Salicylate Toxicity Avoiding the Pitfalls Carson R Harris

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

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

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

Salicylate Overdose �History and Demographics Decline in use, but… ▪ Prophylactic for migraine, colon ca ▪ Antiplatelet agent ▪ Decline in incidence of Reye’s Childproof caps – 1970 s legislature OTC meds ▪ Combined with antihistamines, caffeine, barbs, and opioids

Salicylate Overdose �Salicylate formulations Oil of wintergreen: 98% methyl salicylate ▪ 1400 mg/m. L Bismuth subsalicylate Aggrenox

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/d. L �Potential Toxic Acute dose > 150 mg/kg �Serious toxicity: 300 -500 mg/kg �Chronic toxicity: >100 mg/kg/day

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

Salicylate Overdose �Distribution is facilitated by p. H �Elimination dependent on dose First order kinetic to zero order ▪ From 4 hours to 15 -29 hours

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/d. L; Chem-8 revealed Na 143, Cl 105, K 4. 2, HCO 3 17; the ABGs showed p. H 7. 38, p. O 2 107, and p. CO 2 27 on room air. He was initially treated with reasonable volume and admitted to the ward.

Case 1: ASA �Orders for sodium bicarbonate were given to alkalinize the urine, but this was ineffective in raising urine p. H. 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.

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

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 O 2 consumption and CO 2 production ▪ Increase respiration ▪ Respiratory alkalosis

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

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

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

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

Salicylate Overdose: Clinical Presentation �Early Nausea, vomiting, diaphoresis, tinnitus, deafness ▪ Level 25 -30 mg/d. L Hyperventilation �Later Hypotension, NCPE, oliguria, acidemia, cerebral edema, delirium, seizure, coma

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

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

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 >120 30 to >80

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/d. L Always confirm units! ▪ Mg/d. L vs. mg/L �Done Nomogram (Pediatrics 1960)

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

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

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

Treatment � Gastric lavage / WBI � Activated charcoal - MDAC � Hydration and electrolyte replacement Correct hypokalemia aggressively � Urine alkalinization Increase salicylate excretion 1 -2 m. Eq/kg Na. HCO 3 bolus IV Then 150 m. L in 850 ml D 5 W run 1. 5 -2 times maintenance Caution in elderly and chronic Monitor UO

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

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.

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

ASA Pearls �The Done nomogram, has limited usefulness �Be aware of the proper unit of measure (mg/d. L not mg/L or µg/L or mmol/L)!

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.

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

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.

Questions? ? ?

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

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

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

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

CA - Pharmacokinetics �Distribution (cont’d) Tissue levels usually 10 times plasma levels Protein binding usually exceeds 90% with some variations ▪ p. H dependent �Elimination Genetic component Metabolism influenced by other drugs

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

CA - Pathophysiology �CNS Anticholinergic ▪ Excitation, confusion, hallucination, ataxia Seizures Coma

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

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, R 22, T 99. 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?

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.

CA Overdose – ECG #1

TCA ECG Changes R wave in a. VR >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 a. VR. ▪ may be more predictive of seizure and arrhythmia than prolongation of the QRS complex. R/S ratio >0. 7 in a. VR QT interval prolongation Arrhythmias How do you treat this?

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

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.

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

TCA Toxicity Treatment �What if Na. HCO 3 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

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)

TCA Toxicity Treatment � 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.

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

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