Calcium Channel Blocker and Beta Blocker Overdose, and Digoxin Toxicity Management - Pharmacology EXTRA Supplement (Pharmacology CME)

Table of Contents

 

While relatively uncommon, an overdose of calcium-channel blockers, beta blockers, or digoxin can result in significant morbidity and mortality, and management 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 hypotensive patients. Identifying and treating patients exhibiting toxic effects of these agents can be complex. Standard Advanced Cardiovascular Life Support protocols used for the resuscitation of patients in cardiac arrest may be insufficient 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 diagnosis and management of CCB, beta blocker, and digoxin toxicity.

What are the similarities and differences in the clinical presentations of calcium-channel blocker, beta blocker, and digoxin toxicity?

How do findings in the history, such as the timing of ingestion, affect management?

What are the appropriate assessments, such as laboratory studies and ECG, that will best aid in diagnosis and management of patients presenting with calcium-channel blocker, beta blocker, and digoxin toxicity?

How do the techniques for management of patients with calcium-channel blocker, beta blocker, and digoxin toxicity differ? Which are the most beneficial?

What factors should be taken into consideration when determining disposition of patients with calcium-channel blocker, beta blocker, and digoxin toxicity?

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Pathophysiology and Pharmacokinetics
   1. *Calcium Channel Blockers
   2. *Beta Blockers
   3. *Digoxin
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. *Initial Evaluation
   2. *Evaluation of Calcium Channel Blocker and Beta Blocker Overdose
   3. *Evaluation of Digoxin Toxicity
9. Diagnostic Studies
   1. *Laboratory Studies
      1. **Laboratory Studies for Digoxin Toxicity
   2. *Electrocardiography
      1. **Electrocardiography in Calcium Channel Blocker and Beta Blocker Overdose
   3. **Electrocardiography in Digoxin Toxicity
10. Treatment
    1. *Treatment for Calcium Channel Blocker and Beta Blocker Overdose
       1. **Gastrointestinal Decontamination
       2. **Vasopressors
       3. **Insulin and Glucose
       4. **Glucagon
       5. **Extracorporeal Membrane Oxygenation and Intra-Aortic Balloon Pump
       6. **Lipid Emulsion Therapy
       7. **Calcium
       8. **Atropine
       9. **Phosphodiesterase Inhibitors
       10. **Sodium Bicarbonate
       11. **Pacing
       12. **Dialysis
    2. *Treatment for Digoxin Toxicity
       1. **Bowel Decontamination
       2. **Atropine
       3. **Digoxin-Specific Antibody Fragments
       4. **Electrolyte Maintenance
       5. **Pacing and Cardioversion
       6. **Extracorporeal Management
11. Special Circumstances
    1. *Sotalol
    2. *Use of Calcium in Digoxin Toxicity
12. Controversies and Cutting Edge
    1. *Methylene Blue
    2. *L-Carnitine
    3. *Levosimendan
13. Disposition
14. Summary
15. Risk Management Pitfalls in Calcium Channel Blocker and Beta Blocker Overdose, and Digoxin Toxicity
16. Case Conclusions
17. Clinical Pathway for Emergency Department Management of Calcium Channel Blocker and Beta Blocker Overdose, and Digoxin Toxicity
18. Tables and Figures
    1. Table 1. Selective and Nonselective Beta Blockers
    2. Table 2. Clinical Presentations of Digoxin Toxicity
    3. Table 3. Characteristics of Acute Versus Chronic Digoxin Toxicity
    4. Table 4. Factors Associated With Chronic Digoxin Toxicity
    5. Table 5. Electrocardiographic Manifestations of Calcium Channel Blocker and Beta Blocker Toxicity
    6. Table 6. Dysrhythmias Seen in Digoxin Toxicity
    7. Table 7. Indications for Administration of Digoxin-Specific Antibodies
    8. Table 8. Digoxin Immune Fab Dosing Calculations
    9. Figure 1. First-Degree Heart Block
    10. Figure 2. Scooped ST Segment Seen on Electrocardiogram in Digoxin Toxicity
    11. Figure 3. Junctional Rhythm Seen on Electrocardiogram in Digoxin Toxicity
    12. Figure 4. Paroxysmal Atrial Tachycardia With Variable Block Seen on Electrocardiogram in Digoxin Toxicity
    13. Figure 5. Bidirectional Ventricular Tachycardia Seen on Electrocardiogram in Digoxin Toxicity
19. References

Abstract

While relatively uncommon, an overdose of calcium channel blockers, beta blockers, or digoxin can result in significant morbidity and mortality, and management 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 hypotensive patients. This supplement provides an evidence-based overview of emergency department management of calcium channel blocker overdose, beta blocker overdose, and digoxin toxicity, and focuses on the caveats of treatment for each.

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 return 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 patient 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 immune fab. You also consider what the precipitating factor to her presumed digoxin toxicity might be.

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 glucose 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 therapeutic 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 medications 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 contributed 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 protocols used for the resuscitation of patients in cardiac arrest may be insufficient 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 diagnosis 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 attempt 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. Performing 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 reports, small studies, or retrospective reviews, which have been included here when necessary.

Risk Management Pitfalls in Calcium Channel Blocker and Beta Blocker Overdose, and Digoxin Toxicity

3. “The patient was asymptomatic, so I discharged her home immediately 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.

6. “My ED staff was worried about giving so much insulin to the patient 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.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study will be included in bold type following the references, where available. The most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

1. National Center for Health Statistics. Health, United States, 2012: With Special Feature on Emergency Care. Hyattsville, MD: Centers for Disease Control and Prevention; 2013. Accessed September 1, 2020. (Government statistical report)
2. United States Bureau of the Census. National Hospital Ambulatory Medical Care Survey: 2010 Emergency Department Summary Tables. Durham, NC: United States Bureau of the Census; 2010. Accessed September 1, 2020. (Census data report)
3. Gummin DD, Mowry JB, Spyker DA, et al. 2017 Annual Report of the American Association of Poison Control Centers’ National Poison Data System(NPDS): 35th Annual Report. Clin Toxicol (Phila). 2018;56(12):1213-1415. (Database analysis)
4. Deters M, Bergmann I, Enden G, et al. Calcium channel antagonist exposures reported to the Poisons Information Center Erfurt. Eur J Intern Med. 2011;22(6):616-620. (Analysis of reported poison exposures in Germany; 727 cases)
5. DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity. Toxicol Rev. 2004;23(4):223-238. (Review)
6. Proano L, Chiang WK, Wang RY. Calcium channel blocker overdose. Am J Emerg Med. 1995;13(4):444-450. (Case report; 1 patient)
7. Gladding P, Pilmore H, Edwards C. Potentially fatal interaction between diltiazem and statins. Ann Intern Med. 2004;140(8):W31. (Case report; 1 patient)
8. Varpula T, Rapola J, Sallisalmi M, et al. Treatment of serious calcium channel blocker overdose with levosimendan, a calcium sensitizer. Anesth Analg. 2009;108(3):790-792. (Case report; 2 patients)
9. Shepherd G. Treatment of poisoning caused by beta-adrenergic and calcium-channel blockers. Am J Health Syst Pharm. 2006;63(19):1828-1835. (Review)
10. Olson KR, Erdman AR, Woolf AD, et al. Calcium channel blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2005;43(7):797-822. (Clinical practice guideline)
11. * Levine M, Curry SC, Padilla-Jones A, et al. Critical care management of verapamil and diltiazem overdose with a focus on vasopressors: a 25-year experience at a single center. Ann Emerg Med. 2013;62(3):252-258. (Retrospective chart review; 48 patients) DOI: 2013.03.018
12. Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: an update. Am J Med. 2004;116(1):35-43. (Review)
13. Ramoska EA, Spiller HA, Winter M, et al. A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment. Ann Emerg Med. 1993;22(2):196-200. (Case series, review; 139 patients, 8 receiving atropine)
14. Ferrari R. Major differences among the three classes of calcium antagonists. Eur Heart J. 1997;18 Suppl A:A56-A70. (Comparative analysis of clinical trials)
15. Reith DM, Dawson AH, Epid D, et al. Relative toxicity of beta blockers in overdose. J Toxicol Clin Toxicol. 1996;34(3):273-278. (Prospective study; 60 patients)
16. * Love JN, Howell JM, Litovitz TL, et al. Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol. 2000;38(3):275-281. (Prospective cohort study; 280 exposures) DOI: 100100932
17. Henry JA, Cassidy SL. Membrane stabilising activity: a major cause of fatal poisoning. Lancet. 1986;1(8495):1414-1417. (Review)
18. Weinstein RS. Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med. 1984;13(12):1123-1131. (Review)
19. Katzung B. Drugs used in heart failure. In: Basic and Clinical Pharmacology. Katzung B, Masters S, eds. 12th ed. New York: McGraw-Hill; 2012:211-226. (Textbook chapter)
20. Kockova R, Skvaril J, Cernohous M, et al. Five-year, two-center retrospective analysis of patients with toxic digoxin serum concentration. Int J Cardiol. 2011;146(3):447-448. (Retrospective analysis)
21. Bauman JL, Didomenico RJ, Galanter WL. Mechanisms, manifestations, and management of digoxin toxicity in the modern era. Am J Cardiovasc Drugs. 2006;6(2):77-86. (Review)
22. Belz GG, Breithaupt-Grögler K, Osowski U. Treatment of congestive heart failure--current status of use of digitoxin. Eur J Clin Invest. 2001;31 Suppl 2:10-17. (Review)
23. Kanji S, MacLean RD. Cardiac glycoside toxicity: more than 200 years and counting. Crit Care Clin. 2012;28(4):527-535. (Review)
24. Vivo RP, Krim SR, Perez J, et al. Digoxin: current use and approach to toxicity. Am J Med Sci. 2008;336(5):423-428. (Review)
25. Hack JB. Cardioactive steroids. In: Nelson LS, Lewin NA, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies. 9th ed. New York: McGraw-Hill; 2011:936-945. (Textbook chapter)
26. Rodin SM, Johnson BF. Pharmacokinetic interactions with digoxin. Clin Pharmacokinet. 1988;15(4):227-244. (Review)
27. Haynes K, Hennessy S, Localio AR, et al. Increased risk of digoxin toxicity following hospitalization. Pharmacoepidemiol Drug Saf. 2009;18(1):28-35. (Prospective cohort study; 2030 patients)
28. Gomes T, Mamdani MM, Juurlink DN. Macrolide-induced digoxin toxicity: a population-based study. Clin Pharmacol Ther. 2009;86(4):383-386. (15-year population-based nested case-control study)
29. Lee CY, Marcotte F, Giraldeau G, et al. Digoxin toxicity precipitated by clarithromycin use: case presentation and concise review of the literature. Can J Cardiol. 2011;27(6):870.e15-870.e16. (Case presentation and review)
30. Xu H, Rashkow A. Clarithromycin-induced digoxin toxicity: a case report and a review of the literature. Conn Med. 2001;65(9):527-529. (Case report)
31. Chan AL, Wang MT, Su CY, et al. Risk of digoxin intoxication caused by clarithromycin-digoxin interactions in heart failure patients: a population-based study. Eur J Clin Pharmacol. 2009;65(12):1237-1243. (Retrospective study; 595 cases and 27,020 matched controls)
32. Kerns W, 2nd. Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am. 2007;25(2):309-331. (Review)
33. * Kline JA, Raymond RM, Schroeder JD, et al. The diabetogenic effects of acute verapamil poisoning. Toxicol Appl Pharmacol. 1997;145(2):357-362. (Animal study; 23 dogs) DOI: 1997.8195
34. 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. (Retrospective review; 5 hospitals, 40 patients)
35. Pita-Fernandez S, Lombardia-Cortina M, Orozco-Veltran D, et al. Clinical manifestations of elderly patients with digitalis intoxication in the emergency department. Arch Gerontol Geriatr. 2011;53(2):e106-e110. (Retrospective review)
36. Cooke DM. The use of central nervous system manifestations in the early detection of digitalis toxicity. Heart Lung. 1993;22(6):477-481. (Review)
37. Kemmerer DA. Devious digoxin: a case review. J Emerg Nurs. 2008;34(5):487-489. (Case report; 1 patient)
38. Lee TC. Van Gogh’s vision. Digitalis intoxication? JAMA. 1981;245(7):727-729. (Review)
39. Lely AH, van Enter C. Non-cardiac symptoms of digitalis intoxication. Am Heart J. 1972;83(2):149-152. (Review)
40. Shi L, Sun LD, Odel JG. Colored floaters as a manifestation of digoxin toxicity. Am J Ophthalmol Case Rep. 2018;10:233-235. (Case report)
41. Sporer KA, Khayam-Bashi H. Acetaminophen and salicylate serum levels in patients with suicidal ingestion or altered mental status. Am J Emerg Med. 1996;14(5):443-446. (Retrospective chart review; 1820 patients)
42. Megarbane B, Karyo S, Abidi K, et al. Predictors of mortality in verapamil overdose: usefulness of serum verapamil concentrations. Basic Clin Pharmacol Toxicol. 2011;108(6):385-389. (Chart review; 65 patients)
43. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289(7):871-878. (Post hoc analysis of randomized double-blinded placebo-controlled Digitalis Investigation Group (DIG) trial data; 3782 patients)
44. Sonnenblick M, Abraham AS, Meshulam Z, et al. Correlation between manifestations of digoxin toxicity and serum digoxin, calcium, potassium, and magnesium concentrations and arterial pH. Br Med J (Clin Res Ed). 1983;286(6371):1089-1091. (Prospective study; 50 patients)
45. Raja Rao MP, Panduranga P, Sulaiman K, et al. Digoxin toxicity with normal digoxin and serum potassium levels: beware of magnesium, the hidden malefactor. J Emerg Med. 2013;45(2):e31-e34. (Case report; 1 patient)
46. Tuncok Y, Hazan E, Oto O, et al. Relationship between high serum digoxin levels and toxicity. Int J Clin Pharmacol Ther. 1997;35(9):366-368. (Retrospective study; 1269 patients)
47. Ip D, Syed H, Cohen M. Digoxin specific antibody fragments (Digibind) in digoxin toxicity. BMJ. 2009;339:b2884. (Case report and review)
48. Eyer F, Steimer W, Muller C, et al. Free and total digoxin in serum during treatment of acute digoxin poisoning with Fab fragments: case study. Am J Crit Care. 2010;19(4):391-387. (Case report; 1 patient)
49. Bhatia SJ. Digitalis toxicity--turning over a new leaf? West J Med. 1986;145(1):74-82. (Review)
50. Kirilmaz B, Saygi S, Gungor H, et al. Digoxin intoxication: an old enemy in modern era. J Geriatr Cardiol. 2012;9(3):237-242. (Retrospective review; 71 patients)
51. Erickson CP, Olson KR. Case files of the medical toxicology fellowship of the California poison control system-San Francisco: calcium plus digoxin-more taboo than toxic? J Med Toxicol. 2008;4(1):33-39. (Case report; 1 patient)
52. Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol. 1992;69(18):108G-118G. (Review)
53. Zand F, Asadi S, Katibeh P. Good outcome after digoxin toxicity despite very high serum potassium level. Iran Red Crescent Med J. 2011;13(9):680-681. (Case report; 1 patient)
54. Bismuth C, Gaultier M, Conso F, et al. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol. 1973;6(2):153-162. (Prospective study)
55. Manini AF, Nelson LS, Hoffman RS. Prognostic utility of serum potassium in chronic digoxin toxicity: a case-control study. Am J Cardiovasc Drugs. 2011;11(3):173-178. (Case-control study; 13 fatalities, 13 survivors)
56. Love JN, Enlow B, Howell JM, et al. Electrocardiographic changes associated with beta-blocker toxicity. Ann Emerg Med. 2002;40(6):603-610. (Prospective cohort study; 167 patients)
57. Rennyson SL, Littmann L. Brugada-pattern electrocardiogram in propranolol intoxication. Am J Emerg Med. 2010;28(2):256 e257-e258. (Case report; 1 patient)
58. Irons GV Jr, Orgain ES. Digitalis-induced arrhythmias and their management. Prog Cardiovasc Dis. 1966;8(6):539-569. (Review)
59. * Ma G, Brady WJ, Pollack M, et al. Electrocardiographic manifestations: digitalis toxicity. J Emerg Med. 2001;20(2):145-152. (Review) DOI: 0736-4679(00)00312-7
60. Grimard C, De Labriolle A, Charbonnier B, et al. Bidirectional ventricular tachycardia resulting from digoxin toxicity. J Cardiovasc Electrophysiol. 2005;16(7):807-808. (Case report)
61. Kaneko Y, Nakajima T, Irie T, et al. Ventricular fibrillation following bidirectional tachycardia due to digitalis toxicity. Intern Med. 2011;50(19):2243. (Case report)
62. Menduina MJ, Candel JM, Alaminos P, et al. [Bidirectional ventricular tachycardia due to digitalis poisoning]. Rev Esp Cardiol. 2005;58(8):991-993. (Case report)
63. St-Onge M, Archambault P, Lesage N, et al. Adherence to calcium channel blocker poisoning treatment recommendations in two Canadian cities. Clin Toxicol (Phila). 2012;50(5):424-430. (Retrospective chart review; 103 patients)
64. Bond GR. The role of activated charcoal and gastric emptying in gastrointestinal decontamination: a state-of-the-art review. Ann Emerg Med. 2002;39(3):273-286. (Review)
65. Laine K, Kivisto KT, Laakso I, et al. Prevention of amlodipine absorption by activated charcoal: effect of delay in charcoal administration. Br J Clin Pharmacol. 1997;43(1):29-33. (Volunteer study; 32 patients)
66. No authors listed. Position paper: cathartics. J Toxicol Clin Toxicol. 2004;42(3):243-253. (Position paper)
67. No authors listed. Position paper: whole bowel irrigation. J Toxicol Clin Toxicol. 2004;42(6):843-854. (Position paper)
68. Cumpston KL, Aks SE, Sigg T, et al. Whole bowel irrigation and the hemodynamically unstable calcium channel blocker overdose: primum non nocere. J Emerg Med. 2010;38(2):171-174. (Case report; 2 patients)
69. Love JN. Acebutolol overdose resulting in fatalities. J Emerg Med. 2000;18(3):341-344. (Case report; 2 patients)
70. Pichon N, Dugard A, Clavel M, et al. Extracorporeal albumin dialysis in three cases of acute calcium channel blocker poisoning with life-threatening refractory cardiogenic shock. Ann Emerg Med. 2012;59(6):540-544. (Case series; 3 patients)
71. Holger JS, Engebretsen KM, Fritzlar SJ, et al. Insulin versus vasopressin and epinephrine to treat beta-blocker toxicity. Clin Toxicol (Phila). 2007;45(4):396-401. (Animal study; 10 pigs)
72. Albertson TE, Dawson A, de Latorre F, et al. TOX-ACLS: toxicologic-oriented advanced cardiac life support. Ann Emerg Med. 2001;37(4 Suppl):S78-S90. (Review)
73. Agarwal A, Yu SW, Rehman A, et al. Hyperinsulinemia euglycemia therapy for calcium channel blocker overdose: a case report. Tex Heart Inst J. 2012;39(4):575-578. (Case report; 1 patient)
74. Boyer EW, Shannon M. Treatment of calcium-channel-blocker intoxication with insulin infusion. N Engl J Med. 2001;344(22):1721-1722. (Case report)
75. Engebretsen KM, Kaczmarek KM, Morgan J, et al. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila). 2011;49(4):277-283. (Review)
76. Espinoza TR, Bryant SM, Aks SE. Hyperinsulin therapy for calcium channel antagonist poisoning: a seven-year retrospective study. Am J Ther. 2013;20(1):29-31. (Retrospective chart review; 46 patients)
77. * Greene SL, Gawarammana I, Wood DM, et al. Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study. Intensive Care Med. 2007;33(11):2019-2024. (Prospective observational study; 7 patients) DOI: 00134-007-0768-y
78. Page C, Hacket LP, Isbister GK. The use of high-dose insulin-glucose euglycemia in beta-blocker overdose: a case report. J Med Toxicol. 2009;5(3):139-143. (Case report; 1 patient)
79. Patel NP, Pugh ME, Goldberg S, et al. Hyperinsulinemic euglycemia therapy for verapamil poisoning: a review. Am J Crit Care. 2007;16(5):498-503. (Review)
80. Stellpflug SJ, Harris CR, Engebretsen KM, et al. Intentional overdose with cardiac arrest treated with IV fat emulsion and high-dose insulin. Clin Toxicol (Phila). 2010;48(3):227-229. (Case report; 1 patient)
81. * Yuan TH, Kerns WP 2nd, Tomaszewski CA, et al. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol. 1999;37(4):463-474. (Case series; 5 patients) DOI: 10.1081/clt-100102437
82. Rosser G, Dubrey SW. Massive calcium channel blocker overdose: IV insulin and glucose as a therapy. BMJ Case Rep. Jun 5, 2012. (Case report; 1 patient)
83. Krenz JR, Kaakeh Y. An overview of hyperinsulinemic-euglycemic therapy in calcium channel blocker and beta-blocker overdose. Pharmacotherapy. 2018;38(11):1130-1142. (Review)
84. Cole JB, Arens AM, Laes JR, et al. High dose insulin for beta-blocker and calcium channel-blocker poisoning. Am J Emerg Med. 2018;36(10):1817-1824. (Retrospective review; 199 patients)
85. St-Onge M, Anseeuw K, Cantrell FL, et al. Experts consensus recommendations for the management of calcium channel blocker poisoning in adults. Crit Care Med. 2017;45(3):e306-e315. (Expert consensus statement)
86. Kline JA, Raymond RM, Leonova ED, et al. Insulin improves heart function and metabolism during non-ischemic cardiogenic shock in awake canines. Cardiovasc Res. 1997;34(2):289-298. (Animal study; 20 dogs)
87. Doyon S, Roberts JR. The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med. 1993;22(7):1229-1233. (Case report; 1 patient)
88. Mahr NC, Valdes A, Lamas G. Use of glucagon for acute IV diltiazem toxicity. Am J Cardiol. 1997;79(11):1570-1571. (Case report; 1 patient)
89. Rizvi I, Ahmad A, Gupta A, et al. Life-threatening calcium channel blocker overdose and its management. BMJ Case Rep. May 30, 2012. (Case report; 1 patient)
90. * Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol. 2003;41(5):595-602. (Systematic review; 30 animal studies) DOI: 120023761
91. Hoot NR, Benitez JG, Palm KH. Hemodynamically unstable: accidental atenolol toxicity? J Emerg Med. 2013;45(3):355-357. (Case report; 1 patient)
92. Brubacher JR. Beta-adrenergic antagonists. In: Nelson LS, Lewin NA, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies. 9th ed. New York: McGraw-Hill; 2011:896-909. (Textbook chapter)
93. Durward A, Guerguerian AM, Lefebvre M, et al. Massive diltiazem overdose treated with extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2003;4(3):372-376. (Case report)
94. * de Lange DW, Sikma MA, Meulenbelt J. Extracorporeal membrane oxygenation in the treatment of poisoned patients. Clin Toxicol (Phila). 2013;51(5):385-393. (Review) DOI: 15563650.2013.800876
95. Rooney M, Massey KL, Jamali F, et al. Acebutolol overdose treated with hemodialysis and extracorporeal membrane oxygenation. J Clin Pharmacol. 1996;36(8):760-763. (Case report)
96. Masson R, Colas V, Parienti JJ, et al. A comparison of survival with and without extracorporeal life support treatment for severe poisoning due to drug intoxication. Resuscitation. 2012;83(11):1413-1417. (Retrospective comparative study; 62 patients)
97. Lewis J, Zarate M, Tran S, et al. The recommendation and use of extracorporeal membrane oxygenation (ECMO) in cases reported to the California Poison Control System. J Med Toxicol. 2019; 15(3):169-177. (Retrospective chart review of database registry; 94 cases with ECMO discussed as an option, 16 cases with ECMO use)
98. Wang GS, Levitan R, Toxicology Investigators Consortium, et al. Extracorporeal membrane oxygenation (ECMO) for severe toxicological exposures: review of the Toxicology Investigators Consortium (ToxIC). J Med Toxicol. 2016;12(1):95-99. (Expert consensus and review)
99. 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. (Case report)
100. Frierson J, Bailly D, Shultz T, et al. Refractory cardiogenic shock and complete heart block after unsuspected verapamil-SR and atenolol overdose. Clin Cardiol. 1991;14(11):933-935. (Case report; 1 patient)
101. Bania TC, Chu J, Perez E, et al. Hemodynamic effects of IV fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline. Acad Emerg Med. 2007;14(2):105-111. (Animal study; 14 dogs)
102. No authors listed. Bet 2: intralipid/lipid emulsion in beta-blocker overdose. Emerg Med J. 2011;28(11):991-993. (Review; 8 case reports, 1 case series; 10 patients)
103. 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. (Case report; 1 patient)
104. * LipidRescue™ Resuscitation. 2013. Accessed September 1, 2020. (Website)
105. Young AC, Velez LI, Kleinschmidt KC. IV fat emulsion therapy for intentional sustained-release verapamil overdose. Resuscitation. 2009;80(5):591-593. (Case report; 1 patient)
106. Cave G, Harvey M. IV lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Acad Emerg Med. 2009;16(9):815-824. (Systematic review; 14 animal studies, 1 human study, 4 case reports)
107. Gosselin S, Hoegberg LC, Hoffman RS, et al. Evidence-based recommendations on the use of IV lipid emulsion therapy in poisoning. Clin Toxicol (Phila). 2016;54(10):899-923. (Systematic review and expert consensus)
108. Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016;81(3):453-461. (Review)
109. ACMT position statement: interim guidance for the use of lipid resuscitation therapy. J Med Toxicol. 2011;7(1):81-82. (Guideline)
110. Hayes BD, Gosselin S, Calello DP, et al. Systematic review of clinical adverse events reported after acute IV lipid emulsion administration. Clin Toxicol (Phila). 2016; 54(5):365-404. (Systematic review)
111. 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. (Case report; 1 patient)
112. Kollef MH. Labetalol overdose successfully treated with amrinone and alpha-adrenergic receptor agonists. Chest. 1994;105(2):626-627. (Case report; 1 patient)
113. Hoeper MM, Boeker KH. Overdose of metoprolol treated with enoximone. N Engl J Med. 1996;335(20):1538. (Case report; 1 patient)
114. Shanker UR, Webb J, Kotze A. Sodium bicarbonate to treat massive beta blocker overdose. Emerg Med J. 2003;20(4):393. (Case report; 1 patient)
115. Donovan KD, Gerace RV, Dreyer JF. Acebutolol-induced ventricular tachycardia reversed with sodium bicarbonate. J Toxicol Clin Toxicol. 1999;37(4):481-484. (Case report; 1 patient)
116. Holstege CP, Furbee Ma, Wermuth ME, et al. Wide complex dysrhythmia in calcium channel blocker overdose responsive to sodium bicarbonate therapy. J Toxicol Clin Toxicol. 1998;36(5):509. (Case report)
117. Taboulet P, Cariou A, Berdeaux A, et al. Pathophysiology and management of self-poisoning with beta-blockers. J Toxicol Clin Toxicol. 1993;31(4):531-551. (Review)
118. 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. (Case report)
119. Saitz R, Williams BW, Farber HW. Atenolol-induced cardiovascular collapse treated with hemodialysis. Crit Care Med. 1991;19(1):116-118. (Case report; 1 patient)
120. Ibanez C, Carcas AJ, Frias J, et al. Activated charcoal increases digoxin elimination in patients. Int J Cardiol. 1995;48(1):27-30. (Chart review; 39 patients)
121. Critchley JA, Critchley LA. Digoxin toxicity in chronic renal failure: treatment by multiple dose activated charcoal intestinal dialysis. Hum Exp Toxicol. 1997;16(12):733-735. (Case report; 1 patient)
122. Antman EM, Wenger TL, Butler VP Jr, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation. 1990;81(6):1744-1752. (Retrospective review; 150 patients)
123. Schaeffer TH, Mlynarchek SL, Stanford CF, et al. Treatment of chronically digoxin-poisoned patients with a newer digoxin immune fab--a retrospective study. J Am Osteopath Assoc. 2010;110(10):587-592. (Retrospective study; 14 patients)
124. Ward SB, Sjostrom L, Ujhelyi MR. Comparison of the pharmacokinetics and in vivo bioaffinity of DigiTAb versus Digibind^®. Ther Drug Monit. 2000;22(5):599-607. (Randomized trial; 16 patients)
125. DigiFab^® package insert. Protherics. 2005. (Drug package insert)
126. Digibind^® package insert. GlaxoSmithKline. 2003. (Drug package insert)
127. Chan BS, Isbister GK, O'Leary M , et al. Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1). Clin Toxicol (Phila). 2016;54(6):488-494. (Prospective observational study; 36 patients)
128. Kinlay S, Buckley NA. Magnesium sulfate in the treatment of ventricular arrhythmias due to digoxin toxicity. J Toxicol Clin Toxicol. 1995;33(1):55-59. (Case report; 1 patient)
129. Garcia-Rubira JC, Suarez A, Ibanez B. Ventricular fibrillation after correct pacing in digoxin intoxication. J Emerg Med. 2012;42(4):e93-e94. (Case report)
130. Taboulet P, Baud FJ, Bismuth C, et al. Acute digitalis intoxication--is pacing still appropriate? J Toxicol Clin Toxicol. 1993;31(2):261-273. (Retrospective study; 92 patients)
131. Mowry JB, Burdmann EA, Anseeuw K, et al. Extracorporeal treatment for digoxin poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin Toxicology (Phila). 2016;54(2):103-114. (Systematic review and consensus statement)
132. Wu IL, Yu JH, Lin CC, et al. Fatal cardiac glycoside poisoning due to mistaking foxglove for comfrey. Clin Toxicol (Phila). 2017;55(7):670-673. (Case report)
133. Santos-Araujo C, Campos M, Gavina C, et al. Combined use of plasmapheresis and antidigoxin antibodies in a patient with severe digoxin intoxication and acute renal failure. Nephrol Dial Transplant. 2007;22(1):257-258. (Case report; 1 patient)
134. Link MS, Foote CB, Sloan SB, et al. Torsade de pointes and prolonged QT interval from surreptitious use of sotalol: use of drug levels in diagnosis. Chest. 1997;112(2):556-557. (Case report; 1 patient)
135. Levine M, Nikkanen H, Pallin DJ. The effects of IV calcium in patients with digoxin toxicity. J Emerg Med. 2011;40(1):41-46. (Retrospective chart review; 159 patients)
136. Jang DH, Nelson LS, Hoffman RS. Methylene blue in the treatment of refractory shock from an amlodipine overdose. Ann Emerg Med. 2011;58(6):565-567. (Case report; 1 patient)
137. Aggarwal N, Kupfer Y, Seneviratne C, et al. Methylene blue reverses recalcitrant shock in beta-blocker and calcium channel blocker overdose. BMJ Case Rep. Jan 18, 2013. (Case report; 1 patient)
138. Jang DH, Nelson LS, Hoffman RS. Methylene blue for distributive shock: a potential new use of an old antidote. J Med Toxicol. 2013;9(3):242-249. (Case report)
139. St-Onge M, Ajmo I, Poirier D, et al. L-carnitine for the treatment of a calcium channel blocker and metformin poisoning. J Med Toxicol. 2013;9(3):266-269. (Case report)
140. Teker MG, Ozdemir H, Saidoglu L, et al. Levosimendan as a rescue adjunct in amlodipine intoxication--a case report. Middle East J Anaesthesiol. 2010;20(6):869-872. (Case report)
141. Osthoff M, Bernsmeier C, Marsch SC, et al. Levosimendan as treatment option in severe verapamil intoxication: a case report and review of the literature. Case Rep Med. 2010; 2010. (Case report)
142. Varpula T, Rapola J, Sallisalmi M, et al. Treatment of serious calcium channel blocker overdose with levosimendan, a calcium sensitizer. Anest Analg. 2009;108(3):790-792. (Case report)
143. Love JN, Howell JM, Litovitz TL, et al. Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol. 1994;12(6):799-802. (Prospective cohort study; 280 beta blocker cases) DOI: 0736-4679(94)90487-1
144. * Love JN. Beta blocker toxicity after overdose: when do symptoms develop in adults? J Emerg Med. 1994;12(6):799-802. (Retrospective review; 39 patients)