Salicylate toxicity: Difference between revisions

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== Background ==
==Background==
*Causes:Aspirin, Wintergreen, Pepto-Bismol
*Uncoupling oxidative phosphorylation at mitochondrial - increased metabolic rate and hyperthermia
*Fatal dose:  
*Fatal dose:  
**~10-30g by adult  
**~10-30g by adult  
**~3g by child  
**~3g by child  
*Levels:
**Therapeutic: 10-30mg/dL
**Intoxication: >40-50 mg/dL
**Peak occurs ~6hr after absorption (up to 60hr if enteric-coated or extended release)
*Unit Conversion
**100 mg/dL = 1000 mg/L = 7.24 mmol/L


== Pathophysiology ==
===Salicylate Sources===
*[[Aspirin]]
*Oil of Wintergreen
**Oil of Wintergreen is very concentrated - 5mL contains equivalent of 7.5g of aspirin.<ref>[https://online.epocrates.com/u/29311129/Salicylate+poisoning Epocrates - Salicylate Poisoning] Accessed 06/20/15.</ref>
*[[Bismuth subsalicylate|Pepto-Bismol]]
*Wart removers
*[[Bismuth subsalicylate|Maalox]]
*Alka-Seltzer
 
===Pathophysiology===
''Uncouples oxidative phosphorylation → increased metabolic rate and hyperthermia''
*As level rises, switches from hepatic to renal clearance (slower)  
*As level rises, switches from hepatic to renal clearance (slower)  
*N/V
*[[Nausea/vomiting]]
**Stimulates chemoreceptor trigger zone
**Stimulates chemoreceptor trigger zone
**May cause metabolic alkalosis (contraction alkalosis)
**May cause metabolic alkalosis (contraction alkalosis)
*Respiratory alkalosis
*Respiratory alkalosis
**Activates respiratory center of medulla  
**Activates respiratory center of medulla  
**If have resp acidosis, consider: pulmonary edema, co-ingestion of respiratory depressant or fatigue
**If have respiratory acidosis, consider: pulmonary edema, co-ingestion of respiratory depressant or fatigue
*Anion gap metabolic acidosis
**Leads to compensatory alkaluria: urinary excretion of potassium and sodium bicarb
**Interferes w/ cellular metabolism  
*[[Metabolic Acidosis|Anion gap metabolic acidosis]]
**Normal AG does not exclude ASA toxicity in pt w/ an unknown ingestion (mixed picture)
**Interferes with cellular metabolism  
*Hyperthermia
**Normal AG does not exclude ASA toxicity in patient with an unknown ingestion (mixed picture)
*[[Hyperthermia]]
**Uncouples oxidative phosphorylation
**Uncouples oxidative phosphorylation
**As pH drops more ASA is uncharged; able to cross BBB
**As pH drops more ASA is uncharged; able to cross BBB
*Altered mental status  
*[[Altered mental status]]
**1. Direct toxicity of salicylate species in the CNS  
**Direct toxicity of salicylate species in the CNS  
**2. Cerebral edema  
**Cerebral edema  
**3. Neuroglycopenia  
**Neuroglycopenia  
*** Salicylate toxicity increases CNS utilization of glucose, serum glucose levels may not reflect CNS levels.  
***Salicylate toxicity increases CNS utilization of glucose, serum glucose levels may not reflect CNS levels.  
*Pulmonary edema  
*[[Pulmonary edema]]
**Usually occurs in elderly  
**Usually occurs in elderly  
**Due to increased pulmonary vascular permeability
**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]]


== Clinical Features ==
===Severe (>300mg/kg)===
#Mild (<150mg/kg)
*[[Altered mental status]]
##Tinnitus
*[[Seizure]]
##Hearing loss
*[[Coma]]
##Dizziness
*Cerebral edema
##N/V
*Acute lung injury
#Moderate (150-300mg/kg)
*[[Nausea and vomiting]]
##Tachypnea
*[[Acute renal failure]]
##Hyperpyrexia
*Cardiac [[arrhythmias]]
##Diaphoresis
*[[Shock]]
##Ataxia
##Anxiety
#Severe (>300mg/kg)
##AMS
##Seizure
##Acute lung injury
##N/V
##Renal failure
##Cardiac arrhythmias
##Shock


==Diagnosis==
===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}}
 
==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
*Triple-mixed acid-base disturbance
**Respiratory alkalosis (earliest sign), AG metabolic acidosis, metabolic (contraction) alkalosis  
**Respiratory alkalosis (earliest sign), AG metabolic acidosis, metabolic (contraction) alkalosis  
**Only other entity that produces this pattern is sepsis
**Only other entity that produces this pattern is sepsis
*Elevated ASA level
*Elevated ASA level
**Obtain levels q1-2hr until levels decline and pt's clinical status stabilizes
**Obtain levels q1-2hr until levels decline and patient's clinical status stabilizes
**May be deceptively low early after ingestion and with chronic toxicity
**May be deceptively low early after ingestion and with chronic toxicity


== Work-Up ==
===Levels===
*ASA level
*Therapeutic: 10-30mg/dL
*Chem
*Toxicity: >40-50mg/dL
**Renal failure prevents ASA clearance
*Rapidly absorbed - measurable levels in 30 minutes
**Hypokalemia requires aggressive repletion
*Peak occurs ~6hr after absorption (up to 60hr if enteric-coated or extended release)
***Urinary alkalinization inhibited by excretion of H+ in order to reabsorb K+
 
*Utox
;Unit Conversion: 100mg/dL = 1000mg/L = 7.24 mmol/L
*UA
**Proteinuria
*VBG
*CBC
*ECG


== Treatment ==
==Management==
=== Airway ===
===Airway===
*Avoid intubation unless absolutely necessary!  
*Avoid intubation unless absolutely necessary!  
**Very difficult to achieve adequate minute ventilation on vent  
**Very difficult to achieve adequate minute ventilation on vent
***Sedation/paralysis -> decreased RR -> resp acidosis -> incr ASA crossing BBB  
***Inadequate minute ventilation → ↑ respiratory acidosis → ↑ ASA crossing BBB
*Indications: hypoxemia or hypoventilation
***While on ventilator, adjust RR to maintain goal serum pH 7.5 - 7.59  
*If mechnically ventilate must set increased RR to to maintain pH 7.50 - 7.59
**Indications for intubation: hypoxemia or hypoventilation
* give Na bicarb 50-100 meq prior intubation
**Give [[sodium bicarbonate]] 50-100 meq prior to intubating


=== Breathing ===
===Breathing===
*Acute lung injury may lead to high O2 requirements
*Acute lung injury may lead to high O2 requirements


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


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


=== Glucose ===
===Glucose===
*Give D50 to altered pts regardless of serum glucose concentration  
*Give [[dextrose|D50]] to altered patients regardless of serum glucose concentration  
*Except for fluids used for initial resuscitation, all IVF should be D5W
*Except for fluids used for initial resuscitation, all IVF should be D5W
**ASA toxicity impairs glucose metabolism
**ASA toxicity impairs glucose metabolism


 
===Alkalinization of plasma and urine===
=== Alkalinization of plasma and urine ===
*Not a substitute for dialysis in severe salicylism
*Not a substitute for dialysis in severe salicylism
*Continuous IV infusion of sodium bicarbonate is indicated even in the presence of mild alkalemia from the early respiratory alkalosis per 2013 ACMT guidelines
*Continuous IV infusion of [[sodium bicarbonate]] is indicated even in the presence of mild alkalemia from the early respiratory alkalosis per 2013 ACMT guidelines
*Alkalemia from resp alkalosis is NOT a contraindication to NaHCO3 tx
*Alkalemia from respiratory alkalosis is NOT a contraindication to NaHCO3 treatment
*Mechanism
*Mechanism
**Traps ASA in blood and in renal tubules  
**Traps ASA in blood and in renal tubules  
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**Blood pH goal: = >7.5, <7.6  
**Blood pH goal: = >7.5, <7.6  
**Urine pH goal: 7.5-8  
**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
*Dosing
**NaHCO3 1-2mEq/kg IV bolus; then 3amp bicarb in 1L D5W @ 2-3mL/kg/hr
**NaHCO3 1-2mEq/kg IV bolus; then 3amp bicarb in 1L D5W at 2-3mL/kg/hr
***Maintain urine pH >7.5
***Maintain urine pH >7.5
   
   
*Bolus during intubation
*Bolus during intubation
**If intubation is required, consider administration of sodium bicarbonate by IV bolus at the time of intubation ito maintain a blood pH of 7.45-7.5 over the next 30 minutes
**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 ===
===Dialysis===
Indicated for:  
Indicated for:  
*[[AMS]]  
*[[Altered mental status]]  
*[[Seizure]]  
*[[Seizure]]  
*Refractory acidosis
*[[Pulmonary edema]]
*Pulmonary edema
*[[Coagulopathy]]
*Acute/chronic [[Renal Failure]]  
*Inability to tolerate volume load from bicarb drip (e.g. [[CHF]])
**Will not be able to clear ASA  
*New [[hypoxemia]]
*6hr level >100
*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 pts who have ingested enteric-coated or extended-release preprarations
*Admit all patients who have ingested enteric-coated or extended-release preprarations


== See Also ==
==See Also==
*[[Toxicology (Main)]]
*[[Toxicology (Main)]]
*[[General Psych Workup]]  
*[[General Psych Workup]]  
*[[Acetaminophen (Tylenol)]]  
*[[Acetaminophen (Tylenol)]]  
*[[Antidotes]]
*[[Antidotes]]
*[[Aspirin]]
==Video==
{{#widget:YouTube|id=_t2rFDnmxJw}}


== Source ==
==References==
*UpToDate
<references/>
*Tintinalli
*ACMT 2013 Guidance doc Salicylate toxicity


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

Latest revision as of 19:20, 1 February 2021

Background

  • Fatal dose:
    • ~10-30g by adult
    • ~3g by child

Salicylate Sources

  • Aspirin
  • Oil of Wintergreen
    • Oil of Wintergreen is very concentrated - 5mL contains equivalent of 7.5g of aspirin.[1]
  • 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)

Moderate (150-300mg/kg)

Severe (>300mg/kg)

Chronic Toxicity

Differential Diagnosis

Anion gap metabolic acidosis

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 mild alkalemia from the early respiratory alkalosis per 2013 ACMT guidelines
  • Alkalemia from respiratory alkalosis is NOT a contraindication to NaHCO3 treatment
  • 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[2]
    • 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:

Disposition

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

See Also

Video

{{#widget:YouTube|id=_t2rFDnmxJw}}

References

  1. Epocrates - Salicylate Poisoning Accessed 06/20/15.
  2. Waseem M et al. Salicylate Toxicity. eMedicine. Dec 5, 2015. http://emedicine.medscape.com/article/1009987-workup.
  3. 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. .