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

 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

 History and Demographics  Hippocrates – 5 th ▪ 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

 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

 Salicylate formulations  Oil of wintergreen: 98% methyl salicylate ▪ 1400 mg/mL  Bismuth subsalicylate  Aggrenox

    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

 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

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

 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, HCO 3 and pCO 2 17; the ABGs showed pH 7.38, pO 2 107, 27 on room air. He was initially treated with reasonable volume and admitted to the ward.

  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.

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

   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 Increase respiration 2 production ▪ Respiratory alkalosis

   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

    Dehydration  Hyperpnea  Diaphoresis  Vomiting  Fever (increased muscle metabolism) Vasoconstriction of auditory microvasculature Enhance insulin secretion => hypoglycemia Decrease peripheral glucose utilization => hyperglycemia

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

 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

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

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

 NCPE  Older patients  Smokers  Levels >100 mg/dL  Acidemia  CNS involvement (hallucinations, sz)  Chronic toxicity

Features

Age Etiology Co-ingestions Mental status Presentation Mortality Serum levels

Acute

Young adult Overdose Frequent Normal Early Low w/ Rx 40 to >120

Chronic

Older adult/infants RX misuse Rare Altered Late High 30 to >80

 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)

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

  Severity of ingestion  Serum levels  Acid-base status   Mental status Bedside Tests  Acuteness of ingestion Trinder’s reagent – 10% ferric chloride  Ames phenistix

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

    Gastric lavage / WBI Activated charcoal - MDAC Hydration and electrolyte replacement  Correct hypokalemia aggressively Urine alkalinization  Increase salicylate excretion   1-2 mEq/kg NaHCO 3 bolus IV Then 150 mL in 850 ml D5W run 1.5-2 times maintenance  Caution in elderly and chronic  Monitor UO

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

   Enteric Coated aspirin 

Can cause delayed symptom onset Don't wait for clinical deterioration.

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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

  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.

 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.

 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

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

 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   Enterohepatic re-circulation secretes 30%

Distribution

 Massive OD delays absorption Wide range in Vd (15-40 L/kg) ▪ ▪ ▪ Genetic variation Lipophilic Elderly has higher Vd

 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

  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

 CNS  Anticholinergic ▪ Excitation, confusion, hallucination, ataxia  Seizures  Coma

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

 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?

 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.

     ▪ ▪ 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?

  ABCs  Activated Charcoal: 30-50 gm Sodium Bicarbonate  Dose   Endpoint

What is the mechanism?

  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.

  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.

 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

 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