American Journal of Therapeutics 23, e63–e67 (2016)
Assessment of Digoxin-Specific Fab Fragment Dosages in Digoxin Poisoning Sean Patrick Nordt, MD, PharmD,1* Richard F. Clark, MD,2 Carol Machado, MD,3 and F. Lee Cantrell, PharmD2
Digoxin poisoning still remains a common cause of morbidity and mortality. Fortunately, digoxinspecific Fab fragments are commercially available as an antidote. However, these Fab fragments are several thousand dollars per vial. There is a standardized formula to calculate appropriate Fab fragment dosage based on the serum digoxin concentration. This can greatly reduce the amount of Fab fragment administered. There is also an empiric dosing guideline recommending 6–10 vials be given; however, this may result in higher amounts of Fab fragments being administered than required. We performed this study to assess the amounts of digoxin-specific Fab fragments administered in the treatment of digoxin poisonings recorded in a poison control system database from January 1, 2000, to December 31, 2009, in which digoxin serum concentrations were available. This was a retrospective study of 278 patients, 107 with acute poisonings (group A) and 171 following chronic poisoning (group B). In group A, the calculated Fab dose was higher than the calculated dose based on available concentrations in 39 (36%) of group A and 15 (9%) of group B patients. The average wholesale price cost of the excessive dosages ranged from $4818 to as high as $50,589 per patient. Our data suggests that clinician education on digoxin poisoning and the use of the standardized formula to calculate the Fab dose may decrease over utilization and decrease costs associated with the administration of digoxin-specific Fab fragments in the treatment of digoxin poisonings. Keywords: digoxin, cardiac glycosides, Fab fragment, poisoning
INTRODUCTION Digoxin is a cardiac glycoside used in the treatment of congestive heart failure and atrial fibrillation. Digoxin has a narrow therapeutic index so that toxicity may be seen just above therapeutic concentrations.1 Serum 1
Department of Emergency Medicine, Section of Toxicology, Keck School of Medicine, University of Southern California, Los Angeles, CA; 2California Poison Control System—San Diego Division, San Diego, CA; and 3Department of Surgery, UCSF Fresno, Fresno, CA. The authors have no conflicts of interest to declare. *Address for correspondence: Associate Professor of Emergency Medicine, Department of Emergency Medicine, Section of Toxicology, Keck School of Medicine, University of Southern California, 1200 North State Street, GH 1011, Los Angeles, CA 90033. E-mail: [email protected]
digoxin concentrations should normally be in the range of 0.5–2 ng/mL.2 The routine clinical use of digoxin has somewhat declined over the past decades; however, there is still significant morbidity and mortality associated with digoxin. In 2012, 2025 human exposures to cardiac glycosides were reported to the American Association of Poison Control Centers, with 14 deaths identified as a result of digoxin poisoning.3 Although controversial, digoxin has been suggested to decrease both morbidity and mortality in patients with congestive heart failure receiving therapeutic doses.4,5 This may account for the continued use of digoxin in some populations. Although the clinical presentation of digoxin poisonings can be varied and include gastrointestinal, neurologic, and visual findings; cardiovascular manifestations are the most common cause of death.6–8 Almost any dysrhythmia can occur with digoxin toxicity except for
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a rapidly conducted supraventricular rhythm due to atrioventricular node dysfunction.9 The dysrhythmias most associated with digoxin toxicity include premature ventricular contractions, sinus bradycardia, paroxysmal atrial tachycardia with conduction block, junctional tachycardia, and bidirectional ventricular tachycardia.9 In the treatment of digoxin poisoning, there is an antidote available, DigiFab, a digoxin-specific Fab (Fab) fragment product. Digoxin-specific Fab fragments have greatly reduced morbidity and mortality with digoxin poisoning.10,11 This product is a sheepderived partial immunoglobulin G molecule in which the Fc portion has been cleaved to reduce incidence of anaphylactic reactions.10,12 However, DigiFab is expensive with an acquisition wholesale price (AWP) of $2409 per vial.13 There was formerly another commercially available digoxin-specific product in the United States, Digibind. However, as of March 1, 2011, GlaxoSmithKline Pharmaceuticals discontinued Digibind manufacturer leaving only DigiFab as the sole digoxin-specific antidote.14 In the treatment of digoxin toxicity with digoxinspecific Fab fragments, there is a standardized formula based on the serum concentration, which guides the clinician to give a specific amount of the either Fab fragment product, that is, Digibind or DigiFab.1,8 The formula is digoxin-specific Fab fragment dose in vials 5 (serum digoxin concentration in ng/mL) 3 (weight in kg)/100, generally rounded up to the nearest vial.15 By calculating the dose of Fab based on the serum concentration, a specific dose is given with the goal of inactivating available digoxin. However, many clinicians use an empiric dosing schedule without calculating dose of either 5–6 vials or 10 vials based on whether a chronic or acute poisoning is being treated.8,15 Although this is generally regarded as safe, this can result in more digoxin-specific Fab fragment being administered than is needed to reverse toxicity and greatly increase cost and possibly adverse drug reactions. The aim of this study was to evaluate the dosing method used and amount of digoxin-specific Fab fragments administered in digoxin poisoning cases reported to a poison control system in which digoxin-specific Fab fragments were administered and where digoxin serum concentrations were available.
MATERIALS AND METHODS We performed a retrospective review of the electronic database (Visual Dotlab) of the California Poison Control System (CPCS) from January 1, 2000, to December 31, 2009. The CPCS is the poison system for both American Journal of Therapeutics (2016) 23(1)
Nordt et al
health professionals and consumers, for the state of California. Callers access the CPCS by a toll-free number. Inclusion criteria were patients of any age or sex with an exposure to digoxin reported to the CPCS over the study period who received digoxin-specific Fab fragments. All human cases in which digoxin-specific Fab fragments administration occurred in the treatment of digoxin poisoning were identified. Other cardiac glycoside medications or plants were excluded. Only cases with digoxin concentrations, age, gender, and known outcome were included. In addition, weight in kilograms (kg), serum potassium in milliequivalents per liter (mEq/L), and serum creatinine in milligrams per deciliter (mg/dL) were recorded if available. Cases were separated into 2 groups such as the following: acute poisonings and acute on chronic poisonings (group A) or chronic poisonings (group B). Acute digoxin poisoning generally results from intentional ingestion or from an accidental ingestion such as in children. A similar clinical scenario is when someone who is chronically on digoxin ingests an additional large amount of digoxin. This is known as an acute on chronic ingestion. A different situation is when an individual who is chronically on digoxin becomes toxic as a result of increased accumulation of digoxin within the body, often due to declining renal function, and this is known as chronic digoxin poisoning. This scenario can also results from drug–drug interactions.1,6,8,12 For cases where weight was unknown, standardized weight charts employed used with the 50th percentile for age and gender used.16 The total number of vials administered was recorded. The therapeutically “correct” dose was calculated by the standardized formula using postdistribution digoxin concentrations as described above. The Fab doses were considered supratherapeutic if $2 vials above the calculated dose or too low if #2 vials below the calculated dose. Cost analysis was based on the current AWP of $2409 per vial.13 Descriptive statistical methods were used. All data abstracted were keyed into Microsoft Excel 2003 (Redmond, WA). This study was approved by the institution’s Human Research Protection Program.
RESULTS There were a total of 278 patients who met inclusion criteria, 107 patients were in group A, acute ingestions on chronic poisoning and 171 patients were in group B, chronic poisoning. Fifty-six of the 107 patients in group A were female (52%) and 51 were male (48%) with a mean age of 60.8 years (range, 0.1–97 years) with a mean weight of 67.1 kg (range, 3.5–114 kg). www.americantherapeutics.com
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Digoxin-Specific Fab Fragment Dosing
The mean digoxin serum concentration in group A was 9.1 ng/mL (range, 0.2–35 ng/mL). The serum creatinine was available in 63 (58%), of group A patients with a mean 1.95 mg/dL (range, 0.4–10.7). A serum potassium was available in 88 (80%) of group A patients with a mean of 5.2 mEq/L (range, 3–7.8). Recorded body weights were available in the charts of 53 patients (50%). In group A, the number of vials administered was less than the calculated Fab dose in 12 (11%) patients (range, 1–8 vials) based on the standardized formula. Thirty-nine (36%) of group A patients were administered digoxin-specific Fab doses higher than the calculated dose based on available concentration and weight. An excess of 2–4 vials was reported in 17 (16%) patients, AWP cost $4818 to $9636 per patient. An excess of 5–7 vials in 11 (10%) patients, AWP cost $12,045 to $16,863 per patient. An excess of 8–10 vials in 6 (6%) patients, AWP cost $19,272 to $24,090 per patient and an excess of 13–21 vials in 5 (5%) patients, AWP cost $31,317 to $50,589 per patient. Of the 171 patients in group B, 110 (64%) were female and 61 (36%) were male with a mean age of 75.6 years (range, 1–103 years) with a mean weight of 66.6 kg (range, 12.5–160 kg). The mean serum digoxin concentration was 4.4 ng/mL (range, 1.7–10.6 ng/mL). The serum creatinine was available in 155 (91%) patients with a mean of 2.8 mg/dL (range, 0.4–11 mg/dL). The serum potassium was available in 159 (93%) patients with a mean of 5.2 mEq/L (range, 3–11 mEq/L). Recorded body weights were available in the charts of 124 patients (77%). In group B, the number of vials administered was less than the calculated Fab dose in 28 patients (16%), based on the standardized formula. Fifteen (9%) of group B patients were administered digoxin-specific Fab doses higher than the calculated dose based on available concentration and weight, of which an excess of 2–4 vials given in 10 (6%) patients, AWP cost $4818 to $9636 per patient. An excess of 5–6 vials in 4 (2%) patients, AWP cost $12,045 to $14,454 and an excess of 7 vials in 1 patient was seen with an AWP cost of $16,863. There were a total of 10 deaths in our study population, 5 deaths in each group. However, all received the “correct” calculated dose of Fab based on the standardized formula.
DISCUSSION With acute poisonings, individuals may be asymptomatic for several hours due to the unique pharmacokinetic properties of digoxin.7,8 Digoxin has a biphasic distribution phase after acute ingestions whereby the www.americantherapeutics.com
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serum concentrations in the “central” compartment are greatly elevated; however, tissue concentrations for example, cardiac myocytes are very low.7,8 Over several hours, as digoxin moves from the blood to peripheral tissues, the serum concentration decreases with this movement and the signs and symptoms of toxicity manifest. As a result of this phenomenon; serum digoxin concentrations obtained before 6 hours, that is, the time needed for distribution to occur, may be greatly elevated and cannot be interpreted as a correlate to toxicity but rather only that confirm digoxin has been ingested. Dosage of digoxin-specific Fab fragments should not be made on these serum concentrations before 6 hours in either acute or acute on chronic digoxin ingestions.7,8 Interestingly, in chronic digoxin toxicity, the total body accumulation of digoxin occurs much more slowly, often over weeks. As such, patients can be severely toxic manifesting multiple effects of digoxin with serum concentrations often just above the therapeutic range.6 Digoxin reversibly inhibits the sodium–potassium ATPase pump in the sarcolemma resulting in an increase in intracellular sodium, which then is exchanged for calcium through sodium–calcium channel. This increase in intracellular calcium concentration results in the positive inotropic effects.1,6,9 This inhibition of the sodium–potassium ATPase pump also increases extracellular potassium concentrations, which can cause severe hyperkalemia due to widespread inhibition of sodium–potassium ATPase in multiple organ systems, particularly in acute toxicity.8 In addition, digoxin has a negative chronotropic effect mediated through increased vagal tone. This increased vagal tone decreases sinoatrial node depolarization and increases the refractory period of the atrioventricular node. In digoxin toxicity, there is also increased automaticity, which increases risk of dysrhythmias.9 Hyperkalemia in digoxin poisoning has prognostic indications and has been associated with mortality and is a major manifestation of both acute and chronic cardiac glycoside toxicity and is a result of the widespread inhibition of Na-K-ATPase and the subsequent increase in extracellular potassium.8 In acute toxicity, there is a strong correlation between degree of hyperkalemia and mortality from digoxin overdose. In a study of 91 patients with acute cardiac glycoside poisoning, potassium serum concentrations higher than 5.5 mEq/L had 100% mortality compared with no deaths with serum concentrations less than 5 mEq/L.17 This study was before the approval of digoxin-specific Fab fragments in the 1980s. However, based on these study results, potassium concentrations greater than 5.5 mEq/L are considered an indication for digoxinspecific Fab fragment administration. Interestingly, in American Journal of Therapeutics (2016) 23(1)
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chronic poisonings, hypokalemia can be as concerning. This is because hypokalemia as well as hypomagnesemia can exacerbate digoxin toxicity although severe hyperkalemia may also be seen in chronic poisonings, particularly acute on chronic poisonings.1,6 According to the manufacturer’s package insert, DigiFab is indicated for the treatment of patients with life-threatening or potentially life-threatening digoxin toxicity or overdose, including known suicidal or accidental consumption of fatal doses of digoxin of 10 mg or more in healthy adults, or 4 mg (or more than 0.1 mg/kg) in healthy children, or ingestion of an amount that can cause steady-state serum concentrations of $10 ng/mL.15 In addition, it is indicated following chronic ingestions causing steady-state serum digoxin concentrations of $6 ng/mL in adults or 4 ng/mL in children.15 However, most importantly, digoxinspecific Fab is indicated for clinical manifestations of digoxin poisoning, including severe ventricular arrhythmias, progressive bradycardia, and second- or third-degree heart block not responsive to atropine, serum potassium levels exceeding 5.5 mEq/L in adults or 6 mEq/L in children with rapidly progressive signs and symptoms of digoxin toxicity.15 Our data demonstrate majority of digoxin-poisoned cases received therapeutic doses of Fab product. It is difficult to comment if doses were actually subtherapeutic as clinically more vials may not have been indicated. Also some clinicians may opt to attempt to “partially reverse” rather than “fully reverse” patients for concern of unmasking uncontrolled atrial fibrillation or exacerbating congestive heart failure.10 We found 39% of group A received 2 or more vials than “needed” based on calculated dose using standardized formula. As a retrospective study, it is difficult to determine whether these actually were too high. However, some doses were exceptionally high. These may have been given based on predistribution digoxin concentrations, that is, before 6 hours resulting in greatly elevated serum digoxin concentrations. Calculations based on these predistribution concentrations can be erroneous and result in much higher than indicated doses of digoxin-specific Fab fragment administration. For example, an “early” serum concentration of 35 ng/L would calculate to be 25 vials for a 70-kg adult based on the standard formula where the post distribution serum concentration could be a fraction of this value. At the time of our study period, the 2 digoxinspecific Fab products, DigiFab and Digibind, were still both available, and the formula was standardized for both of these products. Presently, the only digoxinspecific Fab product is DigiFab, with an AWP of $2409 per vial (US dollars).13 One patient in group 1 American Journal of Therapeutics (2016) 23(1)
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received 21 “extra” vials more than calculated, which would be and additional $50,589 AWP cost based on current pricing. Furthermore, this AWP would not directly reflect actual billing costs, which could be much higher. The major limitation of our study is in the retrospective use of poison center data. The certified specialists in the poison information staff of the CPCS use a standardized data collection form and outcome criteria.3 However, there could be omissions from these records, and also these data may not accurately reflect true events. Another limitation is that the actual weights were recorded in only 77% of chronic poisonings and 50% of acute poisonings. Although a few patients may be much heavier than estimated based on the standardized weight charts thus decreasing calculated dose, we suspect would not change calculated dose in most patients. In addition, the present AWP prices may not accurately reflect the cost during the study period or the billed charges. However, the present AWP price is used to emphasize the present cost climate and to support the judicious use of digoxinspecific Fab fragment administration when the serum concentration is immediately available. Finally, during our study period, both digoxin-specific Fab fragment products were available. The CPCS charts do not specify whether DigiFab or Digibind were administered. The charting is coded for digoxin-specific Fab fragments not the brand names. However, when both of these products were commercially available, they were equipotent, and therefore, clinically, no difference would be expected.8
CONCLUSIONS Our data suggest that clinician education on digoxin poisoning and the use of the standardized formula to calculate the dose may decrease over utilization and decrease costs associated with the administration of digoxin-specific Fab fragments. Further prospective studies of digoxin-poisoned patients are needed to further elucidate this hypothesis.
REFERENCES 1. Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but critical complication to recognize. Am J Med. 2012; 125:337–343. 2. Morris SA, Hatcher HF, Reddy DK. Digoxin therapy for heart failure: an update. Am Fam Physician. 2006;74:613– 618. 3. Mowry JB, Spyker DA, Cantilena LR. 2012 Annual Report of the American Association of Poison Control www.americantherapeutics.com
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Digoxin-Specific Fab Fragment Dosing
4.
5.
6.
7. 8.
9. 10.
Centers’ National Poison Data System (NPDS). Clin Toxicol (Phila). 2013;5:949–1229. Ahmed A, Waagstein F, Pitt B, et al. Effectiveness of digoxin in reducing one-year mortality in chronic heart failure in the Digitalis Investigation Group trial. Am J Cardiol. 2009;103:82–87. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525–533. Sharff JA, Bayer MJ. Acute and chronic digitalis toxicity: presentation and treatment. Ann Emerg Med. 1982;11: 327–331. Bayer MJ. Recognition and management of digitalis intoxication. Am J Emerg Med. 1991;9:29–32. Kanji S, MacLean RD. Cardiac glycoside toxicity. More than 200 years and counting. Crit Care Clin. 2012;28: 527–535. Ma G, Brady WJ, Pollack M, et al. Electrocardiographic manifestations: digitalis toxicity. J Emerg Med. 2001;145–152. Antman EM, Wenger TL, Butler VP, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Circulation. 1990;81:1744–1752.
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e67 11. Lapostolle F, Borron SW, Verdier C. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Crit Care Med. 2008;36:3014–3018. 12. Antman EM, Smith TW. Digitalis toxicity. Ann Rev Med. 1985;36:357–367. 13. DigiFabÒ average wholesale price. Cardinal Health Pharmaceutical Distribution. Available at: http://www.cardinal. com/us/en/pharmaceuticaldistribution/rx. Accessed May 30, 2014. 14. DigibindÒ withdrawal and alternative availability. Poisons Information Centre of Ireland. Available at: http:// www.poisons.ie/News_detail.asp?newsId543. Accessed June 18, 2014. 15. DIGIFABÒ DIGOXIN IMMUNE FAB (OVINE) [package insert]. BTG International. Available at: http://www. kodc.or.kr/cmed/down/DigiFab%20Package%20Insert. pdf. Accessed June 18, 2014. 16. Average weight charts. [Halls.MD]. Available at: http:// www.halls.md/chart/height-weight.htm. Accessed June 18, 2014. 17. Bismuth C, Gaultier M, Conso F, et al. Hyperkalemia in acute digitalis poisoning. Prognostic significance and therapeutic implications. Clin Toxicol. 1973;6:153–162.
American Journal of Therapeutics (2016) 23(1)
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Assessment of Digoxin-Specific Fab Fragment Dosages in Digoxin Poisoning Sean Patrick Nordt, MD, PharmD,1* Richard F. Clark, MD,2 Carol Machado, MD,3 and F. Lee Cantrell, PharmD2
Digoxin poisoning still remains a common cause of morbidity and mortality. Fortunately, digoxinspecific Fab fragments are commercially available as an antidote. However, these Fab fragments are several thousand dollars per vial. There is a standardized formula to calculate appropriate Fab fragment dosage based on the serum digoxin concentration. This can greatly reduce the amount of Fab fragment administered. There is also an empiric dosing guideline recommending 6–10 vials be given; however, this may result in higher amounts of Fab fragments being administered than required. We performed this study to assess the amounts of digoxin-specific Fab fragments administered in the treatment of digoxin poisonings recorded in a poison control system database from January 1, 2000, to December 31, 2009, in which digoxin serum concentrations were available. This was a retrospective study of 278 patients, 107 with acute poisonings (group A) and 171 following chronic poisoning (group B). In group A, the calculated Fab dose was higher than the calculated dose based on available concentrations in 39 (36%) of group A and 15 (9%) of group B patients. The average wholesale price cost of the excessive dosages ranged from $4818 to as high as $50,589 per patient. Our data suggests that clinician education on digoxin poisoning and the use of the standardized formula to calculate the Fab dose may decrease over utilization and decrease costs associated with the administration of digoxin-specific Fab fragments in the treatment of digoxin poisonings. Keywords: digoxin, cardiac glycosides, Fab fragment, poisoning
INTRODUCTION Digoxin is a cardiac glycoside used in the treatment of congestive heart failure and atrial fibrillation. Digoxin has a narrow therapeutic index so that toxicity may be seen just above therapeutic concentrations.1 Serum 1
Department of Emergency Medicine, Section of Toxicology, Keck School of Medicine, University of Southern California, Los Angeles, CA; 2California Poison Control System—San Diego Division, San Diego, CA; and 3Department of Surgery, UCSF Fresno, Fresno, CA. The authors have no conflicts of interest to declare. *Address for correspondence: Associate Professor of Emergency Medicine, Department of Emergency Medicine, Section of Toxicology, Keck School of Medicine, University of Southern California, 1200 North State Street, GH 1011, Los Angeles, CA 90033. E-mail: [email protected]
digoxin concentrations should normally be in the range of 0.5–2 ng/mL.2 The routine clinical use of digoxin has somewhat declined over the past decades; however, there is still significant morbidity and mortality associated with digoxin. In 2012, 2025 human exposures to cardiac glycosides were reported to the American Association of Poison Control Centers, with 14 deaths identified as a result of digoxin poisoning.3 Although controversial, digoxin has been suggested to decrease both morbidity and mortality in patients with congestive heart failure receiving therapeutic doses.4,5 This may account for the continued use of digoxin in some populations. Although the clinical presentation of digoxin poisonings can be varied and include gastrointestinal, neurologic, and visual findings; cardiovascular manifestations are the most common cause of death.6–8 Almost any dysrhythmia can occur with digoxin toxicity except for
1075–2765 Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
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e64
a rapidly conducted supraventricular rhythm due to atrioventricular node dysfunction.9 The dysrhythmias most associated with digoxin toxicity include premature ventricular contractions, sinus bradycardia, paroxysmal atrial tachycardia with conduction block, junctional tachycardia, and bidirectional ventricular tachycardia.9 In the treatment of digoxin poisoning, there is an antidote available, DigiFab, a digoxin-specific Fab (Fab) fragment product. Digoxin-specific Fab fragments have greatly reduced morbidity and mortality with digoxin poisoning.10,11 This product is a sheepderived partial immunoglobulin G molecule in which the Fc portion has been cleaved to reduce incidence of anaphylactic reactions.10,12 However, DigiFab is expensive with an acquisition wholesale price (AWP) of $2409 per vial.13 There was formerly another commercially available digoxin-specific product in the United States, Digibind. However, as of March 1, 2011, GlaxoSmithKline Pharmaceuticals discontinued Digibind manufacturer leaving only DigiFab as the sole digoxin-specific antidote.14 In the treatment of digoxin toxicity with digoxinspecific Fab fragments, there is a standardized formula based on the serum concentration, which guides the clinician to give a specific amount of the either Fab fragment product, that is, Digibind or DigiFab.1,8 The formula is digoxin-specific Fab fragment dose in vials 5 (serum digoxin concentration in ng/mL) 3 (weight in kg)/100, generally rounded up to the nearest vial.15 By calculating the dose of Fab based on the serum concentration, a specific dose is given with the goal of inactivating available digoxin. However, many clinicians use an empiric dosing schedule without calculating dose of either 5–6 vials or 10 vials based on whether a chronic or acute poisoning is being treated.8,15 Although this is generally regarded as safe, this can result in more digoxin-specific Fab fragment being administered than is needed to reverse toxicity and greatly increase cost and possibly adverse drug reactions. The aim of this study was to evaluate the dosing method used and amount of digoxin-specific Fab fragments administered in digoxin poisoning cases reported to a poison control system in which digoxin-specific Fab fragments were administered and where digoxin serum concentrations were available.
MATERIALS AND METHODS We performed a retrospective review of the electronic database (Visual Dotlab) of the California Poison Control System (CPCS) from January 1, 2000, to December 31, 2009. The CPCS is the poison system for both American Journal of Therapeutics (2016) 23(1)
Nordt et al
health professionals and consumers, for the state of California. Callers access the CPCS by a toll-free number. Inclusion criteria were patients of any age or sex with an exposure to digoxin reported to the CPCS over the study period who received digoxin-specific Fab fragments. All human cases in which digoxin-specific Fab fragments administration occurred in the treatment of digoxin poisoning were identified. Other cardiac glycoside medications or plants were excluded. Only cases with digoxin concentrations, age, gender, and known outcome were included. In addition, weight in kilograms (kg), serum potassium in milliequivalents per liter (mEq/L), and serum creatinine in milligrams per deciliter (mg/dL) were recorded if available. Cases were separated into 2 groups such as the following: acute poisonings and acute on chronic poisonings (group A) or chronic poisonings (group B). Acute digoxin poisoning generally results from intentional ingestion or from an accidental ingestion such as in children. A similar clinical scenario is when someone who is chronically on digoxin ingests an additional large amount of digoxin. This is known as an acute on chronic ingestion. A different situation is when an individual who is chronically on digoxin becomes toxic as a result of increased accumulation of digoxin within the body, often due to declining renal function, and this is known as chronic digoxin poisoning. This scenario can also results from drug–drug interactions.1,6,8,12 For cases where weight was unknown, standardized weight charts employed used with the 50th percentile for age and gender used.16 The total number of vials administered was recorded. The therapeutically “correct” dose was calculated by the standardized formula using postdistribution digoxin concentrations as described above. The Fab doses were considered supratherapeutic if $2 vials above the calculated dose or too low if #2 vials below the calculated dose. Cost analysis was based on the current AWP of $2409 per vial.13 Descriptive statistical methods were used. All data abstracted were keyed into Microsoft Excel 2003 (Redmond, WA). This study was approved by the institution’s Human Research Protection Program.
RESULTS There were a total of 278 patients who met inclusion criteria, 107 patients were in group A, acute ingestions on chronic poisoning and 171 patients were in group B, chronic poisoning. Fifty-six of the 107 patients in group A were female (52%) and 51 were male (48%) with a mean age of 60.8 years (range, 0.1–97 years) with a mean weight of 67.1 kg (range, 3.5–114 kg). www.americantherapeutics.com
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Digoxin-Specific Fab Fragment Dosing
The mean digoxin serum concentration in group A was 9.1 ng/mL (range, 0.2–35 ng/mL). The serum creatinine was available in 63 (58%), of group A patients with a mean 1.95 mg/dL (range, 0.4–10.7). A serum potassium was available in 88 (80%) of group A patients with a mean of 5.2 mEq/L (range, 3–7.8). Recorded body weights were available in the charts of 53 patients (50%). In group A, the number of vials administered was less than the calculated Fab dose in 12 (11%) patients (range, 1–8 vials) based on the standardized formula. Thirty-nine (36%) of group A patients were administered digoxin-specific Fab doses higher than the calculated dose based on available concentration and weight. An excess of 2–4 vials was reported in 17 (16%) patients, AWP cost $4818 to $9636 per patient. An excess of 5–7 vials in 11 (10%) patients, AWP cost $12,045 to $16,863 per patient. An excess of 8–10 vials in 6 (6%) patients, AWP cost $19,272 to $24,090 per patient and an excess of 13–21 vials in 5 (5%) patients, AWP cost $31,317 to $50,589 per patient. Of the 171 patients in group B, 110 (64%) were female and 61 (36%) were male with a mean age of 75.6 years (range, 1–103 years) with a mean weight of 66.6 kg (range, 12.5–160 kg). The mean serum digoxin concentration was 4.4 ng/mL (range, 1.7–10.6 ng/mL). The serum creatinine was available in 155 (91%) patients with a mean of 2.8 mg/dL (range, 0.4–11 mg/dL). The serum potassium was available in 159 (93%) patients with a mean of 5.2 mEq/L (range, 3–11 mEq/L). Recorded body weights were available in the charts of 124 patients (77%). In group B, the number of vials administered was less than the calculated Fab dose in 28 patients (16%), based on the standardized formula. Fifteen (9%) of group B patients were administered digoxin-specific Fab doses higher than the calculated dose based on available concentration and weight, of which an excess of 2–4 vials given in 10 (6%) patients, AWP cost $4818 to $9636 per patient. An excess of 5–6 vials in 4 (2%) patients, AWP cost $12,045 to $14,454 and an excess of 7 vials in 1 patient was seen with an AWP cost of $16,863. There were a total of 10 deaths in our study population, 5 deaths in each group. However, all received the “correct” calculated dose of Fab based on the standardized formula.
DISCUSSION With acute poisonings, individuals may be asymptomatic for several hours due to the unique pharmacokinetic properties of digoxin.7,8 Digoxin has a biphasic distribution phase after acute ingestions whereby the www.americantherapeutics.com
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serum concentrations in the “central” compartment are greatly elevated; however, tissue concentrations for example, cardiac myocytes are very low.7,8 Over several hours, as digoxin moves from the blood to peripheral tissues, the serum concentration decreases with this movement and the signs and symptoms of toxicity manifest. As a result of this phenomenon; serum digoxin concentrations obtained before 6 hours, that is, the time needed for distribution to occur, may be greatly elevated and cannot be interpreted as a correlate to toxicity but rather only that confirm digoxin has been ingested. Dosage of digoxin-specific Fab fragments should not be made on these serum concentrations before 6 hours in either acute or acute on chronic digoxin ingestions.7,8 Interestingly, in chronic digoxin toxicity, the total body accumulation of digoxin occurs much more slowly, often over weeks. As such, patients can be severely toxic manifesting multiple effects of digoxin with serum concentrations often just above the therapeutic range.6 Digoxin reversibly inhibits the sodium–potassium ATPase pump in the sarcolemma resulting in an increase in intracellular sodium, which then is exchanged for calcium through sodium–calcium channel. This increase in intracellular calcium concentration results in the positive inotropic effects.1,6,9 This inhibition of the sodium–potassium ATPase pump also increases extracellular potassium concentrations, which can cause severe hyperkalemia due to widespread inhibition of sodium–potassium ATPase in multiple organ systems, particularly in acute toxicity.8 In addition, digoxin has a negative chronotropic effect mediated through increased vagal tone. This increased vagal tone decreases sinoatrial node depolarization and increases the refractory period of the atrioventricular node. In digoxin toxicity, there is also increased automaticity, which increases risk of dysrhythmias.9 Hyperkalemia in digoxin poisoning has prognostic indications and has been associated with mortality and is a major manifestation of both acute and chronic cardiac glycoside toxicity and is a result of the widespread inhibition of Na-K-ATPase and the subsequent increase in extracellular potassium.8 In acute toxicity, there is a strong correlation between degree of hyperkalemia and mortality from digoxin overdose. In a study of 91 patients with acute cardiac glycoside poisoning, potassium serum concentrations higher than 5.5 mEq/L had 100% mortality compared with no deaths with serum concentrations less than 5 mEq/L.17 This study was before the approval of digoxin-specific Fab fragments in the 1980s. However, based on these study results, potassium concentrations greater than 5.5 mEq/L are considered an indication for digoxinspecific Fab fragment administration. Interestingly, in American Journal of Therapeutics (2016) 23(1)
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chronic poisonings, hypokalemia can be as concerning. This is because hypokalemia as well as hypomagnesemia can exacerbate digoxin toxicity although severe hyperkalemia may also be seen in chronic poisonings, particularly acute on chronic poisonings.1,6 According to the manufacturer’s package insert, DigiFab is indicated for the treatment of patients with life-threatening or potentially life-threatening digoxin toxicity or overdose, including known suicidal or accidental consumption of fatal doses of digoxin of 10 mg or more in healthy adults, or 4 mg (or more than 0.1 mg/kg) in healthy children, or ingestion of an amount that can cause steady-state serum concentrations of $10 ng/mL.15 In addition, it is indicated following chronic ingestions causing steady-state serum digoxin concentrations of $6 ng/mL in adults or 4 ng/mL in children.15 However, most importantly, digoxinspecific Fab is indicated for clinical manifestations of digoxin poisoning, including severe ventricular arrhythmias, progressive bradycardia, and second- or third-degree heart block not responsive to atropine, serum potassium levels exceeding 5.5 mEq/L in adults or 6 mEq/L in children with rapidly progressive signs and symptoms of digoxin toxicity.15 Our data demonstrate majority of digoxin-poisoned cases received therapeutic doses of Fab product. It is difficult to comment if doses were actually subtherapeutic as clinically more vials may not have been indicated. Also some clinicians may opt to attempt to “partially reverse” rather than “fully reverse” patients for concern of unmasking uncontrolled atrial fibrillation or exacerbating congestive heart failure.10 We found 39% of group A received 2 or more vials than “needed” based on calculated dose using standardized formula. As a retrospective study, it is difficult to determine whether these actually were too high. However, some doses were exceptionally high. These may have been given based on predistribution digoxin concentrations, that is, before 6 hours resulting in greatly elevated serum digoxin concentrations. Calculations based on these predistribution concentrations can be erroneous and result in much higher than indicated doses of digoxin-specific Fab fragment administration. For example, an “early” serum concentration of 35 ng/L would calculate to be 25 vials for a 70-kg adult based on the standard formula where the post distribution serum concentration could be a fraction of this value. At the time of our study period, the 2 digoxinspecific Fab products, DigiFab and Digibind, were still both available, and the formula was standardized for both of these products. Presently, the only digoxinspecific Fab product is DigiFab, with an AWP of $2409 per vial (US dollars).13 One patient in group 1 American Journal of Therapeutics (2016) 23(1)
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received 21 “extra” vials more than calculated, which would be and additional $50,589 AWP cost based on current pricing. Furthermore, this AWP would not directly reflect actual billing costs, which could be much higher. The major limitation of our study is in the retrospective use of poison center data. The certified specialists in the poison information staff of the CPCS use a standardized data collection form and outcome criteria.3 However, there could be omissions from these records, and also these data may not accurately reflect true events. Another limitation is that the actual weights were recorded in only 77% of chronic poisonings and 50% of acute poisonings. Although a few patients may be much heavier than estimated based on the standardized weight charts thus decreasing calculated dose, we suspect would not change calculated dose in most patients. In addition, the present AWP prices may not accurately reflect the cost during the study period or the billed charges. However, the present AWP price is used to emphasize the present cost climate and to support the judicious use of digoxinspecific Fab fragment administration when the serum concentration is immediately available. Finally, during our study period, both digoxin-specific Fab fragment products were available. The CPCS charts do not specify whether DigiFab or Digibind were administered. The charting is coded for digoxin-specific Fab fragments not the brand names. However, when both of these products were commercially available, they were equipotent, and therefore, clinically, no difference would be expected.8
CONCLUSIONS Our data suggest that clinician education on digoxin poisoning and the use of the standardized formula to calculate the dose may decrease over utilization and decrease costs associated with the administration of digoxin-specific Fab fragments. Further prospective studies of digoxin-poisoned patients are needed to further elucidate this hypothesis.
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e67 11. Lapostolle F, Borron SW, Verdier C. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Crit Care Med. 2008;36:3014–3018. 12. Antman EM, Smith TW. Digitalis toxicity. Ann Rev Med. 1985;36:357–367. 13. DigiFabÒ average wholesale price. Cardinal Health Pharmaceutical Distribution. Available at: http://www.cardinal. com/us/en/pharmaceuticaldistribution/rx. Accessed May 30, 2014. 14. DigibindÒ withdrawal and alternative availability. Poisons Information Centre of Ireland. Available at: http:// www.poisons.ie/News_detail.asp?newsId543. Accessed June 18, 2014. 15. DIGIFABÒ DIGOXIN IMMUNE FAB (OVINE) [package insert]. BTG International. Available at: http://www. kodc.or.kr/cmed/down/DigiFab%20Package%20Insert. pdf. Accessed June 18, 2014. 16. Average weight charts. [Halls.MD]. Available at: http:// www.halls.md/chart/height-weight.htm. Accessed June 18, 2014. 17. Bismuth C, Gaultier M, Conso F, et al. Hyperkalemia in acute digitalis poisoning. Prognostic significance and therapeutic implications. Clin Toxicol. 1973;6:153–162.
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