“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 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 ↓ ↓ ↓ ↓ ↓ ↓ 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 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

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, 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 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 doses – 50 -775 mg/dL Acetaminophen (Tylenol)

• Analgesic and antipyretic • Peak concentrations – 4 hours post-ingestion • Normal half-life 2-3 hours; >4 hours hepatic toxicity; >12 hours hepatic coma likely • Acute liver damage threshold; adults 150-250 mg/kg • Children under the age of 10 more resistant to toxicity • Measured by enzymatic / colorimetric methods • Antidote is N-acetylcysteine Acetaminophen: metabolism Acetaminophen: hepatic toxicity Salicylate (Aspirin)

• Analgesic, antipyretic and anti-inflammatory • Therapeutic dose – single dose – 10 mg/kg; daily dose – 40-60 mg/kg • Mild intoxication – 150-200 mg/kg; severe intoxication – 300-500 mg/kg; chronic toxicity - >100 mg/kg/day • Lab results reveal mixed metabolic acidosis / respiratory alkalosis • Tinnitus, hyperthermia, hyperventilation, CNS • Measured by enzymatic / colorimetric methods • Treatment of salicylate overdose – Hydration, glucose, K+ supplements, bicarbonate, hemodialysis Carbon Monoxide

• Most common cause of fatal poisonings – smoke inhalation • Colorless, odorless, tasteless gas • Has 240x the affinity for hemoglobin than oxygen → carboxyhemoglobin (COHb) • Symptoms begin at COHb levels of 10-20% and 50% can be fatal • Nonsmokers – 1-2% COHb, smokers 5-6% COHb • Treatment: fresh air, 100% O2 or hyperbaric oxygen may be indicated UV Absorption of Hb forms

methemoglobin

oxyhemoglobin Absorbance → Absorbance reduced hemoglobin

carboxyhemoglobin

Wavelength (nm) Comparison of absorbencies at different wavelengths allows estimation of the relative concentrations of different forms of hemoglobin

beer-lambert law – A = ɛbc or A = ɛ1bc1 + ɛ2bc2 + ɛ3bc3 …. Lead Poisoning

• Demyelinates nerve fibers • Inhibits Fe incorporation into heme • Chronic lead poisoning causes hypochromic anemia, with basophilic stippling • Treatment – chelation – EDTA • Laboratory Test – whole blood – ICP-MS, atomic absortion, anodic stripping voltammetry • Erythrocyte protoporphyrin is not sensitive to low level Pb exposure, but is a definitive

marker of acute exposure source: www.aafp.org Iron Poisoning • Approximately 5,000 case per year – mostly children • Toxicity of related to the dose of elemental iron

Compound Elemental Iron Ferrous sulfate (hydrate) 20% Ferrous fumarate 33% Ferrous gluconate 12% Ferrous chloride (hydrate) 28% Ferric chloride (hydrate) 20% • Treatment: – Serial monitoring of serum iron – Obtain creatinine, electrolytes, hemoglobin, PT, LFTs and arterial blood gases – Calculate elemental iron dose ingestion; 20-60 mg Fe/kg moderate risk; >60 mg/kg high risk – <350 μg/dL and no symptoms – supportive care – >300 μg/dL and symptoms – deferoxamine infusion Pharmaceutical Overdoses (US testing model)

Overdose/ consult Poisoning Poison Case Control (CDS ordered) Center

Sample sent

Hospital Toxicology TAT = 1 hour Laboratory (basic screen)

Sample sent Reference Laboratory TAT = days to weeks (CDS and confirmations) Pharmaceutical overdoses: new model (ABCC) ER, ICU hospital #2 ER, ICU ER, ICU hospital consult hospital #1 #3 Poison Control Center sample sent from GC-MS consult local hospital to LC-MS/MS regional tox lab GC-MS/MS LC-TOF Regional Toxicology LC-QTOF Laboratory Pharmaceutical Overdoses: method options

LC-MS/MS m/z = 255 Diphenhydramine C17H21NO 2C-T-4 255.162308 C13H21NO2S LC-HRMS 255.129303 LC-HRMS LC-MS/MS (QTOF, Orbitrap) Retention Time Retention Time Nominal Mass Accurate Mass Fragmentation Fragmentation 255.007858 Library Searching Library Searching Isotope Pattern Targeted Data Untargeted Data Collection Collection

Mass (m/z) Self-Assessment Questions 1. Which toxidrome is characterized by Salivation, Lacrimation, Urination, Diarrhea, GI upset, Emesis – “SLUDGE”? a) Anticholinergic b) Cholinergic c) Sympatomemetic d) Sedative-hypnotic 2. A blood ethanol concentration of 130 mg/dL will contribute how much to a serum osmolality? a) 2.8 mOsm/kg b) 3.5 mOsm/kg c) 28 mOsm/kg d) 35 mOsm/kg e) 280 mOsm/kg 3. By what mechanism does N-acetylcystine help prevent hepatic damage in acetaminophen overdose? a) Blocks absorption of acetaminophen b) Provides a source of glutathione c) Prevents hepatic conjugation of acetaminophen d) Blocks acetaminophen receptors on hepatocytes e) Forms an in active complex with acetaminophen