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

• 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

Definition of “Poisoning”

• 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)

Monitoring Poisonings

Poisoning / Overdose Trends

Poisoning / Overdose Trends

AAPCC: Top 25 human exposures

AAPCC: Top 25 pediatric exposures

Increase in Exposure – Top 4

• 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

Poisoning: Treatment Approach

• 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

Treatment: ABC’s or CAB

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,

hypertension • Agitation, delirium, seizures • Mydriasis • Decreased bowel sounds

• Nonselective antihistamines • Tricyclic antidepressants • Antipsychotic drugs • Benztropine • Scopolamine, atropine • Jimsonweed, deadly nightshade,

amanita muscaria

Cholinergic – Nicotinic / Muscarinic

• Bradycardia(M), Tachycardia(N) • Hypertension (N) • Miosis • Bronchorrhea • Salivation, Lacrimation,

Urination, Diarrhea, GI upset, Emesis – “SLUDGE”

• Organophosphates, carbamates • Physostigmine • Pilocarpine • Betel nut • Mushrooms: clitocybe dealbata,

C. illudens, Inocybe lacera • Black widow spider venom (N)

Sympathomimetic • Hyperthermia, tachycardia, hypertension

• Agitation, delirium, seizures • Mydriasis • Increased bowel sounds • Dry, flushed skin

• Cocaine, amphetamines • Theophylline, caffeine • Salicylates • Monoamine oxidase (MAO)

inhibitors • Sedative/hypnotic withdrawal

Opioid • Hypopnea/bradypnea • Lethargy, obtundation • Miosis

• All opiates and phenothiazines • Hypoglycemic agents • Clonidine

Sedative-hypnotic • Hypothermia, bradypnea/ hypopenia

• Lethargy, stupor, obtundation

• Ethanol • Benzodiazepines, barbiturates • Meprobamate, methaqualone,

chloral hydrate

Blood Pressure

Heart Rate

Resp. Rate

Temp. Pupil size

Bowel sounds

Diaph-oresis

Anticholinergic ↑ ↑ ↑ ↓ ↓

Cholinergic ↓ ↑ ↑

Opioid ↓ ↓ ↓ ↓ ↓ ↓ ↓

Sympathomimetic ↑ ↑ ↑ ↑ ↑ ↑ ↑

Sedative-hypnotic ↓ ↓ ↓ ↓ ↓ ↓

Poisoning Evaluation: toxidromes

psychiatryonline.org

Illicit Drugs: Mechanism of Action

• 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

Essential Laboratory Tests

Toxic Alcohols

• Ethanol • Methanol • Isopropanol • Acetone • Ethylene glycol

• 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

Pharmacokinetics: Review

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

Acetate

Acetaldehyde

UGT 1A1 UGT 2B7 SULTs

Ethylsulfate (EtS) Ethylglucuronide (EtG)

ADH1B ADH1C

ALDH2

CYP2E1

Urine ~ 80 hours Urine ~ 80 hours

Serum ~ 3.5 hours

Ethanol Metabolism

Ethanol Measurement

• Enzymatic methods – alcohol dehydrogenase • CH3CH2OH CH3CHO

• 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

NAD+

ADH

NADH 340 nm

• 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

Other toxic alcohols

• 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

Osmolal Gap

Anion Gap

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

(Na+ + K+) – (Cl- + HCO3-) = 16 (range 10-20)

Ingestion of Alcohols: Lab Findings

Alcohol Osmolal Gap

Metabolic Acidosis with anion gap

Serum Acetone

Urine Oxalate

Ethanol + - - -

Methanol + + - -

Isopropanol + - + -

Ethylene glycol + + - +

• 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?

• Ethanol, methanol results negative • Ethylene glycol positive 162 mg/dL, range of

toxic doses – 50 -775 mg/dL

Case Study

Alcohol Osmol Gap

Metabolic Acidosis with anion gap

Serum Acetone

Urine Oxalate

Ethanol + - - -

Methanol + + - -

Isopropanol + - + -

Ethylene glycol + + - +

• 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 (Tylenol)

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

• 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

Carbon Monoxide

Wavelength (nm)

Abso

rban

ce →

methemoglobin

oxyhemoglobin

reduced hemoglobin

carboxyhemoglobin

UV Absorption of Hb forms

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 • 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

Compound Elemental Iron

Ferrous sulfate (hydrate) 20%

Ferrous fumarate 33%

Ferrous gluconate 12%

Ferrous chloride (hydrate) 28%

Ferric chloride (hydrate) 20%

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

Self-Assessment Questions