Calcium Channel Blocker and
Beta Blocker Overdose, and
Digoxin Toxicity Management
W
hile relatively uncommon, an over-dose of calcium channel blockers, beta blockers, or digoxin can result in signifi-cant morbidity and mortality, and manage-ment can be complex. An acute overdose will require different management strategies than chronic toxicity while on therapeutic dosing. Toxicity from these agents must be considered in bradycardic and hypoten-sive patients. This supplement provides an evidence-based overview of emergency de-partment management of calcium channel blocker overdose, beta blocker overdose, and digoxin toxicity, and focuses on the ca-veats of treatment for each.PHARMACOLOGY ::
SEPTEMBER 2020
EXTRA!
Prior to beginning this activity, see the “CME Information“ on page 40.
This supplement is eligible for 4 Pharmacology CME credits. AUTHORS
Wesley Palatnick, MD, FRCPC, FACMT Tomislav Jelic, MD, FRCPC, FACEP
Quick Links
• Emergency Department Evaluation • Laboratory Studies
• Electrocardiography
• Treatment for CCB and Beta Blocker Overdose
• Treatment for Digoxin Toxicity
PHARMACOLOGY EXTRA EDITOR-IN-CHIEF
Christopher Sampson, MD
Associate Professor of Clinical Emergency Medicine, University of Missouri School of Medicine, Columbia, MO
Case Presentations
A 44-year-old man with a history of atrial fibrillation and major depressive disorder presents to the ED via EMS after collapsing at home. His initial vital signs are as follows: blood pressure, 92/40 mm Hg; heart rate, 41 beats/min; respiratory rate, 14 breaths/min; and fingerstick glucose, 112 mg/dL. His GCS score is 15. You begin volume resuscitation, and obtain the patient's history. EMS personnel said they saw an empty pill bottle near where the patient was found, but they did not bring it with them, so the police re-turn to the patient’s home to retrieve the bottle. The patient says that he has not been taking any antidepressants recently, and he has been taking metoprolol for rate control of his atrial fibrillation. Upon completion of your primary survey, and after administering a liter of normal saline, you find the patient’s GCS score has deteriorated to 8, his heart rate to 38 beats/min, and his blood pressure to 84/32 mm Hg. The nurse informs you that she can no longer feel a carotid pulse. Could this be an overdose? What drugs can cause a bradycardic arrest? And how reliable was this pa-tient in reporting his history?
Just then, an 83-year-old woman with generalized weakness and a past medical history of heart failure is brought into the ED by her daughter. She has sinus bradycardia at 33 beats/min, and her blood pressure is 94/52 mm Hg. She states that she was recently started on an ACE inhibitor, and her cardiologist told her that her baseline creatinine clearance has declined significantly. You learn that she is also on digoxin for heart failure, so you order a digoxin level. While waiting for the results, you consider whether this patient’s clinical presentation is an acute indication for digoxin im-mune fab. You also consider what the precipitating factor to her presumed digoxin toxicity might be.
AUTHORS
Wesley Palatnick, MD, FRCPC, FACMT
Professor, Department of Emergency Medicine, University of Manitoba; Attending Physician, Department of Emergency Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada
Tomislav Jelic, MD, FRCPC, FACEP
Assistant Professor, Department of Emergency Medicine, University of Manitoba; Attending Physician, Department of Emergency Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada
PEER REVIEWER
Karan Pratap Singh, MD, MBA, FAAEM
Chief Quality Officer, San Gorgonio Memorial Hospital, Banning, CA; Assistant Professor of Emergency Medicine, Loma Linda University School of Medicine, Loma Linda, CA
Later that evening, a 32-year-old woman is brought to your ED via EMS after her boyfriend found her slumped over in a chair. He states that they were arguing last evening and that she was quite upset. Her boyfriend provides her medical history that is significant for migraine headaches, and he knows that she is taking verapamil for them. Her fingerstick glu-cose is normal, her heart rate is 28 beats/min, and her blood pressure is 74/36 mm Hg. You consider what the best initial step in management of this patient would be and wonder if she overdosed on the verapamil. Is there a role for GI decontamination? What about hemodialysis?
Introduction
Due to the increased prevalence of cardiovascular disease in the United States,1 cardiovascular medications (especially calcium channel blockers [CCBs] and beta blockers) are some of the most prescribed therapeu-tic agents on the market.2 There has also been a rise in the number of toxicity cases from these medications. The 2017 report of the American Association of Poison Control Centers found that cardiovascular medi-cations accounted for > 107,000, or 4.24%, of all toxicity cases reported and nearly 8% of fatalities.3 Of the cardiovascular agents, CCBs were most often implicated in fatal cases, with 37 deaths. The availability of sustained-release formulations of these drugs appears to have contrib-uted to the increase in morbidity and mortality from CCB overdose. Beta blocker toxicity resulted in 18 deaths. Digoxin toxicity was reported in 1851 patients, with 25 deaths.3
Identifying and treating patients exhibiting toxic effects of these agents can be complex. Standard Advanced Cardiovascular Life Support proto-cols used for the resuscitation of patients in cardiac arrest may be insuf-ficient due to the complex physiologic changes that occur with poisoning from these agents, and specialized treatments are often necessary. This supplement presents the current evidence on best practices in the diag-nosis and management of CCB, beta blocker, and digoxin toxicity. Critical Appraisal of the Literature
A search of literature from 1990 to 2020 was conducted in PubMed and Ovid MEDLINE® using the search terms beta blocker toxicity/poisoning, calcium channel blocker toxicity/poisoning, digitalis toxicity/poisoning, and digoxin toxicity/poisoning. The Cochrane Database of Systematic Reviews was also searched. While more than 1000 papers were found, only 144 were of sufficient quality to be included in this review. In an at-tempt to provide the most current recommendations, most studies that were conducted prior to 1990 were excluded. An attempt was made to
use literature with human patients rather than animal models. Perform-ing high-quality randomized studies in the acutely poisoned patient is difficult, which is important to remember when reviewing the toxicology literature. Most of the evidence in the toxicology literature is case re-ports, small studies, or retrospective reviews, which have been included here when necessary.
Pathophysiology and Pharmacokinetics Calcium Channel Blockers
CCBs are used in the treatment of hypertension, cardiac arrhythmias, and angina pectoris. Calcium plays a critical role in intracellular messaging as well as in myocyte contraction. Blocking calcium channels interferes with the intracellular cascade, which then interferes with formation of the actin-myosin complex. The inability to form actin-actin-myosin complexes results in decreased inotropy, chronotropy, and smooth muscle relaxation.
Commonly used CCBs are divided into 3 main classes: (1) dihydropyridines (prototypical agents: nifedipine, amlodipine, nicardipine); (2) phenylal-kylamines (prototypical agent: verapamil); and (3) benzothiazepines (pro-totypical agent: diltiazem).4 Each class exhibits particular affinity for the L-type calcium channels in cardiac myocytes and vascular smooth muscle.5 Agents in the dihydropyridine class bind to L-type calcium channels in vascular smooth muscle, whereas the phenylalkylamines bind to vascular and cardiac L-type calcium channels. CCBs are generally well absorbed in the gastrointestinal tract and undergo significant first-pass metabolism.6 CCBs are metabolized via the cytochrome system; thus, there is a risk for drug-drug interactions.7
The clinical presentation of CCB overdose varies depending on the agent ingested. In the setting of overdose, verapamil and diltiazem cause severe bradycardia and variable heart blocks.5,8-12 Drugs in the dihydropyridine class (including nifedipine) tend to produce hypotension more often than conduction abnormalities, and they can cause a reflex tachycardia soon after overdose.5,6,13,14 In an overdose, receptor selectivity is essentially lost.4 Since CCBs are highly protein bound and have a large volume of distribu-tion, hemodialysis is not helpful in management of overdose.6
Beta Blockers
Beta-adrenergic receptor antagonists are used to treat several medical conditions including hypertension, congestive heart failure, thyrotoxicosis, angina pectoris, acute coronary syndromes, and essential tremor. These agents are available in tablet form, sustained-release formulations, and in combination with other agents.
While several subtypes of beta receptors exist, the beta-1 and beta-2 receptors are of clinical importance. Beta-1 receptors are G-coupled, cyclic adenosine monophosphate (cAMP) receptors and are found primar-ily on cardiac myocytes. Their function is to enhance calcium release from the sarcoplasmic reticulum, thus increasing inotropy and chronotropy.5 Beta blockers interfere with this calcium release from the sarcoplasmic reticulum, and actin-myosin coupling is prevented, resulting in decreased inotropy and chronotropy. Beta-2 receptors are found in the lungs and the vascular smooth muscle. Their mechanism of action is less well under-stood, but activation results in smooth muscle relaxation. Some agents act on both types of beta receptors (eg, propranolol), while others are more selective and bind with greater affinity to the beta-1 receptors (eg, meto-prolol). See Table 1 for a list of selective and nonselective beta blockers.
Table 1. Selective and Nonselective Beta Blockers
Type of Beta Blocker Medication Name
Selective beta blockers • Metoprolol • Esmolol • Atenolol • Bisoprolol • Acebutolol Nonselective alpha and beta blockers • Carvedilol
• Labetalol Nonselective beta blockers • Nadolol
• Propranolol • Sotalol • Timolol • Pindolol
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Additional properties can influence the clinical effects of the various beta blockers. Of note, not all of these properties are present in all agents. Lipophilicity increases drug entry into the central nervous system, which can increase neurologic side effects, including seizures (in therapeutic dos-ing) or decreased level of consciousness (in overdose). The more lipophilic agents will have greater nervous system permeability (eg, propranolol). Some beta blockers (eg, propranolol and acebutolol) exhibit membrane stabilizing activity (MSA), or sodium-channel blockade, which can lead to fatal arrhythmias in the setting of overdose. With therapeutic doses, there is little to no MSA activity; however, in overdose, QRS widening may be seen.15 The inhibition of myocardial fast sodium channels causes QRS widening and increases the potential for other dysrhythmias. MSA is also postulated to contribute to the seizure activity and central nervous system depression seen in overdose of some beta blockers.5 Co-ingestion is an important factor in the development of cardiovascular instability, as many cardiac patients are taking both CCBs and beta blockers, which can lead
to AV node block.16 However, exposure to beta blockers with MSA, even in the absence of co-ingestants, was associated with an increased risk of cardiovascular instability in a 2000 prospective study.16 Older papers have also reported significant mortality in patients who overdosed on beta block-ers with MSA properties.17,18 Though the study populations in these papers were small, they demonstrate the importance of identifying these agents correctly and appreciating their potential for significant complications.
Digoxin
For many years, digoxin has been a first-line treatment of atrial dys-rhythmias and congestive heart failure. Approximately 65% to 80% of a digoxin dose is absorbed, mostly in the gastrointestinal tract. Digoxin has a high volume of distribution, and it is excreted primarily through the kidneys.19 With a half-life of 36 hours and a narrow therapeutic level (0.64-1.2 nmol/mL or 0.5-0.9 ng/mL), digoxin therapy has the potential for serious adverse effects.20,21 One important distinction between di-goxin (available in North America) and digitoxin (available in Europe) is that digitoxin is primarily metabolized via enterohepatic circulation, and, thus, can be used in patients with renal failure.22 Both drugs will still exhibit the same toxic effects in the setting of overdose.
Digoxin functions by blocking the sodium-potassium adenosine triphos-phatase (ATPase) pump, resulting in an increase in intracellular sodium. Higher levels of intracellular sodium increase the resting membrane po-tential, causing a decreased exchange of sodium and calcium. Intracel-lular calcium levels are then increased, resulting in more calcium being released from the sarcoplasmic reticulum, leading to increased contractil-ity of the cardiac muscle cells.23 Digoxin also increases vagal tone and can manifest parasympathomimetic effects (such as bradycardia).21 At toxic concentrations, there is an increase in automaticity in all cardiac cells other than the sinoatrial node due to increased influx of sodium into the cell, which increases phase 4 depolarization. Coupled with a lowered resting membrane potential, this increases the risk of dysrhythmias.24
Drug-drug interactions and electrolyte abnormalities such as hypomagne-semia, hypercalcemia, hypernatremia, and hypokalemia can affect digoxin levels, resulting in a narrow therapeutic window.21,23,25 The postulated mechanisms include: (1) reduction of protein binding of digoxin, result-ing in increased bioavailability; (2) alteration in renal function or electro-lyte levels; and (3) inactivation of P-glycoproteins in the gastrointestinal and genitourinary tracts, resulting in increased digoxin absorption and decreased excretion, respectively.23,25-27 Changes in volume status and electrolyte abnormalities are also associated with the potential to induce digoxin toxicity.23 Additionally, bacteria present within the bowels can
metabolize digoxin to an inactive form. However, the use of antibiotics decreases gut flora, and may result in an increase in digoxin absorption, potentially inducing toxicity.25,28-31
Differential Diagnosis
The differential diagnosis of the bradycardic hypotensive patient is exten-sive, and includes acute coronary syndromes (usually inferior myocardial infarction with various heart blocks), hyperkalemia, endocrine disorders (specifically hypothyroidism), hypothermia, and poisoning. Clonidine and cholinergic toxicity should also be considered.
Prehospital Care
The approach in the prehospital setting is similar to any other acute poison-ing. Airway, breathing, and circulation must be evaluated, managed, and reassessed frequently. Even though patients may have normal vital signs initially, rapid decompensation can occur during transport, and emergency medical services (EMS) personnel should anticipate this. Establishing in-travenous (IV) access early is crucial, and all patients should be placed on a cardiac monitor. A fingerstick glucose check should be performed on patients with any alteration in level of consciousness, and treatment should be initiated for abnormal values. If the patient is in cardiac arrest, standard Advanced Cardiac Life Support algorithms should be followed.
EMS personnel should attempt to determine what types of medica-tions are present in the patient’s home. The scene should be surveyed for evidence of pills or empty pill bottles, which should be brought to the emergency department (ED) to aid in diagnosis and management of the patient. If capable, EMS should perform a 12-lead electrocardiogram (ECG) to provide additional information when transferring the patient to the receiving facility. This is vital, as ST-segment elevation acute coronary syndromes can present with bradycardia, heart block, and hypotension. Patients should be transported rapidly to the nearest treating facility. Emergency Department Evaluation
Initial Evaluation
Airway, breathing, and circulation should be assessed and managed as necessary. All patients should have at least 2 large-bore IV lines estab-lished and should be placed on cardiorespiratory monitoring. If peripheral IV access cannot be established, an intraosseous line is a reasonable tem-porary measure while awaiting central line placement. All patients should have ECG monitoring initiated immediately upon arrival. The history
should include a focus on the time of ingestion and the amount ingested, if known. In addition to other medications the patient is taking, potential precipitating factors should be identified (eg, gastroenteritis leading to volume and electrolyte imbalances). Patients should be monitored closely and reassessed frequently, as clinical status can change rapidly.
Evaluation of Calcium Channel Blocker and Beta Blocker Overdose
If the patient is initially stable, a history should be obtained, concentrat-ing on the followconcentrat-ing: what was concentrat-ingested, the amount concentrat-ingested, the time of ingestion, any co-ingestions, the formulation of the ingested product (im-mediate vs sustained release), and other medications the patient is taking. In unstable patients, other causes of shock, such as trauma, hemorrhage, or sepsis, should be assessed and excluded, if possible. In these patients, the history may need to be obtained from EMS and family members. The majority of patients with a toxic ingestion of either a CCB or a beta blocker will present with bradycardia and hypotension. Differentiating between a CCB or a beta blocker can be difficult clinically. While it has been reported that beta blockers may produce hypoglycemia and that hyperglycemia is a marker of CCB overdose,5,32,33 these findings are rare and should not be relied upon for diagnosis. Hyperglycemia is the result of blocked calcium channels, which inhibits the release of insulin, and while hyperglycemia should not be used to differentiate the toxins, it may have prognostic value in the setting of CCB toxicity. A retrospective review of 40 patients by Levine et al found that, in patients with a CCB
over-dose, an elevated serum glucose level correlated with severe toxicity.34 End-point markers examined were the need for vasopressors and cardiac pacing, and death. The review found that, in patients with at least 1 end-point marker, there was a statistically significant elevation in serum glucose compared to patients with no end-point markers. While this study was well conducted, it did not include any CCBs from the dihydropyridine group, nor has it been prospectively validated.
Evaluation of Digoxin Toxicity
Digoxin toxicity may occur due to an acute ingestion or it may be chronic, occurring while on therapy. Acute toxicity may present initially as a brady-cardia with or without hypotension. Chronic toxicity may be more difficult to diagnose, as the initial presentation may be vague and extra-cardiac manifestations may predominate. The patient may present with vague symptoms such as nausea (seen in 45% of patients), loss of appetite (seen in 28%), abdominal pain (seen in 26%), and neuropsychiatric manifesta-tions (eg, delirium, confusion, seizures; seen in 4.8% of patients).23,35-37 Chronic toxicity may occur as a result of alterations in electrolyte levels (such as hypokalemia), alterations in excretion or absorption of digoxin,
or even changes in volume status. Patients with an acute overdose may remain asymptomatic for hours, due to the time required for digoxin to distribute to the tissues. This does not occur in chronic toxicity because digoxin levels are already in a steady state in the body.35
Visual changes, including photophobia, photopsia, decreased visual acuity, scotomas, and xanthopsia (yellow halos) have also been described, but they are uncommon.38 A review published in 1972 found that 95% of patients taking digitalis exhibited some visual disturbances.39 In a more recent retro-spective review of 42 patients with digoxin toxicity, only 1 patient exhibited visual disturbances.35 It is likely that the high incidence of visual disturbances in older studies were due to the variability in digitalis preparations and the lack of serum monitoring available during that era. Table 2 outlines the clinical presentations of digoxin toxicity. Table 3 provides a comparison of characteristics of acute versus chronic digoxin toxicity. Table 4 identifies potential precipitating causes of chronic digoxin toxicity.
Table 2. Clinical Presentations of Digoxin Toxicity23,35,40
• Visual disturbances (halos, color disturbances) • Hallucinations • Anhedonia • Confusion • Seizures • Delirium • Weakness • Weight loss • Fatigue • Anorexia
• Nausea and/or vomiting • Abdominal pain
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Table 3. Characteristics of Acute Versus Chronic Digoxin Toxicity
Characteristic Acute Digoxin Toxicity Chronic Digoxin Toxicity
Age Younger Older
Cardiovascular status Normal myocardium Underlying cardiovascular disease Digoxin level High Normal to high
Potassium level Normal to high Low to normal Predominant symptom type Cardiac Noncardiac Cardiac symptoms Atrioventricular conduction
blocks are common Various dysrhythmias
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Table 4. Factors Associated With Chronic Digoxin Toxicity
• Age
• Hypothyroidism • Hepatic disease • Renal disease
• Low potassium or magnesium levels
• High calcium or sodium levels • Alkalosis
• Hypoxemia
• Drug interactions: quinidine, verapamil, amiodarone, spironolactone, macrolides
Diagnostic Studies Laboratory Studies
Patients with suspected cardiotoxic overdose require a complete blood count, chemistry with extended electrolytes (calcium, magnesium, phos-phate), glucose, coagulation studies, lactate, and a digoxin level. Serum salicylate, acetaminophen, osmolality, and ethanol levels should be ob-tained, especially in patients with any alteration in mental status,41 as well as beta-human chorionic gonadotropin in female patients. Arterial or venous blood gas levels will provide useful information about acid-base status, basic electrolyte levels, and hemoglobin levels, and is a useful initial screen-ing tool. Computed tomography of the brain should be obtained in patients who are intubated or who have a decreased level of consciousness, in order to exclude a structural etiology of the central nervous system depression. Urine drug screens are of limited utility in acute management of the over-dose patient and should not be obtained routinely. Additionally, serum levels of CCBs or beta blockers are not widely available, and there is no correlation between serum concentration and toxicity.42
Laboratory Studies for Digoxin Toxicity
Serum digoxin level testing is available in most institutions, with a thera-peutic range of 0.8 to 2 ng/mL. In an acute overdose, it is most beneficial to draw serum digoxin levels 6 hours after the time of ingestion to allow time for tissue equilibration. If the sample is drawn too soon, it may be falsely elevated, as it takes 4 to 6 hours for digoxin to equilibrate to the tissue. A review of serum digoxin levels in the Digitalis Investigation Group trial demonstrated that rising serum digoxin levels are associated with an increase in mortality.43 Other sources of cardiac glycosides may cause el-evation of serum digoxin concentrations, but these levels do not correlate with the degree of toxicity from these agents.
As with any laboratory result, digoxin levels must be interpreted in the clini-cal context of the patient. It is criticlini-cal to note that patients with elevated levels may not necessarily exhibit signs of digoxin toxicity and that patients with subtherapeutic levels may be toxic.21,44-46 The digoxin level is even less useful when attempting to differentiate subacute or chronic digoxin toxicity. The serum concentration of digoxin at steady state can be used to calculate the antidote dose (see Table 8, page 22).
Patient management should be based solely on clinical status after treatment with the antidote; treatment with digoxin-specific antibody fragments will cause a false elevation of serum digoxin levels after treat-ment.47,48 Potassium and magnesium levels must be monitored and cor-rected in patients with potential digoxin toxicity. Hypokalemia has the
potential to cause digoxin toxicity, even when digoxin is at therapeutic levels.21,49,50 Hypokalemia enhances the cardiac effects of digoxin, and induces dysrhythmias even at lower digoxin concentrations.24,49 In hypoka-lemic patients with chronic digoxin toxicity, potassium should be adminis-tered until normal ranges are reached.49
Hyperkalemia, on the other hand, can be an indication of acute digoxin toxicity. Hyperkalemia occurs as a result of blockade of the sodium/ potassium-ATPase pump, but it can also occur from renal failure, or the use of potassium-sparing diuretics, angiotensin-converting enzyme inhibi-tors, or potassium supplementation.51 High levels of potassium slow the conduction of electrical impulses within the heart, leading to a progres-sive widening of the PR and QT intervals, and the QRS complex. In acute digitalis overdose, hyperkalemia is associated with increased risk for both morbidity and mortality.23,52,53 Bismuth et al reported that, in patients with acute digitoxin overdose, a serum potassium level > 5.5 mEq/L was associ-ated with 100% mortality.54 While the study included only 91 patients from a single center, it does highlight the risk of significant deterioration of the hyperkalemic patient in this setting. This study led to the recommendation that a potassium level > 5.5 mEq/L is an indication for digoxin antibodies. A retrospective study of patients presenting with chronic digoxin toxicity found that patients treated with digoxin-specific antibody fragments had a significant mortality risk if the potassium level was > 5 mEq/L (odds ratio of death, 36.7).55
Electrocardiography
Electrocardiography in Calcium Channel Blocker and Beta Blocker Overdose
The ECG is essential in evaluation of a patient with suspected cardiovas-cular toxicity. While bradycardia is commonly seen, a wide variety of dys-rhythmias and heart blocks are possible. See Table 5 for a summary of the most common ECG findings in CCB and beta blocker overdose.
Table 5. Electrocardiographic Manifestations of Calcium Channel Blocker and Beta Blocker Toxicity48
• Normal sinus rhythm • Sinus tachycardia • Sinus bradycardia • PR prolongation
• Variable atrioventricular blocks • Junctional rhythms
• Bundle branch blocks • QT prolongation
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Beta blockers decrease cardiac automaticity and impede the conduc-tion velocity through the atrioventricular node, producing PR prolonga-tion. Love et al performed a prospective cohort study examining the ECG findings in patients with beta-blocker toxicity. In this study of 12 patients, first-degree heart block was the most common finding. QRS
complex prolongation was also seen, and 7 of 12 patients had both first-degree heart block and prolongation of the QRS complex.56 (See Figure 1.) The study also included 2 patients with acebutolol exposure who demonstrated a disproportionate prolongation of the QTc interval as well as an R wave > 3 mm in the aVR lead. Both of these patients developed ventricular tachydysrhythmias.56 A case report published by Rennyson and Littmann also found a Brugada-type pattern in the set-ting of propranolol poisoning.57
Figure 1. First-Degree Heart Block
A prolonged PR interval (> 200 ms [5 small squares]) is an early sign of beta blocker or calcium channel blocker toxicity — even in the absence of significant bradycardia.
Used with permission from www.lifeinthefastlane.com; available at: https://litfl.com/first-degree-heart-block-ecg-library/
Electrocardiography in Digoxin Toxicity
Digoxin toxicity can produce a variety of dysrhythmias as a result of conduc-tion delays and increased automaticity. A landmark paper in 1966 reviewed the key ECG manifestations found in patients with digoxin toxicity;58 a sum-mary can be found in Table 6. At therapeutic serum levels, digoxin may pro-duce a scooped appearance of the ST segment.59 (See Figure 2, page 13.) ECG manifestations may demonstrate a junctional rhythm seen as a narrow QRS interval or may demonstrate ventricular tachycardia. (See Figure 3, page 13.) A commonly seen dysrhythmia in digoxin toxicity is paroxysmal atrial tachycardia with atrioventricular node block. (See Figure 4, page 14.) A rarer dysrhythmia, bidirectional ventricular tachycardia, is sometimes considered pathognomonic for digitalis toxicity, but it is also encountered in aconitine toxicity.59-62 (See Figure 5, page 14.)
Table 6. Dysrhythmias Seen in Digoxin Toxicity
• Sinus bradycardia • Ventricular tachycardia • Bradydysrhythmias • Tachydysrhythmias
• Premature atrial and ventricular contractions • Junctional rhythm
• Variable degrees of heart block
• Paroxysmal atrial tachycardia with heart block • Atrial flutter and fibrillation with slow
ventricular response • Ventricular fibrillation
• Bidirectional ventricular tachycardia • Increased PR interval
• Increased automaticity
Figure 2. Scooped ST Segment Seen on Electrocardiogram in Digoxin Toxicity
Digoxin effect shows “sagging” ST segments and “scooped” T waves.
Used with permission from www.lifeinthefastlane.com; available at: https://litfl.com/digoxin-effect-ecg-library/.
Figure 3. Junctional Rhythm Seen on Electrocardiogram in Digoxin Toxicity
In a junctional rhythm, the cardiac rhythm occurs from the atrioventricular node, generating a rate of 40-60 beats/min, and the QRS complexes are typically narrow (< 120 ms [3 small squares]). Used with permission from www.lifeinthefastlane.com; available at:
Figure 4. Paroxysmal Atrial Tachycardia With Variable Block Seen on Electrocardiogram in Digoxin Toxicity
This is a classic ECG of digoxin toxicity showing atrial tachycardia (P waves at 150 bpm) and high-grade second-degree atrioventricular block (A:V ratio of 4:1) with frequent premature ventricular complexes (PVCs).
Used with permission from www.lifeinthefastlane.com; available at: https://litfl.com/digoxin-toxicity-ecg-library/
Figure 5. Bidirectional Ventricular Tachycardia Seen on Electrocardiogram in Digoxin Toxicity
Bidirectional ventricular tachycardia is a rare ventricular dysrhythmia characterized by a beat-to-beat alternation of the frontal QRS axis. There is a broad complex tachycardia with a frontal-plane axis that alternates by 180 degrees with each successive beat.
Used with permission from www.lifeinthefastlane.com; available at: https://litfl.com/bidirectional-ventricular-tachycardia-bvt-ecg-library/
Treatment
Treatment for Calcium Channel Blocker and Beta Blocker Overdose
Although overdoses of CCBs and beta blockers are uncommon, they have a high mortality rate, and management may be complicated, so consulta-tion with a toxicologist or poison control center is recommended. A 2012 retrospective study of 103 patients with CCB toxicity found that patients who had similar presenting signs but whose care followed recommenda-tions of the Quebec Poison Control Center (QPCC) had a mortality rate of 0% compared to a mortality rate of 10% in patients who did not receive QPCC-recommended management. The group whose care did not follow the recommendations of the QPCC had significantly delayed time to initial consultation.63 From this study, it would appear that delay of or lack of initiation of high-dose insulin therapy, or inappropriate administration of glucagon may have played key roles in worsened outcomes.
Gastrointestinal Decontamination
Prevention of the absorption of CCBs and beta blockers from the gastro-intestinal tract seems to be a logical method to slow or prevent systemic toxicity from occurring. However, this must be done with caution, with particular attention to airway protection. Emesis should not be induced. Activated charcoal can be considered if patients present to the ED within 1 to 2 hours of ingestion; however, due to the risk of aspiration, this is no longer routinely recommended by the American Academy of Clinical Toxicologists.64 In a volunteer study of 32 healthy patients, charcoal admin-istration was found to decrease absorption by nearly 50% at 2 hours from ingestion. The effect was lost if charcoal was given at 6 hours post inges-tion.65 Dosing of oral activated charcoal is 25 to 100 grams. If an extended-release formulation of the overdosed agent is identified and activated charcoal is being considered, then activated charcoal can be administered up to 2 hours post ingestion of the overdosed agent. There is currently insufficient evidence to recommend the use of cathartic agents in any overdose. A 2004 position statement by the American Academy of Clinical Toxicologists states that routine cathartic use has no role in management of patients who have overdosed.66
Whole-bowel irrigation should be strongly considered in patients who have ingested a sustained-release formulation of CCBs or beta blockers and who are hemodynamically stable.67 The identification of whether an ingestion is sustained release or immediate release is a critical component of manage-ment, and all efforts should be made to elicit this information. For adults, polyethylene glycol dosed at 1500 to 2000 mL/hr by mouth or via nasogastric/ orogastric tube should be administered until rectal effluent is clear. However, in patients who are unstable, whole-bowel irrigation may be deleterious. A case series of 2 hemodynamically unstable patients who received
whole-bow-el irrigation reported poor outcomes.68 While the first patient had a delayed presentation (3 hours post ingestion), the other patient presented within 15 minutes of ingestion. Both patients were not intubated prior to hemodynamic collapse, and they both aspirated their gastrointestinal contents. This illus-trates that whole-bowel irrigation in an unstable patient with an unsecured airway may lead to poor patient outcomes.
Vasopressors
Vasopressors are commonly used in the management of hypotension that occurs in the setting of CCB or beta blocker overdose. A wide variety of agents, including epinephrine, norepinephrine, vasopressin, and dopa-mine have been used, with variable success.5,11,13,32,69,70 While this may not be due to a direct failure of the vasopressor, it demonstrates that, even when multiple agents are used to treat the overdose, the toxicity may be too great for the agents to be effective. While no head-to-head compari-sons in humans have been performed, an animal study comparing insulin therapy to vasopressin and epinephrine found that insulin therapy was superior, producing a better blood pressure and heart rate response.71 Standard dosing of these agents may not be adequate, and higher doses (as well as the use of multiple agents) may be required in patients with severe overdose.32,72 If a vasopressor is being considered, then epineph-rine may be the preferred agent. If the clinical presentation is hypotension only, then norepinephrine may be more appropriate. Dopamine is not ideal, especially in patients with cardiac insults, because it has arrhythmo-genic effects.
In a 2013 retrospective review of 48 patients, ischemic complications from the use of vasopressors for treatment of CCB overdose were assessed. De-spite using higher than suggested dosing regimens of vasopressors, only 2 of 33 patients exhibited ischemic complications as a result of vasopres-sor use.11 Patients receiving vasopressors should undergo invasive blood pressure monitoring. Selecting which vasopressor to use depends on the provider’s comfort level, as no single agent has been shown to be superior to another when treating CCB or beta blocker toxicity.32
Insulin and Glucose
Patients who present with bradycardia and stable blood pressure should be observed and monitored closely. For patients who are severely poi-soned with a CCB or a beta blocker, and are bradycardic and hypotensive, high-dose insulin therapy is the mainstay of treatment, as supported by several studies.5,32,73-85 The most commonly accepted theory of the mecha-nism of action of high-dose insulin therapy is that insulin supports the heart metabolically during shock states.32 In healthy myocardium, free fatty acids are the primary energy source. In shock states, the preferred energy
substrate is glucose. However, in CCB and beta blocker overdose, effects on endogenous insulin release interfere with this process. Administration of insulin promotes carbohydrate metabolism by increasing glucose up-take into the myocyte as well as by increasing lactate upup-take and provid-ing further substrate for energy.32,33,86
An initial IV bolus of 0.5 to 1 unit/kg of regular insulin should be admin-istered, followed by an infusion of 0.5 to 1 unit/kg/hr, titrated to a mean arterial pressure that ensures adequate end-organ perfusion.32 Insulin can be increased by 50% every 20 minutes until a goal systolic blood pressure or mean arterial pressure is reached. It is recommended that the insulin infusion should not exceed 10 units/kg/hr.83 With the bolus dose of insulin, 25 g of IV dextrose should be given concurrently, followed by an infusion of 0.5 g/kg/hr of 5% dextrose solution (5 g/100 mL). For example, the aver-age adult weighing 80 kg would receive 800 mL/hr of 5% dextrose solu-tion. It may be necessary to use more-concentrated formulations (such as 10% or higher) to decrease the volume administered. If the use of more-concentrated glucose is required, the placement of a central line is recom-mended.32 The average adult would receive 400 mL/hr of the 10% con-centration of dextrose (10 g/100 mL). Glucose levels should be monitored frequently.17 Due to the high dosing required for this therapy, clinical staff should be reassured regarding the dosing and educated to avoid errors or complications. Additional dosing checks should be conducted by multiple staff members.
Potential complications of high-dose insulin therapy are hypoglycemia and hypokalemia. However, a 2013 retrospective review of 46 patients receiv-ing high-dose insulin therapy found that no hypoglycemic events occurred (although 13 patients in the review were underdosed with the insulin).76 Potassium and magnesium levels should be monitored, as they may fluctu-ate during treatment. While no evidence-based consensus exists regarding the ideal time frame for checking serum potassium and glucose levels, it is reasonable to check serum glucose every 30 minutes until glucose levels stabilize and then every hour thereafter, and to check electrolyte levels every hour until the patient is stable and then every 2 hours thereafter.
Glucagon
Glucagon is produced in the pancreas and plays a key role in glucose homeostasis by increasing the amount of cAMP. It is postulated that gluca-gon bypasses the normal catecholamine-driven production of cAMP. Dur-ing CCB or beta blocker toxicity, the amount of cAMP is reduced, leadDur-ing to negative inotropic and chronotropic effects.
It should be noted that glucagon therapy has been largely replaced by insulin and glucose administration. However, several case reports describe
good success with its use early in the management of the overdose pa-tient.9,87-91 In a systematic review of 30 animal model studies, glucagon was found to increase heart rate with minimal effects on blood pressure.90 Ini-tial dosing is 3 to 5 mg IV over 1 to 2 minutes. If no improvement in hemo-dynamic status is noted within 5 minutes, a repeat dose of 4 to 10 mg IV can be used.90,92 As a result of its short half-life, a maintenance infusion is recommended if hemodynamic effect is noted from the initial bolus dose; the maintenance rate is 2 to 5 mg/hr IV. The most common adverse effects are nausea and vomiting, and patients should be pretreated with an anti-emetic prior to administration of glucagon.
Extracorporeal Membrane Oxygenation and Intra-Aortic Balloon Pump
Extracorporeal membrane oxygenation (ECMO) has been used in the management of refractory shock due to CCB or beta blocker overdose.93-95 Robust evidence is lacking at this time, however. Masson et al compared the survival of patients with and without extracorporeal life support; 14 patients were enrolled in the ECMO arm and 48 patients in the conven-tional therapy arm. In the ECMO arm, 86% of patients survived compared to 48% in the conventional treatment arm, concluding that in the absence of hemodynamic response to standard treatment, ECMO improves rates of survival.96 Another retrospective review spanning nearly a decade assessed early initiation of ECMO in all critically ill poisoned patients.97 Toxicity from cardiovascular drugs composed the largest number of patients in the study at 38. ECMO was recommended by a toxicologist in 9 out of 12 patients. However, the patients did not receive ECMO, and all 9 died. A review of da-tabases98 and expert consensus85 have concluded that critically ill poisoned patients who are in shock that is refractory to standard therapy or who are in cardiac arrest should be considered for extracorporeal life support. The sooner extracorporeal life support is initiated, the more favorable the out-come.98 With a growing number of centers with access to ECMO capabili-ties, this treatment option should be given consideration.
There are a few case reports of good outcomes using an intra-aortic balloon pump in patients with CCB or beta blocker toxicity.99,100 However, balloon pumps should be reserved for cases where there is no access to ECMO.
Lipid Emulsion Therapy
The use of lipid emulsion therapy has become more prevalent in the man-agement of cardiovascular instability in the setting of cardiotoxic medica-tion overdose. While initially described in the management of cardiovas-cular collapse secondary to local anesthetic toxicity, it has been used in the management of hemodynamic instability that is unresponsive to sup-portive care in a number of overdose situations, including the ingestion of CCBs and beta blockers.80,101-105 While the exact mechanism is unclear, 3 proposed theories for the mechanism of lipid emulsion therapy have been
described. The most accepted mechanism is the establishment of a new medium to which the lipid-soluble drug will equilibrate (a so-called lipid sink), pulling the toxin from the tissue into the lipid solution. Another pro-posed mechanism is the enhancement of fatty acid transport across the mitochondrial membrane, thus enhancing the ability of the cell to produce the necessary energy to function and increasing cardiac myocyte calcium levels, resulting in increased inotropy.106
A recent evidence-based guideline on the use of lipid emulsion therapy in CCB and beta blocker toxicity gave a neutral recommendation for its use in patients in cardiac arrest or with life-threatening toxicity.107 The guide-lines advocate that high-dose insulin therapy should be used, in addition to ECMO therapy, due to a more favorable safety profile. In a center that does not have access to ECMO, lipid emulsion therapy may be considered as a treatment option, particularly in patients who are in cardiac arrest and patients in refractory shock despite receiving other first-line agents.108 The suggested dosing regimen is 20% lipid emulsion given as a 1.5-mL/kg IV bolus over 2 to 3 minutes, followed by a 0.25-mL/kg/min infusion.109 A repeat bolus dose can be administered if the patient is in asystole or pulseless electrical activity arrest, or if the patient improves after the initial dose but then becomes hemodynamically unstable.109 Infusions should continue for approximately 10 minutes after achieving stabil-ity. The recommended upper limit of lipid is 10 to 12 mL/kg in the first 30 minutes. This should be taken into consideration to determine how much lipid the patient should receive and at what point after the bolus and infusion the patient will reach the maximum recommended amount. Once lipid emulsion therapy has been administered, it may interfere with many biochemical laboratory levels such as glucose, magnesium, and creatinine, but not potassium.
While lipid emulsion therapy may be a rescue treatment for critically ill patients who do not respond to first-line treatments, its administration is not without complications. Hayes et al performed a systematic review highlighting the adverse effects of lipid emulsion therapy. In the review, 114 studies were included, of which 83 were based on human subjects. Complications included acute kidney injury, fat embolism, pancreatitis, extracorporeal circulation machine obstruction, and increased susceptibil-ity to infection.110 As with every intervention, the risk-benefit ratio must be weighed, and consultation with a toxicologist is encouraged.
Calcium
Although it seems like a natural reversal agent (particularly for CCB toxici-ty), the evidence for calcium administration is weak. There are case reports describing both efficacy and lack of efficacy in using calcium for CCB
over-dose.5,32 Dosing of calcium is also not well defined, and no dose-effect re-lationship was found in a study where doses ranged from 4.5 to 95.3 mEq of calcium.13 Dosing recommendations commonly found in the literature are 10 to 20 mL of 10% calcium chloride or 30 to 60 mL of 10% calcium gluconate.5,32 Since calcium chloride contains 3 times the amount of ion-ized calcium, less is required. Calcium chloride should be given through a central line to avoid injury in case of extravasation into the tissue. Calcium gluconate can be administered safely via a peripheral IV line. No more than a single dose of calcium is recommended, as its efficacy is uncertain and too much calcium or calcium administered too rapidly can precipitate deleterious effects such as arrhythmias.
Atropine
While atropine is used in the management of a bradycardic, hypotensive patient, it is rarely effective in either CCB or beta blocker overdose.13,18,32 In a study of 139 patients who overdosed on a CCB, 8 patients received atropine. It was found to have had a positive effect in only 2 patients.13 A trial of atropine dosed at 0.5 to 1 mg IV every 2 minutes, up to a total of 3 mg, may be considered, if necessary.
Phosphodiesterase Inhibitors
A few case reports describe the efficacy of phosphodiesterase inhibitors (eg, amrinone, milrinone, and enoximone), which function by preventing the degradation of cAMP within the cell, in both CCB and beta blocker toxic-ity.111-113 In 2 of these cases, the phosphodiesterase inhibitor was added to glucagon, with both cases showing improvement in hemodynamic status and mental status.111,112 A potential side effect of phosphodiesterase inhibi-tors is hypotension secondary to vasodilation, which may be detrimental to the already-hypotensive patient. Additionally, several of the phosphodi-esterase inhibitors have prolonged half-lives, which makes them difficult to titrate.5 Therefore, routine use of these agents is not recommended.
Sodium Bicarbonate
Sodium bicarbonate may be useful if there is a widened QRS complex, indi-cating the presence of a sodium-channel blockade.114-116 In the setting of a wide QRS complex and CCB or beta blocker toxicity, it may be reasonable to administer a trial bolus of sodium bicarbonate. If the QRS shortens, consider-ation can be given to an infusion of sodium bicarbonate; however, this is not used routinely in management of either CCB or beta blocker overdose.
Pacing
Either transthoracic or transvenous pacing may be considered if the pa-tient's condition remains refractory to other therapies. The goal heart rate should be 50 to 60 beats/min.32 However, the efficacy of pacing is unclear in the literature.13,18,117,118 While heart rate may rise, inotropy may not neces-sarily rise, making the usefulness of pacing doubtful.
Dialysis
Because CCBs are highly protein bound and have a large volume of dis-tribution, hemodialysis is not indicated or useful. A 2012 report described 3 patients treated successfully with extracorporeal albumin dialysis, utiliz-ing a molecular adsorbent recirculatutiliz-ing system that allowed for selective removal of protein-bound toxins;70 however, this modality is not widely available. Most beta blockers are not dialyzable, as they are also highly protein-bound. The exceptions to this are atenolol, acebutolol, nadolol, timelol, and sotalol, which demonstrate unique hydrophilic properties and have minimal protein binding.32,95,119
Treatment for Digoxin Toxicity Bowel Decontamination
In acute digoxin toxicity that presents within 1 to 2 hours of ingestion, it is reasonable to administer oral activated charcoal at a dose of 25 to 100 g to prevent absorption.120,121 It is critical to ensure that the patient is able to protect his or her airway if charcoal administration is being considered. Consultation with a local toxicologist for guidance should be considered, as charcoal administration is an area of controversy.
Atropine
Bradycardia may occur due to the vagal effects of digoxin, and a trial of atropine (0.5-1 mg IV in an adult) is reasonable and may be the only treat-ment required.
Digoxin-Specific Antibody Fragments
The definitive treatment for digoxin toxicity is digoxin-specific antibody fragments (digoxin immune Fab). Bradycardic patients may be treated initially with atropine. If there is an inadequate response, then digoxin immune Fab is indicated. The Fab antibody fragments bind to digoxin found in the vascular space, creating a gradient between the tissue and the serum. This results in digoxin being released from the tissue into the vascular space.
A landmark study of 150 patients in 1990 demonstrated clear efficacy of di-goxin immune Fab in patients with severe didi-goxin toxicity.122 More than 90% of patients had a positive response, and 75% of these patients exhibited a response within 60 minutes of digoxin immune Fab administration. What is most astounding is that 54% of the 56 patients who were in cardiac arrest survived.122 In a 2010 study, symptoms in 3 out of 7 patients improved within 4 hours of administration of digoxin immune Fab.123 A 2000 in vivo study randomized 16 patients to equal doses of 2 different brands of digoxin and found no major clinical differences between the 2 agents.124 The indications for administration of digoxin immune Fab can be found in Table 7. (See page 22.)
Table 7. Indications for Administration of Digoxin-Specific Antibodies25,125,126
• Ingestion of ≥ 10 mg of digoxin (4 mg in children)
• Acute digoxin ingestion with a serum steady-state level > 10 ng/mL • Chronic digoxin toxicity with a serum steady-state level > 6 ng/mL
• Any cardiac dysrhythmia, irrespective of serum digoxin level, not managed by more conservative treatments
• Serum potassium levels > 5.5 mEq/L with an acute digoxin overdose • Toxicity with nondigoxin cardioactive steroids (ie, plant or animal)
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A single vial of digoxin immune Fab binds 0.5 mg of digoxin. Serum di-goxin levels (or estimates of the amount ingested) can be used to calcu-late the required dosage of digoxin immune Fab. (See Table 8.) Empirical-ly, 5 to 10 vials can be administered intravenously to adults presenting with acute digoxin toxicity, with a repeat dose, if necessary.125,126 Another ap-proach for acute digoxin toxicity is to administer 2 vials of digoxin immune Fab and repeat hourly as required.127 In a patient with chronic toxicity, an empiric dose of 1 to 2 vials may be administered and can be repeated, if necessary.125,126 Another approach for chronic digoxin toxicity is to adminis-ter 1 vial of digoxin immune Fab and repeat hourly as required.127
Table 8. Digoxin Immune Fab Dosing Calculations20,24,25
Number of vials = serum digoxin concentration (ng/mL) x patient weight (kg) 100
Number of vials = serum digoxin concentration (nmol/L) x 0.781 x patient weight (kg) 100
Number of vials = amount ingested (mg) x 80% bioavailability 0.5 (mg/vial)
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To read more about calculating digoxin immune fab dosing and access the MDCalc tool, go to: https://www.mdcalc.com/digifab-dosing-digox-in-poisoning.
Laboratory tests can measure total digoxin, which will include the bound di-goxin after treatment with didi-goxin immune Fab. Therefore, after administration of digoxin immune Fab, serum levels of digoxin may be significantly elevated. Further management should be based solely on clinical status, and serum levels should no longer be used to guide therapy.23,125,126 Fab fragments are renally excreted, and in patients with underlying renal dysfunction, prolonged observa-tion after treatment is necessary to ensure complete resoluobserva-tion of toxicity.
Electrolyte Maintenance
In a patient with an acute digoxin overdose, hyperkalemia is an indication for the administration of digoxin immune Fab.54 If there is an anticipated
decrease potassium levels using dextrose, insulin, or sodium bicarbon-ate may be considered as a temporizing measure; however, care must be taken as these patients are at risk for becoming hypokalemic once digoxin immune Fab treatment is initiated.25
Hypokalemic patients are often hypomagnesemic as well.49 Patients pre-senting with hypokalemia or hypomagnesemia should have the deficiency corrected, particularly if they are to undergo treatment with digoxin im-mune Fab.23,45 A 2013 case report described a patient who presented with digoxin toxicity with abdominal pain and palpitations, normal digoxin and potassium levels, but severe hypomagnesemia. The symptoms resolved with magnesium replacement, suggesting that magnesium deficiency may play a role in digoxin toxicity.45 IV magnesium may be considered for the management of ventricular dysrhythmias associated with digoxin toxicity, if digoxin immune Fab is not readily available.128
Pacing and Cardioversion
Cardiac pacing is not recommended in patients with digoxin toxicity. There are numerous case reports of patients undergoing cardiac pacing who then deteriorate with unstable rhythms.23,120,129 In a 1993 retrospective study of 92 patients with digoxin toxicity, complications from pacing oc-curred in 36% of patients, with a fatal outcome in 13%.130
Similarly, cardioversion should be avoided in patients with digoxin toxicity, as the myocardium becomes sensitized and there is a significant risk of the rhythm deteriorating to ventricular fibrillation.
Extracorporeal Management
Extracorporeal management is generally not indicated for digoxin toxicity. Digoxin has a large volume of distribution and is highly protein bound, so hemodialysis is not indicated.131 The use of extracorporeal life support is not well defined for digoxin toxicity. A single case report of a patient who inadvertently ingested foxglove and was placed on ECMO found a poor outcome presumed to be due to mechanical complications.132 A 2007 case report described a patient with acute renal failure and digoxin toxicity who was successfully treated with digoxin immune Fab and plasmapheresis.133 Special Circumstances
Sotalol
Sotalol, a beta blocker that blocks the in-flowing potassium channel, has the potential to prolong the QT interval and induce ventricular dysrhyth-mias, including torsades de pointes.134 Sotalol toxicity that presents with bradycardia and hypotension should be treated as any other beta blocker; however, if the patient demonstrates torsades de pointes, standard
treat-ments such as magnesium or overdrive pacing should be considered.92 Given the high benefit-to-risk ratio, it is reasonable to administer magne-sium sulfate prophylactically in patients who present with a sotalol inges-tion and a prolonged QTc interval.
Use of Calcium in Digoxin Toxicity
Calcium administration is standard practice in the management of hy-perkalemia; however, in the setting of acute digoxin toxicity, the use of calcium is controversial. There are case reports of digoxin-toxic and hy-perkalemic patients who were given calcium and then subsequently went into cardiac arrest.23 The concept of the digoxin-toxic patient being given calcium that precipitated a “stone heart” arose from a paper published in the 1930s, detailing 2 patients who received IV calcium and subsequently died of cardiac arrest. However, the serum potassium or calcium levels of these patients were unknown. Animal studies that corroborated the “stone heart” theory were found to have administered calcium rapidly in the set-ting of high serum calcium levels (> 5 mmol/L or 20 mg/dL).23
More recent literature suggests that administration of calcium is safe in these patients.51,135 A 2011 study by Levine et al of 159 patients exhibit-ing cardiac glycoside toxicity found that 23 patients received IV calcium. Five of those 23 patients died, and none of the deaths occurred within an hour of calcium administration. The mortality rate in the group that did not receive calcium was 20%, with no statistical significance between the 2 groups.135 Furthermore, a multivariate analysis of the patient data was conducted to ensure no errors occurred in the association of calcium and death. Again, calcium was found to have played no role in the death of these patients.61 Based on these more recent data, it is appropriate to administer IV calcium in bradycardic patients with wide-complex rhythms who are likely to have hyperkalemia and in whom it is unknown whether or not they are taking digoxin. Hyperkalemia in a patient known to have digoxin toxicity is an indication for the administration of digoxin immune Fab, a known safe treatment, rather than calcium.
Controversies and Cutting Edge Methylene Blue
Two recent case reports describe the use of methylene blue in the man-agement of severe CCB and beta blocker overdose.136,137 Due to the ef-fects on sodium channels from the overdose, cyclic guanosine monophos-phate (cGMP) accumulates in vascular smooth muscle, resulting in vasodi-latation as well as a decreased response to vasopressors. Methylene blue decreases the production of cGMP by inhibiting nitric oxide synthase and guanylate cyclase. The use of methylene blue has also been described for
management of other refractory shock states, such as sepsis and anaphy-laxis.138 The suggested dose from these papers is 2 mg/kg over 20 min-utes, followed by a 1-mg/kg/hr infusion until the patient's hemodynamic status stabilizes. However, despite these reports, methylene blue is not routinely indicated in either CCB or beta blocker toxicity.
L-Carnitine
A case report of a severe amlodipine and metformin overdose described the use of L-carnitine for management.139 The patient had ingested 3 grams of amlodipine and presented in refractory shock despite maximal therapy. The patient received 6 g of L-carnitine intravenously, followed by 1 g every 4 hours, and survived to discharge. The postulated mechanism of action of L-carnitine is reversal of free fatty acid metabolism from glu-cose in the myocytes, thus decreasing insulin resistance and increasing uptake and oxidation of free fatty acids.139 However, despite this report, L-carnitine is not routinely indicated in either CCB or beta blocker toxicity.
Levosimendan
There are a few case reports detailing the use of levosimendan in the man-agement of hemodynamically unstable CCB or beta blocker overdose. However, vasodilation can potentially worsen hypotension, and lack of avail-ability of this medication in all regions decreases its usefulness.140-142
Disposition
Asymptomatic patients who have overdosed on a short-acting CCB or beta blocker should be observed for a period of at least 6 hours.143,144 If they remain asymptomatic, they may be discharged. Patients who become symptomatic must be treated and admitted for monitoring. Patients who have ingested sustained-release formulations should be observed for effects for up to 24 hours. It should be noted that sotalol has a unique type III antiarrhythmic activity and a long half-life that can potentially put patients at significant risk for delayed toxicity, so pro-longed observation is recommended.144
Patients with digoxin toxicity should be admitted if they are symptomatic. Patients who remain asymptomatic 6 hours after an acute ingestion and have 2 documented digoxin levels that are stable or declining (in the set-ting of normal electrolytes and normal renal function) may be discharged with close follow-up.
Patients who have deliberately overdosed should be evaluated by psy-chiatry. Likewise, elderly patients who have taken their medications incorrectly should be evaluated for cognitive compromise and the ability to care for themselves.
Summary
With an aging population and increasing comorbidities, the use of CCBs and beta blockers has become more prevalent. Patients with CCB or beta blocker overdose can be treated in a fairly similar manner by initiating basic interventions first, including resuscitation, IV fluids, and continuous cardiac monitoring. These patients may decompensate rapidly and antici-pating this may prevent an unfavorable outcome. If basic interventions do not resolve hemodynamic instability, high-dose insulin therapy should be initiated and vasopressors administered, if needed. If the patient remains unstable, ECMO should be considered as a treatment option, if available. If the aforementioned therapies fail to improve the patient’s clinical status, lipid emulsion therapy is recommended.
Acute digoxin overdose is uncommon, but when it does occur, it may pres-ent with life-threatening dysrhythmias and heart blocks. Prompt administra-tion of digoxin immune Fab may be life-saving. Chronic digoxin toxicity is more common, but it may be insidious and often presents with extra-cardiac symptoms. One must have a high level of suspicion in these patients. A digoxin level should always be ordered in the elderly patient with vague symptoms who is taking digoxin. Again, treatment with digoxin immune Fab may be indicated. Further management should be based on clinical status. Case Conclusions
In the 44-year-old patient with atrial fibrillation and no carotid pulse, you initiated CPR and successfully intubated him. You then repeated another fluid bolus. After 2 rounds of CPR, you began to wonder what else could be done. After giving a bolus insulin dose, you asked the nurses to start an infusion of insulin at a dose of 1 unit/kg/hr with dextrose, and you also ini-tiated lipid emulsion therapy. After approximately 10 minutes, the patient remained pulseless. You began to consider ECMO, but a pulse was found on the next check. You continued the lipid emulsion infusion, and the ICU team was notified.
You received the blood work results on the 83-year-old woman who was taking digoxin for heart failure, and her digoxin level was markedly el-evated at 6.43 ng/mL. The patient weighed 95 kg, so you calculated the correct dosing of digoxin immune Fab and administered 7 vials IV, leading to resolution of her bradycardia and hypotension. She was admitted to the ICU for monitoring of her cardiac status.
For the young woman who had been taking verapamil for migraine and sud-denly collapsed, you intubated her tracheally, administered IV atropine and calcium, and started her on a norepinephrine infusion. However, despite
these therapies, she remained hypotensive and bradycardic. You then ad-ministered an infusion of high-dose insulin (1 unit/kg/hr), with 10% dextrose. Her hemodynamic status began to stabilize, with resolution of her hypoten-sion and bradycardia. She was admitted to the ICU for further management. Risk Management Pitfalls in Calcium Channel Blocker and
Beta Blocker Overdose, and Digoxin Toxicity
1. “I’ll just wait on the digoxin level results to guide treatment.” Patients with acute digoxin overdose may be asymptomatic, despite an
elevated digoxin level, if blood is drawn before digoxin has equilibrated in the tissues. In an acute overdose, it is most beneficial to draw serum digoxin levels 6 hours after the time of ingestion to allow for tissue equilibration. If the sample is drawn too soon, it may be falsely elevated, as it takes 4 to 6 hours for digoxin to equilibrate to the tissue. When the drug has entered the cell, patients may manifest toxicity despite a drop in the digoxin level. As with any laboratory result, digoxin levels must be interpreted in the clinical context of the patient. It is critical to note that patients with elevated levels may not necessarily exhibit signs of digoxin toxicity and that patients with subtherapeutic levels may be toxic.
2. “The patient’s bradycardia and hypotension did not resolve after administering digoxin immune Fab. I’ll just give more.”
Do not forget to rule out other cardiotoxic medications as potential causes for this clinical scenario. Particularly in patients with suicidal ingestion, multiple agents may be contributing to the clinical scenario. 3. “The patient was asymptomatic, so I discharged her home
immedi-ately after the treatment was completed.”
Asymptomatic patients who have overdosed on a short-acting CCB or beta blocker should be observed for a period of at least 6 hours. If they remain asymptomatic, they may be discharged. Patients who become symptomatic must be treated and admitted for monitoring. Patients who have ingested sustained-release formulations should be observed for effects for up to 24 hours.
4. “Is there really any harm in administering calcium to a patient with digoxin toxicity?”
Based on more recent data, it is appropriate to administer IV calcium in bradycardic patients with wide-complex rhythms who are likely to have hyperkalemia and in whom it is unknown whether or not they are taking digoxin. Hyperkalemia in the digoxin-toxic patient is an indication for the administration of digoxin immune Fab, a known safe treatment, rather than calcium.
5. “I treated my patient with digoxin immune Fab, and now the se-rum level is higher than before! Did I administer this incorrectly?” After administration of digoxin immune Fab, serum concentration
measurements of digoxin are no longer useful. The patient’s clinical status should be used to guide whether or not the patient requires further digoxin immune Fab treatment.
6. “My ED staff was worried about giving so much insulin to the pa-tient who overdosed on a beta blocker.”
Patients with either CCB or beta blocker toxicity may require very high doses of insulin (up to 1 unit/kg/hr, which is 70 unit/hr in a 70-kg patient) to support the heart metabolically during shock states. Due to the high dosing required for this therapy, clinical staff should be reassured regarding the dosing and educated to avoid errors or complications. Additional dosing checks should be conducted by multiple staff members.
7. “The patient wasn’t bradycardic, so I thought it couldn’t be a CCB or beta blocker overdose.”
The ECG is essential in evaluation of a patient with suspected cardiovascular toxicity. While bradycardia is commonly seen, a wide variety of dysrhythmias and heart blocks are possible. Other ECG findings include normal sinus rhythm, sinus tachycardia, PR prolongation, variable atrioventricular blocks, junctional rhythms, bundle branch blocks, and QT prolongation.
8. “I’m not sure we have lipid emulsion in my ED.”
The guidelines advocate that high-dose insulin therapy should be used, in addition to ECMO therapy, due to a more favorable safety profile. In a center that does not have access to ECMO, lipid emulsion therapy may be considered as a treatment option, particularly in patients who are in cardiac arrest and patients in refractory shock despite receiving other first-line agents. The suggested dosing regimen is 20% lipid emulsion given as a 1.5 mL/kg bolus over 2 to 3 minutes, followed by a 0.25-mL/kg/min infusion. As with every intervention, the risk-benefit ratio must be weighed, and consultation with a toxicologist is encouraged.
9. “The patient was unsure if he was taking a CCB or a beta blocker, so I used the patient’s glucose levels to find out.”
The majority of patients with a toxic ingestion of either a CCB or a beta blocker will present with bradycardia and hypotension. Differentiating between a CCB or a beta blocker can be difficult clinically. While it has been reported that beta blockers may produce hypoglycemia and that hyperglycemia is a marker of CCB overdose, these findings are rare and should not be relied upon for diagnosis. Additionally, treatment of CCB and beta blocker overdose is similar, so differentiation between them is not needed.
10. “I wasn’t sure if a CCB overdose required consultation with the poison control center.”
Cardiovascular medication poisonings are complicated to manage, and some treatment options may be unfamiliar to the treating staff. Contact the local poison center or toxicologist for guidance on management.
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright © 2020 EB Medicine. www.ebmedicine.net. No part of this publication may be reproduced in any format without written consent of EB Medicine. Class I
• Always acceptable, safe • Definitely useful
• Proven in both efficacy and effectiveness Level of Evidence:
• One or more large prospective studies are present (with rare exceptions) • High-quality meta-analyses • Study results consistently positive and
compelling
Class II • Safe, acceptable • Probably useful Level of Evidence:
• Generally higher levels of evidence • Nonrandomized or retrospective studies:
historic, cohort, or case control studies • Less robust randomized controlled trials • Results consistently positive
Class III • May be acceptable • Possibly useful
• Considered optional or alternative treat-ments
Level of Evidence:
• Generally lower or intermediate levels of evidence
• Case series, animal studies, consensus panels • Occasionally positive results
Indeterminate
• Continuing area of research • No recommendations until further
research Level of Evidence: • Evidence not available • Higher studies in progress • Results inconsistent, contradictory • Results not compelling
Class of Evidence Definitions