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Original Contribution  |   October 2010
Treatment of Chronically Digoxin-Poisoned Patients With a Newer Digoxin Immune Fab—A Retrospective Study
Author Notes
  • From the Rocky Vista University College of Osteopathic Medicine in Parker, Colorado (Dr Schaeffer); University of Colorado Denver School of Medicine (Dr Schaeffer) and School of Pharmacy (Dr Bogdan); Rocky Mountain Poison and Drug Center—Denver Health (Dr Schaeffer, Ms Mlynarchek, Mr Stanford, and Dr Bogdan); University of Connecticut School of Medicine in Farmington and Hartford Hospital in Connecticut (Dr Delgado); University of Virginia School of Medicine in Charlottesville (Dr Holstege); and St Barnabas Medical Center in New York City and New York City Poison Center (Dr Olsen). Mr Stanford's MA is in biomechanics. 
  • Address correspondence to Tammi H. Schaeffer, DO, Rocky Mountain Poison and Drug Center, 777 Bannock St, MC 0180, Denver, CO 80204-4507.E-mail: tammi.schaeffer@rmpdc.org 
Article Information
Cardiovascular Disorders
Original Contribution   |   October 2010
Treatment of Chronically Digoxin-Poisoned Patients With a Newer Digoxin Immune Fab—A Retrospective Study
The Journal of the American Osteopathic Association, October 2010, Vol. 110, 587-592. doi:10.7556/jaoa.2010.110.10.587
The Journal of the American Osteopathic Association, October 2010, Vol. 110, 587-592. doi:10.7556/jaoa.2010.110.10.587
Abstract

Context: Digoxin is used in the treatment of patients with cardiac dysfunction, though toxicity sometimes results from the use of this medication. In 1986, the US Food and Drug Administration (FDA) approved a digoxin immune Fab for the treatment of such patients. In 2001, the FDA approved a newer digoxin immune Fab, a digoxin-specific antibody (DSAb) known as DigiFab (Protherics Inc, Brentwood, Tennessee), though minimal literature exists on the clinical effects of this DSAb.

Objectives: To characterize a cohort of patients presenting with chronic digoxin toxicity and to describe the clinical course of these patients with the use of DSAb.

Methods: A retrospective study included patients with life-threatening cardiotoxicity and serum digoxin level greater than 2 ng/mL who were treated at two US hospitals from 2003 to 2006. Trained investigators abstracted data from patients' medical records and assessed changes in clinical and laboratory parameters at regular intervals (0-4, >4-12, >12-24, and >24-72 hours) after treatment with DSAb. An expert panel reviewed electrocardiogram results to identify life-threatening manifestations of digoxin toxicity before and after DSAb treatment. Efficacy of treatment was assessed as rates of improvement in clinical parameters and cardiotoxic effects. Rates of adverse drug reactions were used to characterize safety. All data were analyzed with descriptive statistics.

Results: Fourteen patients (mean [SD] age, 71.3 [10.4] years) were treated for chronic digoxin toxicity. At presentation, 12 patients had a heart rate of less than 45 beats per minute, 1 had third-degree heart block, and 1 had asystole. Mean serum digoxin level was 3.6 ng/mL. Eleven patients had abnormal renal function. After administration of DSAb, clinical parameters improved in all patients. Within 24 hours, cardiotoxicity resolved in 7 of 9 evaluable patients. Two adverse drug reactions possibly related to DigiFab occurred, both of which resolved with conventional measures. Two patients died from conditions unrelated to treatment.

Conclusion: The newer DSAb appears to be a safe and effective treatment for resolving digoxin toxicity in adults, as indicated by electrocardiogram and clinical assessments. Because patients with multiple comorbidities may be at greater risk for digoxin toxicity, they should be closely monitored during treatment with digoxin.

Despite its inherent toxicity, digoxin continues to be widely used in the treatment of patients with cardiac dysfunction, including congestive heart failure (CHF) and cardiac arrhythmias. Although the use of digoxin for CHF has declined in recent years, the incidence of toxicity from digoxin has remained steady.1 The reported incidence of signs and symptoms consistent with digoxin toxicity ranges from 1% to 30% of patients using digoxin, depending on the criteria for toxicity and the specific cohort studied.25 
The evaluation and treatment of patients with digoxin toxicity are often categorized by the chronicity of the ingestion. Early studies on the treatment of patients with symptomatic digoxin toxicity included more acute poisonings than chronic poisonings.6,7 More recently, Lapostolle et al8 reviewed medical records from 20 hospitals in France and found that 86% of patients presenting with digoxin toxicity were chronically intoxicated. This percentage may represent a change toward increased chronicity in digoxin-poisoned patients. 
Chronic digoxin toxicity is manifested in elderly patients and in patients taking medications that affect electrolyte levels and renal function.9 Although such patients are known to be predisposed to toxicity, further characterization of sensitive populations could allow for identification of variables predicting toxicity. Improved understanding of these variables could lead to reductions in the considerable healthcare costs associated with managing digoxin toxicity.10 
The use of antibody treatment has resulted in substantial improvement in the treatment of patients with serious digoxin toxicity.6,7,11,12 The majority of existing reports on the safety and efficacy of antibody treatment concern Digibind (digoxin immune Fab [ovine] [DIFab]; GlaxoSmithKline plc, Brentford, England), which, in 1986, became the first digoxin-specific Fab to be approved by the US Food and Drug Administration (FDA). In 2001, the FDA approved DigiFab (digoxin immune Fab [ovine] [DSAb]; Protherics Inc, Brentwood, Tennessee), a digoxin-specific antibody targeted for use by patients with life-threatening digoxin toxicity. 
Although both DIFab and DSAb have been shown to possess similar pharmacokinetic properties13 and are clinically interchangeable, minimal literature exists on the clinical use of DSAb to date. 
The present report has two main objectives: (1) to characterize a cohort of patients presenting with chronic digoxin toxicity, and (2) to describe the clinical course associated with the use of the newer antibody treatment, DSAb, in these patients. 
Methods
Investigators from two hospitals (Hartford Hospital in Connecticut, University of Virginia Medical Center in Charlottesville) reviewed medical records of patients who were treated with DSAb for life-threatening effects of digoxin toxicity. Records were identified from queries of the hospital pharmacy databases for patients for whom DSAb was dispensed. Only records of patients treated between January 2003 and July 2006 were included. Before accessing the records, institutional review board approval, with a waiver of informed consent, was obtained by the investigator from each site. 
Medical records were initially reviewed to evaluate study entrance criteria. Patients of any age and either sex with life-threatening cardiotoxicity, a history of digoxin ingestion (either chronic or acute), and a serum digoxin level of at least 2 ng/mL before DSAb treatment were included. Life-threatening cardiotoxicity was defined as the presence of one or more of the following rhythm disturbances, as revealed by electrocardiogram (ECG) results within 6 hours before initiation of DSAb treatment: asystole, ventricular tachycardia or fibrillation, second- or third-degree heart block, or a ventricular rate of less than 45 beats per minute (bpm). 
Patients' ECG results (ie, ECG charts and rhythm strips)—with all protected health information removed—were submitted to, and reviewed by, an expert consensus panel consisting of two site investigators (J.D., C.P.H.) and two other physicians (T.H.S., D.O.). All panel members were experienced board-certified emergency department physicians and medical toxicologists. To eliminate potential reviewer bias, no panel member reviewed any record of a patient who was treated at his or her own institution. Thus, ECG results from each patient were reviewed by three panelists. 
Unanimous or majority vote by the consensus panel was required for a patient's record to meet the inclusion criterion of life-threatening cardiotoxicity. Any patient without life-threatening cardiotoxicity was excluded from the study. Other exclusion criteria were known or suspected ingestion of a digitalis-containing compound other than digoxin (eg, digitoxin, purple foxglove) and known cardiac pacing at baseline. 
Data from each eligible medical record were collected by the site investigator using a standardized case report form. Before collection of study data, investigators completed a training process to facilitate accuracy and consistency of data collection. The training process included a trainer (C.F.S.) instructing the four panel members in abstraction of a sample medical record, followed by feedback to correct any errors and to reinforce adherence to study definitions. 
Study data included demographic characteristics of patients; details of digoxin exposure; medical and medication history; baseline findings (eg, blood urea nitrogen [BUN]/creatinine ratio, cardiac abnormalities, serum digoxin level, serum potassium level); details of treatment (including concomitant therapies); posttreatment response (as revealed by ECG and clinical assessments); and drug-related adverse events. Investigators evaluated patients' responses to treatment as changes in ECG results at regular intervals after the end of DSAb treatment (0-4, >4-12, >12-24, >24-72 hours), relative to baseline and as permitted by available data. At each posttreatment time interval, each investigator assigned a value of improved (no or lesser life-threatening effect compared to baseline), worsened (greater life-threatening effect compared to baseline), not improved (same life-threatening effect compared to baseline), or no data (no recording available with which to compare to baseline) to ECG results. 
Copies of all ECG charts and rhythm strips recorded up to 72 hours after the end of DSAb were de-identified, randomly ordered, and submitted for consensus panel review. Randomization was performed to prevent panel reviewers from identifying abnormalities based on relative comparisons among serial recordings for a single patient. 
Reviewers identified the presence or absence of specific life-threatening cardiotoxic effects on each posttreatment ECG recording by using the same criteria and procedures that were followed during baseline ECG review. At each posttreatment interval, results for each patient were reviewed, and one of the four designations describing cardiac response relative to baseline (ie, improved, worsened, not improved, no data) was assigned to the results. Heart rate and blood pressure measurements were used to assess cardiac response for time intervals during which no ECG rhythm strips were made. 
The extent of clinical efficacy of DSAb was characterized by rates of improvement over time in life-threatening cardiotoxic effects. Drug safety was characterized by rates of serious (eg, life-threatening, requiring inpatient hospitalization) and nonserious drug-related adverse events. 
All data were analyzed with descriptive statistics. Continuous variables were analyzed using means, and categorical variables were analyzed using medians. Categorical variables were sex and ethnicity. All other variables were continuous. Statistical analyses were performed using SPSS software (version 15.0; SPSS Inc, Chicago, Illinois). 
Results
A total of 49 medical records were screened for DSAb administration (Figure). Of these records, 21 were excluded for not meeting entrance criteria. These excluded records were from patients who had serum digoxin levels less than 2 ng/mL, an implanted pacemaker, or no baseline ECG. Of the 28 patients who met initial entrance criteria, 14 were excluded after ECG evaluation revealed no electrocardiographic abnormality. This exclusion left 14 charts in the study. 
Demographic characteristics of the included patients are presented in Table 1. The majority of patients were elderly white adults (mean [SD] age, 71.3 [10.4] years), though age ranged from 47 to 90 years. There was an equal distribution of patients by sex. 
Table 1
Baseline Characteristics of Participants in Retrospective Study of DSAb* (N=14)

Characteristic

Value
Age, y
□ Mean (SD) 71.3 (10.4)
□ Range47-90
Sex, No.
□ Men7
□ Women 7
Race, No.
□ Black 1
□ White11
□ Unknown 2
Height, cm
□ Mean (SD) 164.3 (14.6)
Weight, kg
□ Mean (SD)
79.5 (20.1)
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Height of 2 patients was unknown (n=12).
 Weight of 1 patient was unknown (n=13).
Table 1
Baseline Characteristics of Participants in Retrospective Study of DSAb* (N=14)

Characteristic

Value
Age, y
□ Mean (SD) 71.3 (10.4)
□ Range47-90
Sex, No.
□ Men7
□ Women 7
Race, No.
□ Black 1
□ White11
□ Unknown 2
Height, cm
□ Mean (SD) 164.3 (14.6)
Weight, kg
□ Mean (SD)
79.5 (20.1)
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Height of 2 patients was unknown (n=12).
 Weight of 1 patient was unknown (n=13).
×
All 14 included patients were taking digoxin for a prescribed indication before the DSAb treatment of the present study. Reported indications for digoxin were atrial fibrillation (9 patients), CHF (2 patients), or both of these conditions (3 patients). All patients had digoxin toxicity related to accidental or unintentional chronic exposure (ie, ingestion of a prescribed dose that, because of the inability to excrete digoxin, accumulated over a period greater than 24 hours). No patient in the present study was identified as having acute or acute-on-chronic toxicity. Patients reported a mean of 6.1 (range, 3-9) for the number of body systems affected by comorbid conditions in their medical history. 
Table 2 shows presenting values for cardiac abnormalities, serum digoxin levels, and BUN/creatinine ratios. Life-threatening cardiac rhythm abnormalities present before DSAb treatment included slow ventricular rate (<45 bpm) in 12 patients, third-degree (ie, complete) heart block in 1 patient, and asystole in 1 patient. 
Table 2
Presenting ECG and Laboratory Values for Participants in Retrospective Study of DSAb* (N=14)

Patient

Cardiac Abnormality

Serum Digoxin, ng/mL

BUN/Creatinine, mg/dL (Ratio)
1VR4.846/2.8 (16.4)
2 VR 5.2 51/1.3 (39.2)
3VR3.455/2.7 (20.4)
4 VR 6.5 63/3.1 (20.3)
5VR6.523/1.2 (19.2)
6 VR 2.2 19/1.3 (14.6)
7HB32.752/8.6 (6.0)§
8 VR 3.3 86/2.6 (33.1)
9VR2.222/1.4 (15.7)
10 VR 3.4 ...
11VR2.341/1.3 (31.5)
12 VR 3.1 102/3.5 (29.1)
13A2.227/1.0 (27.0)
14 VR 3.2 30/0.7 (42.9)
 Abbreviations: A, asystole; BUN, blood urea nitrogen; ECG, electrocardiogram; HB3, third-degree heart block; VR, ventricular rate <45 beats per minute;... indicates no data.
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Electrocardiogram recording from previous, routine hospital visit (ie, prebaseline) was available in patient's medical record. No life-threatening rhythm abnormality was present in that recording.
 Dehydration defined by BUN/creatinine ratio ≥20:1.
 §Patient 7 had end-stage renal failure and was on hemodialysis.
Table 2
Presenting ECG and Laboratory Values for Participants in Retrospective Study of DSAb* (N=14)

Patient

Cardiac Abnormality

Serum Digoxin, ng/mL

BUN/Creatinine, mg/dL (Ratio)
1VR4.846/2.8 (16.4)
2 VR 5.2 51/1.3 (39.2)
3VR3.455/2.7 (20.4)
4 VR 6.5 63/3.1 (20.3)
5VR6.523/1.2 (19.2)
6 VR 2.2 19/1.3 (14.6)
7HB32.752/8.6 (6.0)§
8 VR 3.3 86/2.6 (33.1)
9VR2.222/1.4 (15.7)
10 VR 3.4 ...
11VR2.341/1.3 (31.5)
12 VR 3.1 102/3.5 (29.1)
13A2.227/1.0 (27.0)
14 VR 3.2 30/0.7 (42.9)
 Abbreviations: A, asystole; BUN, blood urea nitrogen; ECG, electrocardiogram; HB3, third-degree heart block; VR, ventricular rate <45 beats per minute;... indicates no data.
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Electrocardiogram recording from previous, routine hospital visit (ie, prebaseline) was available in patient's medical record. No life-threatening rhythm abnormality was present in that recording.
 Dehydration defined by BUN/creatinine ratio ≥20:1.
 §Patient 7 had end-stage renal failure and was on hemodialysis.
×
The mean presenting serum digoxin level of patients was 3.6 ng/mL. At baseline, 13 patients had renal function data available, and 11 of these patients had abnormal renal function, as denoted by elevated serum creatinine levels (Table 2). Although there was poor correlation between serum creatinine and serum digoxin levels (correlation coefficient for bivariate analysis [r] = 0.1), 8 of the 13 patients had dehydration, as defined by a BUN/creatinine ratio of greater than or equal to 20:1. Five of these 8 patients were being treated with diuretics. 
The mean presenting potassium level of patients was 5.4 mmol/L. During the assessment intervals, there was a general progression toward normalization of potassium level, with a mean potassium level of 4.3 mmol/L by the final interval (>24-72 hours). 
Patients were prescribed a mean of 10.4 outpatient medications, including digoxin. Cardiovascular drugs were the most commonly prescribed medication (ie, mean of 5.1 cardiovascular medications, including means of 1.4 anti-arrhythmics and 0.7 diuretics). Endocrine medications were the second most commonly prescribed medication (mean, 2.9 medications). 
Figure.
Algorithm depicting review of patient charts for inclusion in a retrospective study on the use of the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee) for the treatment of chronically digoxin-poisoned patients. Abbreviations: DSAb, digoxin-specific antibody; ECG, electrocardiogram.
Figure.
Algorithm depicting review of patient charts for inclusion in a retrospective study on the use of the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee) for the treatment of chronically digoxin-poisoned patients. Abbreviations: DSAb, digoxin-specific antibody; ECG, electrocardiogram.
All patients received at least one intravenous dose of DSAb. Thirteen patients received a single dose, and 1 patient received a second dose 28.5 hours after the first dose. The number of vials of DSAb ranged from 1 to 7 per dose (median, 2 vials). 
Table 3 lists characteristics of concomitant treatments (eg, atropine, glucose/insulin, vasopressor) provided to each patient before, during, and up to 72 hours after the end of DSAb treatment. Eleven patients received one or more concomitant treatments before, during, and/or after DSAb. 
Table 3
Concomitant Treatments Administered to Participants in Retrospective Study of DSAb* (N=14)


Concomitant Treatments
Patient
Before DSAb
During DSAb
After DSAb
1Atr, GI, FNoneNone
2 Atr, F None GI, Mg
3Atr, GI, VVV
4 GI, V None E
5F, MgNoneMg
6 F None None
7ENoneE
8 GI None P, F
9NoneNoneNone
10 F None E, F
11NoneNoneNone
12 V V GI, V
13NoneNoneNone
14 Atr None None
 Abbreviations: Atr, atropine; E, enhanced elimination (ie, hemodialysis-hemoperfusion); F, fluid resuscitation; GI, glucose-insulin; Mg, magnesium; P, pacemaker; V, vasopressor(s).
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
Table 3
Concomitant Treatments Administered to Participants in Retrospective Study of DSAb* (N=14)


Concomitant Treatments
Patient
Before DSAb
During DSAb
After DSAb
1Atr, GI, FNoneNone
2 Atr, F None GI, Mg
3Atr, GI, VVV
4 GI, V None E
5F, MgNoneMg
6 F None None
7ENoneE
8 GI None P, F
9NoneNoneNone
10 F None E, F
11NoneNoneNone
12 V V GI, V
13NoneNoneNone
14 Atr None None
 Abbreviations: Atr, atropine; E, enhanced elimination (ie, hemodialysis-hemoperfusion); F, fluid resuscitation; GI, glucose-insulin; Mg, magnesium; P, pacemaker; V, vasopressor(s).
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
×
Table 4 shows results of cardiac assessments at each posttreatment time interval, including a general progression toward improvement over time in patients with evaluable data. Although 14 patients were studied, not all patients had evaluable data at all time intervals. 
Table 4
Changes in Cardiac Abnormalities in Digoxin-Poisoned Patients After Treatment With DSAb,* Relative to Baseline (N=14)


Hours After DSAb Treatment
Patient
0-4
>4-12
>12-24
>24-72
1UIII
2 U ... U I
3IIII
4 I I I I
5...UUI
6 ... ... ... I
7......II
9 U I I I
10......II
12 I ... I I
13.........I
14§ U U ... ...
Patients Showing Improvement, No. 34711
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Patient 8 and patient 11 did not have evaluable data for any posttreatment time interval.
 Patient 5 received a second dose of DSAb 28.5 hours after the end of the first dose.
 §Patient 14 did not show correction of slow ventricular rate during the first two posttreatment intervals and had no data with which to assess improvement during the last two intervals. She had advanced metastatic lung cancer and died 1 week after completion of DSAb treatment.
 Improvement ratings based on electrocardiogram and clinical (ie, blood pressure, heart rate) assessments of cardiac abnormalities of patients for whom data were available (see Table 2).
Table 4
Changes in Cardiac Abnormalities in Digoxin-Poisoned Patients After Treatment With DSAb,* Relative to Baseline (N=14)


Hours After DSAb Treatment
Patient
0-4
>4-12
>12-24
>24-72
1UIII
2 U ... U I
3IIII
4 I I I I
5...UUI
6 ... ... ... I
7......II
9 U I I I
10......II
12 I ... I I
13.........I
14§ U U ... ...
Patients Showing Improvement, No. 34711
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Patient 8 and patient 11 did not have evaluable data for any posttreatment time interval.
 Patient 5 received a second dose of DSAb 28.5 hours after the end of the first dose.
 §Patient 14 did not show correction of slow ventricular rate during the first two posttreatment intervals and had no data with which to assess improvement during the last two intervals. She had advanced metastatic lung cancer and died 1 week after completion of DSAb treatment.
 Improvement ratings based on electrocardiogram and clinical (ie, blood pressure, heart rate) assessments of cardiac abnormalities of patients for whom data were available (see Table 2).
×
At the first posttreatment interval (0-4 hours), 3 of 7 evaluable patients showed improvement based on ECG findings. Within the >4-to-12-hour interval, 4 of 6 evaluable patients demonstrated improvement. Within the >12-to-24-hour interval, improvement was found in 7 of 9 evaluable patients. By 72 hours after the end of DSAb treatment, improvement occurred in 11 of 11 evaluable patients. Worsening of cardiac abnormalities was not detected in any patient at any posttreatment time interval. 
The remaining 3 patients did not have sufficient data with which to determine DSAb efficacy by 72 hours posttreatment. Patient 8 and patient 11 did not have evaluable data available for any posttreatment time interval. Although these individuals met entrance criteria and were entered into the study, they were unable to be evaluated in final assessment. Patient 14 did not show correction of slow ventricular rate (<45 bpm) during the first two posttreatment intervals and had no data with which to assess improvement during the last two intervals. This patient had advanced metastatic lung cancer and, within 24 hours after hospital admission, she began to be treated with “comfort measures only” (ie, hospice care). 
A total of 14 adverse events were reported in 10 patients. Two adverse events (hypotension and tachycardia) were deemed possibly related to DSAb administration. Both of these adverse events were nonserious, requiring only conventional treatment (eg, fluids, oxygen). The remaining 12 adverse events were determined to not be related to DSAb administration. Of these 12 events, 2 were serious—cardiac arrest and respiratory failure—and 10 were nonserious—abdominal pain, anorexia (2 events), anxiety, bronchospasm, fatigue, fever, hypotension, presyncope, and tachycardia. 
Two deaths (patient 4 and patient 14) were reported during the study period. Both deaths occurred more than 5 days after the end of DSAb treatment, and neither death was deemed related to DSAb administration. 
Patient 4 was a man, aged 65 years, in whom overwhelming sepsis developed from gallstone pancreatitis and cholecystitis. His slow ventricular rate responded favorably to DSAb, but his underlying condition worsened during the next several weeks. He died from respiratory failure 6 weeks after receiving DSAb. 
Patient 14 (referred to previously) was a woman, aged 67 years, with advanced, end-stage lung cancer. She was admitted to the hospital with the intention of managing her pain and “easily correctable” problems. However, within 24 hours after admission and administration of DSAb, treatment orders were changed to “comfort measures only.” This patient was subsequently discharged, and she died 1 week after completion of DSAb treatment. 
Comment
Despite reports involving a high proportion of patients with acute digoxin toxicity when antibody treatment first became available,6,7,11,12 the population of the present study had predominantly chronic digoxin toxicity, which is consistent with other reports in recent years.8 This chronic pattern of digoxin toxicity likely reflects the most current clinical experience with digoxin poisoning in the United States. 
The present study found a generally beneficial response to the newer digoxin immune Fab, DSAb, though study patients did not respond as rapidly as those reported in earlier studies of the previously approved digoxin immune Fab, DIFab.6,12,14 This difference may be a reflection of the change from acute to chronic ingestions and/or the presence of other illnesses and comorbidities in our cohort, including the cardiovascular disease that prompted the use of digoxin. 
Although only 3 of 7 patients with evaluable data demonstrated cardiac improvement by 4 hours after DSAb administration, it is important to recognize that 3 patients had no chance of demonstrating improvement in cardiac abnormalities within this interval because they did not have posttreatment ECG results available until after 12 hours. As secondary endpoints, heart rate and blood pressure—possibly indirect markers of improvement—trended toward the normal range in most patients during the assessment period. However, it is difficult to know if the overall improvement in patients was caused by DSAb, management of the underlying disease, or both. Because other metabolic processes often precipitate chronic digoxin toxicity, symptomatic and supportive care concomitant with the use of DSAb should be continued. 
Dehydration associated with elevated creatinine levels was prevalent within the cohort of the present study. Diuretics are a common medication, in addition to digoxin, taken by patients with CHF. Loss of fluids can precipitate dehydration, with resultant decreases in glomerular filtration rate and clearance of drugs, including digoxin. This clearance decrease can predispose patients to toxicity, even when taking their usual, prescribed doses. The hydration status of patients with CHF should be closely monitored to balance these dehydration effects with the fluid overload commonly seen in this patient population. 
Hydration status is also associated with various electrolyte abnormalities. Although potassium levels improved over time in evaluated patients, presenting potassium levels are more clinically relevant for prognosticating acute digoxin overdose.15 In patients with chronic digoxin toxicity, by contrast, changes in potassium levels could be related to other factors, such as hydration status and concomitant medications other than digoxin. 
Hussain et al1 reported increases in the incidence of digoxin toxicity and in the use of DSAb—despite an overall decrease in use of digoxin for CHF. Because their study used a CHF registry, however, patients taking digoxin for atrial fibrillation were not captured.1 It is unclear whether the increased digoxin toxicity and increased use of DSAb reported by Hussain et al1 are results of an increase in recommendations to use DSAb by poison centers. Furthermore, the finding of decreased use of digoxin for CHF1 may be associated with an increased use of digoxin for heart rate control. 
The present study found that DSAb has a favorable safety profile, as evidenced by few drug-related adverse events. Interestingly, we found that 14 of 28 patients initially screened for inclusion were treated with DSAb in the absence of relevant ECG findings. This use of DSAb suggests a comfort level among healthcare providers with administering DSAb—almost as a diagnostic tool (eg, to remove the possibility of digoxin toxicity from differential diagnosis)—in cases with no clear ECG evidence of digoxin toxicity. 
Limitations
Initially, we attempted to include additional hospitals in our analysis besides the two that were included. However, when we contacted those hospital pharmacies and evaluated their records, we found there was no way to know whether the drug product used was DIFab or DSAb. In those hospitals, the pharmacy stock was intermixed without documentation regarding which product was actually dispensed. Thus, we were able to include only two hospitals. 
Our analysis was open to pediatric patients, as well as adult patients. However, we found no pediatric charts that met entrance criteria. The lack of these young patients in our analysis may limit the generalizability of the results. The ability to generalize our results for all cases of digoxin toxicity is also limited by the small sample size of the present study. 
We found no evidence of serum sickness in any patient. However, the length of hospitalization (median, 4.6 days) may have been too brief to sufficiently detect the manifestation of signs or symptoms associated with that condition. Finally, the present study was a retrospective chart review, and it has the expected limitations inherent in any study with that design. 
Conclusion
DigiFab appears to be a well-tolerated and effective treatment for adults who have ECG changes consistent with chronic, life-threatening digoxin toxicity. Older patients with multiple comorbidities may be more at risk for digoxin toxicity. Thus, these patients should be closely monitored during treatment with digoxin, especially in regard to concomitant medications and renal status. 
 Financial Disclosures: Rocky Mountain Poison and Drug Center—Denver Health (Dr Schaeffer, Ms Mlynarchek, Mr Stanford, Dr Bogdan) received financial compensation from Protherics Inc (the manufacturer of DigiFab) for this clinical research project. Staff members of Rocky Mountain Poison and Drug Center received only their regular salary for participation, with no compensation from Protherics Inc. Authors who were members of the consensus panel (Drs Schaeffer, Delgado, Holstege, Olsen) received honoraria as compensation for the time it took to review and evaluate electrocardiogram results.
 
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Allen NM, Dunham GD. Treatment of digitalis intoxication with emphasis on the clinical use of digoxin immune Fab. DICP. 1990;24(10):991-998.
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Hickey AR, Wenger TL, Carpenter VP, et al. Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study. J Am Coll Cardiol. 1991;17(3):590-598.
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Lloyd BL, Smith TW. Contrasting rates of reversal of digoxin toxicity by digoxin-specific IgG and Fab fragments. Circulation. 1978;58(2):280-283. http://circ.ahajournals.org/cgi/reprint/58/2/280. Accessed August 3, 2010.
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Figure.
Algorithm depicting review of patient charts for inclusion in a retrospective study on the use of the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee) for the treatment of chronically digoxin-poisoned patients. Abbreviations: DSAb, digoxin-specific antibody; ECG, electrocardiogram.
Figure.
Algorithm depicting review of patient charts for inclusion in a retrospective study on the use of the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee) for the treatment of chronically digoxin-poisoned patients. Abbreviations: DSAb, digoxin-specific antibody; ECG, electrocardiogram.
Table 1
Baseline Characteristics of Participants in Retrospective Study of DSAb* (N=14)

Characteristic

Value
Age, y
□ Mean (SD) 71.3 (10.4)
□ Range47-90
Sex, No.
□ Men7
□ Women 7
Race, No.
□ Black 1
□ White11
□ Unknown 2
Height, cm
□ Mean (SD) 164.3 (14.6)
Weight, kg
□ Mean (SD)
79.5 (20.1)
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Height of 2 patients was unknown (n=12).
 Weight of 1 patient was unknown (n=13).
Table 1
Baseline Characteristics of Participants in Retrospective Study of DSAb* (N=14)

Characteristic

Value
Age, y
□ Mean (SD) 71.3 (10.4)
□ Range47-90
Sex, No.
□ Men7
□ Women 7
Race, No.
□ Black 1
□ White11
□ Unknown 2
Height, cm
□ Mean (SD) 164.3 (14.6)
Weight, kg
□ Mean (SD)
79.5 (20.1)
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Height of 2 patients was unknown (n=12).
 Weight of 1 patient was unknown (n=13).
×
Table 2
Presenting ECG and Laboratory Values for Participants in Retrospective Study of DSAb* (N=14)

Patient

Cardiac Abnormality

Serum Digoxin, ng/mL

BUN/Creatinine, mg/dL (Ratio)
1VR4.846/2.8 (16.4)
2 VR 5.2 51/1.3 (39.2)
3VR3.455/2.7 (20.4)
4 VR 6.5 63/3.1 (20.3)
5VR6.523/1.2 (19.2)
6 VR 2.2 19/1.3 (14.6)
7HB32.752/8.6 (6.0)§
8 VR 3.3 86/2.6 (33.1)
9VR2.222/1.4 (15.7)
10 VR 3.4 ...
11VR2.341/1.3 (31.5)
12 VR 3.1 102/3.5 (29.1)
13A2.227/1.0 (27.0)
14 VR 3.2 30/0.7 (42.9)
 Abbreviations: A, asystole; BUN, blood urea nitrogen; ECG, electrocardiogram; HB3, third-degree heart block; VR, ventricular rate <45 beats per minute;... indicates no data.
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Electrocardiogram recording from previous, routine hospital visit (ie, prebaseline) was available in patient's medical record. No life-threatening rhythm abnormality was present in that recording.
 Dehydration defined by BUN/creatinine ratio ≥20:1.
 §Patient 7 had end-stage renal failure and was on hemodialysis.
Table 2
Presenting ECG and Laboratory Values for Participants in Retrospective Study of DSAb* (N=14)

Patient

Cardiac Abnormality

Serum Digoxin, ng/mL

BUN/Creatinine, mg/dL (Ratio)
1VR4.846/2.8 (16.4)
2 VR 5.2 51/1.3 (39.2)
3VR3.455/2.7 (20.4)
4 VR 6.5 63/3.1 (20.3)
5VR6.523/1.2 (19.2)
6 VR 2.2 19/1.3 (14.6)
7HB32.752/8.6 (6.0)§
8 VR 3.3 86/2.6 (33.1)
9VR2.222/1.4 (15.7)
10 VR 3.4 ...
11VR2.341/1.3 (31.5)
12 VR 3.1 102/3.5 (29.1)
13A2.227/1.0 (27.0)
14 VR 3.2 30/0.7 (42.9)
 Abbreviations: A, asystole; BUN, blood urea nitrogen; ECG, electrocardiogram; HB3, third-degree heart block; VR, ventricular rate <45 beats per minute;... indicates no data.
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Electrocardiogram recording from previous, routine hospital visit (ie, prebaseline) was available in patient's medical record. No life-threatening rhythm abnormality was present in that recording.
 Dehydration defined by BUN/creatinine ratio ≥20:1.
 §Patient 7 had end-stage renal failure and was on hemodialysis.
×
Table 3
Concomitant Treatments Administered to Participants in Retrospective Study of DSAb* (N=14)


Concomitant Treatments
Patient
Before DSAb
During DSAb
After DSAb
1Atr, GI, FNoneNone
2 Atr, F None GI, Mg
3Atr, GI, VVV
4 GI, V None E
5F, MgNoneMg
6 F None None
7ENoneE
8 GI None P, F
9NoneNoneNone
10 F None E, F
11NoneNoneNone
12 V V GI, V
13NoneNoneNone
14 Atr None None
 Abbreviations: Atr, atropine; E, enhanced elimination (ie, hemodialysis-hemoperfusion); F, fluid resuscitation; GI, glucose-insulin; Mg, magnesium; P, pacemaker; V, vasopressor(s).
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
Table 3
Concomitant Treatments Administered to Participants in Retrospective Study of DSAb* (N=14)


Concomitant Treatments
Patient
Before DSAb
During DSAb
After DSAb
1Atr, GI, FNoneNone
2 Atr, F None GI, Mg
3Atr, GI, VVV
4 GI, V None E
5F, MgNoneMg
6 F None None
7ENoneE
8 GI None P, F
9NoneNoneNone
10 F None E, F
11NoneNoneNone
12 V V GI, V
13NoneNoneNone
14 Atr None None
 Abbreviations: Atr, atropine; E, enhanced elimination (ie, hemodialysis-hemoperfusion); F, fluid resuscitation; GI, glucose-insulin; Mg, magnesium; P, pacemaker; V, vasopressor(s).
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
×
Table 4
Changes in Cardiac Abnormalities in Digoxin-Poisoned Patients After Treatment With DSAb,* Relative to Baseline (N=14)


Hours After DSAb Treatment
Patient
0-4
>4-12
>12-24
>24-72
1UIII
2 U ... U I
3IIII
4 I I I I
5...UUI
6 ... ... ... I
7......II
9 U I I I
10......II
12 I ... I I
13.........I
14§ U U ... ...
Patients Showing Improvement, No. 34711
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Patient 8 and patient 11 did not have evaluable data for any posttreatment time interval.
 Patient 5 received a second dose of DSAb 28.5 hours after the end of the first dose.
 §Patient 14 did not show correction of slow ventricular rate during the first two posttreatment intervals and had no data with which to assess improvement during the last two intervals. She had advanced metastatic lung cancer and died 1 week after completion of DSAb treatment.
 Improvement ratings based on electrocardiogram and clinical (ie, blood pressure, heart rate) assessments of cardiac abnormalities of patients for whom data were available (see Table 2).
Table 4
Changes in Cardiac Abnormalities in Digoxin-Poisoned Patients After Treatment With DSAb,* Relative to Baseline (N=14)


Hours After DSAb Treatment
Patient
0-4
>4-12
>12-24
>24-72
1UIII
2 U ... U I
3IIII
4 I I I I
5...UUI
6 ... ... ... I
7......II
9 U I I I
10......II
12 I ... I I
13.........I
14§ U U ... ...
Patients Showing Improvement, No. 34711
 *DSAb indicates the digoxin-specific antibody DigiFab (digoxin immune Fab [ovine]; Protherics Inc, Brentwood, Tennessee).
 Patient 8 and patient 11 did not have evaluable data for any posttreatment time interval.
 Patient 5 received a second dose of DSAb 28.5 hours after the end of the first dose.
 §Patient 14 did not show correction of slow ventricular rate during the first two posttreatment intervals and had no data with which to assess improvement during the last two intervals. She had advanced metastatic lung cancer and died 1 week after completion of DSAb treatment.
 Improvement ratings based on electrocardiogram and clinical (ie, blood pressure, heart rate) assessments of cardiac abnormalities of patients for whom data were available (see Table 2).
×