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 intuba on – 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 excre on of acids) • Diabetic Ketoacidosis –DKA (also AKA) → acetaldehyde → acetylCoA → B‐hydroxybutyrate, acetoacetate • Paraldehyde, Phenformin, Propylene glycol • Isoniazide → lac c acidosis 2° to seizure activity OR Iron → lac c acidosis → uncoupling of oxida ve phosphoryla on • 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 + ‐ + ‐ 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
11 4/24/2015
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
12 4/24/2015
UV Absorption of Hb forms
methemoglobin → oxyhemoglobin 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
13 4/24/2015
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)
14 4/24/2015
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
15