Download Treatment of 150 cases of life-threatening digitalis

1744
Clinical Investigation
Treatment of 150 Cases of Life-Threatening
Digitalis Intoxication With Digoxin-Specific
Fab Antibody Fragments
Final Report of a Multicenter Study
Elliott M. Antman, MD, Thomas L. Wenger, MD, Vincent P. Butler Jr., MD,
Edgar Haber, MD, and Thomas W. Smith, MD
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One hundred fifty patients with potentially life-threatening digitalis toxicity were treated with
digoxin-specific antibody fragments (Fab) purified from immunoglobulin G produced in sheep.
The dose of Fab fragments was equal to the amount of digoxin or digitoxin in the patient's body
as estimated from medical histories or determinations of serum digoxin or digitoxin concentrations. The youngest patient received Fab fragments within several hours of birth, and the
oldest patient was 94 years old. Seventy-five patients (50%) were receiving long-term digitalis
therapy, 15 (10%) had taken a large overdose of digitalis accidentally, and 59 (39%) had
ingested an overdose of digitalis with suicidal intent. The clinical response to Fab was
unspecified in two cases, leaving 148 patients who could be evaluated. One hundred nineteen
patients (80%) had resolution of all signs and symptoms of digitalis toxicity, 14 (10%)
improved, and 15 (10%) showed no response. After termination of the Fab infusion, the median
time to initial response was 19 minutes, and 75% of the patients had some evidence of a
response by 60 minutes. There were only 14 patients with adverse events considered to possibly
or probably have been caused by Fab; the most common events were rapid development of
hypokalemia and exacerbation of congestive heart failure. No allergic reactions were identified
in response to Fab treatment. Of patients who experienced cardiac arrest as a manifestation of
digitalis toxicity, 54% survived hospitalization. Reasons for partial responses and nonresponses, in descending order of frequency, were underlying heart disease that was the true
cause of some of the presumed manifestations of suspected digitalis toxicity, too low a dose of
Fab, and treatment of patients who were already moribund. Thus, a treatment response can be
expected in at least 90% of patients with solid evidence of advanced and potentially
life-threatening digitalis toxicity. (Circulation 1990;81:1744-1752)
A
dvanced digitalis intoxication can have a fatal
outcome, particularly in patients with underlying cardiac dysfunction or those who have
ingested massive doses of digitalis accidentally or
with suicidal intent. Important possible clinical find-
From the Department of Medicine (E.M.A., T.W.S.), Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, The Division of Clinical
Research (T.L.W.), Burroughs Wellcome Co., Research Triangle
Park, North Carolina, the Department of Medicine (V.P.B.Jr.),
Columbia University College of Physicians and Surgeons, New
York, and the Cardiac Unit (E.H.), Massachusetts General Hospital, Boston, Massachusetts.
Address for correspondence: Dr. Elliott M. Antman, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street,
Boston, MA 02115.
Supported in part by grants HL-19259 (Project V) and HL10608 from the National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, Maryland.
Received December 27, 1989; accepted February 6, 1990.
ings after massive digitalis ingestion include hyperkalemia, atrioventricular block, and malignant ventricular tachyarrhythmias. Although hemodialysis or
hemoperfusion may help control hyperkalemia, these
approaches are generally inadequate for treatment of
advanced toxicity because of the extensive tissue
distribution of digoxin and are of limited value for
prompt reversal of life-threatening toxicity. The need
to improve treatment of advanced digitalis intoxication was an important stimulus for the development
of a specific means for reversal of established cardiac
glycoside effects.
Exogenous antibodies have been used in the management of many disease states, initially including
diphtheria and tetanus and more recently including
organ transplant rejection.' The concept of therapeutic use of specific exogenous antibodies was extended
to the treatment of digitalis intoxication by the
Antman et al Digitalis Intoxication
development of antibodies with a high affinity and
specificity for digoxin. The initial clinical report of
the use of purified digoxin-specific Fab fragments for
treatment of advanced digoxin toxicity occurred in
1976.2 Based on several such favorable responses, a
multicenter clinical trial using purified digoxinspecific Fab fragments was initiated. Interim reports
were published when 26 and 63 patients had been
enrolled2,3; the present report is the summary of this
prospective multicenter study of 150 patients with
life-threatening digitalis intoxication who were
treated with purified digoxin-specific Fab fragments.
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Methods
Preparation of Punified Fab Fragments of
Digoxin-Specific Antibodies
As described previously, sheep were immunized
with a digoxin-serum albumin conjugate and antisera
were collected from animals that responded with
high titers of antibody with high affinity and specificity for digoxin.4-6 Intact antibody was cleaved with
papain, yielding digoxin-specific Fab fragments.5i7
The Fab fragments were isolated and purified by
passing the papain digest through an affinity chromatography step.5 The final purified Fab fragments were
determined to be both sterile and pyrogen free by
standard tests, and the material was then lyophilized
in 40-mg aliquots.8 Material prepared by this method
is stable under recommended storage conditions for
at least 3 years (package insert for Digoxin Immune
Fab [ovine], Digibind®).
Clinical Trial Design
An open-label multicenter clinical trial of Fab
treatment for life-threatening digitalis intoxication
was then undertaken. In brief, 21 geographically
distributed U.S. medical centers ("Appendix") were
supplied with Fab (designated BB Investigational
New Drug 874 by the U.S. Food and Drug Administration). A common protocol was used that was
approved by each institutional committee for the
protection of human subjects. The goals of the investigation were to evaluate the ability of Fab fragments
to reverse the toxic effects of digitalis and simultaneously provide sufficient safety information to warrant
approval of the drug for treating patients with potentially life-threatening digitalis toxicity. Secondary
objectives were to define the pharmacokinetics and
pharmacodynamics of Fab fragment treatment and to
assess the antigenicity of purified polyclonal sheep
Fab fragments in humans. The two key inclusion
criteria were that patients had actual or potentially
life-threatening cardiac rhythm disturbances, hyperkalemia, or both caused by digitalis intoxication and
that these conditions were refractory to or likely to be
refractory to treatment with conventional therapeutic
modalities.
After informed consent was obtained from the
patient or next of kin, screening for hypersensitivity
was performed by a skin test and a small (1 mg)
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TABLE 1. Calculation of Equimolar Dose of Digoxin-Specific
Fab Fragments
Calculation of body load of digoxin
Ingested amount (mg)xbioavailability of digoxin tablets
=mgx0.8
Serum digoxin concentration (ng/ml) x5.6* xweight (kg)
1,000
Calculation of dose Fab fragments
MW Fab (50,0) -64 xbody load (mg)=Fab dose (mg)
MW digoxin (781)
Body load of digoxin (mg) =vials of Fab fragments
0.6 mg neutralized/40 mg vial
*Volume of distribution of digoxin in average adult (1/kg).
Example
Serum digoxin concentration (SDC)=2 ng/ml on maintenance
therapy
Weight=65 kg
Ingested amount= 18 mg digoxin (tablets)
Body load= [ingested amountxo.8]+ [SDCx5.6x65
1,000
=14.4+0.728=15.128 mg
Dose of Fab fragments=64x15=960 mg
15 = 25
Number of vials= 0.6
intravenous test dose. Whenever possible, the Fab
fragments were administered intravenously during 2
hours in the early stages of the protocol and later in
the study during 15-30 minutes (in isotonic saline)
after having been passed through a sterile 0.22-,tm
membrane filter. The dose of Fab fragments was
calculated to be equal on a mole-for-mole basis to the
amount of digoxin or digitoxin in the patient's body,
estimated from the medical history or determinations
of serum digoxin or digitoxin concentrations (Table
1). Clinical and laboratory data were recorded
before, during, and after Fab treatment. Serum glycoside concentrations were measured by immunoassay before and after the administration of Fab as
previously described.9,10 When clinically feasible,
multiple blood and urine samples were obtained for
more detailed assessment of the effects of Fab
administration on digoxin pharmacokinetics using
special procedures to determine total and free glycoside concentrations.
Recorded on each patient's case report form was
the response to Fab treatment for sinus bradycardia,
atrioventricular block, ventricular premature depolarizations, asystole, ventricular tachycardia, ventricular fibrillation, supraventricular tachyarrhythmias
characteristic of digitalis intoxication, nausea and
vomiting, hyperkalemia, and central nervous system
disturbances, all signs of digitalis toxicity. An overall
response to therapy with digoxin-specific antibody
fragments was assigned to each patient using the
following scheme. The term "resolved" indicated
complete resolution of all signs and symptoms of
toxicity; life-threatening cardiac arrhythmias had to
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Circulation Vol 81, No 6, June 1990
resolve during an accelerated time course (within
minutes to a few hours after treatment). In addition,
evidence was sought for rapid resolution of hyperkalemia by frequent measurements of serum potassium
levels. The term "improved" was used when some but
not all of the signs of suspected toxicity resolved or
improved. The term "no response" indicated the
failure of any of the signs of toxicity to improve.
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Statistics
The data were described by the median plus lower
and upper quartiles rather than the mean±SD
because in many instances the data were not symmetrically distributed. The lower and upper quartiles
describe the 25th and 75th percentiles of the data
points; that is, one fourth of the data will be less than
or equal to the lower quartile and one fourth will be
equal to or more than the upper quartile.
A logistic regression model was used to assess the
relation between covariates and the probability of a
slow response to Fab. A slow response to treatment
was defined as an initial response time of more than
60 minutes after Fab administration, which represented the upper quartile of the sample. Covariates
examined were the presence or absence of cardiac
disease, setting of digitalis toxicity (long-term therapeutic use vs. acute ingestion), and predefined age
categories.
The significance of changes in serum potassium
between pretreatment and posttreatment values
(4±2 hours after Fab administration) was evaluated
with a two-tailed Wilcoxon signed-rank test. Differences were considered significant atp less than 0.05.
Results
Clinical Characteristics of Patients
Between December 1974 and April 1986, 150
patients received digoxin-specific antibody fragments. Because patients were often treated under
urgent clinical circumstances, complete data were
not always available for every patient. Seventy-seven
patients were female, 69 were male, and one infant
had ambiguous genitalia. Gender was not recorded in
three cases. Twenty-five of the patients were children
between the ages of 1 day and 4 years (median age, 3
months). The remaining 125 patients were 16 years
old or older (median age, 65 years). One fourth
(lower quartile) of the adults were 54 years old or
younger, and one fourth (upper quartile) were 75
years old or older. The youngest patient treated in
the protocol received Fab fragments within several
hours of birth, and the oldest patient was 94 years
old. One hundred twenty-one patients (81%) had
concurrent cardiac disease.
One hundred thirty-nine patients (93%) suffered
from digoxin intoxication, and five (3%) suffered
from digitoxin intoxication; the type of glycoside was
unspecified in the remaining patients. Seventy-five
patients (50%) were receiving long-term digitalis
therapy, 15 (10%) had taken a large overdose of
150 patients
Refractory VT
68 (46%)
49 (33%)
High grade AV block 79 53%)
56 37%)
Hyperkalemia
Excluslon= 2 patients
VF
Response Unknown
148 Patients Evaluated]
No Resonse
15 (1(1%)
Response
133(90%)
Resolved
119(80%)
Improved
14 (10%)
FIGURE 1. Clinical response to Fab fragment treatment in
150 patients with potentially life-threatening digitalis intoxication. VT, ventricular tachycardia; VT, ventricular fibrillation;
A V atrioventricular.
digitalis accidentally, and 59 (39%) had ingested an
overdose of digitalis with suicidal intent. In 53 cases
of single overdoses (accidental or suicidal), the
ingested dose could be estimated from the clinical
information; the median ingested dose of digoxin was
12.5 mg (range, 0.14-62.5 mg) and of digitoxin was
12.0 mg (range, 2.0-40.0 mg).
The cardiovascular manifestations of digitalis toxicity were known in 148 cases and consisted of secondor third-degree atrioventricular block in 79 patients
(53%), ventricular tachycardia in 68 patients (46%),
ventricular fibrillation in 49 patients (33%), ventricular asystole in 16 patients (11%), and hyperkalemia in
56 patients (37%) (Figures 1 and 2). Attempted
conventional therapeutic interventions included ventricular pacing in 72 patients (48%), DC cardioversion
in 31 patients (21%), cardiopulmonary resuscitation in
38 patients (26%), antiarrhythmic drug therapy in
81 patients (54%), atropine in 33 patients (22%),
calcium channel antagonists in six patients (4%), and
,8-adrenoceptor blockers in 11 patients (7%). In addition, standard measures for treatment of hyperkalemia were used, including glucose and insulin, bicarbonate infusions, and enemas with potassium-binding
resins.
At the time of enrollment into the study, the
median serum digoxin concentration of the patients
was 8.0 ng/ml (lower quartile, 5.0; upper quartile,
13.1). The median serum digitoxin concentration was
156 ng/ml. The median digoxin-specific Fab fragment
dose was 200 mg (120-480 mg); the highest dose
given was 1,600 mg (40 vials). Fab fragments were
administered intravenously during a median of 20
minutes (20-30 minutes). The median time from
ingestion of glycoside to initiation of Fab treatment
was 12 hours (7-25 hours).
In 121 patients, serum creatinine measurements
were available before initiation of Fab treatment.
Based on a definition of 1 mg/dl or less in infants and
children and 1.5 mg/dl or less in adults, 48 patients
(40%) had normal function and 73 (60%) had abnormal function. Of 18 children who had a baseline
serum creatinine, 11 had abnormal values ranging
Antman et al Digitalis Intoxication
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lmV[
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FIGURE 2. Tracing of left anteriorfascicular tachycardia arising as a result of digitialis-induced increased automaticity in or near
the left anterior fascicle. Tachycardia morphology includes right bundle branch block with right-axis deviation. Reproduced with
permission. 11
from 1.2 to 3.1 mg/dl (median, 2.2 mg/dl). In 62
adults with an abnormal baseline creatinine, the
median was 2.8 and the upper quartile had levels of
4.1 or more. Five patients were on dialysis when Fab
was administered.
Response to Treatment With Digoxin-Specific
Fab Fragments
Although intradermal and intravenous sensitivity
testing before Fab infusion were recommended, clinical circumstances did not always permit these
screening maneuvers. The results of skin testing were
reported in 94 cases and were nearly uniformly
negative; only one patient had erythema but without
wheal or induration. None of the 77 patients who
underwent intravenous testing exhibited a reaction,
including the patient who had erythema on intradermal testing. No allergic reactions were identified
during or after administration of the therapeutic
dose of Fab fragments.
The clinical response to Fab was unspecified in two
cases, leaving 148 patients who were evaluated (Figure 1). One hundred nineteen patients (80%)
resolved all signs and symptoms of digitalis toxicity,
14 (10%) improved, and 15 (10%) showed no
response. All of the five patients with digitoxin
toxicity were complete responders. Four of the five
patients on dialysis were complete responders, and
the fifth improved after Fab administration.
The times to initial improvement in signs and
symptoms of toxicity and to complete response were
analyzed in 80 patients for whom information was
available. Therapeutic responses noted during Fab
infusion were assigned a 0-minute response time.
The time to initial response was 19 minutes (0-60
minutes) from termination of the infusion. The time
to complete response was 88 minutes (30-360 minutes). Thus, most patients who responded had clinically evident improvement by 1 hour after termination of infusion and complete response by 4 hours.
The time to initial response was analyzed to determine whether the presence of concurrent cardiac
disease, type of digitalis intoxication (long-term dosing vs. single overdose), and age (.70 vs. >70 years
and .12 vs. >12 years) were associated with a
particularly slow response (>60 minutes after Fab
administration; i.e., the upper quartile of the sample). None of the above three factors was significantly
associated with a particularly slow initial response.
Partial responders and nonresponders were carefully evaluated for causes of less-than-complete resolution. Of the 14 patients classified as improved but
in whom not all of the potential signs of putative
toxicity resolved, two were moribund at the time of
treatment, two received an inadequate dose of Fab
due to limited supplies of the drug, two had concomitant toxicities with other cardioactive drugs, and
eight had coincident medical conditions that caused
signs and symptoms initially ascribed to digitalis. Of
the 15 cases of failure to respond to Fab, five were
moribund at the time of treatment (one also received
an inadequate dose of Fab), four were believed in
retrospect to definitely not be suffering from digitalis
toxicity, five were believed in retrospect to probably
not be suffering from digitalis toxicity, and one was
classified as a true nonresponder. The true nonre-
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Circulation Vol 81, No 6, June 1990
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sponder was a 71-year-old, 40-kg woman on long-term
digoxin treatment who developed intermittent highgrade atrioventricular block and malignant ventricular
tachyarrhythmias in association with a serum digoxin
concentration of 9.7 ng/ml. She was given 130 mg Fab
(calculated dose, 148 mg), but high-grade atrioventricular block recurred 1 hour after the infusion. Her signs
of digitalis toxicity resolved during a time course
consistent with the natural history of her condition,
not during the accelerated time course observed in the
patients who were classified as responders.
Of the 150 patients, 107 (71%) survived to hospital
discharge. Of the 43 who died, 20 had complete
resolution of toxicity, 12 had improvement in signs of
toxicity, and 11 had no response to Fab. The majority
of the 43 deaths could be ascribed to underlying heart
disease still present after resolution of digitalis toxicity
or to other medical illnesses. Of the patients who were
moribund before treatment with Fab fragments, the
majority ultimately died of the consequences of neurologic and cardiovascular complications of their protracted pretreatment cardiac arrest or low output
status. However, several of these patients demonstrated remarkable resolution of both their digitalis
toxicity and their apparently moribund state. Notably,
of the 56 patients whose digitalis toxicity culminated in
cardiac arrest, 30 (54%) survived hospitalization after
treatment with Fab fragments.
Laboratory Evidence of Response to Fab Fragments
A dramatic fall in serum potassium concentration
can occur after reversal of severe digitalis toxicity
because reversal of Na,K-ATPase inhibition tends to
reestablish rapidly the normal transmembrane potassium gradient. Serum potassium concentrations
before and 2 and 6 hours after treatment were available in 82 cases and indicated a significant reduction
from a median of 5.0 to 4.1 meq/l (p=0.0001). This
reduction occurred despite concomitant administration of potassium chloride in some cases. The time
course of decline in serum potassium concentration
was consistent with the rapid time course of arrhythmia response; that is, declines in serum potassium
were often noted within 1 hour and appeared complete within 4 hours (Figure 3).
Adverse Responses to Treatment With Digoxin-Specific
Fab Fragments
Adverse events related to Fab administration were
initially raised as a possibility in 32 of the 150
patients. In only 14 of these 32 patients were the
reported adverse events judged to be possibly or
probably caused by Fab. Relatively rapid development of hypokalemia was observed in six of the 150
patients (4%). Four patients (3%) experienced exacerbations of congestive heart failure after Fab treatment; this was thought possibly to have been caused
by loss of inotropic support from digitalis therapy.
However, because many patients with poor ventricular function also received multiple other treatments,
it is not possible to determine a true incidence of
6.0
5.6
zr 5.2
(:r
f (N 135)
4.8
{ (N = 34)
- 44
(N=28)
.N=17)
(~
4.0 h
3.6
11
Pre- 0
Treatment
l
A~~~~
2
~~~~
(
A
3
4
TIME (HOURS) POST Fab
FIGURE 3. Plot of change in serum potassium concentration
after treatment with Fab. The pretreatment value is the last
measurement recorded before the start of the Fab infusion.
Vertical lines, interquartile ranges; horizontal hatches, medians. The decline in serum potassium concentration appears
complete by 4 hours.
decompensation with emergence of overt heart failure in this patient population. Two patients suffered
mild hypotensive episodes; each had been hemodynamically unstable before the Fab infusion. Another
patient complained of nausea just after Fab treatment; this patient also had nausea as a clinical
manifestation of digitalis toxicity before treatment. A
neonate, several hours old, developed transient
apnea during the Fab infusion.
The dominant pattern of serial serum creatinine
measurements was one of stable or improved renal
function after Fab therapy. Three patients with pretreatment serum creatinine levels in the normal range
had posttreatment values of 1.5 mg/dl or more. In all
three cases, the rise in serum creatinine was clearly
ascribable to decreased renal perfusion before Fab.
One patient was described as oliguric, and the other
two had cardiac arrests before Fab treatment.
Serum Digoxin Measurements After Fab Treatment
Laboratory evidence for the binding of digoxin or
digitoxin by the Fab fragments was available in the
posttreatment serum drug concentrations in 11
patients studied early in the trial. In all cases, the
concentration of free, pharmacologically active
digoxin or digitoxin in the serum fell to near-0 levels
within 1-2 minutes of administration of Fab fragments. The total serum digoxin concentration,
reflecting pharmacologically inactive antibody-bound
drug, rose rapidly to values 10- to 20-fold those
before treatment (Figure 4). Equilibrium dialysis or
ultrafiltration are required to measure the free
digoxin concentration after treatment because in a
patient's serum, Fab interferes with conventional
assay techniques.12,13
Discussion
Based on a substantial body of experimental evidence demonstrating antibody-mediated reversal of
Antman et al Digitalis Intoxication
Rhythm:
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1749
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FIGURE 4. Flow diagram illustrating temporal relations between recorded cardiac rhythms, ingestion of suicidal overdose of
digoxin (19 mg), and results of treatment with digoxin-specific Fab fragments. The patient is a 60-year-old woman with a history
of rheumatic heart disease and atrial fibrillation (AF). About 26 hours after her suicidal ingestion, she developed atrioventricular
junctional rhythm (AVJR); later, she developed fascicular tachycardia (Figure 2) that was initially mistaken for supraventricular
tachycardia (SVT). After treatment with Fab fragments, there is abrupt rise in total serum digoxin concentrations but a fall in free
serum digoxin concentrations (determined by radioimmunoassay after equilibrium dialysis). CHB, complete heart block.
Reproduced with permission.20
cardiac glycoside effects in experimental models
extending from isolated membrane Na,K-ATPase
preparations to intact animals, it was predicted
nearly two decades ago that an immunochemical
approach might be clinically successful in reversing
digitalis toxicity.5,14-16 The advantages of the smaller
size of the Fab fragment (molecular weight, 50,000)
include a more rapid onset of action due to enhanced
diffusion into the interstitial space and, in patients
with normal renal function, relatively rapid clearance
of digoxin bound to Fab fragments in the urine
(half-life, 16 hours).17-19 The latter point minimizes
the chance of late release of bound digoxin and
reemergence of toxicity. Although the average intrinsic affinity constant for digoxin is 30- to 100-fold that
for digitoxin, the affinity for the latter was still
considered high enough to permit evaluation of the
clinical efficacy of digoxin-specific Fab antibody fragment treatment for life-threatening intoxication with
either digoxin or digitoxin.4,8 This was confirmed by
our observations in the five patients suffering from
digitoxin toxicity.
The proposed sequence of events that occurs after
infusion of digoxin-specific Fab fragments includes
rapid binding of intravascular digoxin and diffusion
of the Fab fragments into the interstitial space with
binding of free digoxin.3 The decreased extracellular
free digoxin creates a concentration gradient that
promotes egress of tissue stores of digoxin into the
extracellular fluid, where it is also rapidly bound.
Thus, the free digoxin molecules that dissociate from
membrane receptors are subsequently rapidly bound
and cannot reassociate with the inhibitory site on the
a-subunit of Na,K-ATPase.21 This dissociation event
and the subsequent step of binding to Fab are
critically important processes in the reversal of digitalis toxicity. Characteristically, the total extracellular
digoxin concentration rises dramatically, but such
digoxin is pharmacologically inactive because only
the unbound form can associate with myocardial
receptor sites.3
Experience in the multicenter trial reported here
indicates that purified Fab fragments of high affinity
and specificity for digoxin rapidly and safely reverse
advanced digitalis toxicity in humans. An initial
response was usually seen within 60 minutes in
patients suffering from digitalis toxicity, and complete reversal of glycoside effects was usually evident
within 4 hours of administration. True nonresponders were rare, and lack of response should raise
the suspicion that too low a dose of Fab fragments
Circulation Vol 81, No 6, June 1990
1750
was
given
or,
alternatively, that the clinical signs and
symptoms are not caused by digitalis toxicity.
No acute allergic reactions or serum sickness-type
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illnesses were recognized in conjunction with Fab
fragment treatment. The anticipated adverse reactions caused by relatively rapid reversal of the effects
of digitalis, such as worsened left ventricular function
or hypokalemia, were noted in less than 10% of
treated patients. It should be noted, however, that
excretion through renal mechanisms and therapeutic
maneuvers to reduce hyperkalemia before Fab
administration may result in total body potassium
depletion with persisting high or normal serum potassium concentrations. In this clinical context, rapid
onset of hypokalemia should be anticipated when
toxicity is reversed by digoxin-specific Fab fragments.
Serum potassium levels should be monitored and
potassium supplementation used as needed to avoid
hypokalemia. As previously noted, after Fab treatment, the standard immunoassay and other methods
for measurement of serum digoxin concentration
usually give unreliable results that are likely to be
misleading as estimates of the state of digitalization.
Furthermore, unless absolutely required for inotropic support or arrhythmia management, "back titration" with digoxin is usually unnecessary and should
not be attempted for at least 7 days or possibly longer
in patients with impaired renal function.
There were 18 patients with a pretreatment serum
creatinine concentration of more than 4.0 mg/dl,
including five who were on dialysis. These patients
responded to Fab treatment in a manner similar to
patients with normal renal function. However, a
theoretic possibility exists that digoxin could be rereleased with recurrence of toxicity when excretion of
the Fab-digoxin complex is slowed by renal failure.
Whereas the absence of this phenomenon in the
present study suggests that recurrence of toxicity will
be uncommon, it remains a possibility under certain
circumstances (e.g., very large digitalis load, very
poor renal function, low Fab dose). One such case
occurred after commercial release of Fab. A dialysis
patient developed third-degree atrioventricular block
from digitalis toxicity, responded rapidly and completely within 4 hours of Fab treatment, but had
recurrence of second- and third-degree block 10 days
later. No further Fab was given, and the block
resolved during an additional 10 days of observation
(Burroughs Wellcome Company, data on file).
Recurrence of toxicity occurred in two of the 150
patients. Neither had renal failure, and each received
less than fully neutralizing doses of Fab. In each case,
resolution of toxicity was followed within 4-8 hours
by recurrent signs and symptoms of toxicity. In one
case, no further Fab was available, and the patient
died within 24 hours of a massive ingestion of
digoxin.
Although not a randomized clinical trial, this trial
provides abundant evidence of a pronounced effect
of Fab treatment on survival of patients with lifethreatening digitalis toxicity. The nature and severity
TABLE 2. Relation of Pretreatment Hyperkalemia to Outcome in
Patients Without Prior Cardiac Insufficiency or Diuretics
Pretreatment
serum K+
(meq/l)
<5
>5<6.4
>6.4
Gaultier et al22
Patients Deaths
(n)
(n)
42
1
17
6
10
9
%
2
35
90
Present study
Patients Deaths
(n)
(n)
30
1
24
6
8
1
%
3
25
12.5
of the clinical digitalis toxicity encountered, the poor
prognosis with standard treatment, and the dramatic
successes in early clinical experiences present important ethical concerns regarding denial of antibody
therapy to critically ill patients. The present study
reports relatively good survival rates of patients with
elevated serum potassium before treatment; this contrasts to the observations of Gaultier and Bismuth,22
who reported a mortality rate of 55% for conventionally treated patients who were not on diuretic therapy, did not have prior cardiac insufficiency, and had
pretreatment serum potassium concentrations of 5.0
meq/l or more (Table 2).
Further evidence of a striking effect on outcome
can be found in the survival rates of patients with
digitalis-induced cardiac arrest. Whereas survival
after standard therapy in this setting is uncommon
(Table 3), more than one half of the patients treated
with Fab survived to discharge. In addition, the rapid
time course of resolution of toxicity during 1-4 hours
instead of several days not only serves as evidence of
response but also improves substantially the ease of
patient care.
The digoxin-specific antibody fragments used in
this trial were supplied by Wellcome Research Laboratories, UK. Favorable experience with a similar
preparation in other countries as well as with
digoxin-specific antibody fragments from other suppliers may be considered supportive of the conclusions of this trial.1223-30
In 1986, the U.S. Food and Drug Administration
approved the marketing for clinical use of purified
digoxin-specific Fab fragments (Digibinds) as an
orphan drug. A postmarketing surveillance study is
underway and is anticipated to provide data on more
than 700 additional patients treated with Fab. Preliminary review of these data supports our observations in this 150-patient multicenter trial.
Clinical Implications
Although less elegant than reversal of opiate overdose with the competitive antagonist naloxone,
TABLE 3. Relation of Pretreatment Cardiac Arrest to Outcome
Patients (n)
Experienced cardiac arrest
Died
Mortality (%)
Gaultier et a122
Present study
9
9
100
56
26
46
Antman et al Digitalis Intoxication
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digoxin-specific Fab fragment treatment has gained a
place as established therapy for life-threatening digitalis toxicity. An initial treatment response can be
expected within 1 hour in 75% of such cases. Important treatment-related side effects such as exacerbation of congestive heart failure, increased ventricular
response in atrial fibrillation, or hypokalemia occur
in less than 10% of patients, and idiosyncratic
adverse reactions such as allergic manifestations
occur in less than 1% (preliminary results of postmarketing surveillance study). Although serum
digoxin measurements are not reliable for 1-2 weeks
after Fab treatment, this is generally not an important clinical problem. A trial is underway examining
the clinical usefulness of digoxin-specific Fab fragments for the simultaneous diagnosis and treatment
of digitalis toxicity that has not advanced to an
overtly life-threatening stage.
Besides demonstrating effectiveness as an antidote
to digitalis toxicity, this trial supports the theoretic
advantages of using Fab fragments rather than whole
antibodies in humans. Future developments could, in
principle, include the production of even smaller
immunoglobulin fragments with reduced immunogenicity in humans by recombining the variable regions
of the light and heavy immunoglobulin chains to form
a 23,000-Da Fv fragment with framework regions of
human immune specificity.31,32 Such measures could
lead the way to antibody reversal of toxicity from
other drugs or endogenous substances.
Appendix
Investigators and Hospital or University Affiliations
Vance J. Plumb, MD, Department of Medicine,
University ofAlabama, School of Medicine, Birmingham, Alabama; Frank I. Marcus, MD, Department of
Internal Medicine, Health Sciences Center, University of Arizona, Tucson, Arizona; James E. Doherty,
MD, Chief, Cardiovascular Research, Veterans
Administration Medical Center, Little Rock, Arkansas;
Kenneth I. Shine, MD, Jan H. Tillisch, MD, William
Stevenson, MD, Division of Cardiology, Center for
the Health Sciences, UCLA School of Medicine, Los
Angeles, California; Kanu Chatterjee, MD, William
W. Parmley, MD, Department of Medicine, University of California, Moffitt Hospital, San Francisco,
California; Alan S. Nies, MD, Health Science Center, University of Colorado, Denver, Colorado;
Lawrence S. Cohen, MD, David Rutlen, MD, Forrester Lee, MD, Yale University School of Medicine,
New Haven, Connecticut; Robert J. Myerburg, MD,
Director, Division of Cardiology, University of Miami
School of Medicine, Miami, Florida; Robert C.
Schlant, MD, Emory University School of Medicine,
Atlanta, Georgia; Harry A. Fozzard, MD, Craig
January, MD, Department of Medicine, University of
Chicago, Chicago, Illinois; Philip R. Reid, MD,
Enrico Veltri, MD, The Johns Hopkins University
Hospital and Sinai Hospital, Baltimore, Maryland;
Thomas W. Smith, MD, Chief, Cardiovascular Divi-
1751
sion, Brigham and Women's Hospital, Boston, Massachusetts; Edgar Haber, MD, Hasan Garan, MD,
Department of Cardiology, Massachusetts General
Hospital, Boston, Massachusetts; Allan S. Jaffe, MD,
Washington University School of Medicine, Barnes
Hospital, St. Louis, Missouri; Vincent P. Butler Jr.,
MD, Department of Medicine, College of Physicians
and Surgeons, Columbia University, New York; Robert M. Califf, MD, Gary D. Dunham, RPh, Department of Medicine, Duke University Medical Center,
Durham, North Carolina; Robert J. Toltzis, MD,
Division of Cardiology, University of Cincinnati Medical Center, Cincinnati, Ohio; Francis E. Marchlinski,
MD, John A Kastor, MD, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania; Robert J.
Luchi, MD, Anthony Ware, MD, Baylor College of
Medicine, Methodist Hospital, Houston, Texas;
James T. Willerson, MD, Health Science Center,
University of Texas, Dallas, Texas.
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KEY WORDS * digitalis * antibodies * Fab fragments
Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab
antibody fragments. Final report of a multicenter study.
E M Antman, T L Wenger, V P Butler, Jr, E Haber and T W Smith
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Circulation. 1990;81:1744-1752
doi: 10.1161/01.CIR.81.6.1744
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