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Management of Specific Overdoses

Lauren Chen

Overview

There are 5 main classes of drugs/toxins that induce bradycardia and hypotension (ABCDO)

  • Alpha-2 agonist
  • Beta-blockers
  • Calcium channel blockers
  • Digoxin and cardiac glycosides
  • Acetylcholinesterase inhibitors (Organophosphates)

Key Points:

  • Physical exam, labs, and ECG can be helpful in determining the class of drug/toxicant
  • Ensure physical exam includes vitals (including RR) pupils, heart/lung exam, abdominal exam including bowel sounds, and peripheral pulses
  • Obtain a blood glucose to differentiate beta blocker (hypoglycemia or normoglycemia) versus calcium channel blocker (hyperglycemia) toxicity

Alpha-2 Agonists

Background

  • Examples: Clonidine, dexmedetomidine, guanfacine, tizanidine, methyldopa
  • Mechanism: Centrally acting inhibition of norepinephrine release decreased noradrenergic activity

Evaluation

  • Physical Exam: Early/transient HTN, attenuated sympathetic response (decreased HR, BP), opioid toxidrome (pinpoint pupils, CNS depression, respiratory depression)
  • Laboratory abnormalities: None associated with overdose
  • ECG: Sinus bradycardia

Management

  • IVF and high dose naloxone
  • Naloxone may reverse the CNS and respiratory depression as well as hypotension
  • Vasopressors such as norepinephrine/epinephrine are used if naloxone does not work

Quick dosing reference:

  • Naloxone 10mg IVP followed by 5 mg/hr if there is no response

Beta blockers (BB’s)

Background

  • Mechanism: Competitively block catecholamines at beta-adrenergic receptors decreased inotropy and chronotropy; impaired gluconeogenesis and glycogenolysis
  • Lipophilic BB’s (propranolol, metoprolol): Cross the blood brain barrier -> CNS depression
  • Membrane stabilizing BB’s (propranolol): QRS prolongation, dysrhythmias, and seizures
  • Sotalol: Potassium channel blocking properties QTc prolongation and dysrhythmias

Evaluation

  • Physical Exam: CNS depression, seizures, myocardial depression, respiratory depression
  • Laboratory abnormalities: Hypoglycemia or normoglycemia
  • ECG: Sinus bradycardia, AV block (low grade), QRS widening (propranolol), QTc prolongation (sotalol)

Management

  • IVF, Calcium
  • Glucagon: Stimulates adenylcyclase increased cAMP increase HR and BP
  • Epinephrine or Norepinephrine should be first line vasopressors
  • Intralipid infusion if refractory HoTN or pt codes from a lipophilic BB (i.e. Propranolol)
  • BB induced arrhythmias: Sodium bicarbonate (adjunct QRS widening) and Mg for QTc prolongation induced Torsades de pointes
  • Hemodialysis for significant sotalol toxicity

Quick dosing reference:

  • Calcium: 3g calcium gluconate
  • Glucagon:
    • 10 mg over 10 min (vomiting occurs if administered too fast)
    • Infusion 3-5 mg/h (need infusion as half-life is 6 minutes)
  • Atropine: 0.5-1mg q3-5min
  • Intralipid (Lipid Emulsion) 20% infusions: 1.5 cc/kg bolus followed by 0.25 cc/kg/min for 60 minutes (for 70 kg adult: 1 liter over 1 hour) for refractory hypotension or if patient codes), max dose is 10 ml/kg or 1200 ml whichever is greater however, there is limited guidance on a max dose - if using lipid emulsion therapy, please call Toxicology or Poison Control immediately

Calcium channel blockers (CCB’s)

Background

  • Two categories: Dihydropyridines (DHP) and non-dihydropyridines (Non-DHP)
  • DHP (amlodipine, nifedipine): Peripheral > central channels, selectivity is lost in overdose
  • Non-DHP (diltiazem, verapamil): Primarily cardiac calcium channels
  • Mechanism:
    • DHP: arterial vasodilation reflex tachycardia
    • Non-DHP: peripheral vasodilation, decreased inotropy, bradycardia. Calcium mediated insulin inhibition in the pancreas hyperglycemia

Evaluation

  • Physical Exam: Markedly preserved mental status until patient is about to code
  • Labs: Hyperglycemia (elevated serum glucose concentrations are associated with severe overdose and sequelae)
  • ECG: Bradyarrhythmia, high-degree heart block (3rd degree)

Management

  • IVF, vasopressors if needed
  • Bradycardia: Atropine (not effective for second- or third-degree block), calcium, glucagon
  • Hypotension + bradycardia:
    • High dose insulin/euglycemic therapy (HIE)
    • Give with dextrose. Titrate insulin like a pressor. Blood pressure may take up to 20 minutes to change
    • May increase contractility through increasing the cardiac utilization of glucose. Not likely to help with vasodilation or bradycardia
  • Vasopressors (norepinephrine or epinephrine). May consider phenylephrine for DHT induced vasoplegic shock with tachycardia
  • Intralipid should be used in code/refractory hypotensive situations for lipophilic CCB’s (verapamil, amlodipine, diltiazem)
  • Methylene blue for refractory distributive shock can be considered, but consult toxicology prior to using

Quick dosing reference:

  • Calcium: 3g calcium gluconate
  • Glucagon
    • 10 mg over 10 min (vomiting occurs if administered too fast; max 10 mg/hr)
    • Infusion 3-5 mg/h (need infusion as half-life is 6 minutes)
  • Atropine: 0.5-1mg q3-5min
  • If hypotensive and bradycardic:
    • High-dose insulin 0.5-1 unit/kg bolus followed by 0.5-1 unit/kg/hour infusion titrated to up to 10 units/kg/ hour. Call Toxicology immediately if exceeding 3 units/kg/hour.
    • Intralipid infusions: 20% infusions: 1.5 cc/kg bolus followed by 0.25 cc/kg/min for 60 minutes (for 70 kg adult: 1 liter over 1 hour) for refractory hypotension or if patient codes), max dose is 10 ml/kg or 1200 ml whichever is greater however, there is limited guidance on a max dose - if using lipid emulsion therapy, please call Toxicology or Poison Control immediately.

Digoxin and Cardiac Glycosides

Background

  • Examples: Digoxin, yellow oleander, lanatoside C, foxglove, lily of the valley, bufo toads
  • Mechanism: Blockade of Na/K ATPase increased intracellular calcium increased contractility and may delay after depolarizations/shorten repolarization of the atria and ventricles trigger arrhythmias; increased vagal tone

Evaluation

  • Physical Exam: Lethargy, nausea, vomiting, reported yellow halos in visual fields (chronic)
  • Laboratory abnormalities: Hyperkalemia (marker of acute toxicity although does not cause; correlates with mortality)
  • ECG: Any abnormality (though Afib RVR is unlikely, more likely to have a regular pulse due to 3rd degree block in the setting of Afib), biventricular tachycardia is classic but rarely seen

Management

  • Digoxin fab fragments
    • Indications: Hemodynamic instability, significant unstable arrhythmia, end organ damage secondary to hypoperfusion (renal failure), or potassium ≥5.0 mEq/L
    • It can also be indicated for pts with high post distribution digoxin levels even if they are asymptomatic. However, please contact poison control/toxicology for guidance.
  • For pts with severe symptomatic bradycardia when digoxin fab fragments are not available, atropine is recommended but will likely not be effective
  • Given the sensitivity of the myocardium with digoxin, pacers can trigger significant dysrhythmias and only recommended if no access to digoxin fab fragments or fab fragment failure

Quick reference dosing:

  • Digoxin fab fragments: Number of vials = [(serum level times the weight of the patient)/100] rounded up. Empiric treatment 10 vials. NOTE: In acute on chronic toxicity or chronic toxicity, please contact the Poison Center or Medical Toxicology for guidance as less vials may be recommended to try to avoid adverse events from worsening heart failure or atrial fibrillation
    • Unclear dosing for natural toxins (often empirically 10 vials for an adult)
  • Atropine (if digoxin fab fragments are not available): 0.5-1mg q3-5min

Acetylcholinesterase Inhibitors

Background

  • Examples: Organophosphates (e.g. insecticides), carbamates, physostigmine, rivastigmine, donepezil
  • Mechanism: Inhibition of the breakdown of acetylcholine increased acetylcholine stimulation of muscarinic and nicotinic receptors

Evaluation

  • Physical Exam:
    • Muscarinic: Diarrhea/Diaphoresis, Urination, Miosis, Bronchorrhea/Bronchospasm, Bradycardia, Miosis, Emesis, Lacrimation, Salivation (DUMBBELS mnemonic)
    • Nicotinic: Fasciculations, muscle weakness, and/or muscle paralysis
    • Intermediate syndrome: Neurologic syndrome after resolution of cholinergic excess, decreased DTR, proximal muscle weakness, respiratory insufficiency, neck flexion weakness, CN abnormalities
  • Laboratory abnormalities: Standard lab tests are not helpful.
  • ECG: Sinus bradycardia, QTc prolongation

Management

  • Atropine, Pralidoxime, Benzodiazepines
  • Secretions: Titrate atropine to dry secretions (can require large amounts i.e. 50 mg).
  • Bronchorrhea: Atropine as below; excessive watery mucous from the lungs can cause patients to drown in their own secretions
  • Organophosphate poisoning: Pralidoxime to reactivate the acetylcholinesterase enzyme
  • Seizures: Benzodiazepines

Quick dosing reference

  • Atropine: 1-2 mg (mild-moderate symptoms) vs 3-5mg (severe) IV repeated every 2-20 minutes or 1mg followed by doubling doses every 5 minutes until bronchorrhea is no longer present followed by an infusion 10-20% of the loading dose per hour (max 2 mg/hour)
  • Pralidoxime: 30mg/kg (max 2g) loading dose followed by 8-10 mg/kg/hr (max 650mg/hr); WHO dosing is 2000 mg bolus followed by 500 mg/hr infusion. Pralidoxime use for other acetylcholinesterase inhibitors should be used only with Poison Control/Medical Toxicology guidance

Alcohol

Background

  • One standard drink = 12oz regular beer = 5oz wine = 1.5oz 80% distilled spirit
  • Absorption primarily in duodenum/small intestine (80%) with 80-90% of absorption in \<60 min in ideal conditions (i.e. empty stomach)
  • Mechanism: Metabolism via alcohol dehydrogenase. Withdrawal due to CNS overactivity from decreased inhibitory tone (GABA) and unregulated excess excitation (glutamate binding to NMDA, dopamine)

Evaluation

  • Physical Exam:
    • Intoxication: Slurred speech, disinhibition, incoordination, unsteady gait, memory impairment, nystagmus, stupor, coma, hypotension, tachycardia
    • Wernicke encephalopathy: Encephalopathy, oculomotor dysfunction, gait ataxia
    • Withdrawal: Anxiety, agitation, restlessness, insomnia, tremor, diaphoresis, palpitations, HA, n/v, hallucinations (onset 12-24h after last drink), seizures (12-48hr), DTs (72-96hr)
  • Laboratory abnormalities: EtOH level, Peth, UDS, hypoglycemia, hyperlactatemia, hypoK, hypoMg, hypoCa, hypophos

Management

  • Intoxication: Supportive care
  • Withdrawal: Thiamine, folate, multivitamin, IV fluid for intravascular depletion
  • Psychomotor agitation: Benzodiazepines (long-acting preferred) including diazepam, lorazepam, and chlordiazepoxide. Lorazepam for acute alcoholic hepatitis/liver dysfunction.
  • Seizures: CIWA scoring and benzodiazepines. If h/o DTs, consider phenobarbital taper. If status, consider escalation to propofol

Quick dosing reference:

  • Diazepam: 5-10mg IV every 5-10min until appropriate sedation (severe) or per CIWA protocol
  • Lorazepam: 2-4mg IV every 15-20min or per CIWA protocol
  • Thiamine: Administer before glucose containing fluids. WE prevention 100mg IV QD x3d. For WE 500mg IV TID x3d followed by 250mg QD x3d, then 100mg QD.

Opioids

Background

  • Examples: Natural opiates (morphine, codeine), semi-synthetic (hydrocodone, hydromorphone, oxycodone, oxymorphone, heroin, buprenorphine), synthetic opioids (fentanyl, meperidine, tramadol)
  • Mechanism: Multiple receptors with wide range of clinical effects including sedation, analgesia, respiratory depression, GI dysmotility, bradycardia, miosis, anxiolysis

Evaluation

  • Physical Exam
    • Intoxication: AMS, miosis, hypoventilation, decreased bowel sounds, seizures, coma
    • Withdrawal: Mydriasis, yawning, piloerection, diaphoresis, rhinorrhea, increased BS
  • Laboratory abnormalities: None specific to opioid toxicity
  • ECG: QT prolongation (loperamide, methadone, very large doses of oxycodone), QRS widening (loperamide)

Management

  • Intoxication: Supplemental oxygenation/ventilation support, naloxone, ACLS
    • IV naloxone preferable. However, if no IV access, apneic, or patient in critical condition, can use intranasally or IM. Switch to IV when able
    • Consider alternative etiologies of respiratory depression if no response after 10mg
  • Withdrawal: COWs scoring and protocol
    • Symptom control: ondansetron (nausea, vomiting), loperamide (diarrhea), hydroxyzine (anxiety), methocarbamol (cramps), dicyclomine (abdominal cramps)
    • Acute, severe: Methadone or buprenorphine, do NOT use for iatrogenic withdrawal (i.e following naloxone administration)
    • Iatrogenic or patients trying to overcome addition: Clonidine taper

Quick dosing reference

  • Intranasal naloxone: 4 or 8mg as single dose in one nostril. Repeat q2-3min, alternating nostrils
  • IV naloxone: 0.4-2mg q2-3min. Consider initial lower dose (0.04-0.2mg) in patients with opioid dependence to avoid withdrawal or if concerned for concomitant stimulant overdose. However, if apneic, use higher doses, if mildly bradypneic in a known chronic user, can try smaller doses repeated every 2 minutes until patient is breathing at a normal rate while using bag mask ventilation to support the patient
  • Methadone 10mg IM or 20mg PO. Usually need to discuss with psych to give.
  • Buprenorphine 4-8mg sublingual. If symptoms persist after 60min, can give subsequent dose. Maximum 24mg in 24hr. Usually need to discuss with psych to give.
  • Clonidine 0.1-0.3mg every hour until symptom resolution, maximum 0.8mg per 24hr

Sodium Channel Blockers

Background

  • Examples: Class I antiarrhythmics, tricyclic antidepressants (amitriptyline, imipramine) anticonvulsants (carbamazepine, lamotrigine), cocaine, insecticides
  • Mechanism: decreases depolarization of non-nodal cardiac myocytes
  • Consider other concomitant effects (e.g. TCA with anticholinergic and K channel blockade)

Evaluation

  • Physical Exam: Depends on ingestion
  • Pure Na channel blockade: classically bradycardia but sodium channel blocking drugs often have anticholinergic properties resulting in tachycardia
  • TCAs: typically tachycardia, cardiogenic shock, hypotension, AMS, seizures, respiratory depression, anticholinergic symptoms
  • Laboratory abnormalities: No specific abnormalities
  • ECG: QRS widening, QTc prolongation, ventricular dysrhythmia (Vfib, Vtach, TdP), new right axis deviation

Management

  • Sodium bicarbonate (mainstay)
    • Indications: hypotension, QTC >100ms, QT prolongation
    • Mechanism: increases serum pH and extracellular Na to help offload Na channels
    • Goal pH: 7.5-7.55
  • Magnesium if arrhythmias refractory to sodium bicarb
  • IVF and vasopressor support as needed
  • TCA toxicity: consider lipid emulsion (discuss with poison control prior)

Quick dosing reference

  • Sodium bicarb: Initial 1-2mEq/kg bolus q5min until pH is 7.45 to 7.55, QRS will hopefully narrow to less than 120 msec at this pH but it may remain prolonged. Then recommend infusion 150mEq in 1L D5W at 150ml/h (contact poison control or toxicology for guidance on discontinuation
  • Intralipid infusions: 20% infusions: 1.5 cc/kg bolus followed by 0.25 cc/kg/min for 60 minutes (for 70 kg adult: 1 liter over 1 hour) for refractory hypotension or if patient codes), max dose is 10 ml/kg or 1200 ml whichever is greater however, there is limited guidance on a max dose - if using lipid emulsion therapy, please call Toxicology or Poison Control immediately