Salicylate toxicity

Background

• Salicylates are commonly available in numerous over-the-counter products, and toxicity may occur from acute (intentional or accidental) and chronic ingestion.
• Fatal dose:
  • ~10-30g by adult
  • ~3g by child

Salicylate Sources

• Aspirin
• Oil of Wintergreen
  • Oil of Wintergreen is very concentrated - 5mL contains approximately 7g of aspirin.
• Pepto-Bismol
• Wart removers
• Maalox
• Alka-Seltzer

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
• 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

Mild (<150mg/kg)

• Tinnitus
  • Tinnitus is early sign - providers used to dose ASA to onset of tinnitus.
• Hearing loss
• Dizziness
• Nausea and vomiting
  • Common with acute toxicity

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

• Usually neurologic abnormalities, especially in elderly
  • Agitation
  • Paranoia
  • Memory deficits
  • Confusion
  • Stupor
• Hyperventilation
• Tremor
• Papilledema
• Higher morbidity (pulmonary edema, seizures, renal failure) and mortality rate compared with acute toxicity

Differential Diagnosis

Anion gap metabolic acidosis

• Lactic acidosis
  • Sepsis, shock, liver disease, CO, CN, metformin, methemoglobin
  • Short bowel syndrome
  • Propylene glycol infusions for lorazepam and phenobarbital
• Renal failure
  • Uremia
• Ketoacidosis
  • DKA
  • Alcoholic Ketoacidosis
  • Starvation ketoacidosis
• Ingestions
  • Acetaminophen toxicity
  • Aspirin toxicity
  • Increased osm gap
    • Methanol
    • Ethylene glycol
  • Normal osm gap
    • Salicylate toxicity
    • Iron
    • INH

Evaluation

Work-Up

• ASA level
• Acetaminophen level (possible co-ingestant)
• Metabolic panel
  • Renal failure prevents ASA clearance
  • Hyperglycemia in periphery (CSF will have low glucose due to CNS hypermetabolic state)
  • Hypokalemia requires aggressive repletion - this differentiates from DKA which tends to have hyperkalemia or normokalemia at initial presentation
    • Urinary alkalinization inhibited by excretion of H+ in order to reabsorb K+
• Mag and phos
• Urine toxicology screen
• Urinalysis
• VBG
• CBC
• 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

Airway

• Avoid intubation unless absolutely necessary!
  • Very difficult to achieve adequate minute ventilation on vent
    • Inadequate minute ventilation → ↑ respiratory acidosis → ↑ ASA crossing BBB
    • While on ventilator, adjust RR to maintain goal serum pH 7.5 - 7.59
  • Indications for intubation: hypoxemia or hypoventilation
  • Give sodium bicarbonate 50-100 meq prior to intubating

Breathing

• Acute lung injury may lead to high O2 requirements

Circulation

• Hypotension is common due to systemic vasodilation
• IVF +/- K+ (if no cerebral edema, no pulmonary edema)
  • If these are present consider pressors

Decontamination

• Charcoal 1g/kg up to 50g PO
  • Effectively absorbs ASA
  • Give multiple doses if tolerated
    • 25g PO q2hr x 3 doses OR 50g q4hr x 2 doses after initial dose
• Whole-bowel irrigation
  • Consider for ingestion of large amount of enteric-coated or extended-release forms

Glucose

• Give D50 to altered patients regardless of serum glucose concentration
• Except for fluids used for initial resuscitation, all IVF should be D5W
  • ASA toxicity impairs glucose metabolism

Alkalinization of plasma and urine

• Not a substitute for dialysis in severe salicylism
• Continuous IV infusion of sodium bicarbonate is indicated even in the presence of alkalemia from respiratory alkalosis
  • 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
  • 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
  • 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

• Admit all patients who have ingested enteric-coated or extended-release preprarations

See Also

• Toxicology (Main)
• General Psych Workup
• Acetaminophen (Tylenol)
• Antidotes
• Aspirin