on amount ingested 3
    • Acute ingestion: usually a single overdose
      • With ingestion amounts above 150 mg/kg, toxicity is dose-dependent
        • Mild to moderate toxicity: 150 to 300 mg/kg 1 2
          • Associated with mild to moderate symptoms (eg, tinnitus, vomiting, hyperventilation) 9
        • Severe toxicity: higher than 300 mg/kg 1 2
          • Associated with severe symptoms (eg, acidosis, seizures, altered mental status, hyperthermia) 9 10
        • Potentially fatal toxicity: higher than 500 mg/kg 1 2 11
    • Chronic ingestion
      • No standardized amount or set dose is recognized as having the potential to cause toxicity with chronic exposure
      • Potentially more serious and likely more common than acute ingestion

Diagnosis

Clinical Presentation

History

  • Aspirin or its equivalent
    • Acute ingestion of more than 150 mg/kg or 6.5 g requires evaluation for possible acute toxicity 2
    • Any intentional overdose warrants emergent evaluation for acute toxicity and psychiatric evaluation 2
  • Other common products that contain salicylate 6
    • Oil of wintergreen (methyl salicylate)
      • Ingestion of the following amounts requires emergent evaluation: 2
        • Younger than age 6 years: any amount more than a lick or taste
        • Older than age 6 years: more than 4 mL
      • Onset of symptoms usually occurs within 2 hours of ingestion 12
    • Antidiarrheals (bismuth subsalicylate) and effervescent antacids
    • Topical analgesic ointments and liniments
    • Combination medications (eg, opioids with salicylate)
    • Alternative medication products (eg, willow bark)
  • Other possible drugs taken may be disclosed in the setting of acute ingestion
    • Up to one-third of presumed primary intentional salicylate overdoses are complicated by coingestion (eg, alcohol, benzodiazepines, tricyclic antidepressants) 12
  • Acute toxicity: common symptoms
    • Early symptoms include triad of hyperventilation, tinnitus, and gastrointestinal symptoms; dehydration can develop 8
      • Hyperventilation
        • Hyperpnea and tachypnea
        • Occurs from direct stimulation of the respiratory center of the medulla
        • Often missed owing to transient nature of symptom or age of patient
      • Ototoxicity
        • Hallmark symptom of acute toxicity is tinnitus
        • Tinnitus occurs early
        • Temporarily diminished auditory acuity can develop
        • Acute salicylate concentration from 20 to 40 mg/dL results in symptoms related to ototoxicity 8
      • Gastrointestinal symptoms
        • Nausea, vomiting, abdominal pain, and anorexia
          • Caused by irritation of gastric mucosa and stimulation of chemoreceptor trigger zone
        • Rare: aspirin concretion or bezoar forms in stomach, exacerbating gastrointestinal irritation 8
          • Enteric-coated aspirin preparations are often responsible
      • Other early symptoms
        • Diaphoresis
        • Dehydration
          • Diminished urine output, decreased tear production, and thirst
          • From sensible losses (eg, vomiting) and insensible losses (eg, respiratory losses, fever, increased metabolic activity) 6
          • More common in children
    • Later symptoms and symptoms of increasingly severe poisoning
      • Central nervous system effects
        • More common in children younger than age 5 years and in patients with chronic toxicity 3
        • Can be due to any or all of the following:
          • Direct toxic effects of drug
          • Low central nervous system glucose concentrations
          • Development of cerebral edema
        • Altered mental status (eg, confusion, hallucinations, agitation, lethargy, coma)
        • Vertigo or dizziness
        • Seizures
      • Hyperthermia
        • Occurs from uncoupling of oxidative phosphorylation 8
        • More common manifestation in children
  • Uncommon symptoms of acute toxicity
    • Dyspnea or frothy sputum may be a manifestation of pulmonary edema
      • More often develops in people who are elderly, who smoke, and who have chronic salicylate toxicity
      • Caused by increased pulmonary capillary permeability
    • Bleeding is rare
      • Caused by salicylate effects on clotting factors, capillary fragility, decreased platelet adhesiveness, and thrombocytopenia
    • Acute renal failure is rare
      • Caused by antiprostaglandin effects of salicylate (eg, renal vasoconstriction, reduced renal blood flow, reduced glomerular filtration rate)
  • Chronic toxicity 1
    • Diagnosis of chronic salicylate poisoning is often delayed
    • Most often occurs in elderly people
    • Often initially misdiagnosed owing to insidious onset, lack of history of an overdose, and presence of nonspecific clinical findings
    • Often occurs in context of chronic pain treatment or recurrent dosing in association with viral illness
    • Patients present with nonspecific findings, including general decline in functioning, altered mental status (eg, confusion, hallucinations, agitation), fever, dehydration, or hyperglycemia
    • Initial diagnostic evaluation focuses on evaluation for sepsis, cardiogenic pulmonary edema, diabetic ketoacidosis, or cerebrovascular accident; unexplained metabolic acidosis may prompt consideration of diagnosis

Physical examination

  • Common findings in acute toxicity include
    • Hyperventilation
      • Hyperpnea
        • Patients may hyperventilate despite having a respiratory rate within reference range by increasing tidal volume 8
        • Very common and sometimes subtle finding 7
      • Tachypnea
    • Decreased auditory acuity
    • Diaphoresis
    • Tachycardia
    • Pallor
    • Dehydration
      • Dry mucous membranes
    • Hyperthermia
  • Clinical findings associated with severe toxicity include: 3
    • Hyperthermia
    • Central nervous system findings
      • Signs of progressive central nervous system deterioration
        • Ataxia
        • Deafness
        • Confusion
        • Psychosis
        • Agitation
        • Delirium
        • Stupor
        • Coma
        • Seizures
  • Rales on auscultation suggest noncardiogenic pulmonary edema

Causes and Risk Factors

Causes

  • OTC preparations and prescription medications
    • Most cases are caused by the ingestion of aspirin; numerous available forms include: 13
      • Tablets (325 mg, 500 mg)
      • Enteric-coated tablets (81 mg, 325 mg, 500 mg, 650 mg)
      • Time-release tablets (81 mg, 650 mg)
      • Buffered tablets (325 mg, 500 mg)
      • Chewable tablets (81 mg)
      • Gum (227.5 mg per piece of gum)
      • Suppository (300 mg, 600 mg)
      • Salicylate in common OTC medications and preparationsTrade or common nameCompoundTypical dosages or amountsAspirinAcetylsalicylic acid81 to 325 mgPepto-BismolBismuth subsalicylate1050 mg/30 mL or 262.5 mg/15 mL oral suspension; 262 mg tabletDoan’sMagnesium salicylate580 mgSunscreenHomosalateOil of wintergreenMethyl salicylateTopical keratolytics (eg, Compound W, Dr. Scholl’s Callus Removers, Selsun Blue Naturals, Dermarest, Neutrogena Acne Oil Free Wash)Salicylic acidDisalcidSalsalate500, 750 mgAspercremeTrolamine salicylate View full sizeCitation: Data from Aspirin and Other Salicylates. In: ToxEd [database online]. Tampa, FL: Elsevier; 2017. Updated January 15, 2014. ToxEd http://www.toxed-ip.com/ToxEdView.aspx?id=129470; and Clinical Pharmacology. ClinicalKey website. Accessed June 1, 2017. https://www.clinicalkey.com/pharmacology/
    • Numerous OTC and prescription products contain aspirin or salicylate analogues; available forms include: 14
      • Herbal preparations
        • Pure oil of wintergreen contains 98% methyl salicylate 12
      • Gastrointestinal preparations
        • Bismuth subsalicylate preparations (eg, Pepto-Bismol, Kaopectate) contain any of the following: 13
          • 102 mg of salicylate per 262-mg bismuth subsalicylate tablet
          • 129 mg of salicylate per 15 mL (8.6 mg of salicylate per milliliter of 262 mg/15 mL) of bismuth subsalicylate liquid
        • Effervescent antacids (eg, Alka-Seltzer)
        • 5-aminosalicylate (ie, mesalamine) is a salicylic acid compound used to treat ulcerative colitis
      • Analgesics
        • Migraine relief medications (eg, Excedrin contains acetaminophen, aspirin, caffeine; Fiorinal contains aspirin, butalbital, caffeine)
        • Narcotic-containing pain relievers (eg, Percodan)
        • Some analgesics contain sodium salicylate compounds
      • Salicylate-containing NSAIDs
        • Salsalate contains a salicylsalicylic acid compound
        • Trilisate contains a choline magnesium trisalicylate compound
        • Arthropan is a choline salicylate compound
        • OTC preparations such as Doan’s pills and Magan contain a magnesium salicylate compound
      • Topical products containing salicylates
        • Many liniments, lotions, creams, ointments, and patches 15 that are used to treat musculoskeletal and arthritis pain contain methyl salicylate in concentrations from 10% to 30% 3
          • Bioavailability largely unknown
        • Topical Aspercreme contains a trolamine salicylate compound
        • Many topical keratolytics and wart removers contain salicylic acid
        • Some sunscreens contain homomenthyl salicylate
  • Aspirin absorption
    • Aspirin is rapidly absorbed in the acidic medium of the upper gastrointestinal tract and hydrolyzed to form salicylic acid at therapeutic doses 1
    • Absorption is erratic in overdose; 1 peak concentration may not be achieved for 4 to 6 hours or longer after ingestion 12
    • Increased risk for delayed toxicity from delayed absorption can occur with: 7
      • Ingestion of large quantities
      • Salicylate-induced gastric pylorospasm
      • Formation of drug concretion or drug bezoar
      • Extended-release or enteric-coated preparations
  • Pharmacokinetics are markedly altered and complex with overdose
    • Metabolism and elimination of salicylic acid
      • Hepatic metabolism is saturated and renal elimination is delayed in overdose; result is a substantially longer drug half-life in overdose 12
      • Metabolism and elimination kinetics change in overdose
        • Elimination half-life is 2 to 4.5 hours at therapeutic doses 11
        • Elimination half-life can be up to 36 hours in overdose 11
      • Renal elimination is mainly dependent on pH and hydration status in overdose
        • Urinary excretion of salicylate is minimal when urine pH is acidic; with increasing urinary pH, more filtered drug is trapped in an ionized state in the urine and unavailable for reabsorption (“ion trapping”) 1
    • Distribution of salicylate is related to many factors
      • Protein binding
        • In therapeutic doses, most salicylate is bound to protein in vascular space with a small apparent volume of distribution 1
        • In overdose, serum protein binding becomes saturated, leading to rapid rise in free salicylate concentrations 1
      • Serum pH
        • Drug is a weak acid with pKa of 3.0; volume of distribution and drug toxicity is highly dependent on pH 1
        • At a lower pH, more un-ionized salicylate is available to move freely into extravascular compartments across cell membranes and volume of distribution increases; hence, end-organ toxicity increases 1
        • At a higher pH, more salicylate is in ionized form, and cell membranes are less permeable to drug in this form; hence, drug is trapped from crossing cell membranes and less end-organ toxicity results
    • Mechanism of toxicity includes:
      • Direct and indirect respiratory center stimulation 3
      • Uncoupling of oxidative phosphorylation
      • Inhibition of amino acid metabolism
      • Stimulation of glycolysis, gluconeogenesis, and catabolism of proteins and fats

Risk factors and/or associations

Age
  • Exposures in children younger than age 6 years are usually unintentional
    • Unintentional exposures have declined in the United States since implementation of child-resistant packaging, availability of alternatives (ie, ibuprofen, acetaminophen), and knowledge of Reye syndrome risk associated with aspirin
  • Acute, intentional ingestion can occur in older children, adolescents, and adults
  • Elderly people are at risk for chronic toxicity, usually owing to unintentional overdose:
    • Changes in renal and hepatic function
    • Slower onset of symptoms and signs
    • Often masquerades as other illnesses and diagnosis is not considered
    • Polypharmacy contributes to confusion about medication content and doses
Other risk factors/associations
  • Patients who take salicylates for chronic medical conditions (eg, osteoarthritis, rheumatoid arthritis) are at higher risk for chronic toxicity
  • Patients with underlying mental health issues are at increased risk for intentional ingestion
  • Young children at increased risk of toxic exposure include:
    • Infants breastfed by mothers who are taking salicylates
    • Infants and toddlers given teething gels that contain salicylates
  • Noncardiogenic pulmonary edema caused by salicylates is most common in: 11
    • Older patients
    • People who smoke
    • Patients with chronic intoxication
    • Patients with severe poisoning (eg, acidosis, seizures)

Diagnostic Procedures

Primary diagnostic tools

  • History and physical examination prompt consideration of this diagnosis
  • Although elevated salicylate concentration confirms diagnosis and guides therapy, clinical presentation is the most important measurement of toxicity
  • Promptly begin treatment of salicylate toxicity once the diagnosis is seriously considered, pending laboratory confirmation 1 6
  • Involve local poison center staff and consult with medical toxicologist early to facilitate appropriate diagnosis 7
  • Blood salicylate concentration confirms diagnosis; obtain at time of presentation 9
    • A concentration greater than 30 mg/dL is usually associated with toxicity with an acute ingestion
    • End-organ toxicity of salicylates correlates poorly with blood concentration 12
    • When interpreting salicylate concentration, consider effect of blood pH on the drug’s ability to reach toxic tissue concentrations (ie, appreciable volume of distribution) 12
  • All patients with symptoms or with intentional ingestion: perform the following laboratory examinations:
    • Electrolytes, calculated anion gap, and glucose, BUN, and creatinine levels 16
  • In patients with moderate to severe poisoning, perform additional testing, including the following:
    • Arterial blood gas and baseline urine pH levels 1
      • Venous blood gas with pulse oximetry is acceptable in lieu of arterial blood gas level
    • Prothrombin time, partial thromboplastin time, and liver function tests 1
    • Testing for concomitant acetaminophen toxicity with acetaminophen concentration 12
    • Consider testing for other coingestion based on clinical presentation 12
  • Radiographic examinations are rarely helpful in a salicylate-poisoned patient; do not delay definitive treatment while waiting for radiographic examination
    • Obtain chest radiograph if pulmonary edema is suspected on examination (eg, respiratory distress, hypoxia)
    • Obtain head CT if cerebral edema is suspected on examination (eg, severely altered mental status)
    • Concretion or bezoar may be visible incidentally on abdominal radiograph when obtained for other reasons
  • Hyperpnea is a common and sometimes subtle finding early in toxicity; failure to appreciate hyperpnea can lead to delayed diagnosis and treatment 7

Laboratory

Imaging

Differential Diagnosis

Most common

  • Consider other causes of abnormal vital signs, gastrointestinal symptoms, and mental status changes pending salicylate level; none will have a toxic salicylate concentration
  • Diabetic ketoacidosis
    • Decompensated state of diabetes that presents with the biochemical triad of hyperglycemia, ketonemia, and increased anion gap metabolic acidosis (ie, increased gap caused by ketones)
    • Similar features: tachycardia, hyperventilation, weakness, nausea, vomiting, dehydration, and mental status changes
    • Differentiating features: people with diabetic ketoacidosis experience polyuria, polydipsia, polyphagia, absence of fever, acetone breath, and negative salicylate concentrations
    • Diagnosed by: hyperglycemia, positive urine and serum ketones, decreased arterial pH, elevated anion gap, and decreased serum bicarbonate
  • Renal failure
    • Similar features: nausea, vomiting, diminished urine output, and increased anion gap metabolic acidosis (increased gap caused by uremia)
    • Differentiating features: people with renal failure have absence of fever, pallor, increased effective circulating volume, edema, historical features (eg, hypertension, diabetes, vascular disease, chronic kidney disease), hyperkalemia, and negative salicylate concentrations
    • Diagnosed by: markedly elevated BUN and creatinine levels and abnormal urinalysis result
  • Sepsis
    • Similar features: tachycardia, tachypnea, dehydration, fever, mental status changes, metabolic acidosis (increased gap caused by lactic acidosis), and hyperglycemia
    • Differentiating features: patients with sepsis have significant WBC count abnormalities (eg, leukocytosis, leukopenia), thrombocytopenia, elevated C-reactive protein, and negative salicylate concentrations
    • Diagnosed by: positive blood cultures
  • Gastroenteritis (Related: )Traveler’s diarrhea
    • Similar features: vomiting, abdominal pain, fever, dehydration, and metabolic acidosis with significant dehydration
    • Differentiating features: patients with gastroenteritis have diarrhea, their metabolic acidosis from gastrointestinal losses tends to be associated with an anion gap within reference range, and they have negative salicylate concentrations
    • Diagnosed by: clinical course and positive stool studies, when indicated
  • Methanol or ethylene glycol toxicity (Related: ) 18Ethylene glycol toxicity
    • Similar features: history of overdose, vomiting, abdominal pain, hyperpnea, altered mental status, seizures, and positive anion gap metabolic acidosis (ie, increased gap caused by alcohols)
    • Differentiating features: patients with methanol or ethylene glycol toxicity have negative salicylate concentrations and increased osmolar gap
      • Methanol: ocular manifestations (eg, visual changes, blindness, abnormal pupillary reflexes) and methanol or ethanol odor to breath
      • Ethylene glycol: cranial nerve deficits, abnormal reflexes (eg, hypo- or hyperreflexia), and renal manifestations (eg, hematuria, oxalate calculus, urine fluorescence, azotemia)
    • Diagnosed by: measured serum or plasma methanol and ethylene glycol concentrations
  • Isoniazid toxicity 12
    • Similar features: history of overdose, refractory seizures, coma, positive anion gap metabolic acidosis (increased gap caused by drug), possibly vomiting and depressed mental status
    • Patient may have history of tuberculosis treatment
    • Differentiating features: patients with isoniazid toxicity have abnormal reflexes (eg, hyperreflexia, areflexia), lack fever and hyperpnea, and have negative salicylate concentrations
    • Confirmed by measured serum isoniazid concentration. Clinical use is limited owing to lengthy turn around time for isoniazid concentration
  • Dementia (Related: )Alzheimer disease
    • Elderly with chronic salicylate poisoning often present with features similar to dementia
    • Similar features: mental status changes, especially cognitive impairment and decline in function that worsens with time
    • Differentiating features: patients with dementia have unexplained metabolic acidosis, negative salicylate concentrations, and subtle examination features (eg, lack of hyperpnea, hearing loss/tinnitus); often, dementia is accompanied by neurologic deficits (eg, dysphagia, apraxia) and memory loss
    • Diagnosed by: clinical presentation and course of illness

Treatment

Goals

  • Reduce and prevent absorption of salicylates and achieve gastrointestinal decontamination: use activated charcoal 4
  • Enhance renal elimination of salicylates with urinary alkalinization and volume repletion 4
  • Prevent central nervous system toxicity with normalization of blood pH
  • Provide potassium and glucose supplementation
  • Enhance elimination with hemodialysis when indicated
  • Monitor electrolytes, acid-base status, urinary pH, and serial salicylate concentrations

Disposition

Admission criteria

Signs and symptoms of mild to moderate toxicity

Criteria for ICU admission
  • Signs and symptoms of serious toxicity (for treatment and monitoring)

Recommendations for specialist referral

  • Early in poisoning, if there is any concern about significant ingestion or findings suggestive of toxicity, consult medical toxicologist and local poison center staff for diagnosis and treatment recommendations 7 10
  • Consider early consultation with nephrologist about possible future need for hemodialysis to eliminate delays when dialysis is urgently indicated 6
  • Consult mental health practitioner—psychiatrist, psychologist, or counselor—after toxicity resolves regarding any patient with intentional ingestion for further mental health treatment recommendations

Treatment Options

Except with very high concentrations, treatment is based on symptoms, signs, and laboratory test results rather than on absolute salicylate concentration alone 4

  • Management algorithms are available 4

Gastrointestinal decontamination

  • Activated charcoal 6
    • Administer for a suspected toxic or life-threatening dose in a patient with an intact or protected airway in consultation with local poison control staff and/or medical toxicologist 5
    • Activated charcoal decreases absorption of dose by 50% to 80% 12
    • Most effective when administered within 1 hour of ingestion; 9 administration up to several hours after overdose may be indicated owing to erratic and often delayed absorption in overdose 1
    • Consider out-of-hospital administration by trained first responders in consultation with local poison control center staff for acute ingestion of toxic dose when no contraindications are present (eg, patient is alert, cooperative, and not vomiting) and administration does not delay transport 2
    • Depressed mental status, risk for aspiration, and vomiting are contraindications to administration
  • Consider whole bowel irrigation with polyethylene glycol-electrolyte solution in specific cases in consultation with a medical toxicologist 6
    • May be indicated for patients with rising concentration or signs of incomplete absorption, ingestion of large amounts of sustained release or enteric-coated preparations
  • Use of multiple-dose activated charcoal is controversial; consider it only in consultation with medical toxicologist 6
    • May be indicated after ingestion of substantial amounts of enteric-coated or sustained-release products or when ongoing absorption occurs as a result of pharmacobezoars or aspirin concretions 1 4

Enhanced elimination techniques

  • Bicarbonate administration 6
    • Mainstay treatment of moderate toxicity; either administer bolus then begin infusion or immediately start infusion 3
    • Indicated for patients with salicylate toxicity alone or in combination with hemodialysis 6
      • Threshold for initiating urinary alkalinization is not well defined; prudent to institute treatment if patient is symptomatic or exhibits acid-base abnormality 1
    • Serves to both alkalinize urine and normalize blood pH
      • Achieving a slightly alkalemic blood pH traps a charged form of the drug in the blood, limiting central nervous system toxicity
        • Goal blood pH is 7.45 to 7.5; 9 pH of blood should not exceed 7.55 4
      • Urinary alkalinization traps charged (ionized) form of drug in urine and enhances renal excretion
        • Increasing urine pH from 5 to 8 results in a 10- to 20-fold increase in renal salicylate excretion 4
        • Goal urine pH is higher than 7.5 to 4 68 3
      • Correct hypokalemia
        • Presence of hypokalemia prevents urinary alkalinization
        • Correction of hypokalemia is essential when serum potassium concentrations are low
    • Do not discontinue alkalinization until both of the following occur: 4
      • Salicylate concentration decreases to therapeutic range
      • Signs and symptoms of toxicity resolve
  • Volume replacement
    • Volume depletion from sensible (eg, vomiting, natriuresis) and insensible (eg, respiratory, fever) losses is almost universal at time of presentation in symptomatic adults 6
    • Volume depletion is often underappreciated in poisoning; 4 to 6 L/m² deficit is common 3 6
    • Begin fluid resuscitation with alkalinized IV fluids to correct extracellular volume depletion early in course of toxicity 6 8
  • Intermittent hemodialysis 10
    • Intermittent hemodialysis is preferred modality of extracorporeal treatment 10
      • Acceptable alternatives include hemoperfusion and continuous renal replacement therapy techniques when hemodialysis is not available 10
    • Hemodialysis is a very effective, definitive treatment and can resolve toxicity in hours 6
    • Additional advantages of hemodialysis include providing tighter control of acid-base balance and electrolyte abnormalities while simultaneously removing drug 4
    • Indications for hemodialysis vary depending on patient age, acuity of toxicity, salicylate concentration, associated ingestions or other comorbidities, and ability to tolerate sodium bicarbonate and fluid administration 6
    • Note: continue alkalinization in patients undergoing hemodialysis between extracorporeal treatment sessions 10 to reduce blood drug concentrations quickly, prevent acidemia, and promote as much renal elimination of drug as possible 4

Drug therapy

  • Activated charcoal 3 4
    • Activated Charcoal Oral suspension; Infants: 1 g/kg/dose PO. Dosages can be repeated PRN, q4h to q6h.
    • Activated Charcoal Oral suspension; Children: 1 to 2 g/kg/dose or 25 to 50 g/dose PO. Dosages can be repeated PRN, q4h to q6h.
    • Activated Charcoal Oral suspension; Adults and Adolescents: 50 g as a single dose; not recommended for multiple dosage regimens.
  • Sodium bicarbonate
    • Initial bolus
      • Sodium Bicarbonate Solution for injection; Adults, Adolescents, and Children: 1 to 2 mEq/kg IV bolus, followed by infusion. Adult dose is typically 50 to 100 mEq. 3
    • Continuous infusion
      • Sodium Bicarbonate Solution for injection; Adults, Adolescents, and Children: 150 mEq in 1 L of D5W. 6
        • Potassium chloride (30 to 40 mEq/L) may be added to the solution to prevent hypokalemia. 6
        • Run solution at 150 to 200 mL/h in adults and 1.5 to 2 times the IV fluid maintenance rate in children. 3
        • Rate of infusion should be sufficient to induce urine output of 2 to 3 mL/kg/h. 6

Nondrug and supportive care

Provide potassium supplementation 6

  • Potassium depletion can cause increased reabsorption of bicarbonate in the proximal renal tubules and cause difficulty in achieving alkaline urine; urinary alkalinization promotes urinary loss of potassium 9 8
  • Maintain a serum potassium concentration within reference range or close to it to facilitate urinary alkalinization 6

Provide glucose supplementation 6

  • Uncoupling of mitochondrial oxidative phosphorylation results in abnormal glucose homeostasis altering serum glucose levels, often causing hypoglycemia 8
  • Central nervous system glucose use increases with poisoning; central nervous system glucose concentration can be low despite serum glucose concentrations within reference range 6

Other general supportive measures

  • Provide continuous positive pressure ventilation support for patients with signs of pulmonary edema 1
    • Expect improvement in pulmonary edema as drug concentrations fall
  • Treat seizures with standard seizure protocol (eg, benzodiazepines) and address other potential clinical causes (eg, hypernatremia, hypoglycemia, hypocalcemia) 1
  • Begin general supportive measures to manage suspected increased cranial pressure (eg, elevate head of bed, consider mannitol) 3
  • Start evaporative cooling (eg, tepid water spray and fans) techniques and use cooling blankets for patients with hyperthermia 3

Airway protection issues

  • Endotracheal intubation can rapidly worsen toxicity and increase mortality unless a healthy or slightly alkaline pH is maintained via hyperventilation and IV sodium bicarbonate administration 6
    • Sudden loss of respiratory compensation for acidosis results in precipitous fall in blood pH and acute, rapid distribution of salicylate into the central nervous system
  • Preintubation measures that may offset rapid distribution of drug into central nervous system include the following:
    • Administer sodium bicarbonate IV bolus at time of intubation in an attempt to maintain blood pH of 7.45 to 7.50 6
    • Hyperventilate any acidemic patient with a spontaneously ventilating PCO₂ of less than 20 mm Hg with bag-valve mask 6
    • Consider simultaneous hemodialysis while securing airway to remove salicylate and organic acids that rapidly accumulate during intubation procedure 8
  • Endotracheal intubation may be indicated in patients with the following issues: 6
    • Deteriorating mental status
    • Signs of acute severe lung injury
    • Significant, uncontrollable agitation
  • Immediately postintubation measures:
    • Obtain blood gas
    • Take extreme care to match or exceed patient’s intrinsic preintubation minute ventilation 7
    • Maintain alkalemia (pH 7.45-7.5) in ventilated patients to prevent redistribution of drug into central nervous system 9

Avoid

  • Routine use of Done nomogram for treatment decisions: unreliable and has limited applicability to most poisoned patients 1 8
  • Acidemia: acidosis worsens end-organ toxicity 6
  • Forced diuresis: lacks benefit and can potentially cause harm (eg, patient may develop pulmonary edema and hypokalemia) 4
  • Acetazolamide administration: acetazolamide produces alkaline urine but lowers blood pH
  • Intubation unless absolutely indicated: can acutely worsen toxicity
Procedures
Hemodialysis 10

General explanation

  • Blood is removed using a large-bore arterial cannula; passed through a semipermeable membrane to filter out excess fluid, electrolytes, urea, organic acids, other metabolic waste products, and certain drugs; and returned to the patient through a large-bore venous cannula
  • All decisions regarding technical aspects of hemodialysis require consultation with a nephrologist

Indication

  • Base decision to initiate hemodialysis on overall clinical condition and not salicylate concentration alone, especially in patients with chronic toxicity or delayed presentation following acute overdose 10
    • Consider hemodialysis 6
      • For patient with chronic toxicity or delayed presentation with clinical indications for hemodialysis and concentration of 40 mg/dL or higher
      • For patient with acute toxicity despite minimal or absent signs and symptoms of toxicity when concentrations are approaching 100 mg/dL 6
  • Severe salicylate poisoning 6 10
  • Significant central nervous system abnormalities such as cerebral edema, seizure, or altered mental status 10
  • Acute lung injury (eg, pulmonary edema, failing respiratory capacity, or acute respiratory distress syndrome requiring supplemental oxygen) 10
  • Impaired glomerular filtration rate not responsive to volume repletion
  • Significant hyperthermia (an indicator of mitochondrial toxicity from salicylates)
  • Refractory or profound acidemia (ie, systemic pH less than or equal to 7.20) 10
  • Fluid overload that precludes administration of sodium bicarbonate (eg, renal insufficiency or failure, pulmonary edema, cerebral edema) 10
  • Failure of standard therapy 10 as indicated by either:
    • Deteriorating clinical condition, especially if achievement of urine alkalinization is delayed or inadequate, regardless of salicylate concentration
    • Rising salicylate concentrations despite administration of sodium bicarbonate and supportive care associated with significant severe symptoms (ie, central nervous system manifestations, pulmonary manifestations, hyperthermia)
  • Refractory or profound electrolyte disturbance
  • Patients with impaired renal function
    • Recommended with salicylate concentration higher than 90 mg/dL, even if patient shows fairly minor clinical signs and symptoms 10
    • Suggested with salicylate concentration over 80 mg/dL, even if patient shows fairly minor clinical signs and symptoms 10

Acute overdose

  • Patients with renal function within reference range
    • Recommended with salicylate concentration greater than 100 mg/dL, even if patient shows fairly minor clinical signs and symptoms 6
    • Suggested with salicylate concentration greater than 90 mg/dL, even if patient shows fairly minor clinical signs and symptoms 10

Chronic poisoning or delayed presentation after acute overdose

  • Consider with salicylate concentration over 40 mg/dL when other manifestations of toxicity are present (eg, acid-base disturbances, acute lung injury, central nervous system abnormalities) 6

Contraindications

  • Hypotension, which precludes adequate arterial removal of blood

Complications

  • Hypotension
  • Hypertension
  • Arrhythmia
  • Muscle cramping
  • Nausea and vomiting
  • Headache and confusion
  • Air embolism

Interpretation of results

  • Cessation of therapy is recommended when clinical improvement is apparent and when at least 1 of the following is true: 10
    • Salicylate concentration is lower than 19 mg/dL 10
    • Hemodialysis is performed for at least 4 to 6 hours when salicylate concentrations are not readily available 10

Comorbidities

  • Concomitant ingestion of central nervous system depressants (eg, alcohol, benzodiazepines) may enhance salicylate toxicity independent of toxic effects that occur directly from these medications themselves 3
  • Patients with preexisting renal disease, liver disease, and heart failure often are better managed with hemodialysis owing to propensity toward clinical deterioration with fluid and sodium bicarbonate administration

Special populations

  • Pregnant women near term
    • Fetus is at high risk for toxicity from salicylate exposure and at high risk for hemodynamic consequences of hemodialysis
    • Consult with medical toxicologist and obstetrician to determine if emergent delivery or hemodialysis is indicated for near-term pregnancy, especially if evidence of fetal distress is present
    • Consult with medical toxicologist and obstetrician to determine if hemodialysis is indicated for any pregnancy not near term, especially if evidence of fetal distress is present
      • No existing guidelines are in place that distinguish a specific maternal serum salicylate concentration indicating need for maternal hemodialysis
  • Neonate
    • Exchange transfusion is an accepted alternate to hemodialysis when indicated 10
  • Elderly
    • Maintain a high suspicion for chronic toxicity in elderly; delayed diagnosis and missed diagnosis is common in this age group. Frequent misdiagnoses include sepsis and dementia; 1 clue is unexplained metabolic acidosis

Monitoring

  • Monitoring for patients requiring treatment of toxicity
    • Monitor symptoms, urine output, electrolytes, acid-base status, urinary pH, and serial salicylate concentrations 1 6
      • Closely monitor serial drug concentration and blood pH to assess trends 8
      • Closely monitor electrolytes and acid-base status to avoid excessive electrolyte replacement (eg, potassium) and/or alkalinization 6
      • Frequently monitor urinary pH to assess efficacy of urinary alkalinization 6
      • Monitor for change in clinical status to determine need to escalate to hemodialysis
      • Monitor urine output and make fluid adjustments to maintain urine output of 2 to 3 mL/kg/hour 6
      • Monitor calcium concentrations during alkalinization therapy; replacement calcium may be required because hypocalcemia can complicate treatment
    • Continue close monitoring until a clear downward trend in salicylate concentration is observed, metabolic stability is confirmed by serial blood gas analysis, and patient signs and symptoms are resolving 1 8
  • Monitoring for findings of toxicity following a potential overdose or toxic exposure
    • Consult local poison control center staff for specific individualized recommendations
    • In general, patients require serial salicylate concentration and observation for clinical manifestations of toxicity for a minimum of 12 hours given potential for delayed and erratic absorption of drug in overdose 1
    • Medically clear patients who: 1
      • Do not have clinical manifestations of salicylate toxicity
      • Do have normal acid-base status
      • Do have 2 falling salicylate concentrations in the therapeutic range spaced 3 to 4 hours apart
  • Failure to appreciate continued or delayed absorption of salicylate or total body salicylate burden can occur when relying on only 1 or 2 drug concentration levels; establish a clear trend in salicylate concentration before concluding absorption is complete or total body burden is decreasing 8

Complications and Prognosis

Complications

  • Severe poisoning can result in metabolic acidosis, seizures, coma, hyperthermia, noncardiogenic pulmonary edema, and renal failure
    • Death occurs in up to 5% of patients with severe poisoning 4
  • Death from acute toxicity 19
    • Marked metabolic acidosis heralds the development of severe toxicity and end-organ failure; pulmonary edema, cerebral edema, and myocardial depression develop 8
    • Severe volume depletion leads to concomitant hypotension 8
    • Central nervous system depression with seizures secondary to hypoxia, hypoglycemia, and direct central nervous system toxicity precede cardiopulmonary arrest 8

Prognosis

  • Mild to moderate toxicity
    • Prognosis is favorable given appropriate medical management
    • Overall mortality is low 4
  • Severe poisoning can result in death and significant morbidity
    • Patients with significant ingestion often present alert with minimal symptoms, then rapidly deteriorate from toxicity 20 21
    • Delay in diagnosis is associated with increased mortality rate (15%) compared with early diagnosis with prompt initiation of treatment 4
    • Features associated with increased mortality include: 11
      • Coma, fever, and noncardiogenic pulmonary edema
      • Age older than 70 years
      • Severe poisoning with acidemia
  • Chronic toxicity
    • Associated with overall higher morbidity and mortality rates (up to 25%) 12
    • Noncardiogenic pulmonary edema (ie, salicylate-induced increased pulmonary capillary permeability) is the most common cause of significant morbidity 3

Screening and Prevention

Screening

At-risk populations

  • Elderly 3
    • Taking medications for chronic pain
    • With mental status changes
  • Individuals presenting with intentional ingestion with suicidal intent 3 16

Screening tests

  • Monitor for signs of toxicity using history and physical examination; obtain salicylate concentration if there are any signs or symptoms of toxicity 4

Prevention

  • Maintain strict adherence to salicylate dosing instructions
  • Do not take aspirin-containing products in addition to therapeutic or preventative daily aspirin dosing
  • Avoid use of aspirin in children, unless other indications exist for use (eg, Kawasaki disease)
  • Keep salicylate medications and salicylate-containing products (eg, oil of wintergreen) out of reach of children with child-resistant packaging intact

REFERENCES

  1. Little M: Toxicology emergencies. In: Cameron P et al, eds: Textbook of Adult Emergency Medicine. 4th ed. London, England: Churchill Livingstone; 2015:951-1033 View In Article | Cross Reference 

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