- β-Blockers are rapidly absorbed with the onset of symptoms as soon as 30 minutes after ingestion. Cardiovascular manifestations include hypotension, bradycardia, heart block, and heart failure.
- Absorption of β-blockers can be decreased by the administration of activated charcoal.
- Glucagon may reverse the toxic effects of β-blockers.
- Patients who do not respond to glucagon are treated with aggressive fluid resuscitation, vasopressors, and atropine. Refractory cases may require invasive supportive measures.
- A patient who ingested a non–sustained-release β-blocker can be discharged home after 8 hours of observation if they have a normal exam, mental status, vital signs, and EKG.
- A history of sustained-release β-blocker preparation ingestion requires admission to a monitored setting for 24 hours.
β-Adrenergic Blocking Agents
The mortality rate following β-blocker overdose is much than that for calcium channel blockers or digoxin, but in terms of absolute numbers they are the second leading cause of death from cardiovascular medications.1 American Association of Poison Control Centers data from 2006 indicates 18 853 β-blocker exposures. Two thousand eight hundred and twelve of these involved children younger than 6 years and 712 involved 6- to 19-year-olds. 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.2
The pharmacologic effects of β-blocking drugs are mediated through modulation of intercellular signals and calcium secondary to inhibited adrenergic activation.3 β1-Antagonism causes decreased cardiac contractility and conduction. β2-Antagonism causes 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 causes 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, betaxolol, and oxprenolol.9
Sotalol is a β-blocker which has class III antiarrhythmic properties.10 In overdose, it may prolong the QT interval, resulting in ventricular arrhythmias, including torsades de pointes. Each different β-blocker may have only some of the described activities, and the clinical manifestations may vary.
The absorption, distribution, and elimination of β-blockers vary with the preparation. Extended-release formulations of β-blockers can have a marked delay in the onset of toxic effects. Conversely, standard release β-blockers are rapidly absorbed, with 30% to 90% bioavailability. The elimination half-life varies from 2 to 24 hours, but can be significantly increased in overdose.
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 causes bronchospasm, and usually affects 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 caused by direct toxicity, hypoxia, hypoglycemia, or shock.
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.6,12 The QRS may be prolonged with ingestions of β-blockers with membrane-stabilizing effects. Propranolol and sotalol have been associated with ventricular arrhythmias.12 Deaths from β-blockers 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.
All patients with a history of β-blocker ingestion are placed on a cardiac monitor and receive an electrocardiogram (ECG). Laboratory tests for blood levels of β-blockers are available from reference laboratories but are not helpful in the acute setting. Serum electrolytes are obtained. Serum glucose is assessed. Arterial blood gas and chest radiograph may be useful in the patient with respiratory signs or symptoms.
The effects of β-blocker ingestion range from negligible to catastrophic. A well-looking patient should not be reassuring, since they can decompensate quickly. Patients with normal mental status should be decontaminated with activated charcoal. Gastric lavage has limited utility, and should only be used in patients with potentially life threatening ingestions who present within 1 hour of ingestion. 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 and/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 and dopamine may improve both heart rate and blood pressure.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 for bradycardia.
Bradycardia and hypotension refractory to pharmacologic intervention may benefit from temporary pacing, although this will not reverse the myocardial depression in severe overdose.17,18 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.18,19 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.19–21 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.
A patient with a history of immediate-release β-blocker ingestion is observed on a cardiac monitor for 8 hours after ingestion.22,23 Patients who have signs of cardiovascular, respiratory, or CNS toxicity are admitted to an intensive care setting. Patients with a history of ingestion of extended-release preparations or sotalol are admitted and monitored for 24 hours. 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.
- Onset of symptoms in calcium channel blocker overdose can be as soon as 30 minutes after ingestion. Time to onset can be greatly increased with sustained-release preparations.
- Absorption of calcium channel blockers can be decreased by the administration of activated charcoal.
- In all cases of calcium channel blocker overdose, cardiovascular effects predominate.
- For calcium channel blocker overdose with hypotension that persists despite the administration of fluids, calcium salts and glucagon, therapy with vasopressors is indicated.
- High-dose insulin therapy is effective in the management of refractory calcium channel blocker overdose.
- An asymptomatic patient who ingested a non–sustained-release calcium channel blocker can be medically cleared after an 8-hour observation period.
- Ingestion of a sustained-release calcium channel blocker preparation requires admission and monitoring for at least 24 hours.
Calcium Channel Blockers: Introduction
The American Association of Poison Control Centers annual report indicated 10 031 calcium channel blocker exposures in 2006. 1363 exposures occurred in children younger than 6 years and 234 occurred in those aging between 6 and 19 years. 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.
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 node, excitation–contraction coupling in cardiac and smooth muscle, as well as pancreatic insulin secretion.3,24
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.25–27 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, 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.
Most calcium channel blockers undergo hepatic metabolism with extensive first pass effect, have a large volume of distribution, and are highly protein bound.24,28 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 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, bradyarrhythmias, and heart failure. Hyperglycemia occurs frequently with significant overdoses, and may correlate with the severity of poisoning.29 Patients with cardiac disease and those on other medications that suppress heart rate and contractility may develop severe toxic effects after mild overdose, or even at therapeutic doses.
The different pharmacologic profile of calcium channel blockers will cause variation in toxic effects, but in all cases cardiovascular effects predominate. Verapamil and diltiazem typically cause bradycardia and hypotension. Hypotension may be caused by sinoatrial node depression, atrioventricular node depression leading to AV blocks, or decreased peripheral vascular resistance. 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 ARDS. Neurologic sequelae include depressed sensorium, cerebral infarction, and seizures. Nausea, vomiting, and constipation can occur.
Drug levels for calcium channel blockers are available by reference laboratories but are not helpful in an acute overdose. An ECG is obtained. Electrolytes are 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. An abdominal radiograph may be useful in patients with a history of ingesting sustained-release tablets, since some calcium channel blockers are radiopaque, and concretions can occur.
The effects of calcium channel blocker ingestion range from negligible to catastrophic. A well-looking patient should not be reassuring, since they can decompensate quickly. Patients with normal mental status should be decontaminated with activated charcoal. Gastric lavage has limited utility, and should only be used in patients with potentially life threatening ingestions who present within 1 hour of ingestion. Whole bowel irrigation can be considered for asymptomatic patients who present early after overdosing on a sustained-release formulation, but it should be used with great caution as there is no evidence of improved outcomes with whole bowel irrigation, and it may complicate the management of patients who subsequently become hypotensive. In the event of significant toxicity, standard PALS resuscitation techniques, including advanced airway management, apply, followed by focused therapies for calcium channel blocker toxicity.
Following initial resuscitation, therapy focuses on enhancing calcium channel function. However, treatment may have little effect when the calcium channel is severely poisoned.30–33 Calcium salts increase extracellular calcium concentration, and may reverse hypotension because of vasodilation, especially in less severe overdoses. However, improvement is usually transient in the serious overdose setting, and there is little or no effect on heart rate or conduction. Atropine may be helpful for patients with symptomatic bradycardia or heart block. Isoproterenol or pacemaker devices may be useful. A trial of glucagon is reasonable when coingestion with a β-blocker is suspected. It is not as effective for calcium channel blocker poisoning as it is for β-blocker poisoning. Nausea and vomiting are frequent side effects of glucagon. This becomes relevant in the patient who may subsequently require intubation.
Vasopressors should be utilized early for patients who do not respond to intravenous fluid, calcium, and atropine. An agent with combined α- and β-effects, such as high-dose dopamine or norepinephrine, is appropriate. Phenylephrine and dobutamine may also be effective. More than one agent may be required.
Hyperinsulinemia–euglycemia therapy (HIE) 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.34 The evidence in support of HIE is limited to animal studies, adult case reports and case series.9,35–39 Despite this limitation, given the lack of alternative therapies, HIE should be utilized early for severe calcium channel blocker overdose.16,36,41
The protocol for HIE is 1 unit/kg regular insulin intravenous bolus followed by 0.5 units/kg/hr intravenous infusion.41 An intravenous dextrose bolus of 0.25 gm/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. Potassium is monitored and replaced to maintain serum potassium levels at 2.8 to 3.2 mEq/L.
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.42–44 Hemodialysis, hemofiltration, and hemoperfusion are unlikely to be effective for calcium channel blocker overdose. Most calcium channel antagonists have a large volume of distribution, are highly protein bound, and subject to hepatic metabolism making them poor candidates for extracorporeal removal.
Patients who have signs of cardiovascular, respiratory, or CNS compromise are admitted to an intensive care unit. Patients with a history of sustained-release ingestion are observed for at least 24 hours. Those patients with no signs of toxicity, no history of sustained-release ingestion, and no ECG abnormalities can be observed for 8 hours after the time of ingestion. If they do not develop any signs of toxicity or ECG abnormalities during this period, they may be medically cleared.
- Plants that contain cardiac glycosides include foxglove, oleander, lily of the valley, and red squill.
- Digoxin acts by poisoning the Na+-K+ ATPase pump in the heart. High serum potassium may be seen after acute overdose.
- A toxic dose of greater than 0.1 mg/kg may be an indication for antidotal therapy.
- Both hyperkalemia and hypokalemia can predispose to digoxin-induced cardiac dysrhythmias.
- Almost any cardiac dysrhythmia may be seen with digoxin toxicity. Accelerated junctional rhythms, premature ventricular contractions (PVCs), paroxysmal atrial tachycardia, and atrioventricular blocks are more commonly seen rhythms in this setting.
- Atropine is effective for digoxin-induced bradycardia.
- Calcium chloride, potassium, and bretylium should be avoided in treating digoxin toxicity.
- Digoxin immune Fab fragments are indicated in any patient exhibiting a life-threatening dysrhythmia, regardless of the digoxin level.
Digoxin is used today for the treatment of congestive heart failure and supraventricular dysrhythmias. In addition, there are several plants that contain cardiac glycosides (digoxinlike substances), including foxglove, oleander, lily of the valley, and red squill.
Historically, mortality because of digoxin overdose has been related to the type of cardiac arrhythmia induced by toxicity and the degree of associated hyperkalemia. Mortality rates of 68% for patients exhibiting digoxin-induced sustained ventricular tachycardia and 100% for ventricular fibrillation were noted prior to the development of digoxin immune Fab fragments. According to the American Association of Poison Control Centers, in 2007 there were a total of 2610 cardiac glycoside ingestions. Of these 293 were in children aging 6 years, 52 were in children between the ages of 6 and 19 years, and there were a total of 22 deaths in all age groups (accounting for almost half of all deaths because of cardiovascular drug ingestions)1
Digoxin is a positive inotrope that increases the force and velocity of myocardial contractions. In the failing heart, it can increase the cardiac output and decrease elevated end-diastolic pressures.
On the cellular level, digoxin presumably functions by binding to and inactivating the Na+-K+ ATPase pump in the heart. This results in increased intracellular sodium concentration. In addition, enhanced contractility depends on intracellular ionized calcium concentrations during systole. At toxic concentrations, it is felt that intracellular calcium concentrations are markedly increased, and that the membrane potential is unstable, which leads to dysrhythmias.
There are numerous factors that predispose the patient to digoxin toxicity, the most common of which is electrolyte imbalance.45 Both hypokalemia and hyperkalemia can increase the possibility of developing digoxin toxicity. Hyperkalemia in particular can result in significant conduction delays. Hypokalemia is common in patients on diuretic therapy and can predispose patients to the effects of chronic digoxin toxicity. Hypomagnesemia, hypercalcemia, renal insufficiency, and underlying heart disease all predispose to digoxin toxicity.46
The presentation of digoxin toxicity is highly varied, and depends largely on whether it results from an acute overdose or is a manifestation of chronic toxicity.46
In the acute setting, patients tend to have more dramatic, clinical, and laboratory parameters than in chronic toxicity. Symptoms can be abrupt, with severe nausea, vomiting, and diarrhea. Associated complaints include weakness, headache, paresthesias, and altered color perception. Cardiovascular symptoms include palpitations and dizziness that may be secondary to hypotension. Movement disorders may also be present.47
Patients with chronic toxicity tend to have more vague complaints, although many of the symptoms of acute overdose also occur. Malaise, anorexia, and low-grade nausea and vomiting are common. Patients with chronic toxicity tend to be more symptomatic at lower levels than those with acute overdoses.
Cardiovascular toxicity is the most important factor in determining morbidity and mortality. There are multiple dysrhythmias associated with digoxin toxicity, the most common being frequent premature ventricular beats. Other dysrhythmias can be supraventricular, nodal, or ventricular. Common disturbances are junctional escape beats and accelerated junctional rhythm, paroxysmal atrial tachycardia with AV block, and AV block of varying degrees. There is no single pathognomonic rhythm. Lethal cardiac disturbances rarely occur in children with normal hearts, but serious AV conduction disturbances can occur.48
A history of the exact amount of digoxin ingested is extremely helpful. A dose greater than 0.1 mg/kg is an indication that serious consequences can occur.
A serum digoxin level is indicated whenever there is clinical suspicion of toxicity.46,49 In an overdose situation, the level is most accurate if obtained ≥6 hours after the ingestion. The therapeutic digoxin range is between 0.8 and 1.8 ng/mL. Unfortunately, there is poor correlation between the digoxin level and clinical manifestations. In an acute overdose, a level as high as 2.6 ng/mL does not correlate well with toxicity. In a chronic overdose, toxicity can occur at lower levels. The fatality rate approaches 50% when the serum digoxin level exceeds 6 ng/mL.
Other necessary laboratory studies include a complete blood count, serum electrolytes, calcium, magnesium, blood urea nitrogen, and creatinine. Cardiac monitoring is essential, as is a 12-lead electrocardiogram.
Digoxin-intoxicated patients can be highly unstable. All patients require a secure airway, intravenous access, and cardiac monitoring. (See Fig. 116-1 for initial evaluation and treatment of digoxin toxicity.)
Flow chart for initial evaluation and treatment of acute digoxin toxicity.
Syrup of ipecac is contraindicated and should not be used because of the potential for sudden hemodynamic instability, deterioration of consciousness, and the subsequent potential for vomiting and aspiration. Gastric lavage has limited utility, and should only be used in patients with potentially life-threatening ingestions who present within 1 hour of ingestion. Activated charcoal is indicated as a single dose. Multiple doses of charcoal have been reported to be of value for digitoxin preparations in which there is avid enterohepatic circulation, and may be of value for digoxin. However, the advent of Digibind has supplanted consideration for enhanced elimination with MDAC. Whole-bowel irrigation should be avoided in patients with potential for hemodynamic instability.
Digoxin immune Fab fragments are specific antidigoxin antibodies derived from sheep. In order to decrease the risk of immunogenicity, only the Fab fragment is used.50 Specific indications include an ingestion of greater than 0.1 mg/kg, a digoxin level of greater than 10.0 ng/mL, potassium greater than 5 mEq/L, or the presence of a life-threatening dysrhythmia. In chronic digoxin poisoning significant toxicity may occur at much lower serum levels. Standard modalities to treat hyperkalemia may also be used, with the exception of calcium salts. In the face of digoxin toxicity the administration of calcium may exacerbate the development of dysrhythmias.
The dose of Fab fragments is based either on the amount ingested or on the serum level. Each vial of Fab fragments contains 38 mg of protein that will bind 0.6 mg of digoxin. Specific guidelines for dosing Fab fragments are available on the package insert.
Allergic reactions to Fab fragments are rare.50 Skin testing can be performed, but is usually not necessary. In cases where Fab fragments have been effective, results have been achieved 30 minutes to 4 hours after administration. After administration of Fab fragments, subsequent digoxin levels will be falsely elevated for several days, because the bound digoxin is measured along with the free drug.51 Certain laboratories can assay free digoxin levels which avoids this problem.
In addition to the administration of Fab fragments, standard treatment of dysrhythmias or AV blocks is indicated. Atropine or temporary pacing may be necessary to temporize while Fab fragments are taking effect. Cardioversion and lidocaine are appropriate in the event of ventricular tachycardia or fibrillation. Treatment with intravenous phenytoin or magnesium sulfate has been shown to be useful in digoxin-induced tachydysrhythmias. Drugs to avoid in the treatment of digoxin-induced cardiac toxicity include calcium, bretylium tosylate, sotalol, isoproterenol, and quinidine. Direct-current cardioversion should only be used as a last resort for unstable, life-threatening arrhythmias. If utilized, it should be dosed at the lowest energy possible.
Diuresis, hemodialysis, and hemoperfusion do not aid in the removal of digoxin or digitoxin. Plasma exchange is also not expected to be useful.
Children with trivial ingestions (less than 0.05 mg/kg) who are asymptomatic and have no detectable levels of digoxin 4 hours after the ingestion can be discharged from the emergency department after 6 hours of observation. Any child with signs or symptoms of toxicity is admitted to a pediatric intensive care unit.