- USES: Used primarily to treat hypertension. Also used as a treatment for akathisia, essential tremor, hypertrophic subaortic stenosis, pheochromocytoma, stable angina, tachydysrhythmias, thyrotoxicosis, congestive heart failure, congenital heart conditions, and for migraine headache prophylaxis and variceal hemorrhage prophylaxis. Bimatoprost/timolol and travoprost/timolol ophthalmic combinations are indicated for the reduction of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma. Refer to beta-blocking agents document for more information. PHARMACOLOGY: Inhibition/competitive blockade of beta-adrenergic receptors. TOXICOLOGY: The toxicity of beta-blockers is an extension of their therapeutic effects. They cause bradycardia, heart-block and hypotension. Propranolol has sodium channel blocking properties and may cause ventricular dysrhythmias. EPIDEMIOLOGY: Poisoning is uncommon but can be very severe. May occur via oral, intravenous or ophthalmic administration. MILD TO MODERATE POISONING: Decreased heart rate and hypotension. SEVERE POISONING: Atrioventricular blocks, intraventricular conduction delays, and congestive heart failure can occur with more severe poisoning. Coma and cardiopulmonary arrest can develop secondary to severe hypotension/bradycardia. Bronchospasm may develop, particularly in patients with asthma or COPD, and respiratory depression may develop in patients with severe hypotension. Propranolol is highly lipid-soluble and may cross the blood brain barrier and cause seizures. Propranolol may cause QRS widening resulting in ventricular dysrhythmias due to sodium channel blockade. Renal failure and pulmonary edema may develop in patients with prolonged hypotension. Hypoglycemia may develop in diabetics or those with decreased glycogen stores (eg, children, fasting, exercising); manifestations of hypoglycemia (tremor, tachycardia) may be masked by clinical effects of beta-blocker toxicity. OCULAR EXPOSURE: Ophthalmic preparations containing beta-blockers may cause systemic manifestations. ONSET: Symptoms usually occur within 6 hours, but can be as early as 20 minutes and may be delayed with sustained release products. ADVERSE EFFECTS: Hypotension, bradycardia, first-degree heart block, dizziness, fatigue, depression, pruritus, rash, diarrhea, dyspnea, bronchospasm, hypoglycemia, and seizures are among the adverse effects. Superficial punctate keratitis, corneal erosion, burning sensation, eyelid pruritus, eye dryness, eye pain, photophobia, eye discharge, visual disturbances, eyelid erythema, and blepharal pigmentation have been reported in up to 10% of patients receiving bimatoprost/timolol ophthalmic solution. Eye pain, ocular discomfort, dry eye, and eye pruritus have been reported in up to 10% of patients receiving travoprost/timolol maleate (polyquaternium-1-preserved).
Range of Toxicity:
- TOXICITY: The toxic dose is variable depending on the particular agent. The following ingestions should be considered potentially toxic: ACEBUTOLOL: ADULT: greater than 600 mg; CHILD: greater than 12 mg/kg. ATENOLOL: ADULT: greater than 200 mg; CHILD: greater than 2 mg/kg. CARVEDILOL: ADULT: greater than 50 mg; CHILD: greater than 0.5 mg/kg. LABETALOL: ADULT: greater than 400 mg; CHILD: greater than 20 mg/kg. METOPROLOL: ADULT: greater than 450 mg IR or greater than 400 mg SR; CHILD: greater than 2.5 mg/kg IR or greater than 5 mg/kg SR. NADOLOL: ADULT: greater than 320 mg; CHILD: greater than 2.5 mg/kg. PROPRANOLOL: ADULT: greater than 240 mg; CHILD: greater than 4 mg/kg IR, or greater than 5 mg/kg SR. TIMOLOL: ADULT: greater than 30 mg (tablets); CHILD: any amount.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Place patient on a cardiac monitor, give fluids for hypotension, and atropine for bradycardia. MANAGEMENT OF SEVERE TOXICITY: Perform early orotracheal intubation for airway protection if the patient has altered mental status. Initially manage hypotension with intravenous fluids (500 mL boluses up to 2L) and atropine for symptomatic bradycardia. Glucagon should be considered if the patient does not respond appropriately to intravenous fluids. Give catecholamines to those who do not respond to intravenous fluids and glucagon. No one catecholamine has been shown to be consistently effective; dopamine, norepinephrine and epinephrine may be considered. High doses may be required. If catecholamines are required despite glucagon and intravenous fluids, high-dose insulin euglycemia should be considered. Catecholamines should be titrated down when high-dose insulin euglycemia therapy starts to take effect. Intravenous lipid emulsion should be considered in patients with refractory hypotension. Other non-pharmacological therapies include: cardiac pacing, placement of an intraaortic balloon pump, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO). Seizures (rarely progress to status epilepticus) may require aggressive use of benzodiazepines (e.g. 1 to 2 mg lorazepam IV and increase as needed) and/or propofol. Monitor for dysrhythmias and treat accordingly.
- Decontamination: PREHOSPITAL: Activated charcoal if recent, substantial ingestion, and patient able to protect airway. HOSPITAL: Activated charcoal if recent, substantial ingestion, and patient able to protect airway. After airway protection consider gastric lavage in recent, large ingestion, or whole bowel irrigation.
- Airway management: Perform early in a patient with severe intoxication (depressed mental status, seizures, dysrhythmias).
- Hypotensive episode: Initially manage hypotension with intravenous fluids (500 mL boluses up to 2L) and atropine for symptomatic bradycardia.
- Antidote: GLUCAGON: Patients who do not respond to intravenous fluids (500 mL boluses up to 2L) and atropine should be treated with glucagon. Initial dosing is 5 to 15 mg by slow IV push followed by an infusion rate of 5 to 15 mg/hour. Glucagon may also induce nausea/vomiting, as well as elevate blood glucose.
- Insulin: High-dose insulin euglycemia (HIS) may be considered in patients who do not respond adequately to fluids and catecholamines. HIS is another potential therapy with some positive animal data and case-based human evidence. Administer a bolus of 1 unit/kilogram of insulin followed by an infusion of 0.1 to 1 units/kilogram/hour, titrated to a systolic blood pressure of greater than 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to titrate insulin infusion. High-dose insulin euglycemia therapy may allow the practitioner to decrease the dose of catecholamines and avoid the adverse effects of prolonged high dose catecholamines. Before, during, and after the therapy, monitor for hypoglycemia and hypokalemia. Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (Adult: 25 to 50 mL dextrose 50%; Children: 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hour in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. As the patient improves, insulin resistance abates and dextrose requirements will increase. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued. Administer supplemental potassium initially if patient is hypokalemic (serum potassium less than 2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium of 2.5 to 2.8 mEq/L.
- Fat Emulsion: Another potential pharmacological treatment is with lipid emulsion therapy, though at this point in time, there is only animal data supporting its use in beta-blocker toxicity; in theory it may be effective for lipid soluble beta blockers such as propranolol. The dose of 20% lipid emulsion is 1.5 mL/kg over 1 minute followed immediately with an infusion at a rate of 0.25 mL/kg/min, and to repeat the bolus dosing every 3 to 5 minutes up to 3 mL/kg total dose until circulation is restored. If BP declines, increase the infusion rate to 0.5 mL/kg/min. A maximum dose of 8 mL/kg is recommended. For example, the resuscitation of an adult weighing 70 kg is equivalent to taking a 500 mL bag of 20% lipid emulsion and drawing up 50 mL twice and giving it IV push, and then attaching the infusion bag to an IV and running it in over 15 minutes.
- Inamrinone: A phosphodiesterase inhibitor which also has theoretical benefit via decreasing breakdown of myocardial cAMP. The dosing is 1 mg/kg bolus then 3 to 6 mcg/kg/minute. It is very rarely used because, although it increases inotropy, it may induce peripheral vasodilation and is difficult to titrate due to a relatively long half-life.
- Calcium: Calcium chloride has been effective for propranolol, concurrent administration of atenolol and verapamil, and a mixed metoprolol/verapamil overdose that were refractory to conventional therapy. Administer calcium chloride 0.2 mL/kg or calcium gluconate 0.6 mL/kg intravenously.
- Bradycardia: Atropine, glucagon (50-150 mcg/kg bolus followed by an infusion 1-5 mg/hr), and pacemaker.
- Seizure: Seizures (may rarely progress to status epilepticus) may require aggressive use of benzodiazepines (e.g. 1-2 mg lorazepam IV and increase as needed) and/or propofol.
- Conduction disorder of the heart: QRS widening or ventricular tachycardia may respond to sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg bolus, repeat as needed; endpoints include resolution of dysrhythmias, narrowing of QRS complex and blood pH 7.45 to 7.55. Use lidocaine (1 mg/kg intravenous bolus followed by 20 to 50 mcg/kg/min intravenous infusion) if sodium bicarbonate is not successful.
- Monitoring of patient: Monitor vital signs and mental status. Specific beta-blocker plasma levels are not clinically useful or readily available. No specific lab work is needed in most patients. Obtain an ECG and institute continuous cardiac monitoring. Monitor serum electrolytes and renal function in patients with significant hypotension or dysrhythmias. Monitor blood glucose in children, diabetics, and patients with altered mentation.
- Enhanced elimination procedure: Hemodialysis and hemoperfusion may be useful for beta blockers with small volumes of distribution such as atenolol, sotalol and nadolol; experience is limited to a few case reports. Hemodialysis and hemoperfusion are not useful for beta-blockers with large volumes of distribution.
- Patient disposition: HOME CRITERIA: Healthy, asymptomatic patients with an inadvertent ingestion of less than or equal to a maximum daily dose for age may be monitored at home. OBSERVATION CRITERIA: Patients with underlying cardiovascular or respiratory disease, those ingesting more than a maximum daily dose, those who co-ingest calcium channel blockers, and those with deliberate overdose of beta-blocking agents should have a baseline ECG and be monitored for a minimum of 6 hours. Patients who develop signs of toxicity during observation should be admitted, while those who are asymptomatic after 6 hours may be discharged, following psychiatric consultation if indicated. Longer observation (at least 8 hours) is required for patients ingesting sustained release products. ADMISSION CRITERIA: Symptomatic patients with cardiovascular symptoms (ie, hypotension, bradycardia) or central nervous system toxicity (ie, somnolence, seizures, coma) should be admitted to an intensive care setting for further observation/treatment and monitored until they are asymptomatic for a prolonged period (several hours) without therapy. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with toxicity (hypotension, seizures, dysrhythmias), or in whom the diagnosis is not clear.