Strange and Schafermeyer's Pediatric Emergency Medicine, Fourth Edition (Strange, Pediatric Emergency Medicine) 4th Ed.



Cardiovascular Drugs

Scott M. Leikin

Jerrold B. Leikin


• β-Blocker and calcium channel blocker poisoning have significant morbidity, and their hallmark is bradycardia and hypotension.

• If standard Pediatric Advance Life Support Protocols (PALS) do not restore adequate cardiovascular function, stepwise administration of glucagon, hyperinsulinemia–euglycemia therapy (HIE) and lipid emulsion should be considered.

• Administration of specific anti-digoxin Fab antibody fragments is a highly effective treatment for digoxin poisoning.

• Consider naloxone if PALS protocols fail to reverse clonidine toxicity.


In 2011, the American Association of Poison Control Centers documented 3.229 β-blocker exposures in children younger than 5 years and 723 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.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 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 produces 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.58 Drugs with significant membrane-stabilizing properties include propranolol, acebutolol, 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 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 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. 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 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.11CNS depression can be a consequence of 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-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.


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.


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 112). 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.15An 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 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 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. 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.1619

The protocol for HIE is 1 unit/kg regular insulin intravenous bolus followed by 0.5 units/kg/h intravenous infusion.1719 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.

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.2224 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.2528 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. Clinical experience of this protocol in children has been limited.


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.29,30 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 2011 the American Association of Poison Control Centers documented 1326 calcium channel blocker exposures in children younger than 5 years and 278 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.1


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.3234 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.


Most calcium channel blockers undergo hepatic metabolism with extensive first pass effect, have a large volume of distribution, and are highly protein bound.31,35 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 exceed 3 L/kg and 80%, respectively.35 Almost all agents are primarily eliminated through the kidneys.


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.


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. 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 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


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.


The effects of calcium channel blocker ingestion can 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. Whole bowel irrigation can be considered for asymptomatic patients who present early after ingesting a sustained-release formulation, but should be avoided in patients with unstable vital signs.37 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.35,3840 Atropine may be helpful for patients with symptomatic bradycardia or heart block. Isoproterenol or pacemaker devices may also be useful. A trial of glucagon is reasonable to treat hypotension, especially when coingestion with a β-blocker is suspected.35 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 is usually required for significant ingestions.

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.4143 The evidence in support of HIE is limited to animal studies, adult case reports, and case series.9,4148 Despite this limitation, given the lack of alternative therapies, HIE should be utilized early for severe calcium channel blocker overdose.16,45,49,50 The protocol for HIE is outlined in the previous β-blocker toxicity section.

ILE as described in the previous section has been utilized to treat verapamil or diltiazem overdose although clinical experience has been limited to patients greater than 18 years old.5153 The dose is as outlined in the previous β-blocker toxicity section.

Interventions such as intra-aortic balloon pump, ECMO, or cardiac bypass are considerations for patients with toxicity refractory to all other therapy.4244 Hemodialysis, hemofiltration, and hemoperfusion are unlikely to be effective for calcium channel blocker overdose. 5456 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.35


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.


Digoxin is used for the treatment of congestive heart failure and supraventricular dysrhythmias. There are several plants that contain cardiac glycosides (digoxin-like substances), including foxglove, oleander, lily of the valley, and red squill. The introduction of digoxin-immune Fab fragments as a specific antidote has reduced the morbidity and mortality of this poisoning. In 2011, the American Association of Poison Control Centers documented 190 cardiac glycoside exposures in children aged less than 5 years and 26 in children between the ages of 6 and 19 years. The incidence of pediatric cardiac glycoside exposures have been declining in recent years; in fact, no pediatric deaths solely due to cardiac glycoside exposure reported to Poison Centers in 2011.1


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 alpha subunit of the Na+-K+ ATPase pump in the membrane of myocardial cells. 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. Enhancement of vagal activity and decreased AV nodal conduction also occur. Due to automaticity and conduction disturbances, re-entrant tachydysrhythmias are common.

There are numerous factors that predispose the patient to digoxin toxicity, the most common of which is electrolyte imbalance.57 Both hypokalemia and hyperkalemia can increase the likelihood of developing digoxin toxicity. Hyperkalemia, due to an egress of potassium 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.58


Oral digoxin is well absorbed by passive diffusion in the upper small intestine.35 The onset of action is within 1 to 2 hours. The elimination half-life in full-term neonates, infants, and children are approximately 40, 20, and 35 hours, respectively. The volume of distribution also varies with age; in neonates, the volume of distribution is 7.5 to 10 L/kg, whereas in older children it is approximately 16 L/kg. Excretion is primarily renal for digoxin.35


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.58

In the acute setting, patients tend to have more dramatic, clinical, and laboratory parameters than in chronic toxicity. Symptoms can be abrupt, with marked 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.59

As a substrate of CYP3A4, several medications administered concurrently with digoxin may result in digoxin toxicity. These include macrolide antibiotics (especially clarithromycin), propafenone, quinidine, famciclovir, fluoxetine, and cimetidine.60

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.61

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. Other than bidirectional ventricular tachycardia, there is no single pathognomonic rhythm. Lethal cardiac disturbances rarely occur in children with normal hearts, but serious AV conduction disturbances can occur.62


A history of the exact amount of digoxin ingested is extremely helpful. An exposure 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.5863 In an overdose situation, the level is most helpful if obtained ≥6 hours after the ingestion. The therapeutic serum digoxin range is between 0.8 and 1.8 ng/mL. However, there is poor correlation between the digoxin level and clinical manifestations. In an acute overdose, a level as high as 2.6 ng/mL may not correlate 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 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 ECG.


Digoxin-intoxicated patients can be highly unstable. All patients require a secure airway, intravenous access, and cardiac monitoring. If the patient has ingested a potentially toxic dose less than 1 hour before being assessed, administer activated charcoal. Indications for digoxin-specific Fab antibody fragments include an acute ingestion of greater than 0.1 mg/kg (or over 4 mg total), a digoxin level of greater than 10.0 ng/mL following acute ingestion, potassium greater than 5 mEq/L in adults or over 6 mEq/L in children, or the presence of a life-threatening dysrhythmia. In chronic digoxin poisoning, significant toxicity may occur at much lower serum concentrations; thus, antidotal therapy should be considered in chronic ingestions resulting in steady state serum digoxin levels of over 6 ng/mL in adults, or over 4 ng/mL in children. 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. Specific guidelines for dosing Fab fragments are available on the package insert.

Allergic reactions to Fab fragments are rare with a pruritic rash or facial swelling most often reported.64 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 elevated for several days, because the bound digoxin is measured along with the free drug.65,66 Certain laboratories can assay-free digoxin levels which avoids this problem.

In addition to the administration of Fab fragments, standard treatment of hyperkalemia, dysrhythmias, or AV blocks is indicated.

Atropine (0.02 mg/kg with a maximum single intravenous dose of 0.5 mg in young children or 1 mg in adolescents) or temporary pacing may be necessary while awaiting Fab fragment effects. 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 be used only 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 (<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.


In 2011, the American Association of Poison Control Centers documented 1926 clonidine exposures in children younger than 5 years and 1646 in 6- to 19-year-olds. Use of clonidine has been increasing, especially in children.1Traditionally, clonidine hydrochloride has been used to treat mild-to-moderate hypertension. Over the past several years it has been utilized to treat opiate withdrawal (especially in neonatal abstinence syndrome), adjunctive therapy for pain control, migraine prophylaxis, impulse control disorder, and attention-deficit/hyperactivity disorder.67 It is also used as a chemical submissive agent, especially in Russia.35


Clonidine stimulates α2-adrenergic receptors in the brainstem, thus, activating neural inhibition, which results in decreasing sympathetic outflow. The cardiovascular effects of such inhibition include a decrease in vasomotor tone and bradycardia. Formulations include tablets (both immediate release and extended release), injection for epidural use and transdermal patch. An oral solution for use in neonatal abstinence syndrome or pediatric use can be compounded.68,69


The onset of action after the ingestion of conventional tablets is usually within 1 hour while the duration can last 6 to 10 hours. Symptom development following ingestion of extended-release tablets may not occur until approximately 5 hours after ingestion.70 Clonidine is lipid soluble and distributes readily into extravascular sites with a volume of distribution of 2.1 L/kg. Protein binding is 20% to 40%. It is metabolized in the liver to inactive metabolites. The half-life elimination in individuals with normal renal function is 6 to 20 hours; in renal impairment half-life can be as long as 40 hours. This is due to the fact that elimination is primarily urinary with 32% of the drug being excreted as unchanged. The usual therapeutic serum reference range is approximately 1 to 2 ng/mL.35 Serum clonidine levels in excess of 67 ng/mL have been associated with serious toxicity.69


The signs and symptoms of acute clonidine poisoning mirror those of opiate overdose. Central nervous system depression may be quite pronounced and can be associated with respiratory depression including intermittent apneic episodes. Sinus bradycardia is often present and may be associated with a first-degree AV block along with hypotension, which may be profound. Hypertension can be an initial manifestation in ingestions over 7 mg. Pupils are usually pinpoint.70 The patient may also exhibit hyporeflexia, and hypothermia can occur in severe cases; however, these signs usually resolve within 8 hours. Xerostomia may occur. Visual hallucinations may occur in patients with chronic toxicity. Onset of symptoms is typically within 30 minutes of ingestion and usually peaks at 2 to 4 hours. As little as a single dose of clonidine (0.1 mg or 0.01 mg/kg) may cause toxic effects on a toddler.35,70,71,72


If the patient has ingested a potentially toxic dose less than 1 hour before being assessed, administer activated charcoal. If extended-release tablets or multiple clonidine patches are ingested, whole bowel irrigation may be considered.73 Manage airway, breathing and circulation as per PALS protocols. Monitor vital signs and oxygen saturation. If symptomatic bradycardia develops, then atropine at 15 μg/kg intravenously may be given. Administer crystalloid for hypotension. If the patient does not respond then vasopressor support is indicated, norepinephrine 0.1 to 0.2 μg/kg/min intravenously titrated to response. Hemodialysis would not be expected to be of benefit.

Naloxone has been reported to reverse clonidine toxicity; however, these effects are inconsistent. It can be considered for the treatment of clonidine-induced hypotension, central nervous system depression, or apnea. It appears that naloxone is approximately 31% effective in this regard, and rebound hypertension would not be expected to occur following its admission.35 The dose of naloxone is 0.01 to 0.1 mg/kg intravenously titrated to effect.35


Symptomatic patients should be admitted to an intensive care unit. Asymptomatic patients should be observed for 4 to 6 hours after the ingestion of conventional tablets and up to 24 hours after the ingestion of modified-release tablets or patches.


1. Bronstein AC, Spyker DA, Cantilera LR Jr, Rumack BH, Dart RC. 2011 Annual Report of the American Association of Poison Control Centers’ National Poisoning and Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila). 2012;12:911–1164.

2. Frishman WH. Clinical differences between beta-adrenergic blocking agents: Implications for therapeutic substitution. Am Heart J. 1987;113(5):1190–1198.

3. Katz AM. Selectivity and toxicity of antiarrhythmic drugs: molecular interactions with ion channels. Am J Med. 1998;104(2):179–195.

4. Frishman WH. Clinical significance of beta 1-selectivity and intrinsic sympathomimetic activity in a beta-adrenergic blocking drug. Am J Cardiol. 1987;59(13):33F–37F.

5. Henry JA, Cassidy SL. Membrane stabilising activity: a major cause of fatal poisoning. Lancet. 1986;1(8495):1414–1417.

6. Love JN, Enlow B, Howell JM, Klein-Schwartz W, Litovitz TL. Electrocardiographic changes associated with beta-blocker toxicity. Ann Emerg Med. 2002;40(6):603–610.

7. Frishman W, Jacob H, Eisenberg E, Ribner H. Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 8. Self-poisoning with beta-adrenoceptor blocking agents: recognition and management. Am Heart J. 1979;98(6):798–811.

8. Weinstein RS. Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med. 1984;13(12):1123–1131.

9. Brubacher J. β-Adrenergic agonists. In: Hoffman RS, Nelson LS, Howland M, et al., eds. Goldfrank's Toxicologic Emergencies. 8th ed. New York, NY: McGraw-Hill; 2007: Chapter 59.

10. Hohnloser SH, Woosley RL. Sotalol. N Engl J Med. 1994;331(1):31–38.

11. Reith DM, Dawson AH, Epid D, Whyte IM, Buckley NA, Sayer GP. Relative toxicity of beta blockers in overdose. J Toxicol Clin Toxicol. 1996;34(3):273–278.

12. Delk C, Holstege CP, Brady WJ. Electrocardiographic abnormalities associated with poisoning. Am J Emerg Med. 2007;25(6):672–687.

13. Pollack CV Jr. Utility of glucagon in the emergency department. J Emerg Med. 1993;11(2):195–205.

14. Taboulet P, Cariou A, Berdeaux A, Bismuth C. Pathophysiology and management of self-poisoning with beta-blockers. J Toxicol Clin Toxicol. 1993;31(4):531–551.

15. Yagami T. Differential coupling of glucagon and beta-adrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol. 1995;48(5):849–854.

16. Kerns W II. Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am. 2007;25(2):309–331.

17. Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High dose insulin therapy in beta-blocker and calcium channel blocker poisoning. Clin Toxicol (Phila). 2011:49(4):277–283.

18. Megarbane B, Karvo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calcium channel antagonist and beta-blocker overdose. Toxicol Rev. 2004:23(4):215–222.

19. Stellpflug SJ, Harris CR, Engebretsen KM, Cole JB, Holger JS. Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high dose insulin. Clin Toxicol (Phila). 2010:48(3):227–229.

20. Kenyon CJ, Aldinger GE, Joshipura P, Zaid GJ. Successful resuscitation using external cardiac pacing in beta adrenergic antagonist-induced bradyasystolic arrest. Ann Emerg Med. 1988;17(7):711–713.

21. Lane AS, Woodward AC, Goldman MR. Massive propranolol overdose poorly responsive to pharmacologic therapy: use of the intra-aortic balloon pump. Ann Emerg Med. 1987;16(12):1381–1383.

22. Rooney M, Massey KL, Jamali F, Rosin M, Thomson D, Johnson DH. Acebutolol overdose treated with hemodialysis and extracorporeal membrane oxygenation. J Clin Pharmacol. 1996;36(8):760–763.

23. Saitz R, Williams BW, Farber HW. Atenolol-induced cardiovascular collapse treated with hemodialysis. Crit Care Med. 1991;19(1):116–118.

24. Salhanick SD, Wax PM. Treatment of atenolol overdose in a patient with renal failure using serial hemodialysis and hemoperfusion and associated echocardiographic findings. Vet Hum Toxicol. 2000;42(4):224–225.

25. Jamaty C, Bailey B, Lorocque A, Notebaert E, Sanogo K, Chauny JM. Lipid emulsions in the treatment of acute poisoning: a systemic review of human and animal studies. Clin Toxicol (Phila). 2010:48(1):1–27.

26. Meehan TJ, Gummin DD, Kostic MA, et al. Beta blocker toxicity successfully treated with intraneous fat emulsion: a case series. Clin Toxicol (Phila). 2009:47(7):734.

27. Cave GR, Harvey MG. Lipid emulsion may augment early blood pressure recovery in a rabbit model of atenolol toxicity. J Med Toxicol. 2009:5(1):50–51.

28. Harvey MG, Cave GR. Intralipid infusion ameliorates Propranolol-induced hypotension in rabbits. J Med Toxicol. 2008:4(2):71–76.

29. Love JN. Beta blocker toxicity after overdose: When do symptoms develop in adults? J Emerg Med. 1994;12(6):799–802.

30. Love JN, Howell JM, Litovitz TL, Klein-Schwartz W. Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol. 2000;38(3):275–281.

31. Pitt B. Diversity of calcium antagonists. Clin Ther. 1997;19(suppl A):3–17.

32. Taira N. Differences in cardiovascular profile among calcium antagonists. Am J Cardiol. 1987;59(3):24B–29B.

33. Barrett TD, Triggle DJ, Walker MJ, Maurice DH. Mechanism of tissue-selective drug action in the cardiovascular system. Mol Interv. 2005;5(2):84–93.

34. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol. 1984;24:387–423.

35. Leikin JB, Palouchek FP, eds. Poisoning and Toxicology Handbook. 4th ed. Boca Raton, FL: CRC Press; 2008.

36. Levine M, Boyer EW, Pozner CN, et al. Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med. 2007;35(9):2071–2075.

37. Cumpston KL, Aks SE, Sigg T, Pallasch E. Whole bowel irrigation and the hemodynamically unstable calcium blocker overdose: primum non nocere. J Emerg Med. 2010:38(2):171–174.

38. Yuan TH, Kerns WP 2nd, Tomaszewski CA, Ford MD, Kline JA. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol. 1999;37(4):463–474.

39. Wolf LR, Spadafora MP, Otten EJ. Use of amrinone and glucagon in a case of calcium channel blocker overdose. Ann Emerg Med. 1993;22(7):1225–1228.

40. Haddad LM. Resuscitation after nifedipine overdose exclusively with intravenous calcium chloride. Am J Emerg Med. 1996;14(6):602–603.

41. Kline JA, Raymond RM, Leonova ED, Williams TC, Watts JA. Insulin improves heart function and metabolism during non-ischemic cardiogenic shock in awake canines. Cardiovasc Res. 1997;34(2):289–298.

42. Hadjipavlou G, Hafeez A, Messer B, Hughes T. Management of lecanidiphine overdose with hyperinsulinaemic euglycaemia therapy: case report. Scand J Trauma Resuscitation and Emergency Med. 2011:19(8):1–5.

43. Agarwal A, Yu SW, Rehman A, Henkle JQ. Hyperinsulinemia euglycemia therapy for calcium channel blocker overdose: a case report. Tex Heart Inst J. 2012:39(4):575–578.

44. Boyer EW, Shannon M. Treatment of calcium-channel-blocker intoxication with insulin infusion. N Engl J Med. 2001;344(22):1721–1722.

45. Boyer EW, Duic PA, Evans A. Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning. Pediatr Emerg Care. 2002;18(1):36–37.

46. Rasmussen L, Husted SE, Johnsen SP. Severe intoxication after an intentional overdose of amlodipine. Acta Anaesthesiol Scand. 2003;47(8):1038–1040.

47. Marques M, Gomes E, de Oliveira J. Treatment of calcium channel blocker intoxication with insulin infusion: case report and literature review. Resuscitation. 2003;57(2):211–213.

48. Harris NS. Case records of the Massachusetts General Hospital. Case 24–2006. A 40-year-old woman with hypotension after an overdose of amlodipine. N Engl J Med. 2006;355(6):602–611.

49. Ortiz-Munoz L, Rodriguez-Ospina LF, Figueroa-Gonzalez M. Hyperinsulinemic-euglycemic therapy for intoxication with calcium channel blockers. Bol Asoc Med P R. 2005;97(3 Pt 2):182–189.

50. Lheureux PE, Zahir S, Gris M, Derrey AS, Penaloza A. Bench-to-bedside review: hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers. Crit Care. 2006;10(3):212.

51. Liang CW, Diamond SJ, Hagg DS. Lipid rescue of massive verapamil overdose: a case report. J Med Case Rep. 2011:5:399.

52. Montiel V, Gougnard T, Hantson P. Dilitazem poisoning treated with hyperinsulemic euglycemic therapy and intravenous lipid emulsion. Eur J Emerg Med. 2011:18:121–123.

53. French D, Armenian P, Ruan W, et al. Serum verapamil concentrations before and after intralipid therapy during treatment of an overdose. Clin Toxicol (Phila). 2011:49(4):340–344.

54. Holzer M, Sterz F, Schoerkhuber W, et al. Successful resuscitation of a verapamil-intoxicated patient with percutaneous cardiopulmonary bypass. Crit Care Med. 1999;27(12):2818–2823.

55. Frierson J, Bailly D, Shultz T, Sund S, Dimas A. Refractory cardiogenic shock and complete heart block after unsuspected verapamil-SR and atenolol overdose. Clin Cardiol. 1991;14(11):933–935.

56. Hendren WG, Schieber RS, Garrettson LK. Extracorporeal bypass for the treatment of verapamil poisoning. Ann Emerg Med. 1989;18(9):984–987.

57. Williamson KM, Thrasher KA, Fulton KB, et al. Digoxin toxicity: an evaluation in current clinical practice. Arch Intern Med. 1998;158:2444–2449.

58. Kelly RA, Smith TW. Recognition and management of digitalis toxicity. J Am Coll Cardiol. 1991;17:590.

59. Sekkul EA, Kaminer S, Sethi KD. Digoxin-induced chorea in a child. Mov Disord. 1999;14(5):877–879.

60. Gomes T, Mamdani MM, Jourlink DN. Macrolide-induced digoxin toxicity: a population-based study. Clin Pharm Ther. 2009;86(4):383–386.

61. Haynes, K, Hennessy S, Localio AR, et al. Increased risk of digoxin toxicity following hospitalization. Pharmacoepidemiol Drug Saf. 2009:18(1):28–35.

62. Wells TG, Young RA, Kearns GL. Age-related differences in digoxin toxicity and its treatment. Drug Saf. 1992;7:135–151.

63. Lewis RP. Clinical use of serum digoxin concentrations. Am J Cardiol. 1992;69:97G–107G.

64. Woolf AD, Wenger TL, Smith TW, Lovejoy FH Jr. Results of multicenter studies of digoxin-specific antibody fragments in managing digitalis intoxication in the pediatric population. Am J Emerg Med. 1991;9(2 suppl 1):16–20.

65. Valdes R Jr, Jortani SA. Monitoring of unbound digoxin in patients treated with anti-digoxin antigen-binding fragments: a model for the future? Clin Chem. 1998;44:183–185.

66. Eyer F, Steimer W, Muller C, Zilker T. Free and total digoxin in serum during treatment of acute digoxin poisoning with fab fragments: case study. Am J Crit Care. 2010:19(9):387–391.

67. Duong S, Chung K, Wigal SB. Metabolic, toxicological and safety considerations for drugs used to treat ADHD. Expert Opin Drug Metab Toxicol. 2012:8(5):543–552.

68. Leikin JB, MacKendrick WP, Maloney GE, et al. Use of clonidine in the prevention and management of neonatal abstinence syndrome. Clin Toxicol (Phila). 2009:47(6):551–555.

69. Faroogi M, Seifert S, Kunkel S, et al. Toxicity from a clonidine suspension. J Med Toxicol. 2009;5(3):130–133.

70. Klein-Schwartz W. Trendy and toxic effects from pediatric clonidine exposures. Arch Pediatric Adolesc Med. 2002;156(4):392–396.

71. Benson BE, Spyker DA, Troutman WG, Watson WA. TESS-based dose-response using pediatric clonidine exposures. Toxicol Appl Pharmacol. 2006;213(2):145–151.

72. Sinha Y, Cranswick NE. Clonidine poisoning in children: a recent experience. J Ped Child Health. 2004;40(12):678–680.

73. Horowitz R, Mazor SS, Aks SS, Leikin JB. Accidental clonidine patch ingestion in a child. Am J Ther. 2005:12(3):272–274.