Salicylate toxicity: Difference between revisions

(Add MedicationDose SMW annotations (sodium bicarbonate, activated charcoal); dosing verified per ACMT guidelines)
(Major update: EXTRIP HD indications, intubation danger, CNS glucose deficiency, alkalinization protocol with K requirement, oil of wintergreen warning, zero-order kinetics, references with PMIDs)
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==Background==
==Background==
*Salicylates are commonly available in numerous over-the-counter products, and toxicity may occur from acute (intentional or accidental) and chronic ingestion.
*Aspirin (acetylsalicylic acid) is the most common salicylate
*Fatal dose:  
*Other salicylate sources: bismuth subsalicylate (Pepto-Bismol), oil of wintergreen ('''most concentrated — 1 teaspoon = ~7g aspirin'''), topical agents (Ben-Gay)
**~10-30g by adult
*Therapeutic level: '''10-30 mg/dL'''
**~3g by child
*Toxic ingestion: '''>150 mg/kg'''
 
*Lethal dose: '''~500 mg/kg'''
===Salicylate Sources===
*Mechanism of toxicity:
*[[Aspirin]]
**'''Uncouples oxidative phosphorylation''' → impaired aerobic metabolism, heat generation
*Oil of Wintergreen
**Direct CNS stimulation of respiratory center → respiratory alkalosis (early)
**Oil of Wintergreen is very concentrated - 5mL contains approximately 7g of aspirin.<ref>Wintergreen. Drugs.com. https://www.drugs.com/npp/wintergreen.html. Published January 2, 2025. Accessed July 30, 2025.</ref>
**'''Accumulation of organic acids''' → anion gap metabolic acidosis (late)
*[[Bismuth subsalicylate|Pepto-Bismol]]
**Inhibits Krebs cycle, disrupts lipid and amino acid metabolism
*Wart removers
*Pharmacokinetics change in overdose:
*[[Bismuth subsalicylate|Maalox]]
**'''Zero-order kinetics at toxic levels''' (saturable metabolism)
*Alka-Seltzer
**'''Delayed absorption''' with enteric-coated or sustained-release formulations
 
**'''Bezoar formation''' possible with massive ingestion
===Pathophysiology===
''Uncouples oxidative phosphorylation → increased metabolic rate and hyperthermia''
*As level rises, switches from hepatic to renal clearance (slower)
*[[Nausea/vomiting]]
**Stimulates chemoreceptor trigger zone
**May cause metabolic alkalosis (contraction alkalosis)
*Respiratory alkalosis
**Activates respiratory center of medulla
**If have respiratory acidosis, consider: pulmonary edema, co-ingestion of respiratory depressant or fatigue
**Leads to compensatory alkaluria: urinary excretion of potassium and sodium bicarb
*[[Metabolic Acidosis|Anion gap metabolic acidosis]]
**Interferes with cellular metabolism
**Normal AG does not exclude ASA toxicity in patient with an unknown ingestion (mixed picture)
*[[Hyperthermia]]
**Uncouples oxidative phosphorylation
**As pH drops more ASA is uncharged; able to cross BBB
*[[Altered mental status]]
**Direct toxicity of salicylate species in the CNS
**Cerebral edema
**Neuroglycopenia
***Salicylate toxicity increases CNS utilization of glucose, serum glucose levels may not reflect CNS levels.
*[[Pulmonary edema]]
**Usually occurs in elderly
**Due to increased pulmonary vascular permeability
*[[Fetal Effects in pregnancy]]
**Increased fetal morbidity and mortality
**Un-ionized salicylate cross the placenta due to higher fetal pH, where it becomes ionized and accumulates in the fetus
**Due to fetal inability to hyperventilate leads to worsening acidosis
**There can be displacement of bilirubin from protein binding sites allowing it to cross the blood brain barrier, which can lead to kernicterus.
**Due to inhibition of prostaglandin synthesis, can lead to premature closure of the ductus arteriosus


==Clinical Features==
==Clinical Features==
===Mild (<150mg/kg)===
===Acute Toxicity===
*[[Tinnitus]]
*'''Early''': tinnitus, nausea, vomiting, [[tachypnea]] (respiratory alkalosis)
**Tinnitus is early sign - providers used to dose ASA to onset of tinnitus.
*'''Moderate''': diaphoresis, [[tachycardia]], [[hyperthermia]], agitation, confusion
*Hearing loss
*'''Severe''': '''altered mental status''', [[seizures]], '''pulmonary edema''' (noncardiogenic), [[cerebral edema]], coma
*[[Dizziness]]
*'''Classic acid-base pattern''':
*[[Nausea and vomiting]]
**Adults: '''mixed respiratory alkalosis + metabolic acidosis'''
**Common with acute toxicity
**Children: metabolic acidosis predominates (may not have initial respiratory alkalosis phase)
 
===Moderate (150-300mg/kg)===
*[[Tachypnea]]
*[[Hyperpyrexia]]
*[[Diaphoresis]]
*[[Ataxia]]
*[[Anxiety]]
 
===Severe (>300mg/kg)===
*[[Altered mental status]]
*[[Seizure]]
*[[Coma]]
*Cerebral edema
*Acute lung injury
*[[Nausea and vomiting]]
*[[Acute renal failure]]
*Cardiac [[arrhythmias]]
*[[Shock]]


===Chronic Toxicity===
===Chronic Toxicity===
*Usually neurologic abnormalities, especially in elderly
*More insidious and '''often misdiagnosed''' (especially in elderly)
**[[Agitation]]
*Presents with confusion, tinnitus, dehydration, metabolic acidosis
**Paranoia
*May be diagnosed as [[sepsis]], altered mental status workup
**Memory deficits
**[[Confusion]]
**Stupor
*Hyperventilation
*[[Tremor]]
*[[Papilledema]]
*Higher morbidity ([[pulmonary edema]], [[seizures]], [[renal failure]]) and mortality rate compared with acute toxicity


==Differential Diagnosis==
==Differential Diagnosis==
{{Anion gap metabolic acidosis}}
*[[Sepsis]] (similar presentation with tachypnea, metabolic acidosis, AMS)
*Other causes of '''anion gap metabolic acidosis''' (MUDPILES: methanol, uremia, DKA, propylene glycol, INH/iron, lactic acidosis, ethylene glycol, salicylates)
*[[Theophylline toxicity]] (similar features)
*[[Acetaminophen toxicity]] (common coingestion)
*[[Iron toxicity]]


==Evaluation==
==Evaluation==
===Work-Up===
*'''Salicylate level''':
*[[ASA]] level
**Therapeutic: 10-30 mg/dL
*Acetaminophen level (possible co-ingestant)
**Toxic: '''> 30 mg/dL'''
*Metabolic panel
**Severe: '''>90 mg/dL'''
**Renal failure prevents ASA clearance
**'''Repeat level every 2 hours''' until declining (delayed absorption, bezoar)
**Hyperglycemia in periphery (CSF will have low glucose due to CNS hypermetabolic state)
**'''Done nomogram''' (not well validated for chronic or enteric-coated ingestions)
**Hypokalemia requires aggressive repletion - this differentiates from [[DKA]] which tends to have hyperkalemia or normokalemia at initial presentation
*'''ABG/VBG''': assess pH ('''acidemia dramatically worsens toxicity by driving salicylate into CNS''')
***Urinary alkalinization inhibited by excretion of H+ in order to reabsorb K+
*'''BMP''': anion gap, '''glucose''' (CNS hypoglycemia may occur despite normal serum glucose), potassium, bicarbonate, creatinine
*Mag and phos
*'''Acetaminophen level''' (common coingestion)
*[[Urine toxicology screen]]
*'''LFTs, coagulation studies''' (hepatotoxicity, coagulopathy)
*[[Urinalysis]]
*'''Lactate'''
*VBG
*'''Urine pH''': target alkalinization to pH 7.5-8.0
*CBC
*'''CXR''' if concern for pulmonary edema
*PTT, PT/INR
*LFTs
*[[ECG]]
*Chest and abdominal radiographs
 
===Evaluation===
*Triple-mixed acid-base disturbance
**Respiratory alkalosis (earliest sign), AG metabolic acidosis, metabolic (contraction) alkalosis
**Only other entity that produces this pattern is sepsis
*Elevated ASA level
**Obtain levels q1-2hr until levels decline and patient's clinical status stabilizes
**May be deceptively low early after ingestion and with chronic toxicity
 
===Levels===
*Therapeutic: 10-30mg/dL
*Toxicity: >40-50mg/dL
*Rapidly absorbed - measurable levels in 30 minutes
*Peak occurs ~6hr after absorption (up to 60hr if enteric-coated or extended release)
 
;Unit Conversion: 100mg/dL = 1000mg/L = 7.24 mmol/L


==Management==
==Management==
===Airway===
===GI Decontamination===
*Avoid intubation unless absolutely necessary!
*'''Activated charcoal''' 1 g/kg (max 50g): effective if '''within 1-2 hours''' of ingestion
**Very difficult to achieve adequate minute ventilation on vent
**May benefit later with large ingestions, enteric-coated tablets, or bezoar
***Inadequate minute ventilation → ↑ respiratory acidosis → ↑ ASA crossing BBB
**Multiple doses may be considered
***While on ventilator, adjust RR to maintain goal serum pH 7.5 - 7.59
*'''Whole bowel irrigation''' for massive ingestions or sustained-release/enteric-coated tablets
**Indications for intubation: hypoxemia or hypoventilation
**Give [[sodium bicarbonate]] 50-100 meq prior to intubating


===Breathing===
===Alkalinization (Cornerstone of Treatment)===
*Acute lung injury may lead to high O2 requirements
*'''IV sodium bicarbonate'''
*'''Goal: urine pH 7.5-8.0''' and '''serum pH 7.50-7.55'''
**Alkaline urine traps ionized salicylate in renal tubules → enhanced elimination
**Alkaline serum prevents salicylate from crossing blood-brain barrier
*'''Protocol''':
**'''Bolus: 1-2 mEq/kg IV NaHCO3'''
**'''Infusion: 150 mEq NaHCO3 in 1L D5W''' at 150-250 mL/hr
**'''Add 20-40 mEq KCl per liter''' (hypokalemia impairs urinary alkalinization)
*'''CRITICAL''': '''alkalinization will NOT work without adequate potassium replacement'''
*Monitor serum pH, urine pH, and potassium every 1-2 hours


===Circulation===
===Dextrose===
*[[Hypotension]] is common due to systemic vasodilation
*'''Give D50W (50 mL IV)''' empirically if any CNS symptoms (altered mental status, seizures)
*IVF +/- K+ (if no cerebral edema, no pulmonary edema)
*'''CNS glucose may be low even with normal serum glucose''' (salicylate impairs CNS glucose transport)
**If these are present consider pressors
*Add dextrose to maintenance fluids


===Decontamination===
===Hemodialysis===
*[[Charcoal]] 1g/kg up to 50g PO
*'''Most effective method of salicylate removal'''
**Effectively absorbs ASA
*'''EXTRIP Workgroup Indications'''<ref>Juurlink DN, et al. Extracorporeal treatment for salicylate poisoning: systematic review and recommendations from the EXTRIP workgroup. ''Ann Emerg Med''. 2015;66(2):165-181. PMID 25986310</ref>:
**Give multiple doses if tolerated
**'''Recommended''': salicylate level '''> 90 mg/dL''' (acute) or '''> 80 mg/dL''' (chronic)
***25g PO q2hr x 3 doses '''OR''' 50g q4hr x 2 doses after initial dose
**'''Recommended''': altered mental status, new hypoxemia requiring supplemental O2
*[[Whole-bowel irrigation]]
**'''Recommended''': pH ≤ 7.20 despite bicarbonate therapy
**Consider for ingestion of large amount of enteric-coated or extended-release forms
**'''Suggested''': salicylate level > 80 mg/dL (acute), renal failure limiting salicylate clearance, clinical deterioration despite treatment
*Also dialyzes out the metabolic acidosis
*Consult nephrology early


===Glucose===
===What to Avoid===
*Give [[dextrose|D50]] to altered patients regardless of serum glucose concentration
*'''Do NOT intubate unless absolutely necessary'''
*Except for fluids used for initial resuscitation, all IVF should be D5W
**Salicylate patients compensate with profound hyperventilation
**ASA toxicity impairs glucose metabolism
**'''Loss of respiratory compensation''' (even brief during intubation) causes '''rapid acidemia → CNS salicylate accumulation → cardiac arrest'''
 
**If intubation required: '''maximize bicarb, match minute ventilation''' to pre-intubation rate
===Alkalinization of plasma and urine===
*'''Avoid acetazolamide''' (causes metabolic acidosis)
*Not a substitute for dialysis in severe salicylism
*'''Avoid excessive IV fluids''' without bicarb (dilutes serum alkalinity)
*Continuous IV infusion of [[sodium bicarbonate]] is indicated even in the presence of alkalemia from respiratory alkalosis<ref>American College of Medical Toxicology (ACMT). Guideline Document: Management Priorities in Salicylate Toxicity. https://www.acmt.net/wp-content/uploads/2022/06/PRS_130313_Management-Priorities-in-Salicylate-Toxicity.pdf. Published March, 2013. Accessed July 30, 2025.</ref>
**Serum bicarbonate is still deficient
*Mechanism
**Traps ASA in blood and in renal tubules
***Increases elimination; prevents diffusion across BBB
*Indications
**ASA>35 or suspect serious toxicity
*Goals
**Blood pH goal: = >7.5, <7.6
**Urine pH goal: 7.5-8
*Monitor serum electrolytes (to include potassium and magnesium) q2-4hrs during urine alkalinization<ref>Waseem M et al. Salicylate Toxicity. eMedicine. Dec 5, 2015. http://emedicine.medscape.com/article/1009987-workup.</ref>
**HCO3 will drive potassium into cells during drip
**Ensure replacement of magnesium and potassium, as urine will not alkalinize otherwise
*Dosing
**NaHCO3 1-2mEq/kg IV bolus; then 3amp bicarb in 1L D5W at 2-3mL/kg/hr
***Maintain urine pH >7.5
*Bolus during intubation
**If intubation is required, consider administration of sodium bicarbonate by IV bolus at the time of intubation to maintain a blood pH of 7.45-7.5 over the next 30 minutes
 
===Dialysis===
Indicated for:  
*[[Altered mental status]]
*[[Seizure]]
*[[Pulmonary edema]]
*[[Coagulopathy]]
*Inability to tolerate volume load from bicarb drip (e.g. [[CHF]])
*New [[hypoxemia]]
*pH ≤7.20
*High ASA levels<ref>Juurlink DN, et al. Extracorporeal treatment for salicylate poisoning: Systematic review and recommendations from the EXTRIP workgroup.Ann Emerg Med. 2015; 66 (2):165-81.
.</ref>
**Initial levels
***>7.2 mmol/L (100mg/dL)
***>6.5 mmol/L (90mg/dL) in the setting of AKI
**After standard therapy
***>6.5 mmol/L (90mg/dL)
***>5.8 mmol/L (80mg/dL) in the setting of AKI


==Disposition==
==Disposition==
*Admit all patients who have ingested enteric-coated or extended-release preprarations
*'''ICU admission''' for: level >50 mg/dL, acidemia, AMS, pulmonary edema, renal failure
 
*'''Monitored bed''' for moderate toxicity with improving levels
*'''Serial salicylate levels''' every 2 hours until clearly declining
*'''Poison control: 1-800-222-1222'''
*Psychiatric evaluation for intentional ingestions


<div style="display:none">
<!-- SMW MedicationDose annotations for salicylate toxicity medications -->
{{MedicationDose|drug=Sodium bicarbonate|dose=50-100 mEq IV bolus (pre-intubation); then continuous IV infusion titrated to blood pH 7.5-7.6 and urine pH 7.5-8|route=IV/IV drip|context=Alkalinization of plasma and urine|indication=Salicylate toxicity|notes=Indicated even with respiratory alkalosis; not a substitute for dialysis in severe cases}}
{{MedicationDose|drug=Activated charcoal|dose=1 g/kg PO (max 50 g) initial; then 25 g PO q2h x3 or 50 g q4h x2 (multidose)|route=PO|context=GI decontamination (multidose effective)|indication=Salicylate toxicity|notes=Effectively absorbs ASA; multidose charcoal recommended if tolerated}}
</div>
==See Also==
==See Also==
*[[Toxicology (Main)]]
*[[Toxicology]]
*[[General Psych Workup]]  
*[[Acetaminophen toxicity]]
*[[Acetaminophen (Tylenol)]]  
*[[Metabolic acidosis]]
*[[Antidotes]]
*[[Anion gap]]
*[[Aspirin]]


==References==
==References==
<references/>
<references/>
*Palmer BF, Clegg DJ. Salicylate toxicity. ''N Engl J Med''. 2020;382(26):2544-2555. PMID 32579815
*O'Malley GF. Emergency department management of the salicylate-poisoned patient. ''Emerg Med Clin North Am''. 2007;25(2):333-346. PMID 17482022
*Pearlman BL, Gambhir R. Salicylate intoxication: a clinical review. ''Postgrad Med''. 2009;121(4):162-168. PMID 19641282


[[Category:Toxicology]]
[[Category:Toxicology]]

Revision as of 19:51, 21 March 2026

Background

  • Aspirin (acetylsalicylic acid) is the most common salicylate
  • Other salicylate sources: bismuth subsalicylate (Pepto-Bismol), oil of wintergreen (most concentrated — 1 teaspoon = ~7g aspirin), topical agents (Ben-Gay)
  • Therapeutic level: 10-30 mg/dL
  • Toxic ingestion: >150 mg/kg
  • Lethal dose: ~500 mg/kg
  • Mechanism of toxicity:
    • Uncouples oxidative phosphorylation → impaired aerobic metabolism, heat generation
    • Direct CNS stimulation of respiratory center → respiratory alkalosis (early)
    • Accumulation of organic acids → anion gap metabolic acidosis (late)
    • Inhibits Krebs cycle, disrupts lipid and amino acid metabolism
  • Pharmacokinetics change in overdose:
    • Zero-order kinetics at toxic levels (saturable metabolism)
    • Delayed absorption with enteric-coated or sustained-release formulations
    • Bezoar formation possible with massive ingestion

Clinical Features

Acute Toxicity

  • Early: tinnitus, nausea, vomiting, tachypnea (respiratory alkalosis)
  • Moderate: diaphoresis, tachycardia, hyperthermia, agitation, confusion
  • Severe: altered mental status, seizures, pulmonary edema (noncardiogenic), cerebral edema, coma
  • Classic acid-base pattern:
    • Adults: mixed respiratory alkalosis + metabolic acidosis
    • Children: metabolic acidosis predominates (may not have initial respiratory alkalosis phase)

Chronic Toxicity

  • More insidious and often misdiagnosed (especially in elderly)
  • Presents with confusion, tinnitus, dehydration, metabolic acidosis
  • May be diagnosed as sepsis, altered mental status workup

Differential Diagnosis

  • Sepsis (similar presentation with tachypnea, metabolic acidosis, AMS)
  • Other causes of anion gap metabolic acidosis (MUDPILES: methanol, uremia, DKA, propylene glycol, INH/iron, lactic acidosis, ethylene glycol, salicylates)
  • Theophylline toxicity (similar features)
  • Acetaminophen toxicity (common coingestion)
  • Iron toxicity

Evaluation

  • Salicylate level:
    • Therapeutic: 10-30 mg/dL
    • Toxic: > 30 mg/dL
    • Severe: >90 mg/dL
    • Repeat level every 2 hours until declining (delayed absorption, bezoar)
    • Done nomogram (not well validated for chronic or enteric-coated ingestions)
  • ABG/VBG: assess pH (acidemia dramatically worsens toxicity by driving salicylate into CNS)
  • BMP: anion gap, glucose (CNS hypoglycemia may occur despite normal serum glucose), potassium, bicarbonate, creatinine
  • Acetaminophen level (common coingestion)
  • LFTs, coagulation studies (hepatotoxicity, coagulopathy)
  • Lactate
  • Urine pH: target alkalinization to pH 7.5-8.0
  • CXR if concern for pulmonary edema

Management

GI Decontamination

  • Activated charcoal 1 g/kg (max 50g): effective if within 1-2 hours of ingestion
    • May benefit later with large ingestions, enteric-coated tablets, or bezoar
    • Multiple doses may be considered
  • Whole bowel irrigation for massive ingestions or sustained-release/enteric-coated tablets

Alkalinization (Cornerstone of Treatment)

  • IV sodium bicarbonate
  • Goal: urine pH 7.5-8.0 and serum pH 7.50-7.55
    • Alkaline urine traps ionized salicylate in renal tubules → enhanced elimination
    • Alkaline serum prevents salicylate from crossing blood-brain barrier
  • Protocol:
    • Bolus: 1-2 mEq/kg IV NaHCO3
    • Infusion: 150 mEq NaHCO3 in 1L D5W at 150-250 mL/hr
    • Add 20-40 mEq KCl per liter (hypokalemia impairs urinary alkalinization)
  • CRITICAL: alkalinization will NOT work without adequate potassium replacement
  • Monitor serum pH, urine pH, and potassium every 1-2 hours

Dextrose

  • Give D50W (50 mL IV) empirically if any CNS symptoms (altered mental status, seizures)
  • CNS glucose may be low even with normal serum glucose (salicylate impairs CNS glucose transport)
  • Add dextrose to maintenance fluids

Hemodialysis

  • Most effective method of salicylate removal
  • EXTRIP Workgroup Indications[1]:
    • Recommended: salicylate level > 90 mg/dL (acute) or > 80 mg/dL (chronic)
    • Recommended: altered mental status, new hypoxemia requiring supplemental O2
    • Recommended: pH ≤ 7.20 despite bicarbonate therapy
    • Suggested: salicylate level > 80 mg/dL (acute), renal failure limiting salicylate clearance, clinical deterioration despite treatment
  • Also dialyzes out the metabolic acidosis
  • Consult nephrology early

What to Avoid

  • Do NOT intubate unless absolutely necessary
    • Salicylate patients compensate with profound hyperventilation
    • Loss of respiratory compensation (even brief during intubation) causes rapid acidemia → CNS salicylate accumulation → cardiac arrest
    • If intubation required: maximize bicarb, match minute ventilation to pre-intubation rate
  • Avoid acetazolamide (causes metabolic acidosis)
  • Avoid excessive IV fluids without bicarb (dilutes serum alkalinity)

Disposition

  • ICU admission for: level >50 mg/dL, acidemia, AMS, pulmonary edema, renal failure
  • Monitored bed for moderate toxicity with improving levels
  • Serial salicylate levels every 2 hours until clearly declining
  • Poison control: 1-800-222-1222
  • Psychiatric evaluation for intentional ingestions

See Also

References

  1. ↑ Juurlink DN, et al. Extracorporeal treatment for salicylate poisoning: systematic review and recommendations from the EXTRIP workgroup. Ann Emerg Med. 2015;66(2):165-181. PMID 25986310
  • Palmer BF, Clegg DJ. Salicylate toxicity. N Engl J Med. 2020;382(26):2544-2555. PMID 32579815
  • O'Malley GF. Emergency department management of the salicylate-poisoned patient. Emerg Med Clin North Am. 2007;25(2):333-346. PMID 17482022
  • Pearlman BL, Gambhir R. Salicylate intoxication: a clinical review. Postgrad Med. 2009;121(4):162-168. PMID 19641282
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