Beta-Blocker Toxicity

Etiology

The etiology of beta-blocker overdose is closely related to the epidemiology of depression and the presence of coexisting medical conditions that are treated with beta-blockers. In one study, patients who overdosed on beta-blockers were more likely to be women (3:1) with a mean age of 30 years. Two-thirds of these patients overdosed on someone else’s medication or were using beta-blockers for noncardiac indications (e.g., migraine, tremor, thyrotoxicosis).[3][4][5]

Epidemiology

In 2015, According to the American Association of Poison Control Center (AAPCC) database, 10,577 single-exposure cases of beta-blockers were reported, 9.6% (1022) cases of which were coded to have moderate to the major outcome. Eighty-two percent (8706) of these exposures were unintentional. The trend of beta-blocker exposure from the National Poison Data System (NPDS) database reveals 118 more exposures in 2015 compared to 2014 but fewer (eight versus 14) fatal cases. Of all the beta-blockers, propranolol accounts for the majority of cases of beta-blocker toxicity.[6]

Pathophysiology

Traditionally, beta-blockers are classified as selective and non-selective depending on the receptor specificity. Specificity is, however, lost in cases involving overdose. To better understand the toxicity, beta-blockers are classified as lipophilic or lipophobic. Highly lipophilic beta-blockers can easily cross the blood-brain barrier and may cause various central nervous system (CNS) manifestations. While CNS manifestations secondary to beta-blocker overdose are primarily attributed to lipophilicity, water-soluble beta-blockers, for example, atenolol, may also cause tiredness and fatigue.  

Various metabolic and circulatory pathways are dependent on circulating catecholamine that, in turn, is switched off by beta-blockade. While hypotension, bradycardia, decreased myocardial contractility and oxygen consumption account for the hemodynamic instability, hypoglycemia secondary to inhibition of glycogenolysis and gluconeogenesis may also occur.

Toxicokinetics

Beta-blockers are readily absorbed when ingested with peak absorption within one to four hours except for sustained-release preparations. Absorption may also be delayed in cases involving the co-ingestion of drugs which can decrease gastrointestinal motility. While most of the beta-blockers are moderately lipophilic, certain beta-blockers have extensive lipophilicity and have a large volume of distribution. Propranolol, the most lipophilic beta-blocker, can easily cross the lipid cell and blood-brain barrier and may cause seizures in overdose cases.

The liver excretes beta-blockers most frequently. Atenolol, carteolol, and nadolol are the only exceptions that undergo renal excretion. Various beta-blockers may cause sodium or potassium channel blockade and therefore cause prolongation in QRS and QTc interval, respectively. Sodium channel blocking beta-blockers are said to possess “membrane stabilizing activity” which potentiates toxicity in overdose.

History and Physical

Practitioners should take a proper history regarding co-ingestions, particularly anticholinergics and cardiotoxic medications. Co-ingestion involving calcium channel blockers (CCB) may cause profound hypotension and cardiotoxicity. Various other cardiotoxic medications, for example, tricyclic antidepressants and antipsychotics, may potentiate beta-blocker toxicity. Underlying medical illnesses especially patients with underlying cardiac diseases are at increased risk of poor outcomes. Different beta-blockers have different half-lives that may range from several minutes to several hours. Therefore, efforts should be made to determine the exact beta-blocker involved.

Evaluation

Bradycardia associated with hypotension may be the first clue to diagnose beta-blocker overdose. In comparison to calcium channel blocker overdose, which may mimic beta-blocker overdose, patients with BB toxicity have hypoglycemia and altered mental status. While symptoms secondary to beta-blocker overdose usually appear early and are commonly observed within one to two hours, the risk of toxicity is greatest up to 20 hours in cases involving sotalol toxicity. The QTc prolongation secondary to sotalol may prolong up to three to four days and may warrant close observation in a unit setting. Correctable causes of QTc prolongations should be investigated, and medications that may prolong QTc should be avoided. Sustained-release preparations and beta-blockers with longer half-lives may require extended monitoring. Vital signs should be monitored, continuously and 12 lead EKG should be done at frequent intervals.[7]

Treatment / Management

Due to intrinsic lipophilicity, certain beta-blockers may cause CNS depression. Prompt management of the airway is, therefore crucial. The airway should be protected with a cuffed endotracheal tube in all deeply obtunded patients. Premedication with atropine may be necessary especially in children since laryngeal manipulation during intubation may cause additive vagal stimulation and bradycardia. Bronchospasm due to beta-blockade may be treated with supplemental oxygen and inhaled bronchodilators like albuterol. Gastrointestinal decontamination with gastric lavage may be necessary for patients who present shortly after massive ingestions and/or with serious symptoms.

Administer activated charcoal to limit drug absorption to patients with minor symptoms who present later than an hour after ingestion. Consider whole bowel irrigation with polyethylene glycol sustained-release preparation and continued until the rectal effluent is clear. Benzodiazepines are the first line of treatment for seizures that may occur due to the high lipophilicity of certain beta-blockers. Prompt recognition of QRS widening and prolongation of QTc interval is crucial.

Administer sodium bicarbonate for QRS widening and magnesium sulfate for QTc prolongation. Although there have been no controlled trials to prove the efficacy of glucagon in poisoning beta-blocker overdose, glucagon is considered as a useful treatment of choice. Premedication with antiemetic may be considered since treatment with glucagon may induce vomiting.

Other possible side effects of glucagon include hypocalcemia and hyperglycemia. Treatment with calcium salts may provide benefits for hypotensive patients who overdosed on beta-blockers alone or in combination with a calcium channel blocker. Cases refractory to fluids, atropine, and glucagon should be considered candidates for high-dose insulin, euglycemia (HIE) treatment. High-dose insulin, euglycemia is a safe and simple way to augment cardiac contractility and does not need invasive monitoring. High-dose insulin, euglycemia can cause profound hypokalemia and hypoglycemia that can potentiate the cardiotoxicity in the setting of beta-blocker overdose.

Potassium and glucose should, therefore, be checked before initiation of high-dose insulin, euglycemia. In general, 1 U/kg of regular insulin bolus along with 0.5 g/kg dextrose intravenously (IV) is administered. Intravenous dextrose bolus should not be administered if the glucose level is more than 400 mg/dL.

Glucose should be monitored every 30 mins initially for up to four hours to maintain strict glycemic control (glucose 100 mg/dL to 200 mg/dL) by starting 10% dextrose infusion and dextrose 50% IV boluses, as needed. Supportive treatment with vasopressors may be needed since the inotropic effect of high-dose insulin euglycemia may be delayed up to 15 min to 60 min. The choice of vasopressor mainly depends on clinical findings. Phosphodiesterase such as inamrinone and milrinone increase the cAMP and may prove beneficial in increasing inotropy.

Prompt initiation of ECMO and continuation of mechanical life support may be needed until the xenobiotic effect wears off. Toxicity secondary to water-soluble and renally excreted beta-blockers (e.g., acebutolol, atenolol, nadolol, and sotalol) may respond to enhanced elimination techniques such as multiple doses activated charcoal, hemoperfusion or hemodialysis.

Differential Diagnosis

• Antidepressant toxicity

• Carbamazepine toxicity

• Cardiac glycoside plant poisoning

• Cocaine toxicity

• Epidural hematoma in emergency medicine

• Hyperkalemia in emergency medicine

• Meningitis

• Shock, cardiogenic

• Torsade de Pointes

• Toxicity, Calcium channel blockers