In 2016, the American Association of Poison Control Centers documented 3076 single substance β-blocker exposures in children younger than 5 years and 832 in 6- to 19-year-olds.¹ Those producing the greatest morbidity were metoprolol, atenolol, and propranolol. β₁– and β₂-receptor antagonism, intrinsic sympathomimetic activity, and membrane-­stabilizing activity are responsible for the clinical effects of these drugs. α-Antagonist activity is seen with labetalol and carvedilol. β-Adrenergic blocking agents account for almost 60% of pediatric emergency department visits due to the ingestion of an adult prescription medication by a child.²

PHARMACOLOGY

The pharmacologic effects of β-blocking drugs are mediated through modulation of intercellular signals and calcium secondary to inhibited adrenergic activation.³ β₁-Antagonism produces decreased cardiac contractility and conduction. β₂-Antagonism produces increased smooth muscle tone, which may manifest as bronchospasm, increased peripheral vascular tone, and increased gut motility. Although many β-blockers are β₁-selective at therapeutic doses, these drugs have both β₁– and β₂-effects in overdose.

Intrinsic sympathomimetic properties of some β-blockers produce agonist–antagonist activity, which may blunt the bradycardic response in some patients.^2,4 Drugs with intrinsic sympathomimetic activity include acebutolol, carteolol, oxprenolol, penbutolol, and pindolol. The membrane-stabilizing activity characteristic of some β-blockers is a quinidine-like effect, resulting in inhibition of fast sodium channels, decreased contractility, and ventricular arryhythmias.⁵ This effect is additive to the β₁-toxic effects.

β-Blockers with increased intrinsic sympathomimetic activity and decreased membrane-stabilizing properties demonstrate less toxicity than those with increased membrane-stabilizing properties.^5–8 Drugs with significant membrane-stabilizing properties include propranolol, acebutolol, and oxprenolol.⁹

Sotalol is a β-blocker that has class III antiarrhythmic properties.¹⁰ In overdose, it may prolong the QT interval, resulting in ventricular arrhythmias, including torsades de pointes. Each β-blocker may have only some of the described activities, and the clinical manifestations may vary.

PHARMACOKINETICS

The absorption, distribution, and elimination of β-blockers vary with the drug. Extended-release formulations can have a marked delay of onset of toxic effects. Conversely, standard release β-blockers are rapidly absorbed, with 30% to 90% bioavailability. Only penbutolol and propranolol exhibit high lipid solubility and thus can cross the blood–brain barrier. Protein binding ranges from 10% (timolol) to 98% (carvedilol). Most are metabolized in the liver by the cytochrome P-450 2D6 isoenzyme. The elimination half-life varies from 2 to 24 hours, but can be significantly increased in overdose.

PATHOPHYSIOLOGY

Toxicity from acute β-blocker overdose largely results from suppression of the cardiovascular system. Negative inotropic and chronotropic effects result in bradycardia and hypotension. Respiratory compromise in β-blocker overdose can result from cardiogenic shock, decreased respiratory drive, or β₂-antagonist effects. β₂-blockade produces bronchospasm, especially in patients with previously diagnosed asthma. Hypoglycemia can occur secondary to β₂-mediated decrease in glycogenolysis and gluconeogenesis; however, it is not common unless there are associated comorbidities or coingestants.¹¹ CNS depression can be a consequence of direct toxicity, hypoxia, hypoglycemia, or shock. Lipophilic drugs which can cross the blood brain barrier (such as propranolol) can also result in CNS toxicity. Topically applied ophthalmic drops such as timolol can cause hypertension in infants.¹²

CLINICAL PRESENTATION

The onset of symptoms can be as rapid as 30 minutes after ingestion, but most commonly occurs within 1 to 2 hours. Cardiovascular manifestations include hypotension, bradycardia, heart block, and congestive heart failure. Electrocardiographic manifestations of toxicity include sinus bradycardia, prolongation of the PR interval, second- and third-degree AV blockade, and interventricular conduction delays.^6,13 The QRS may be prolonged with ingestions of β-blockers with membrane-stabilizing effects. Propranolol and sotalol have been associated with ventricular arrhythmias.¹³ Deaths from β-blocker toxicity are associated with bradydysrhythmias and asystole; ventricular arrhythmias are less common. Respiratory toxicity includes noncardiogenic pulmonary edema, pulmonary edema, exacerbation of asthma, and decreased respiratory drive. Patients may also present with CNS depression or seizures.

LABORATORY EVALUATION

All patients with a history of β-blocker ingestion should be placed on a cardiac monitor and receive an electrocardiogram (ECG). Blood sugar should be checked. Arterial blood gas and chest radiograph may be useful in the patient with respiratory signs or symptoms.

MANAGEMENT

The effects of β-blocker ingestion range from negligible to catastrophic. Decompensation from a well-appearing state can occur abruptly. Patients with normal mental status who have ingested a potentially toxic dose less than 1 hour before being assessed should be treated with activated charcoal. If a potentially toxic dose of a delayed-release preparation has been ingested and the patient is asymptomatic, consider whole bowel irrigation (see Chapter 113). In the event of significant toxicity, standard PALS resuscitation techniques including advanced airway management should be utilized, followed by focused therapies for β-blocker toxicity.

Glucagon is the agent of choice in β-blocker ingestions resulting in hypotension or bradycardia.^13,14 Glucagon binds to its own receptor site, triggering cAMP-signaling pathways, bypassing the cellular lesion at the β-receptor.¹⁵ An initial bolus of glucagon is administered intravenously at a dose of 0.05 to 0.15 mg/kg IV over 1 minute. If symptoms recur, a repeat bolus is given. An infusion can be started following the bolus dose, with the effective bolus dose infused per hour. The initial effect is seen within several minutes, and should persist for 10 to 15 minutes. Nausea and vomiting are common side effects of glucagon, which can complicate the management of a patient who may subsequently require intubation.

Adrenergic agents are often effective in increasing heart rate, contractility, and peripheral vascular resistance. In cases of severe cardiovascular drug toxicity, large doses may be required.¹⁶ If the response to glucagon is inadequate, epinephrine, dopamine, or vasopressor may improve both heart rate and blood pressure due to vasodilatory shock.⁸ Norepinephrine is effective in situations with low systemic vascular resistance; however, with the myocardial depression seen with severe β-blockade, alternative agents may be more efficacious.¹⁶ Atropine, 0.02 mg/kg IV (minimum single dose 0.1 mg; maximum cumulative dose 1 mg) may be useful to treat bradycardia. Inamrinone (a phosphodiesterase inhibitor) can be utilized to treat hypotension by increasing cardiac output. The dose is 0.75 mg/kg IV bolus over 2 to 3 minutes followed by a maintenance infusion of 5 to 10 μg/kg/min. The IV bolus can be repeated in 30 minutes.

Hyperinsulinemia-euglycemia (HIE) therapy should be considered early in the critically ill patient. Efficacy of HIE is likely attributable to the metabolic effects of insulin, which result in improvement in blood pressure, systolic and diastolic myocardial performance, and survival time. The evidence in support of HIE is limited to animal studies, adult case reports, and case series.^9,17–19 Despite this limitation, given the lack of alternative therapies, HIE should be utilized early for severe β-blocker overdose.^16–19

The protocol for HIE is 1 unit/kg regular insulin intravenous bolus followed by 0.5 units/kg/h intravenous infusion.^17–19 An intravenous dextrose bolus of 0.25 g/kg followed by an infusion of 0.5 g/kg/h may be initiated; however, patients with significant poisoning are not expected to develop hypoglycemia. Serial blood sugar determinations are followed and the dextrose infusion adjusted accordingly.

Patients with bradycardia and hypotension refractory to pharmacologic intervention may benefit from temporary pacing, although this will not reverse the myocardial depression in severe overdose.^20,21 Interventions such as intra-aortic balloon pump, extracorporeal membrane oxygenation (ECMO), or cardiac bypass are considerations for patients with toxicity refractory to all other therapy.^21,22 Hemodialysis, hemofiltration, and hemoperfusion are rarely useful in the setting of β-blocker overdose. Most of the β-blockers have a large volume of distribution and are highly protein bound, making drug removal by hemodialysis impractical. A few drugs, such as nadolol, sotalol, atenolol, and acebutolol, can be dialyzed, but experience is limited to case reports.^22,24 Hemodialysis can be considered in the setting of renal failure and hemodynamic instability in a drug with low volume of distribution and low protein binding.

Intravenous lipid emulsion (ILE) has also been utilized successfully in conjunction with HIE in treating β-blocker overdoses in animal (rabbit model) and human cases, with amelioration of hypotension and subsequent elevation of mean arterial pressure.^25–29 It is thought to act by binding to lipid-soluble drugs and also by improving cardiac fatty acid transport. The dose is 1.5 mL/kg (20% lipid emulsion) administered over 1 minute followed by an infusion of 0.25 to 0.5 mL/kg/min. The bolus can be repeated, although endpoint/cessation of ILE has not been fully defined.²⁵ Clinical experience of this protocol in children has been limited.

DISPOSITION

A patient with a history of significant immediate-release β-blocker ingestion should be observed on a cardiac monitor for approximately 8 hours after ingestion.³⁰ Patients who have signs of cardiovascular, respiratory, or CNS toxicity are admitted to an intensive care setting. A patient who ingested an immediate-release β-blocker can be medically cleared after the 8-hour observation period if there are no signs of toxicity found by clinical examination, ECG, or cardiac monitoring. Patients with a history of ingestion of extended-release preparations or sotalol should be admitted and monitored for approximately 24 hours.

In 2015 the American Association of Poison Control Centers documented 1245 calcium channel blocker exposures in children younger than 5 years and 777 in 6- to 19-year-olds.¹ Because of recognition of this poisoning in conjunction with intensive management, deaths due to calcium channel blocker overdose have been declining in recent years and rarely occur in the pediatric setting (one death involving calcium channel blockers in children were reported to the American Association of Poison Control Centers in 2016).¹

PHARMACOLOGY

Calcium channel blockers are classified as dihydropyridines, phenylalkylamines, or benzothiazepines. Dihydropyridines include nifedipine, isradipine, amlodipine, felodipine, nimodipine, nisoldipine, and nicardipine. Verapamil is a phenylalkylamine, and diltiazem is a benzothiazepine. Calcium channel blockers work at the L-type calcium channel, effecting automaticity at the sinoatrial node, conduction through the atrioventricular (AV) node, excitation–contraction coupling in cardiac and smooth muscle, as well as pancreatic insulin secretion.^3,31

The clinical effects of the three classes of calcium channel blockers differ for several reasons. They bind at different locations on calcium channel receptor subunits, have preference for different resting cell membrane potentials, and bind as a function of channel state.^32–34 Receptor selectivity translates into the dihydropyridines primarily resulting in vasodilation; the nondihydropyridines have more pronounced effects on cardiac conduction. Verapamil affects myocardial contractility, AV node conduction, and peripheral vascular resistance and is one of the more toxic calcium channel blockers in overdose. Diltiazem slows AV node conduction and causes coronary artery dilatation; it has less effect on peripheral vasculature and myocardial contractility. Nifedipine, a dihydropyridine, has the greatest effect on peripheral vascular resistance. It also decreases cardiac contractility, but has minimal effect on AV node conduction. In overdose, all classes of calcium channel blockers can cause significant peripheral vasodilatation, decreased AV conduction, and decreased myocardial contractility.

PHARMACOKINETICS

Most calcium channel blockers undergo hepatic metabolism with extensive first-pass effect, have a large volume of distribution, and are highly protein bound.³¹ The onset of action for immediate-release preparations is 30 minutes, with a half-life from 3 to 7 hours; this can be greatly increased in the setting of overdose and with sustained-release preparations. It is important to be aware that the onset of life-threatening effects from sustained-release preparations may also be delayed because of their prolonged absorption time. The volume of distribution and protein binding for most calcium channel blockers exceeds 3 L/kg and 80%, respectively. Almost all agents are primarily eliminated through the kidneys.

PATHOPHYSIOLOGY

Calcium channel blockers inhibit the calcium ions entering myocardial cells and vascular smooth muscle through the slow L-type calcium channels.

The clinical effects of calcium channel blocker overdose can be life-threatening. Slowing of the sinus node causes bradycardia. Slowing of conduction can cause heart blocks or asystole. Decreased contractility can cause heart failure and shock. Lowered peripheral vascular resistance leads to hypotension, which may exacerbate the hypotension associated with bradycardia, bradydysrhythmias, and heart failure. Patients with cardiac disease and those on other medications that suppress heart rate and contractility (particularly β-adrenergic blocker or digoxin) may develop severe toxic effects after mild overdose, or even at therapeutic doses.

CLINICAL EFFECTS

The different pharmacologic profiles of calcium channel blockers will cause variation in toxic effects, but in all cases cardiovascular effects predominate. Verapamil and diltiazem typically cause significant bradycardia and hypotension, while amlodipine can result in lethargy and profound hypotension without bradycardia.³⁵ Hypotension may be caused by sinoatrial node depression, AV node depression leading to AV blocks, or decreased peripheral vascular resistance. Sinus arrest may also occur. Nifedipine primarily affects the arterioles, causing decreased peripheral vascular resistance, which leads to hypotension and reflex tachycardia.

Neurologic and respiratory findings are usually secondary to cardiovascular toxicity and shock. Respiratory effects include decreased respiratory drive, pulmonary edema, and acute respiratory distress syndrome (ARDS). Neurologic sequelae include depressed sensorium, cerebral infarction, and seizures. Nausea, vomiting, and constipation can occur, particularly with verapamil. Hyperglycemia occurs frequently with significant overdoses and may correlate with the severity of poisoning.³⁶

LABORATORY EVALUATION

An ECG should be obtained and electrolytes evaluated, specifically Na⁺, Ca²⁺, Mg²⁺, and K⁺. Glucose is evaluated since decreased insulin release can lead to hyperglycemia. Chest radiographs are obtained for patients with respiratory signs or symptoms.