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Toxicology Toxicology Presentation Transcript

  • Toxicology Dalhousie Critical Care Lecture Series
  • Objectives
    • Discuss findings of sympathomimetic, anti-cholinergic, cholinergic and narcotic toxidromes
    • Discuss the essential investigations of a potential drug overdose.
    • Demonstrate the ability to calculate an anion gap, serum osmolality and osmolar gap. What is the significance of an elevated AG or osmolar gap?
    • Discuss the presentation and management of common overdoses including:
      • Toxic Alcohols
      • ASA
      • Tylenol
      • TCAs
      • Neuroleptic Malignant Syndrome and Serotonin syndrome
    • Which overdoses require nephrology consults for consideration of dialysis?
  • Overdose
    • Requires high index of suspicion
      • Non-specific symptoms
        • Tylenol O/D
      • Presents as other issues
        • AMI in setting of CO overdose
  • Overdose
    • Suspect in the setting of:
      • Altered LOC/coma
      • Trauma
      • Life threatening arrythmia
      • Unexpected clinical findings
  • Diagnosis - History
    • May be unreliable or incomplete
    • Things to consider
      • History of depression/prior overdose
      • Time of ingestion/last seen well
      • Pill bottles present at scene
      • Time of last refill
      • Medications of family memebers
  • Diagnosis - PE
    • Vitals
      • HR, BP, RR, Temp, O2 sat
    • Neuro
      • LOC, pupils
    • CVS
      • Arrythmias
    • Skin
  • Increased Osmolal Gap
    • Osmolarity = 2x[Na] + glc + urea
    • Osmolar gap = measured – calculated
    • normal = between 270 -290
    • Normal osmolar gap <10
  • Toxicology Critical Care Lecture Series
  • What is a toxidrome?
    • A collection of symptoms and signs that consistently occur after ingestion of a particular toxin or drug class or agent
    • Often identified with a basic history & physical examination
    • Rapid identification of the toxidrome saves time in evaluating and managing a poisoned patient
  • Anticholinergic
    • Mydriasis
    • Blurred vision
    • Fever
    • Flushed dry skin
    • Psycosis, coma
    • Seizures
    • Ileus
    • Urinary retention
    • Hypertension
    • Tachycardia
    • Eg. TCA, antihistamines, atropine, benztropine
    • Blind as a bat, hot as a hare, dry as a bone, red as a beet, mad as a hatter
  • Anticholinergic Toxidrome - Management
    • ABC, supportive care, consider GI decontamination
    • Benzodiazepines
    • Physostigmine – specific antidote.
    • May be used if
      • Severe agitation or psychosis unresponsive to other therapy
      • Sever peripheral and central anticholinergic features
      • NO history of seizures
      • Normal ECG especially QRS duration
      • NO co-ingestion of drugs altering intraventricular conduction
        • E.g. TCA’s
      • Cardio-respiratory monitoring and resus facilities in place
  • Cholinergic
    • Eg. organophosphates, nerve agents
    • DUMBELS
      • D-diaphoresis, diarrhea, decreased BP
      • U-urination
      • M-miosis
      • B-bronchorrhea, bronchospasm, brady
      • E-emesis, excitiation of skeletal muscle
      • L-lacrimation
      • S-salivation, seizures
  • Cholinergic Toxidrome - Management
    • ABC, supportive care
    • Decontamination procedures
    • Atropine
      • ACh antagonist
      • Antimuscarinic
    • Pralidoxime (2-PAM)
      • Regenerates Acetylcholinesterase
      • Removes phosphoryl group from enzyme
      • Must be given early before phosphorylation becomes irreversible (“aging”)
  • Sympathomimetic (adrenergic) toxidrome
    • Increased temp
    • Tachycardia
    • Hypertension
    • Dilated pupils
    • CNS excitiation
      • Seizures
    • Nausea/vomiting
    • Diaphoresis
    Cocaine, MDMA (“ecstasy”), Amphetamines, Phencyclidine (PCP), Theophylline, Decongestants ( Ephedrine Pseudoephedrine Phenylpropanolamine), Caffeine (very large doses)
  • Adrenergic Toxidrome - Management
    • ABC, supportive care, consider GI decontamination
    • Investigations
      • Screen for other drugs & treatable toxins (eg, acetaminophen, salicylate)
      • Electrolytes (esp. sodium), urea, creatinine, blood sugar, anion gap.
      • CK levels to check for rhabdomyolysis
      • Consider cranial CT
      • EKG & Cardiac biomarkers (eg, CPK-MB, troponin)
    • Sedation – treats majority of effects
      • Benzodiazepines
    • Temperature control
    • Treat hypertension unresponsive to benzodiazepines
      • Nitroprusside
      • Nitroglycerine
      • Labetalol (avoid isolated  -blockade in mixed adrenergic agonist toxicity)
  • Narcotic
    • Hypothermia
    • Bradycardia
    • Hypotension
    • Respiratory depression
    • Constricted pupils
    • CNS depression
  • Opioid-Narcotic Toxidrome - Management
    • ABC, supportive care
    • GI decontamination for oral ingestion
    • Naloxone
      • Specific antagonist
      • High doses may be needed for methadone & pentazocine
      • Short half-life compared to opioids
      • Infusion may be required
      • Pulmonary edema and seizures have been reported
  • Serotoninergic Toxidrome Eg. SSRI’s, MAOI’s, ecstasy Diarrhoea, trismus, myoclonus, tremor, rhabdo Other Normal/decreased (SIADH possible) Urination Increased Bowel sounds Increased Reflexes Normal/flushed/sweating Skin Normal Mucous membranes Normal/unreactive Pupils Agitated/irritable Mental status Physical examination Normal/decreased Blood pressure Increased Temperature Increased Heart rate Normal/increased Respiratory rate Vital Signs
  • Serotoninergic Toxidrome - Features
    • Mental status changes
      • Confusion (51%)
      • Agitation (34%)
      • Hypomania (21%)
      • Anxiety (15%)
      • Coma (29%)
    • Cardiovascular
      • Sinus tachycardia (36%)
      • Hypertension (35%)
      • Hypotension (15%)
    • Gastrointestinal
      • Nausea (23%)
      • Diarrhea (8%)
      • Abdominal pain (4%)
      • Salivation (2%)
    • Motor Abnormalities
      • Myoclonus (58%)
      • Hyperreflexia (52%)
      • Muscle rigidity (51%)
      • Restlessness (48%)
      • Tremor (43%)
      • Ataxia/incoordination (40%)
      • Shivering (26%)
      • Nystagmus (15%)
      • Seizures (12%)
    • Other
      • Diaphoresis (45%)
      • Unreactive pupils (20%)
      • Tachypnea (26%)
      • Hyperpyrexia (45%)
    Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13 Mills KC. Serotonin syndrome. Am Fam Physician 1995;52:1475-82
  • Serotoninergic Toxidrome - Management
    • Stop intake of causative agent
    • ABC, supportive care
    • Absorption
      • Gastric lavage in early acute ingestion (1hr)
      • Activated charcoal
    • Benzodiazepines
    • Others
      • Chlorpromazine
      • Diphenhydramine
      • ? Serotonin antagonists e.g. cyproheptadine
  • Diagnosis - Investigation
    • Essential labs
      • CBC, lytes, BUN, Cr, BS
      • Ptt, INR, LFTs
      • ABG (calculate AG)
      • Serum osmo (calculate osmo gap)
      • ASA
      • Acetaminophen
    • Other
      • Drug levels
      • Urine
  • General Management
    • ABC
    • Consider thiamine, dextrose, naloxone if depressed GCS
    • Prevent further absorption
      • Decontaminate eyes, clothes, skin, hair if appropriate
      • Activated charcoal + sorbitol (if < 1 hour from ingestion)
      • Gastric lavage (if < 1 hour from ingestion and life-threatening drug or dose)
        • In general not used
      • Whole bowel irrigation for “body packing” illicit drugs
        • In general not used
    • Enhance elimination
      • Forced diuresis and urinary alkalinisation (salicylates and barbiturates)
      • Multiple dose activated charcoal 0.5 g/kg every 2-4 hours
        • binds toxin and interrupts enterohepatic recirculation
        • mainly life-threatening ingestion of carbamazepine, dapsone, phenobarbital, quinine or theophylline
      • Extracorporeal removal (for active metabolites, delayed toxicity or poor organ clearance)
        • Haemodialysis - low MW (<500 d), soluble, low Vd (< 1L/kg) e.g. methanol, ethylene glycol, salicylates, lithium
        • Haemoperfusion - e.g theophylline, phenobarbital, phenytoin, carbamazepine, paraquat
        • Haemofiltration for large Vd and extensive tissue bound toxins but removes virtually all drugs
    • Antidotes
  • Activated Charcoal
    • Universal absorbent
    • Produced by the controlled burning of various organic products at >600C, washed with inorganic acids and dried
    • Small particle with highly developed internal pore system
      • surface area of 50 gm AC = 10 football fields
    • Absorbs substances in varying degrees
      • If comes into contact with toxin in GI track prior to absorption, can bind and decrease systemic toxicity
  • General Treatment
    • Activated charcoal
      • Inert, non-toxic, non-specific adsorption
      • Risk of aspiration
      • Dose 1g/kg patients weight
      • Ineffective for alcohols or heavy metals
      • ? Multi-dose charcoal
        • may cause GI dialysis for some drugs
        • Check with poison control!!!
  • Activated Charcoal
    • Binds most compounds; easier to remember what it doesn’t
  • Activated Charcoal
    • Big question in the use of AC is when to use it
    • Effectiveness is time dependent – the longer the time from ingestion, the less effective AC is
      • Toxin already absorbed or past pyloris
    • Effectiveness is lost between 1 and 2 hours
  • AC: problem
    • Patients with toxin ingestions will present to the ED >3 hours after poisoning
    • “should not be administered routinely”
  • Drugs and Extracorporeal Removal
    • Haemodialysis
    • M ethanol
    • Ethylene glycol
    • Salicylates
    • Lithium
    • Haemofiltration
    • Procainamide
    • Methotrexate
    • Haemoperfusion (Charcoal)
    • Theophylline
    • Carbamazepine
    • Amanita toxin (if early)
    • Aminoglycosides
    • Paraquat
    • Phenobarbital
    • Phenytoin
    • Sotalol
  • Urinary Alkalinisation
    • Fluoride
    • Isoniazid
    • Salicylic acid
    • Barbiturates
    • Methotrexate
  • Specific Ingestions
  • Acetaminophen
    • Peak plasma <1hr post ingestion
    • Metabolized in liver d/t glucuronidation
    • Toxic metabolite NAPQ1
      • NAPQ1 binds to hepatocytes and causes necrosis
      • Detoxified by glutathione & eliminated by kidneys
    • Toxic threshold adults - 7.5-10g
  • Acetaminophen
    • Phase I (<24 hrs):
      • Anorexia, malaise, N/V, diaphoresis
    • Phase II (24-48 hr):
      • RUQ pain,  LFTs, sx of phase I resolve
    • Phase III (48-96 hr)
      • Severe liver failure
        • Encephalopathy, coagulopathy,  BS
      • Pancreatitis
      • ARF
    • Phase IV (>4 days)
      • Death/full recovery/transplant
  • Acetaminophen
    • Limitations:
      • Requires time of ingestion
      • Very early or late ingestions
      • Chronic ingestions
      • Extended release preparations
      • At risk populations
        • ETOH abuse
  • Acetaminophen
    • Treatment
      • Activated charcoal
        • Given w/I 4-6 hr
        • Reduced absorption by 50-90%
    • NAC
      • Replete glutathione
      • combines directly with NAPQ1
      • Antioxident properties
      • vasodilatory properties
      • Treat:
        • Based on nomogram
        • Level >5 w/o ingestion time known
        • Evidence of hepatotoxicity or level unknown
  • Alcohols
    • Ethylene glycol, methanol, isopropanol
    • Lab:
      • Anion gap MA, elevated osmolar gap
      • Exceptions:
        • Normal AG
          • Not yet formed metabolites
          • Isopropanol ingestion
    • Sx may be delayed if co-ingested with ethanol
  • Ethylene Glycol
    • Oxalic acid  Ca oxalate  ARF
    • Hypocalcemia
    • Myocardial dysfunction (2 0  Ca)
    • 100ml can be lethal
    Ethylene glycol ETOH dehydrogenase Oxalic acid
  • Ethylene Glycol
    • Phase I (30min-12hr)
      • Inebriation, ataxia, seizures, AG-MA, OG, hypocalcemia, crystalluria, cerebral edema
    • Phase II (12-24hr)
      • Myocardial dysfunction, CHF
    • Phase III (2-3 days)
      • ARF
  • Methanol
    • 150-240ml is lethal
    • Presents with:
      • Headache, inebriation
      • Dizziness, ataxia, confusion
      • Vision loss
      • Pancreatitis
    Methanol ETOH dehydrogenase Formic Acid
  • Treatment
    • Inhibit alcohol dehydrogenase
      • Ethanol
      • Fomepizole
    • Removal of alcohol & it’s metabolites
      • Hemodialysis
        • Levels >50mg/dL
        • Significant MA
        • Evidence of end-organ damage
  • Isopropanol
    • Ketonuria
    • Absent AG or MA
    • Hemorrhagic gastritis
    • Generally just supportive care
      • Hemodialysis if:
        • Lethal ingestion (150-240ml)
        • Refractory shock/prolonged coma
    Isopropanol ETOH dehydrogenasez Acetone
  • Salicylate Intoxication
    • Adult lethal dose - 10-30g
    • Sx include:
      • Tinnitus
      • Fever
      • Vertigo
      • Nausea/vomiting/diarrhea
      • AG MA & resp alkalosis
      • Altered LOC/coma
      • ARDS
  • Salicylate Treatment
    • Level check q2h until 2 values decreased from peak
    • Activated charcoal
      • ?multiple dosing
    • Supplemental glucose
    • Alkalinization of serum & urine
      • Resp alkalosis not C/I to HCO3
      • Urine pH = 8
    • Dialysis
  • Salicylate Treatment
    • Hemodialysis Indications
      • Altered LOC
      • Pulmonary or cerebral edema
      • Renal failure
      • Fluid overload that prevents HCO3
      • Plasma level >7.2
      • Deterioration despite therapy
  • TCA Intoxication
    • Rapidly absorbed - peak dose 2-8h
      • T1/2 - 24-72hr
      • Enterohepatic recirculation
      • Delayed absorption d/t anticholinergic effects
  • TCA - Clinical Presentation
    • Cardiac
      • Inhibits fast Na channels - slowed depolarization
        • QRS prolongation
        • Reentry arrhythmias - V-tach, torsade
        • Hypotension, Decreased CO
    • CNS
      • Delerium, seizures, coma
    • Anticholinergic
      •  temp, flushed, dilated pupils, ilieus, urinary retention, sinus tach
  • TCA - Treatment
    • ABCs
    • Activated charcoal - ?multidose
    • Gastric decontamination
    • NaHCO3 - most effective therapy!
      • D/t raised pH and serum [Na]
      • Recommend for QRS >100msec
      • Push amps for arrhythmias
    • Do not give dilantin for seizures!
    • No role for dialysis!!!!
  • B-Blocker Overdose
    • Most are symptomatic within 4 hours of ingestion
      • Asymptomatic pts with a normal EKG after 6hrs generally don’t need ICU
    • SX:
      • Hypotension
      • Bradycardia/A-V block
      • CHF
      • Bronchospasm
      • Decreased LOC, seizures, coma
  •  -blocker Treatment
    • ABCs
    • Activated charcoal
    • Temporary pacing/vasopressors prn
    • Glucagon
      • +ve inotropic and chronotropic effect d/t increased AMP and intracell Ca
      • 5-10mg bolus followed by 1-10mg/h gtt
    • High dose insulin/glucose drip
    • **Atenolol is dialyzable**
  • Ca channel Blocker OD
    • Selectively inhibit the movement of Ca through cardiac and vascular smooth mm
    • Present with
      • Hypotension
      • Bradycardia/conduction delays
      • Confusion/ altered LOC
  • Ca Channel Treatment
    • ACBs
    • Activated charcoal
    • ?Gastric lavage
    • Ca gluconate
    • Glucagon
    • Insulin/glucose infusion
  • CO poisoning
    • Seen with:
      • smoke inhalation
      • SA with car exhaust
      • poorly vented wood or gas stoves
    • CO binds Hg 240X> then O 2
      • Causes tissue hypoxia
    • Serum CO up to 5-10% in smokers or large cities
  • CO poisoning
    • Presentation
      • 5-10% CO
        • H/A, mild dyspnea
      • 10-30%
        • H/A, dizziness, weakness, N/V, dyspnea, cardiac ischemia
      • >50%
        • Coma, seizures, cardiovascular collapse, death
        • 10-30% survivors have delayed neuro deficits
  • CO poisoning - Diagnosis
    • High index of suspicion
    • Serum CO level
      • Measured by co-oximeter of an ABG
      • Pulse oximetry can’t distinguish carboxyHg from oxyHg
      • PO2 on ABG may be normal since it represents dissolved oxygen
    • CT head may specifically demonstrate globus pallidus abnormalities
  • CO Poisoning - Treatment
    • ABCs
    • 100% FiO2
      • T1/2 R/A - 5-6hr
      • T1/2 100% - 40-90min
    • Hyperbaric O2
      • T1/2 - 15-30 min
      • If accessible, suggested for:
        • CO>25%
        • Loss of consciousness, EKG changes, chest pain
        • pH<7.1
  • Antidotes Naloxone Opioids Atropine, pralidoxime Organophosphates Methylene blue Methaemoglobinaemia Ethanol/fomepizole, folate Methanol Pyridoxine Isoniazid Deferoxamine Iron Dextrose, glucagon, ocreotide Hypoglycaemic agents Dimercaprol, EDTA, penicillamine Arsenic, copper, gold, lead, mercury Ethanol/fomepizole, thiamine, pyridoxine Ethylene Glycol Digoxin-specific antibodies Digoxin Amyl nitrite/sodium nitrite/thiosulphate ( Taylor Cyanide Antidote Package) hydroxycobalamin Cyanide Oxygen Carbon Monoxide Flumazenil Benzodiazepines Atropine Anticholinesterases Physostigmine Anticholinergics N-acetylcysteine Acetaminophen Antidote Toxin/effect
  • Summary
    • Familiarity with toxidromes will allow you to assess and manage unconscious overdose/poisoning victims
    • Supportive care and decontamination is the mainstay of most treatments
    • Calculation of the anion gap and osmolar gap will allow you to identify and treat toxic alcohol ingestions prior to end organ damage
    • In known overdoses and poisonings early involvement of a toxicologist/poison control is very helpful to direct specific antidote therapies