Salicylate Toxicity: Avoiding the Pitfalls

1
Salicylate Toxicity Avoiding the Pitfalls

• Carson R. Harris, MD, FAAEM, FACEP
• Regions Hospital Clinical Toxicology Service
• Emergency Medicine Department

2
Salicylates

• Objectives
• Discuss the toxicological effects of salicylate
  overdose
• Identify key management issues
• Discuss the limitations of the Done nomogram and
  how to avoid pitfalls of management

3
Salicylate Overdose

• History and Demographics
• Hippocrates 5th century B.C.
• Powder from the willow bark
• 1800s sodium salicylate for arthritis
• Abdominal pain
• Felix Hoffmann
• Acetylsalicylic acid (ASA)
• Introduced 100 years ago
• Antipyretic, analgesic, anti-inflammatory

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Salicylate Overdose

• History and Demographics
• Decline in use, but
• Prophylactic for migraine, colon ca
• Antiplatelet agent
• Decline in incidence of Reyes
• Childproof caps 1970s legislature
• OTC meds
• Combined with antihistamines, caffeine, barbs,
  and opioids

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Salicylate Overdose

• Salicylate formulations
• Oil of wintergreen 98 methyl salicylate
• 1400 mg/mL
• Bismuth subsalicylate
• Aggrenox

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Salicylate Overdose

• Therapeutic doses
• Pediatric 10-20 mg/kg
• Adults 650-1000 mg q 4-6 hrs
• Produce a serum level of 5-10 mg/dL
• Potential Toxic Acute dose gt 150 mg/kg
• Serious toxicity 300-500 mg/kg
• Chronic toxicity gt100 mg/kg/day

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Salicylate Overdose

• Peak levels
• Therapeutic 1-2 hours
• Therapeutic EC 4-6 hours
• OD 10-60 hours
• Reason for delay ? Concretions, contraction of
  the pylorus or combination of drugs that delay
  gastric emptying (opioids and anticholinergics)
• Liquids absorbed in 1 hr

8
Salicylate Overdose

• Distribution is facilitated by pH
• Elimination dependent on dose
• First order kinetic to zero order
• From 4 hours to 15-29 hours

9
Case 1 ASA

• A 24-year-old male presented to the ED with
  nausea, vomiting, tinnitus, and tachypnea after
  ingesting 100 aspirin tablets. His 4-hour
  salicylate level was 78 mg/dL Chem-8 revealed Na
  143, Cl 105, K 4.2, HCO3 17 the ABGs showed pH
  7.38, pO2 107, and pCO2 27 on room air. He was
  initially treated with reasonable volume and
  admitted to the ward.

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Case 1 ASA

• Orders for sodium bicarbonate were given to
  alkalinize the urine, but this was ineffective
  in raising urine pH. Approximately 6 hours later
  the attending was notified that the patient had
  become confused.
• He was transferred to the ICU where he was
  sedated and intubated.

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Case 1 ASA

• Approximately 20 minutes after intubation, the
  patient rapidly deteriorated and died.

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Salicylate Overdose Pathophysiology

• ASA is hydrolyzed to salicylic acid
• Responsible for therapeutic and toxic effects
• Direct stimulation of respiratory center
• Medulla
• Uncouples oxidative phosphorylation
• Increase in O2 consumption and CO2 production
• Increase respiration
• Respiratory alkalosis

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Salicylate Overdose Pathophysiology

• Renal excretion of bicarb, Na and K
• Metabolic acidosis
• Inhibition of mitochondrial respiration
• Increase pyruvate and lactic acid
• Metabolic acidosis
• Disruption of Krebs cycle metabolism and
  glycolysis
• Hyperglycemia, ketonemia

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Salicylate Overdose Pathophysiology

• Dehydration
• Hyperpnea
• Diaphoresis
• Vomiting
• Fever (increased muscle metabolism)
• Vasoconstriction of auditory microvasculature
• Enhance insulin secretion gt hypoglycemia
• Decrease peripheral glucose utilization gt
  hyperglycemia

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Salicylate Overdose Pathophysiology

• Increase permeability of pulmonary vasculature
• Increase the production of leukotrienes
• Stimulate medullary chemoreceptor trigger zone
• Hematologic effects

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Salicylate Overdose Clinical Presentation

• ASPIRIN Mnemonic
• Altered mental status (lethargy coma)
• Sweating/diaphoresis
• Pulmonary edema
• Increased vital signs (HTN, inc RR, inc T,
  tachycardia)
• Ringing in the ears
• Irritable
• Nausea and vomiting

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Salicylate Overdose Clinical Presentation

• Early
• Nausea, vomiting, diaphoresis, tinnitus, deafness
• Level 25-30 mg/dL
• Hyperventilation
• Later
• Hypotension, NCPE, oliguria, acidemia, cerebral
  edema, delirium, seizure, coma

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Salicylate Overdose Clinical Presentation

• Classic acid-base disturbance
• AGMA
• Respiratory alkalosis with metabolic acidosis
• Acidemia
• Increases tissue distribution
• Brain, heart, lung
• Severe hypokalemia

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Salicylate Overdose Clinical Presentation

• NCPE
• Older patients
• Smokers
• Levels gt100 mg/dL
• Acidemia
• CNS involvement (hallucinations, sz)
• Chronic toxicity

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Clinical Presentation
Features Acute Chronic
Age Young adult Older adult/infants
Etiology Overdose RX misuse
Co-ingestions Frequent Rare
Mental status Normal Altered
Presentation Early Late
Mortality Low w/ Rx High
Serum levels 40 to gt120 30 to gt80
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Salicylate Overdose Laboratory studies

• Salicylate level
• Peak 4-6 hr
• EC and SR preparations late rise
• Every 2-4 hours until clearly decreasing
• Then q 4-6 until lt30 mg/dL
• Always confirm units!
• Mg/dL vs. mg/L
• Done Nomogram (Pediatrics 1960)

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Done Nomogram

• NOT USEFUL for
• Chronic ingestions
• Liquid preparations
• EC or SR
• Acidemia
• Renal failure
• Unknown time of ingestion
• Methylsalicylate

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Laboratory studies

• Severity of ingestion
• Serum levels
• Acid-base status
• Acuteness of ingestion
• Mental status
• Bedside Tests
• Trinders reagent 10 ferric chloride
• Ames phenistix

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Laboratory studies

• Chemistry Panel
• Q 4-6 h
• LFTs
• Coagulation studies
• ABGs
• APAP
• Consider CT, Serum osm, ketones, LP, CO, serum
  Fe, blood cultures

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Treatment

• Gastric lavage / WBI
• Activated charcoal - MDAC
• Hydration and electrolyte replacement
• Correct hypokalemia aggressively
• Urine alkalinization
• Increase salicylate excretion
• 1-2 mEq/kg NaHCO3 bolus IV
• Then 150 mL in 850 ml D5W run 1.5-2 times
  maintenance
• Caution in elderly and chronic
• Monitor UO

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Treatment

• Dialysis
• Serum levels gt 100 in acute
• Levels gt 60 in chronic
• Pulmonary edema
• Renal failure
• CHF
• Poor response to standard Rx
• AMS and acidemia

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ASA Pearls

• Enteric Coated aspirin
• Can cause delayed symptom onset
• Don't wait for clinical deterioration.
• Alert you nephrology team early and call the
  poison center even earlier.
• Serial salicylate levels are imperative.

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ASA Pearls

• One teaspoon of methyl salicylate contains 7,000
  mg of salicylate which is equivalent to
  approximately 21 regular strength aspirin
  tablets!
• The presence of fever is a poor prognostic sign
  in adults!
• Cerebrospinal fluid salicylate levels correlate
  with symptoms better than blood levels

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ASA Pearls

• The Done nomogram, has limited usefulness
• Be aware of the proper unit of measure
• (mg/dL not mg/L or µg/L or mmol/L)!

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ASA Pearls

• Start potassium supplementation early (in the
  absence of renal insufficiency) because
  hypokalemia makes urinary alkalization
  impossible!
• Multiple-dose activated charcoal and
  alkalinization are currently the most popular
  methods of treatment.

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ASA Pearls

• Be aggressive. Dialyze early if signs of toxicity
  are evident.

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ASA Pearls

• ASA and elderly
• Impaired renal function
• Decreased elimination
• Impaired hepatic function
• The risk of salicylate nephrotoxicity is
  increased with age,
• Upper gastrointestinal bleed is associated with
  increased mortality in older age groups.

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Questions???
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CA Overdose

• Mortality and Epidemiology
• From 15 to 1.7 in 1977
• Second leading cause of death from overdose in US
  (Analgesics first).
• Approximately 500,000 overdoses annually
• Female, age 20-29, single, employed, no history
  of drug abuse
• Approximately 70 die pre-hospital

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TCA Overdose

• Indications
• Depression
• Chronic pain syndromes
• OCD
• Panic and Phobic disorders
• Migraine prophylaxis
• Peripheral neuropathies

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CA Overdose

• Acute Toxic Doses
• Fatal ingestions range 10-210 mg/kg
• 2-4 mg/kg is therapeutic, 20 mg/kg is potentially
  fatal
• Variable response

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CA - Pharmacokinetics

• Absorption
• Rapidly and completely absorbed
• Massive OD delays absorption
• Enterohepatic re-circulation secretes 30
• Distribution
• Wide range in Vd (15-40 L/kg)
• Genetic variation
• Lipophilic
• Elderly has higher Vd

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CA - Pharmacokinetics

• Distribution (contd)
• Tissue levels usually 10 times plasma levels
• Protein binding usually exceeds 90 with some
  variations
• pH dependent
• Elimination
• Genetic component
• Metabolism influenced by other drugs

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CA - Pathophysiology

• Therapeutic effects
• Not completely understood
• Blocks serotonin and NE uptake
• Anticholinergic effects
• Cardiac Effects
• Sinus tachycardia, dysrhythmias
• Na channel blockade quinidine effect
• Hypotension
• Alpha adrenergic blockade and NE depletion
• Conduction delays / blocks

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CA - Pathophysiology

• CNS
• Anticholinergic
• Excitation, confusion, hallucination, ataxia
• Seizures
• Coma

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CA - Pathophysiology

• Respiratory
• Pulmonary edema
• ARDS
• Aspiration pneumonia
• Gastrointestinal
• Delayed gastric emptying
• Decreased motility
• Prolonged transit time

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CA Clinical Presentation

• Case 1
• 25 year-old man ingested 60 tablets of Elavil 50
  mg each. He presented to the ED about 45 minutes
  post ingestion agitated and confused. Possibly
  hallucinating. BP 145/94, P 112, R22, T99.6. He
  became more agitated and combative and was
  intubated, lavaged and given AC.
• EKG revealed QRS 108 with rate 114
• What are the critical ECG changes?

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TCA ECG Changes

• Prolongation of the QRS complex
• Blockage of fast sodium channels slows phase 0
  depolarization of the action potential.
• Ventricular depolarization is delayed, leading to
  a prolonged QRS interval. Patients with QRS
  intervals gt100 ms are at risk for seizures and
  patient with QRS intervals gt160 ms are at risk
  for arrhythmias.
• QRS interval is evaluated best using the limb
  leads.

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CA Overdose ECG 1
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TCA ECG Changes

• R wave in aVR gt3 mm
• greater selectivity and toxicity to the distal
  conduction system of the right side of the heart.
  
• effect can be observed as an exaggerated height
  of the R wave aVR.
• may be more predictive of seizure and arrhythmia
  than prolongation of the QRS complex.
• R/S ratio gt0.7 in aVR
• QT interval prolongation
• Arrhythmias
• How do you treat this?

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CA Toxicity Treatment

• ABCs
• Activated Charcoal 30-50 gm
• Sodium Bicarbonate
• Dose
• Endpoint
• What is the mechanism?

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TCA Toxicity Treatment

• Alkalinization
• appears to uncouple TCA from myocardial sodium
  channels.
• Alkalinization may increase protein binding
• Increases the extracellular sodium concentration
• improves the gradient across the channel.

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TCA Toxicity Treatment

• The initial bolus of 1-2 mEq/kg
• A constant infusion of sodium bicarbonate
• commonly accepted clinical practice without any
  controlled studies validating the optimum
  administration
• 100 to 150 mEq of sodium bicarbonate to each
  liter of 5 dextrose,
• the resulting solution is hypotonic or nearly
  isotonic.

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TCA Toxicity Treatment

• What if NaHCO3 doesnt work?
• may require treatment with lidocaine and/or
  magnesium sulfate.
• Class Ia and Ic agents contraindicated
• Beta blockers and CCB
• Worsen or potentiate hypotension

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TCA Toxicity Treatment

• Hypotension, Persistent
• Direct acting alpha agonists, such as
  norepinephrine and phenylephrine
• Dopamine may not be as effective
• Require release of endogenous catecholamines that
  may be depleted during TCA toxicity.
• Dopamine or dobutamine alone may result in
  unopposed beta-adrenergic activity due to TCA
  induced alpha blockade and, therefore, may worsen
  hypotension.
• Vasopressin (ADH)

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TCA Toxicity Treatment

• What about Seizures from TCA
• Usually brief (lt1 min)
• self-limiting
• acidosis increase cardiovascular toxicity.
• Benzodiazepines
• Phenytoin is no longer recommended
• limited efficacy and possible prodysrhythmic.
• Phenobarbital may be used as a long-acting
  anticonvulsant.

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TCA Toxicity Treatment

• Agitation from TCA
• Anticholinergic effects
• Benzodiazepines are also the treatment of choice
• Physostigmine is contraindicated in TCA overdoses
• May cause bradycardia and asystole in the setting
  of TCA cardiotoxicity.
• Flumazenil is contraindicated even in the
  presence of a benzodiazepine co-ingestion.
• Several case reports - seizures

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TCA Overdose

• Emergency department discharge criteria
• At least 6 hour observation period
• No significant sign of toxicity during
  observation period, including normal follow-up
  ECG prior to discharge
• Accidental ingestion
• Appropriate follow-up measures in place
• Adequately supervised home environment