Toxicology

    General Pointers

    • Most toxins require supportive care.
    • Always consider co-ingestions (check serum levels of other agents: i.e. ASA, EtOH, Acetaminophen)
    • Best resource: Goldfranks

     

    Toxidromes

    Anticholinergic

    • Blind as a bat (pupils dilated - mydriasis)
    • mad as a hatter (confusion)
    • red as a beet  (flushed red appearance)
    • hot as a hare (hot, flushed, dry)
    • dry as a bone
    • The bowel and bladder lose their tone, and the heart runs alone (brady).

    Cholinergic

    • Substances that may cause this:
      • Four "anti"s of antihistamines, antipsychotics, antidepressants, and antiparkinsonian drugs
      • Also: atropine, benztropine, datura, and scopolamine. 
    • SLUDGE
      • Salivation
      • Lacrimation
      • Urination
      • Diarrhea
      • Gastrointestinal distress
      • Emesis

    Opioid

    • Opioids are potent respiratory depressors.
    • Opioid intoxication:
      • Miosis
      • Encephalopathy
      • Hypotension
      • Hypothermia
      • Hyporeflexia
    • Exams: Think alternative diagnosis if do not respond to total of 10mg naloxone (mean half-life 1 hour), continuous infusion may be needed.  (In practice can start with 0.1-0.4mg naloxone)
      • Naloxone lasts ~30min-60min
      • If naloxone is effective, set up a drip - effective dose given hourly (titrate to resp rate >9 or agitation)
    • Opioid intoxication does not require intubation, usually can be managed with naloxone.
    • Chronic opioid users receiving naloxone should be watched for withdrawal:
      • Opioid withdrawal symptoms:
        • Delirium
        • Agitation
        • Diaphoresis
        • Tremulousness
        • Hypertension
        • Fever
        • Seizures

     

    Sympathomimetic

    • Shared findings:
      • ↑ HR, ↑ BP, ↑ temp,
      • diaphoresis, mydriasis, agitation,
      • seizure, ↑ CK, ↑ liver chemistry studies
      • ↑ Cr
    • Benzodiazepines are first line for agitation

    • Avoid β-blockers for hypertension

    • NOTE: Haloperidol may worsen hyperthermia

     

     

    Alcohol - Wernicke-Korsakoff

    • Alcohol-induced amnestic disorder
    • Necrotic Lesions in mamillary bodies, thalamus and brainstem
    • Wernike's Encephalopathy:
      • Acute and Reverisble
      • Triad of :
        • 1. Nystagmus (CN VI palsy)
        • 2. Ataxia
        • 3. Confusion
      • Thiamine 100mg PO OD x1-2 weeks.
    • Korsakoff Syndrome
      • Chronic and only 20% reversible with treatment
      • Anterograde amnesia + confabulations
      • Cannot be during delirium or dementia, must persist beyond intoxication and withdrawal
      • Thiamine 100mg PO BID or TID x3-12mo

    Alcohol Withdrawal

    • Alcohol activates GABA Receptor (GABA is inhibitory neurotransmitter) causing CNS depression.
    • Withdrawal suddenly creates CNS hyperactivity:
      • Early symptoms of withdrawal:  Diaphoresis, insomnia, anxiety, tremor, palpitations, headache.
      • Severe: Seizures, hallucinations (Delirium Tremens)
    • Onset: 48-92hrs after last drink, sometimes may persistent for days.
    • Hypokalemia, hypomagnesemia, hypophosphatemia are common, can cause arrhythmias.
    • Mortality: 5%, usually due to arrhythmias, aspiration pneumonia.
    • Treatment:
    1. Benzodiazepines
    • Try to give as needed (not by scheduled dosing or infusion).
    • Find dose that prevents withdrawal without causing severe sedation.
      • CIWA protocol designed to help with this.
    1. Rehydration
    2. Electrolyte correction
    3. Thiamine, Glucose, Folate supplemented routinely
    4. Early nutrition
    5. Multidisciplinary team should address EtOH issues.

     

    Other Alcohols

    Source: MKSAP 17 + Kruse JA. Methanol and ethylene glycol intoxication. Crit Care Clin. 2012 Oct;28(4):661-711

    • Examples:
      • Ethylene Glycol (Antifreeze)
      • Methanol (Wood alcohol)
      • Isopropyl Alcohol
    • All have CNS depressant effects
    • Main Things to remember: (AHD = Alcohol Dehydrogenase)
      • Methanol is metabolized to formic acid causing retinal toxicity
      • Ethylene glycol is metabolized to oxalic acid by AHD --> precipitates in kidneys causing AKI + urine crystals
      • Isopropyl Alcohol does not cause an anion gap

     

    Clinical Manifestations of Ethylene Glycol, Methanol, and Isopropyl Alcohol Ingestion

    Alcohol

    Common Name

    Toxic Metabolite

    Nontoxic Metabolite

    Anion Gap

    Osmolar Gap

    Toxicity

    Antidote

    Ethanol Alcohol   -

    No!

    (**SEE

    NOTE**)

    Yes Liver, etc. Supportive Care

    Methanol

    Wood alcohol

    Formic acid

    -

    Yes

    Yes

    Retina

    (Blindness!)

    Fomepizole, ethanol, dialysis

    Ethylene glycol

    Antifreeze

    oxalic acid (AKI)

    Also Glycolic,

    glyoxylic acids

    -

    Yes

    Yes

    Renal tubules

    (from cystals)

    Fomepizole, ethanol, dialysis

    Isopropyl alcohol

    Rubbing alcohol

    -

    Acetone

    No

    Yes

    CNS depression

    Fomepizole, ethanol, dialysis

    *** - Ethanol should not cause a significant anion gap.  If it does, consider other alcohol ingestion and alcoholic ketoacidosis.

     

    • Management Strategies:
      • Prevent conversion to toxic metabolites (IV fomepizole or ethanol)
      • All can be rapidly removed with dialysis.

     

    Methanol

    • Metabolized by Alcohol Dehydrogenase
    • No ethanol odor
    • Metabolites:
      • Formic Acid (mitochondrial toxin - inhibits cytochrome oxidase)
        • Most susceptible are retina, optic nerve, and basal ganglia
      • Lactate (production of NADH)
    • Poisoning:
      • Early toxicity: 6 hours post-ingestion (inebriation like alcohol)
      • Late signs: 6-24hrs  (scotoma, blurry vision, complete blindness, depressed consciousness, coma, seizures)
    • Treatment: (Same as ethylene glycol)
      • Fomepizole
      • Dialysis (esp if visual impairment)
      • Sodium bicarb to keep pH > 7.3 (to keep methanol in neutral state (protonated), which decreases tissue penetration)
        •  Crit Care Clin. 2012 Oct;28(4):661-711. doi: 10.1016/j.ccc.2012.07.002.    

    Ethyelene Glycol

    • Component of solvents and antifreeze
    • Metabolized by alcohol dehydrogenase to acids to oxalic acid (also glycolic acid, formic acid), precipitates in the kidneys causing AKI.
    • No ethanol odor (odorless)
    • Poisoning
      • Neurologic impairment (similar to ethanol)
      • Seizures, coma.
      • If untreated:  non-cardiogenic pulmonary edema, shock, hypotension. 
      • 24-48hrs later can develop flank pain and kiney failure
      • Renal Failure (metabolized to oxacic acid -->  crystallization in tubules causing AKI)
    • Urine will show calcium oxalate crystals (envelope-shaped crystals)
    • Osmolar gap metabolic acidosis
    • Metabolytes:
      • Glycolic Acid (creates anion gap)
      • Lactate (through NADH production) - elevates serum lactate
      • Oxalic Acid (anion gap, final metabolite - can crystallize in urine, cause renal failure)
    • Management:
      • IV Fomepezole (EtOH dehydrogenase inhibitor)
        • 4 hours after ingestion, 15 mg/kg IV bolus + 10mg/kg q12h x48hrs until ethyl glycol level is 25mEq/L
        • Decreases metabolism of ethylene glycol (metabolites are toxic).
          AND!:
      • Hemodialysis
        • Indications: pH < 7.1, evidence of end orga damage (continue fomepizole q4h)
      • Sodium Biarb to keep pH > 7.3 (minimizes tissue penetration)
      • NOTE: Use of fomepezole alone is not sufficient, usually need both. 
      • Previously used IV ethanol, but no longer needed.

    Isopropyl Alcohol

    • Present intoxicated with an elevated osmolar gap, but NO ANION GAP!

     

     

    Serotonin Syndrome

    • Sudden excess of serotonin
    • Classically mixing MAO inhibitors with SSRIs
    • Symptoms
      • Fever
      • Encephalopathy (agitation)
      • Rigidity
      • Hyperreflexia

     

    Carbon Monoxide

    • Colorless odourless gas, patients often unaware of exposure.
    • Mechanism:
      • Carbon monoxide (CO) has high Hb affinity, outcompetes oxygen forms carboxyhemoglobin.
        • Cannot be detected by pulse oximetry, blood gas analysis is required.
      • Non-smokers have upt o 3% of hemoglobin bound to CO, but heavy smokers can have as high as 15%
    • Toxic level of carboxyhemoglobin is >20%
      • due to shifting deoxyhemoglobin dissociation curve to LEFT, reducing O2 delivery to tissues.
      • Dysfunction of high-O2 demanding organs (CNS and heart)
    • Symptoms:
      • Mild: Headache, Disorientation, Nausea
      • High: Chest pain, severe MS changes, dyspnea, arrhythmias, muscle weakness, coma, death.
    • Management:
      • 100% Oxygen --> Days to months to recover.
      • Up to 40% have delayed cognitive impairment syndrome (DCIS).
      • If carboxyhemoglobin is high (>20%) + symptoms
        • Hyperbaric oxygen treatment to help reduce risk of DCIS if available.
      • Monitor closely for hypoxic organ damage:
        • Blood gasses, co-oximetry, ECGs
    • NOTE:
      • Half-life of carboxyhemoglobin:
        • 300min on ambient air
        • 90min in 100% oxygen
        • 30min in hyperbaric oxygen
      • Consider cyanide toxicity (both common, synergistic, in smokers).

    Cyanide Toxicity

    • Inhalation or ingestion ( Potassium CN- or Sodium CN) usually with attempted suicide/homicide.
    • Cianide blocks oxidative phosphorylation (disables cytochrome oxydase in mitochondria)
      • Leads to effective hypoxia despite adequate O2. --> lactate acidosis, depleted cell energy.
    • Iatrogenic toxicity: Nitroprusside
      • Nitroprusside use (contains cyanide, can accumulate to toxic levels if infusion given at prolongued time)
        • High dose infusions (3-10hrs) can even be fatal.
        • Avoid toxicity by:
          • Shielding drug from light.  (breaks down nitroprusside in solution)
          • Decrease rate and duration of infusion
          • Add sodium thiosulfate to the infusion.
    • Symptoms: Chronic Exposure:
      • Headache, nausea, chest/abdo pain, anxiety.
    • Symptoms: Acute Exposure:
      • Severe organ dysfunction (esp CNS and CVS)
    • Treatment:
      • Agents that speed metabolism + elimination of cyanide.
        • Nitrites (NOT recommended for inhalational cyanide tox - risk of methemoglobin)
        • Sodium thiosylfate
        • hydroxocobalamin
        • Others....

     

    Drugs of Abuse

    Amphetamines

    • Increase central catecholamine activity --> anorexia, tachycardia, hypertension, hyperthermia, psychomotor agitation.
    • Organ Toxicity:
      • Myocardial ischemia / Infarction
      • Strokes
      • Seizures
      • AKI
      • Fulminant hepatic failure
      • Psychosis
    • Ecstasy or 3,4-methylenedioxy-methamphetamine (MDMA)
      • Can cause bruxism (sometimes severe dental damage w/ chronic use)
      • Hyponatremia resulting in cerebral edema.
    • Management:
      • Benzodiazepines + supportive measures.
      • Fluid repletion
      • Nutrition

    Cocaine

    • Potent stimulant
    • Inhaled, Oral, IV, Transmucosal
    • Classic sympathomimetic:
      • Tachycardia, hypertension, hyperthermia, psychomotor agitation.
    • Organ Toxicity:
      • Myocardia Ischemia / MI
      • Atrial/Ventricular Arrhythmias
      • Aortic Dissection / Rupture (from acute HTN0
      • Neuro: Seizures, Strokes, Bronchospasm
      • Pulmonary Edema / Alveolar Hemorrhage
      • Rhabdomyolysis.
    • Management:
      • Benzodiazepines for sympathomimetic symptoms.
      • CCB are considered safe + effective in lowering BP + HR.
      • Labetalol (for Hypertension) because it is non-selective alpha+beta blocker
        • Many experts caution against using Beta-Blockers --> can cause unapposed alpha-vasoconstriction --> more severe HTN. (claim not evidence based)
      • Myocardial Ischemia --> Nitroglycerin + ASA.
        • Plaque rupture / thrombosis possible, always rule out (consider angiography)

     

    Therapeutic Drug Overdoses

    • See Table Below!  Here are some notable common overdoses:

     

    Acetaminophen

    • Toxic dose: 7.5g in 8h period.  (nomogram available for serum levels at 4h mark).
    • Effect:
      • Acute hepatitis  --> fulminant hepatic failure.
    • Treatment:
      • N-Acetylcysteine (oral or IV)!!!
      • Charcoal (if <4hrs of ingestion)
      • If fulminant hepatic failure (see fulminant hepatic failure)
        • ---> Contact hepatology for transplant consideration ASAP!

          Chronic Acetaminophen Use:

    • If malnourished and get 4g/day of acetaminophen, can get toxic (target <2g/day)
    • Pyroglutamic acid
    • Treatment:
      • D/C acetaminophen
      • isotonic NS
      • NAC can be delivered 

     

    Benzodiazepines

    • Toxic dose is variable.
    • Flumazenil can reverse resp depression in benzo overdose, but rarely given due to risk of seizures in chronic benzo users.
    • Benzo overdose usually does not cause life-threatening respiratory depression without co-ingestion of other drugs (i.e. narcotics).
    • Management:
      • Monitor, airway/hemodynamic support if needed.
      • Antitode: Flumazenil (but rarely used: risk of seizures in those that chronically abuse benzodiazepines)

     

    Aspirin

    • Hyperventilation, dehydration, severe intoxication can cause seizures, hypoglycemia, etc...
    • 10-30g can cause toxicity
    • Presentation:
      • Tinnitus, Confusion, low-grade fever, N/V
      • Respiratory alkalosis (ASA stimulates respiratory center)
      • If Severe: Metabolic Acidosis (NOT osmolar gap)
    • Labs:
      • Produces both anion gap metabolic acidosis + respiratory alkalosis (central stimulation of resp center)
      • Nomograms useful for estimated dose ingested (if time of ingestion is known)
      • Careful if sustained release! (can underestimate dose ingested).
      • If chronic and severe:
        • can impair vitamin K metabolism in liver --> rises INR
    • CAUTION: Must hyperventilate to maintain high pH, which keeps ASA from entering CNS and allows clearance.
    • CAUTION: If you try to intubate, the short period of apnea will remove respiratory alkalosis, causing ASA-incuded metabolic acidosis to dominate.  Causes ASA penetration to CNS --> DEATH!!!
      • Avoid intubating ASA overdose patients!
    • Treatment:
      • IV Fluids
      • Sodium bicarb infusion (achieve urine pH > 8.0 [some say 7.5-8.0 target], and >2 mL/kg/h) --> ASA diuresis.
        • Follow lytes, ASA levels q2h to ensure resolving. 
      • Supportive Care:
        • Trend clinical signs, electrolytes, blood gasses q2h
        • Avoid hypokalemia (hypokalemia causes ASA reabsorption in distal tubules)
        • If impaired mentation --> give IV glucose (to avoid ASA-induced neuroglycopenia)
          • -> EVEN IF GLUCOSE NORMAL
      • Indications for hemodialysis:
        • ASA level >80 mg/dL (5.8 mmol/L),

        • Altered mentation

        • Pulmonary edema

        • Advanced Kidney Disease (cannot excrete)

        • Clinical status worsens depiste medical therapy

           

    Digoxin Toxicity

    • Clinical Features:
      • Look for new onset renal failure or dehydration that can cause it to ac
    • Toxicity:
      • CNS: visual disturbances (diplopia, photophobia, etc... many) confusion, weakness
      • GI: diarrhea
      • Renal: AKI
      • Cardiac: ANY cardiac arrhythmia (with exception of rapidly conducted atrial arrhythmias)
    • Labs:
      • Digoxin level >2.6 nmol/L = toxic, but correlates poorly with toxicity (use symptoms!)
        • Best to do it 6hrs post ingestion (earlier can be falsely elevated, has not distributed yet)
      • Hyperkalemia - does not cause death!
        • Treatment with insulin/dextrose/bicarb does not improve mortality
      • AKI - Elevated creatinine
    • Treatment:
      • If within 1-2 hours of ingesting Digoxin --> Activated charcoal (1 g/kg - maximum 50 g)
        • Patient must be awake, alert, protecting airway.
      • Digoxin-specific antibody (very expensive!)
        • Careful! --> exacerbates hypokalemia (monitor lytes).
      • Do not treat hyperkalemia.
        • Do not give Calcium (intracellular concentrations of calcium is high, associated with mortality but dating back to 1933).  currently effect unknown and is not recommended.
      • Be careful with hypokalemia --> correct if K+ is low.

     

    Beta Blocker

    • Generally slows down SA and AV nodes, negative inotropy.
    • Treatment:
      • 1st line:
        • Atropine 0.5mg as per ACLS
        • Fluids (to improve BP)
        • (Glucagon 3-5mg (if response --> 3-5mg/hr IV infusion))
          • Careful: glucagon causes lots of NAUSEA!!! (use gravol, not ondansetron)
        • Insulin + D50 shown has benefit
          • High dose 1 unit/kg/hr with D10 drip  (DKA dose is only 0.1 u/kg/hr)
      • 2nd line:
        • Calcium (chloride or gluconate, but twice more available Ca in chloride than gluconate)
          • (i.e. 1amp has 1g of CaCl OR 2g of CaGluconate)
        • Inotropes/Chronotropes
          • Isoproterenol (B1 agonist)  + add a1 agent such as norepinephrine.
          • Dopamine (2.5-10 mcg/kg/min)
          • Dobutamine + a1 agent such as norepinephrine.
      • May need pacing (transcutaneous or transvenous).
      • Lipophilic B-blockers are dialyzable (carvedilol, labetalol, propranolol)

    Other Drug Overdose

    Therapeutic Drug Toxicities, Antidotes, and Management

    Agent

    Toxic Dose (or Serum Level)

    Toxic Effect or Syndrome

    Pharmaceutical Antidote

    Other Interventions

    Acetaminophen

    7.5 g in 8 hours (nomogram for serum levels at 4 hours)

    Acute hepatitis, fulminant hepatic failure

    N-acetylcysteine PO or IV within 8 hours (may give later as well)

    Charcoal within 4 hours

    Benzodiazepines

    Variable

    CNS and respiratory suppression

    Flumazenil (caution if risk of seizures)

    Ventilatory and hemodynamic support

    β-Blockers

    Variable

    Bradycardia, heart block, hypotension

    Glucagon, calcium chloride

    Transcutaneous or transvenous pacing

    Calcium channel blockers

    Variable

    Bradycardia, heart block, hypotension

    Calcium chloride, glucagon

    Transcutaneous or transvenous pacing

    Digoxin

    >2 ng/mL [2.6 nmol/L] but serum levels have poor correlation with toxicity

    Bradyarrhythmia and tachyarrhythmia; chronic toxicity; CNS and GI symptoms

    Digoxin-specific antibody

    - Avoid correcting hyperkalemia (will correct once given digibind)

    Hemodialysis is not effective

    Sulfonylureas

    One tablet in a child or nondiabetic patient may cause hypoglycemia

    Hypoglycemia and related symptoms

    Dextrose, octreotide; glucagon for short term while dextrose is delayed

    Beware recurrent hypoglycemia even after initial response

    Lithium

    Most overdoses are chronic (serum level upper limit is 1.2 mEq/L for acute mania, 0.8 mEq/L for maintenance; 3.0 mEq/L indicates severe toxicity); note that CNS penetration is slow

    Tremor, nausea, polyuria, diabetes insipidus, arrhythmias, photosensitivity, cardiogenic shock due to CNS effects; neurologic sequelae may be permanent

    No antidote for lithium; medical treatments for secondary arrhythmias, seizures, hypotension

    Hemodialysis for altered mental status, anuria or seizures; IV fluid hydration with careful monitoring of electrolytes, especially in diabetes insipidus

    Salicylates

    Levels >30-40 mg/dL usually mean clinical toxicity; chronic toxicity is more common and more dangerous

    Metabolic acidosis, hyperventilation, dehydration; severe intoxication can cause seizures, hypoglycemia, and electrolyte abnormalities

    Sodium bicarbonate infusion to achieve urine output of >2 mL/kg/h and pH of >8.0 (pH is more important than diuresis)

    Hemodialysis for severe toxicity or poorly tolerated medical therapy

    Theophylline

    Therapeutic range 10-20 µg/mL (56-111 µmol/L), but toxicity can occur in this range

    Nausea, nervousness, tachycardia, CNS stimulation, hypertension, tachypnea, seizures, atrial arrhythmias, hypokalemia, hyperglycemia, ventricular arrhythmias, status epilepticus

    Activated charcoal can be given

    Charcoal hemoperfusion is treatment of choice, but hemodialysis can also be used if hemoperfusion is not available; cardioversion, seizure control, airway management, electrolyte correction

    Tricyclic antidepressants

    Levels do not correlate well with toxicity; better to follow clinical signs and symptoms

    Sudden or delayed onset of seizures, severe arrhythmias, hypotension, rhabdomyolysis, and kidney failure

    Bicarbonate infusion titrated to QT interval improvement on ECG (note that sodium loading is more important than alkalinization); benzodiazepines for seizures

    Hemodialysis is not effective; monitor and correct electrolytes closely; defibrillation; pacing for bradycardia (avoid atropine or catecholamines)

    CNS = central nervous system; ECG = electrocardiogram; GI = gastrointestinal; IV = intravenously; PO = by mouth.

    Source: MKSAP 16

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