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Salicylate Toxicity: Avoiding the Pitfalls

Carson R. Harris, MD, FAAEM, FACEP Regions Hospital Clinical Toxicology Service Emergency Medicine Department. Salicylate Toxicity: Avoiding the Pitfalls. Salicylates. Objectives Discuss the toxicological effects of salicylate overdose Identify key management issues

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Salicylate Toxicity: Avoiding the Pitfalls

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  1. Carson R. Harris, MD, FAAEM, FACEP Regions Hospital Clinical Toxicology Service Emergency Medicine Department Salicylate Toxicity: Avoiding the Pitfalls

  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

  4. Salicylate Overdose • 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

  5. Salicylate Overdose • Salicylate formulations • Oil of wintergreen: 98% methyl salicylate • 1400 mg/mL • Bismuth subsalicylate • Aggrenox

  6. 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 > 150 mg/kg • Serious toxicity: 300-500 mg/kg • Chronic toxicity: >100 mg/kg/day

  7. 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.

  10. 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.

  11. Case 1: ASA • Approximately 20 minutes after intubation, the patient rapidly deteriorated and died.

  12. 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

  13. 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

  14. Salicylate Overdose: Pathophysiology • Dehydration • Hyperpnea • Diaphoresis • Vomiting • Fever (increased muscle metabolism) • Vasoconstriction of auditory microvasculature • Enhance insulin secretion => hypoglycemia • Decrease peripheral glucose utilization => hyperglycemia

  15. Salicylate Overdose: Pathophysiology • Increase permeability of pulmonary vasculature • Increase the production of leukotrienes • Stimulate medullary chemoreceptor trigger zone • Hematologic effects

  16. 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

  17. 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

  18. Salicylate Overdose: Clinical Presentation • Classic acid-base disturbance • AGMA • Respiratory alkalosis with metabolic acidosis • Acidemia • Increases tissue distribution • Brain, heart, lung • Severe hypokalemia

  19. Salicylate Overdose: Clinical Presentation • NCPE • Older patients • Smokers • Levels >100 mg/dL • Acidemia • CNS involvement (hallucinations, sz) • Chronic toxicity

  20. Clinical Presentation

  21. 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 <30 mg/dL • Always confirm units! • Mg/dL vs. mg/L • Done Nomogram (Pediatrics 1960)

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

  23. Laboratory studies • Severity of ingestion • Serum levels • Acid-base status • Acuteness of ingestion • Mental status • Bedside Tests • Trinder’s reagent – 10% ferric chloride • Ames phenistix

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

  25. 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

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

  27. 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.

  28. 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

  29. 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)!

  30. 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.

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

  32. 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.

  33. Questions???

  34. 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

  35. TCA Overdose • Indications • Depression • Chronic pain syndromes • OCD • Panic and Phobic disorders • Migraine prophylaxis • Peripheral neuropathies

  36. 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

  37. 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

  38. CA - Pharmacokinetics • 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

  39. 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

  40. CA - Pathophysiology • CNS • Anticholinergic • Excitation, confusion, hallucination, ataxia • Seizures • Coma

  41. CA - Pathophysiology • Respiratory • Pulmonary edema • ARDS • Aspiration pneumonia • Gastrointestinal • Delayed gastric emptying • Decreased motility • Prolonged transit time

  42. 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?

  43. 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 >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.

  44. CA Overdose – ECG #1

  45. TCA ECG Changes • 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?

  46. CA Toxicity Treatment • ABCs • Activated Charcoal: 30-50 gm • Sodium Bicarbonate • Dose • Endpoint • What is the mechanism?

  47. 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.

  48. 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.

  49. TCA Toxicity Treatment • 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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