Toxicology

Approach to Drug-Induced Bradycardia and Hypotension

 

There are 5 main classes of drugs/toxins that induce bradycardia and hypotension: 

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

 

Key Points:

  • Mnemonic: ABCDO (O for Organophosphates but this is under acetylcholinesterase inhibitors) 
  • Physical exam, ECG, and laboratory findings determine the class of drug/toxin. 
  • Ensure physical exam includes vitals (including respiratory rate) 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. More labs will be detailed below.  

 

Alpha-2 agonists

Agents such as clonidine act centrally and cause variable release of beta-endorphins and decrease release of norepinephrine.   Extremely large doses can cause initial sympathetic outflow of norepinephrine and cause hypertension (about 30 minutes after overdose) followed by hypotension.

 

Physical Exam: Opioid toxidrome due to release of opioid endorphins (pinpoint pupils, CNS depression, Respiratory Depression)

Laboratory abnormalities: None associated with overdose

ECG: Sinus bradycardia 

 

Treatment: 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:  If hypotensive (do not treat isolated bradycardia):

  • Naloxone 10mg IVP followed by 5 mg/hr if there is no response:
  • Norepinephrine (0.01 to 3 mcg/kg/min – adjust rate per ICU protocol) and if no response:
  • Epinephrine (0.05 to 2 mcg/kg/min – adjust rate per ICU protocol)

*See also MICU/CCU drips for dosing recommendations that are not weight-based and may have lower limits depending on patient mass.

 

 

Beta blockers: 

Background/Mechanism of Action: Beta-blockers competitively block the binding of catecholamines at beta-adrenergic receptors resulting in decreased inotropy and chronotropy. Lipophilic beta blockers (propranolol, metoprolol) cross the blood brain barrier and cause CNS depression. Furthermore, membrane stabilizing beta-blockers (propranolol) can result in QRS prolongation, dysrhythmias, and seizures. Sotalol also has potassium channel blocking properties and which can cause QTc prolongation and dysrhythmias. Blood glucose can be low as beta-blockers impair gluconeogenesis and glycogenolysis. The antidote is glucagon which stimulates adenyl cyclase increasing cAMP and increases the heart rate and blood pressure. 

 

Physical Exam: CNS depression

Laboratory abnormalities:  Hypoglycemia or normoglycemia

ECG: Sinus bradycardia but also low degree AV block (i.e. 1st degree). 

 

Treatment: IVF, the antidote, glucagon, calcium, and vasopressors, and intralipid infusion if refractory hypotension or patient codes from a lipophilic beta-blocker (i.e. Propranolol). Glucagon must given IV and dosing is 5-10mg over 10 min (if you give faster, patients will vomit) bolus followed by infusion of 1-5-mg/hr (max is 10 mg/hr). Norepinephrine or epinephrine should be first line vasopressors. VA-ECMO should be considered as a last resort after medical therapy has failed. Hemodialysis is recommended for significant sotalol toxicity. 

 

Quick dosing reference: if patient is hypotensive and bradycardic:

  • Glucagon: 10 mg over 10 min (vomiting occurs if administered too fast)
  • Infusion 1-5 mg/h (need infusion as half-life is 6 minutes)
  • Vasopressors: Norepinephrine (0.01 to 3 mcg/kg/min – adjust rate per ICU protocol)  or epinephrine (0.05 to 2 mcg/kg/min – adjust rate per ICU protocol)
  • Calcium: 3g calcium gluconate
  • Intralipid infusions for propanolol (1 liter over 1 hour) for refractory hypotension or patient codes

 

 

Calcium channel blockers: 

Background/Mechanism of Action:  Calcium channel blockers are divided into two categories: dihydropyridines and non-dihydropyridines (diltiazem/verapamil). Dihydropyridines affect more peripheral calcium channels and non-dihydropyridines affect more cardiac calcium channels. In overdose, the selectivity for the dihydropyridines is lost. Furthermore, in calcium channel blocker poisoning, the heart changes its energy source from free fatty acids to carbohydrates and it is thought that high-dose insulin therapy helps with carbohydrate metabolism. High-dose insulin therapy may help increase contractility through increasing the cardiac utilization of glucose. It is not likely to help with vasodilation or bradycardia. Physical exam is characterized by remarkably preserved mental status until the patient is peri-code. However, in large overdoses selectivity is lost and patients are often bradycardic. The release of insulin is a calcium mediated process and the inhibition of calcium channels in the pancreas prevents insulin release leading to hyperglycemia.

 

Physical Exam: Markedly preserved mental status until patient is about to code; dihydropyridines: reflex tachycardia with bounding pulses (in some cases)

 

Laboratory abnormalities: Hyperglycemia (glucose >330 is poor prognostic sign)

 

ECG: Can show high-degree heart block (3rd degree and complete AV dissociation)

 

Treatment: IVF, vasopressors, calcium, and high-dose insulin/euglycemic therapy (HIE). 

For HIE, the dosing is 1 unit/kg bolus followed by 1 unit/kg/hour infusion titrated up to 10 units/kg/hour to treat hypotension. Dextrose should be given to maintain euglycemia. This should be titrated as a pressor with the awareness than changes in blood pressure can take about 20 minutes to take effect. Intralipid should be used in code/refractory hypotensive situations for lipophilic calcium channel blockers (verapamil, amlodipine, diltiazem). VA-ECMO should be considered as a last resort after medical therapy has failed.

 

Quick dosing reference: if hypotensive and bradycardic:

  • High-dose insulin 1 unit/kg bolus followed by 1 unit/kg/hour infusion titrated to up to 10 units an hour. Call Toxicology if exceeding 3 units/kg/hour 
  • Vasopressors: Norepinephrine (0.01 to 3 mcg/kg/min – adjust rate per ICU protocol) or epinephrine (0.05 to 2 mcg/kg/min – adjust rate per ICU protocol)
  • Calcium: 3g calcium gluconate
  • Intralipid infusions for verapamil, amlodipine, diltiazem (1 liter over 1 hour) for refractory hypotension or patient codes

 

Digoxin and Cardiac Glycosides:

Background/Mechanism of Action: Digoxin and cardiac glycosides (i.e. digitoxin, yellow oleander, lily of the valley, bufo toads) clinically produce nausea, vomiting, and malaise. They also cause yellow halos in visual fields as a chronic effect. The mechanism of action is blockade of Na/K ATP ase which increases intracellular calcium levels to increase contractility. In acute toxicity, potassium levels are a marker of toxicity and the hyperkalemia seen with digoxin toxicity is not what is causing the fatality. Rather it is the level that signals to the clinician the significance of the block of Na/K ATP ase. In one study, 100% of patients with a potassium level of greater than 5.5 died, approximately 50% died with a level between 5 and 5.5 and everyone lived with a level below 5.0.

 

Physical Exam: Lethargy

Laboratory abnormalities: Hyperkalemia (acute)

ECG:  Any abnormality except atrial fibrillation with rapid ventricular response is unlikely. Classic: Biventricular tachycardia

 

Treatment: Digoxin fab fragments (see criteria below)

Digoxin fab fragments are indicated in hemodynamically unstable patients, patients with significant arrhythmias, and potassium >= 5.0 mEq/L. It can also be indicated for patients with high post distribution digoxin levels even if they are asymptomatic. However, please contact poison control/toxicology for guidance. The dosing of digoxin fab fragments for number of vials is the (serum level times the weight of the patient in kg)/100 rounded up. For patients with severe symptomatic bradycardia when digoxin fab fragments are not available, atropine is recommended, though there is a significantly probability that it will not be effective. However, 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 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.
  • Atropine (for severe symptomatic bradycardia if digoxin fab fragments are not available): 0.5 mg IVP every 3 to 5 minutes to a maximum of 3 mg 

 

 

Acetylcholinesterase Inhibitors: 

Background/Mechanism of Action: Acetylcholinesterase inhibitors include organophosphates (can be in insecticides), carbamates, physostigmine, rivastigmine, and donezepil.  These result in increased acetylcholine which stimulate muscarinic and nicotinic receptors giving the characteristic muscarinic toxidrome described below. Nicotinic stimulation can result in tachycardia as well as muscle paralysis.

 

Physical Exam: Diarrhea/Diaphoresis, Urination, Miosis, Bronchorrhea/Bronchospasm, Bradycardia, Miosis, Emesis, Lacrimation, Salivation. These can be summarized with the mnemonic “DUMBBELS.” 

Laboratory abnormalities:  Standard lab tests are not helpful.

ECG:  Sinus bradycardia

 

Treatment: Atropine, Pralidoxime, Benzodiazepines  

Treatment is with atropine titrated to drying secretions (can require large amounts i.e. 50 mg). 

Bronchorrhea is excessive watery mucous from the lungs and is not the same as excess saliva from drooling. Bronchorrhea is life-threatening as patients essentially drown in their own secretions. Atropine dries secretions and is used to treat bronchorrhea. It is a life-saving intervention. Pralidoxime should be used for organophosphate poisoning to reactivate the acetylcholinesterase enzyme and is also effective against the nicotinic effects of anticholinesterase inhibition. The nicotinic effects of acetylcholinesterase inhibitors can result in muscle weakness. Pralidoxime use for other acetylcholinesterase inhibitors should be used only with Poison Control/Medical Toxicology guidance. Benzodiazepines are recommended for treatment of seizures. 

 

Quick dosing reference: if patient has bronchorrhea:

  • Atropine: 1-3 mg IVP 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: 2g loading dose followed by 1 g/hr infusion  
  • Diazepam: 5-10 mg IV every 10-15 minutes to max dose of 30 mg, can be repeated in 2-4 hours if needed

 

Acknowledgments: Donna Seger, MD and Nena Bowman, PharmD for their review and input of this section.