Evaluation of Poisoning and Drug Overdose Kara Lynch, PhD, DABCC University of California San Francisco San Francisco, CA Learning Objectives • Understand the laboratories role in the diagnosis and treatment of toxicology cases • Review the pathophysiology of toxic exposures • Identify the common toxidromes • 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 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 Poisoning / Overdose Trends AAPCC: Top 25 human exposures AAPCC: Top 25 pediatric exposures 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 intubation – 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 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 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 ↓ ↓ ↓ ↓ ↓ ↓ Illicit Drugs: Mechanism of Action psychiatryonline.org 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 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 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 if 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 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 excretion of acids) • Diabetic Ketoacidosis – DKA (also AKA) → acetaldehyde → acetylCoA → B-hydroxybutyrate, acetoacetate • Paraldehyde, Phenformin, Propylene glycol • Isoniazide → lactic acidosis 2° to seizure activity OR Iron → lactic acidosis → uncoupling of oxidative phosphorylation • Lactate • Ethylene glycol → glyoxylate, glycolate, oxalate • Salicylates → ketones, lactate 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, osmolol 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 Case Study • Ethanol, methanol or ethylene glycol? Alcohol Osmol Metabolic Acidosis Serum Urine Oxalate Gap with anion gap Acetone Ethanol + - - - Methanol + + - - Isopropanol + - + - Ethylene glycol + + - + • Ethanol, methanol results negative • Ethylene glycol positive 162 mg/dL, range of toxic