Salicylate Toxicity: Avoiding the Pitfalls
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Transcript of Salicylate Toxicity: Avoiding the Pitfalls
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Carson R. Harris, MD, FAAEM, FACEPRegions Hospital Clinical Toxicology ServiceEmergency Medicine Department
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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
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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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History and Demographics Decline in use, but…▪ Prophylactic for migraine, colon ca▪ Antiplatelet agent▪ Decline in incidence of Reye’s
Childproof caps – 1970s legislature
OTC meds▪ Combined with antihistamines, caffeine, barbs, and opioids
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Salicylate formulations Oil of wintergreen: 98% methyl salicylate▪ 1400 mg/mL
Bismuth subsalicylate Aggrenox
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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 > 150 mg/kg
Serious toxicity: 300-500 mg/kgChronic toxicity: >100 mg/kg/day
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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
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Distribution is facilitated by pH
Elimination dependent on dose First order kinetic to zero order ▪ From 4 hours to 15-29 hours
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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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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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Approximately 20 minutes after intubation, the patient rapidly deteriorated and died.
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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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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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Dehydration Hyperpnea Diaphoresis Vomiting Fever (increased muscle metabolism)
Vasoconstriction of auditory microvasculature
Enhance insulin secretion => hypoglycemia
Decrease peripheral glucose utilization => hyperglycemia
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Increase permeability of pulmonary vasculature
Increase the production of leukotrienes
Stimulate medullary chemoreceptor trigger zone
Hematologic effects
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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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Early Nausea, vomiting, diaphoresis, tinnitus, deafness▪ Level 25-30 mg/dL
HyperventilationLater
Hypotension, NCPE, oliguria, acidemia, cerebral edema, delirium, seizure, coma
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Classic acid-base disturbance AGMA Respiratory alkalosis with metabolic acidosis
Acidemia Increases tissue distribution ▪ Brain, heart, lung
Severe hypokalemia
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NCPE Older patients Smokers Levels >100 mg/dL Acidemia CNS involvement (hallucinations, sz)
Chronic toxicity
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FeaturesFeatures AcuteAcute ChronicChronicAge Young Young
adultadultOlder Older adult/infantsadult/infants
Etiology OverdoseOverdose RX misuseRX misuse
Co-ingestions
FrequentFrequent RareRare
Mental status
NormalNormal AlteredAltered
Presentation EarlyEarly LateLate
Mortality Low w/ RxLow w/ Rx HighHigh
Serum levels 40 to 40 to >>120120 30 to 30 to >>8080
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Salicylate level Peak 4-6 hr EC and SR preparations late rise Every 2-4 hours until clearly decreasing▪ Then q 4-6 until <30 mg/dL
Always confirm units!▪ Mg/dL vs. mg/L
Done Nomogram (Pediatrics 1960)
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NOT USEFUL for Chronic ingestions
Liquid preparations
EC or SR Acidemia Renal failure Unknown time of ingestion
Methylsalicylate
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Severity of ingestion Serum levels Acid-base status Acuteness of ingestion Mental status
Bedside Tests Trinder’s reagent – 10% ferric chloride
Ames phenistix
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Chemistry Panel Q 4-6 h
LFTsCoagulation studiesABGsAPAPConsider: CT, Serum osm, ketones, LP, CO, serum Fe, blood cultures
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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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Dialysis Serum levels > 100 in acute Levels > 60 in chronic Pulmonary edema Renal failure CHF Poor response to standard Rx AMS and acidemia
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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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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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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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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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Be aggressive. Dialyze early if signs of toxicity are evident.
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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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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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Indications Depression Chronic pain syndromes OCD Panic and Phobic disorders Migraine prophylaxis Peripheral neuropathies
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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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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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Distribution (cont’d) 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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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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CNS Anticholinergic▪ Excitation, confusion, hallucination, ataxia
Seizures Coma
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Respiratory Pulmonary edema ARDS Aspiration pneumonia
Gastrointestinal Delayed gastric emptying Decreased motility Prolonged transit time
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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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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 >100 ms are at risk for seizures and patient with QRS intervals >160 ms are at risk for arrhythmias.
▪ QRS interval is evaluated best using the limb leads.
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R wave in aVR >3 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 >0.7 in aVR QT interval prolongation Arrhythmias How do you treat this?
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ABCs Activated Charcoal: 30-50 gm
Sodium Bicarbonate Dose Endpoint
What is the mechanism?
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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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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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What if NaHCO3 doesn’t 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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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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What about Seizures from TCA Usually brief (<1 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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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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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