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Father of Toxicology” 4/24/2015 “All things are poison,” so what should we test for? Evaluation of Poisoning and Drug Overdose Kara Lynch, PhD, DABCC [email protected] University of California San Francisco San Francisco, CA Learning Objectives • Understand the laboratories role in the diagnosis and treatment of the overdosed patient • Review the pathophysiology of toxic exposures • Identify the common toxidromes and causative agents • Calculate the osmolar gap and anion gap • Be able to recognize drug overdoses Paraclesus – “father of toxicology” • “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.” • “The dose makes the poison.” • substances considered toxic are harmless in small doses, and an ordinarily harmless substance can be deadly if over‐consumed Paraclesus, 1490 ‐ 1541 1 4/24/2015 Definition of “Poisoning” • A poisoning occurs when a person’s exposure to a natural or manmade substance has an undesirable effect ‐ CDC • Poisonings can be classified as: – Self‐harm or suicide – Assault or homicide – Unintentional or accidental, when no harm was intended – includes overdoses resulting from drug misuse, drug abuse or taking too much of a drug for medical reasons Monitoring Poisonings • AAPCC – American Association of Poison Control Centers – – National poison data system (NPDS) annual report • DAWN –Drug Abuse Warning Network • SAMHSA World Drug Report –Substance Abuse and Mental Health Services Administration • CDC –Center for Disease Control –National Vital Statistics System (NVSS) Poisoning / Overdose Trends 2 4/24/2015 Poisoning / Overdose Trends AAPCC: Top 25 human exposures AAPCC: Top 25 pediatric exposures 3 4/24/2015 Increase in Exposure –Top 4 Poisoning: Treatment Approach • ABCs (airway, breathing, circulation) • Supportive Care • Antidote if available and indicated • Decontamination (surface and gastrointestional) – Wash skin and irrigate eyes, emesis or gastric lavage, activated charcoal or cathartic, whole‐bowel irrigation • Enhanced Elimination – Hemodialysis – Hemoperfusion – Repeat‐dose charcoal Treatment: ABC’s or CAB • Airway → Endotracheal intubaon – Check gag/cough reflex – Position patient – Clear/suction airway • Breathing → ventilatory failure, hypoxia, bronchospasm – Obtain arterial blood gases – Assist with bag/mask device – Give supplemental oxygen • Circulation → bradycardia, tachycardia, prolonged QRS interval, arrhythmias, hypotension, hypertension – Measure blood pressure/pulse – Monitor electrocardiogram – Start 1‐2 IV lines – Obtain routine bloodwork 4 4/24/2015 Antidote or Specific Treatment Toxin Antidote/Treatment Acetaminophen N‐Acetylcysteine (NAC, Mucomyst) Aluminum or Iron Deferoxamine Anticholinergic agents Physostigmine Arsenic and Mercury Unithiol, Dimercaprol (BAL), oral succimer (DMSA) Benzodiazepines Flumazenil Beta‐blockers Glucagon Calcium channel blockers Calcium Carbon monoxide Oxygen (normobaric or hyperbaric) Cyanide Amyl nitrite, sodium nitrite, sodium tiosulfate Digoxin Digibind (Fab fragments) Ethylene glycol, methanol Ethanol, fomepizole (5‐methylpyrazol), hemodialysis Isoniazid Pyridoxine (Vitamin B6) Lead Calcium EDTA, Dimercaprol (BAL), oral succimer (DMSA) Nitrites, nitrates Methylene blue Opioids Naloxone Salicylates Bicarbonate, hemodialysis, alkaline diuresis Poisoning Evaluation: toxidromes • Toxidrome = A collection of symptoms and signs that consistently occur after ingestion of a particular toxin or drug class • Often identified with a basic history and physical examination • Rapid identification of the toxidrome saves time in evaluating and managing a poisoned patient Poisoning Evaluation: toxidromes Kinetic Anatomy with Web Resource, 3rd Edition 5 4/24/2015 Toxidrome Clinical Manifestation Agents commonly involved Anticholinergic • Hypertermia, tachycadia, • Nonselective antihistamines hypertension • Tricyclic antidepressants • Agitation, delirium, seizures • Antipsychotic drugs • Mydriasis • Benztropine • Decreased bowel sounds • Scopolamine, atropine • Jimsonweed, deadly nightshade, amanita muscaria Cholinergic – • Bradycardia(M), Tachycardia(N) • Organophosphates, carbamates Nicotinic / Muscarinic • Hypertension (N) • Physostigmine • Miosis • Pilocarpine • Bronchorrhea • Betel nut • Salivation, Lacrimation, • Mushrooms: clitocybe dealbata, Urination, Diarrhea, GI upset, C. illudens, Inocybe lacera Emesis –“SLUDGE” • Black widow spider venom (N) Sympathomimetic • Hyperthermia, tachycardia, • Cocaine, amphetamines hypertension • Theophylline, caffeine • Agitation, delirium, seizures • Salicylates • Mydriasis • Monoamine oxidase (MAO) • Increased bowel sounds inhibitors • Dry, flushed skin • Sedative/hypnotic withdrawal Opioid • Hypopnea/bradypnea • All opiates and phenothiazines • Lethargy, obtundation • Hypoglycemic agents • Miosis • Clonidine Sedative‐hypnotic • Hypothermia, bradypnea/ • Ethanol hypopenia • Benzodiazepines, barbiturates • Lethargy, stupor, obtundation • Meprobamate, methaqualone, chloral hydrate Poisoning Evaluation: toxidromes Blood Heart Resp. Temp. Pupil Bowel Diaph‐ Pressure Rate Rate size sounds oresis Anticholinergic ↑ ↑↑↓↓ Cholinergic ↓↑↑ Opioid ↓ ↓ ↓↓↓↓↓ Sympathomimetic ↑ ↑ ↑↑↑↑↑ Sedative‐hypnotic ↓↓↓↓ ↓↓ Essential Laboratory Tests • Serum osmolality and calculation of the osmolar gap • Electrolytes for determination of sodium, potassium and anion gap • Serum glucose • BUN and creatinine for evaluation of renal function • Liver function tests • Complete blood count • Urinalysis to check for crystalluria, hemoglobinuria or myoglobinuria • Stat serum acetaminophen and serum ethanol level • Pregnancy test (females of childbearing age) • Electrocardiogram 6 4/24/2015 Toxic Alcohols • Ethanol • Methanol • Isopropanol • Acetone • Ethylene glycol Pharmacokinetics: Review • First‐order kinetics –rate of elimination is proportional to the amount of drug present • Zero‐order kinetics –rate of elimination is constant regardless of the amount of drug present in the system • Capacity‐limited kinetics – occurs when the rate of elimination shifts from first‐order to zero‐order based on the saturation of the elimination processes (overdoses) • Serum half‐life –time required for serum concentrations to decrease by one half • First‐pass effect – applies to drugs cleared by the liver before reaching systemic circulation • Steady‐state – applies to repeated dosing; reached in about 4 half‐lives Toxic Alcohols: Ethanol • Ethanol or ethanol combined with other drugs accounts for the highest number of toxic exposures • Potent central nervous system depressant • Effects vary with concentration • Common cause of hyperosmolality in the ED • Metabolism follows zero‐order kinetics 7 4/24/2015 Ethanol Metabolism Serum ~ 3.5 hours UGT 1A1 UGT 2B7 SULTs Ethanol ADH1B CYP2E1 ADH1C Ethylglucuronide (EtG) Ethylsulfate (EtS) Acetaldehyde Urine ~ 80 hours Urine ~ 80 hours ALDH2 Acetate Ethanol Measurement • Enzymatic methods – alcohol dehydrogenase ADH • CH3CH2OH CH3CHO + NADH NAD 340 nm • ADH is selective but not specific for ethanol, although current assays have minimal reactivity with non‐ethanol alcohols • Other enzymes that involve NADH can potentially interfere (ie: lactate, LD) • Other methods ‐ Headspace GC‐MS Other toxic alcohols • Toxicity is primarily related to metabolites: – Ethanol → Acetaldehyde → Acetate – Isopropanol → Acetone – Methanol → Formaldehyde → Formic Acid – Ethylene Glycol → Oxalate and Hippuric Acid • Effects: – Isopropanol (Acetone)‐ 2X more potent CNS depressant than ethanol, can cause upper GI bleeding – Methanol –can cause metabolic acidosis, blindness and death after a latent period of 6‐30 hours – Ethylene glycol –same CNS depressant effects as ethanol but with toxic metabolites –myocardial depression and renal necrosis 8 4/24/2015 Other toxic alcohols Osmolal Gap • measured Osmol – calc. Osmol = osmolal gap • Osmolality = 2(Na in mmol/L) + (Glucose in mg/dL / 18) + (BUN in mg/dL / 2.8) • Other contributors: – [ethanol] / 4.6 – [methanol] / 3.2 – [isopropanol] / 6.0 – [ethylene glycol] / 6.2 – [acetone] / 5.8 • Causes: – Methanol – Ethylene Glycol – Diuretics – Isopropanol – Ethanol Anion Gap + + ‐ ‐ (Na + K ) –(Cl + HCO3 ) = 16 (range 10‐20) MUDPILES: • Methanol → formate • Uremia → chronic renal failure (impaired excreon of acids) • Diabetic Ketoacidosis –DKA (also AKA) → acetaldehyde → acetylCoA → B‐hydroxybutyrate, acetoacetate • Paraldehyde, Phenformin, Propylene glycol • Isoniazide → lacc acidosis 2° to seizure activity OR Iron → lacc acidosis → uncoupling of oxidave phosphorylaon • Lactate • Ethylene glycol → glyoxylate, glycolate, oxalate • Salicylates → ketones, lactate 9 4/24/2015 Ingestion of Alcohols: Lab Findings Alcohol Osmolal Metabolic Acidosis Serum Urine Oxalate Gap with anion gap Acetone Ethanol + ‐‐‐ Methanol + + ‐‐ Isopropanol + ‐ + ‐ Ethylene glycol + + ‐ + Case Study • Healthy 50 year‐old man was found unconscious in this home, believed to be down for ~24 hours • Emergency response –GCS 3, vitals normal, oxygen saturation 80%, patient intubated and brought to UCSF ED ‐ • Remarkable lab findings: HCO 3 5, osmolal gap and anion gap >35, pH 6.7, lactate above the ULOQ, creatinine 2.4 • LFTs, tox screen, APAP and salicylate normal • Normal head and abdominal CT, all cultures negative no vasopressors required • Patient received IVFs and died before they could start dialysis Case Study 10 4/24/2015 Case Study • Ethanol, methanol or ethylene glycol? Alcohol Osmol Metabolic Acidosis Serum Urine Oxalate Gap with anion gap Acetone Ethanol + ‐‐‐ Methanol + + ‐‐ Isopropanol
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