Recognition

and Management To?ticity

Ralph A. Kelly,

MD,

and Thomas W. Smith,

The most important step in the management of toxkzftyduetoanyofthecardlacglycoskkslslts recognltlon. Despite the deve4opment of an accurate dlnkal assay for serum levels of dtgoxln

>20years8go,digltalistoxkJtyremalnscomnmn and dlfflcult to confirm, even lf suspected, due prhnarily to 2 factors. First, the signs and symptoms of digitalts toxicity, most commonly an [email protected] oratrialarrhythmiaqwithorwlthoutsomedegree of concurrent atrkwentrkwhu block, often also occur In pattents with congestive heart fallwe (CHF) and underlyl~ coronary atherosderosiswhoarenotrecehMgacardlacglycoside. Second, due to dlgoxln’s narrow therapeutic ratlo,themarkeddegreeofvariabllityInthesensltlvlty of lndlvidual patients to its toxk effectq and the common probiem of obtaining bkod samples inapproprlateiy during the early dtsMnrtiin phase foUowfng dosing, a serum dlgoxln concentratiioftendeesnotseweasarellabIeindicatar of toxicity. Despite these dlfDcultJes in dlagnods, the management of dlgoxin toxkzlty has beenmademuchmoreeffectlvewlththewtdespread availablllty of F(ab) [email protected] of antldigoxin antlbod&. This drug provides the clinkdan wlth a rapidly acting, safe antidote for all commonly used digltalis preparations. Conventlonal therapy for diioxin toxlclly remahrs the mahrtenance of serum potasslum levels h4 mEq/ liter, reversal of decompensat ed CHF or overt myocardial lschemia, attention toserum magnes&m levels and the patient’s acki&ase status, approprtate antiarrhythmkx5 in the event ofventricular arrhythmias, and a temporary pacemaker

From the Cardiovascular Division, Departments of Medicine, Brigham and Women’s IIospital and Harvard Medical School, Boston, Massachusetts. This work was supported in part by grants HLlY21.59 and HL36146 from the National Institutes of Health, Bethesda, MD (TWS), and a Faculty Development Award from the Pharmaceutical Manufacturers Association, Washington, DC (RAK). Address for reprints: Thomas W. Smith, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.

1080

THE AMERICAN

JOURNAL

OF CARDIOLOGY

VOLUME

of Digitalis

69

MD

for h&h-grade atrioventrkAai block. NeverthespedMtyanddocumentedsafety -,-h&h oftheantibodypreparatJonprovidesanee&d safetynetfwtheconthuJinguseofcanlSacglycosddes as first-lins lnotropic agents In the modern therapy of chronic CHF. (AmJCardiol issz;69dO8&ll9G)

ith the advent in the past two decades of new classes of drugs for the treatment of congestive heart failure (CHF) and supraventricular arrhythmias, as well as results from well-designed prospective clinical trials that have more clearly defined the role of cardiac glycosides in CHF, the incidence of digitalis toxicity in patients with CHF has declined. In addition, a new therapeutic modality specific for digitalis intoxication-the use of F(ab) fragments of antidigoxin antibodies-has proven to be safe and effective in the treatment of life-threatening digoxin toxicity.

W

INCIDENCE OF DtGlTAtJS INTOXlCADON MD MORTAl.lTY

Although cardiac glycoside toxicity can be suspected based on nonspecific symptoms and electrocardiographic findings, it is often difficult to document. It is particularly difficult to evaluate epidemiologic data from studies on the incidence of digoxin toxicity that wcrc performed before the development of assays to measure serum digoxin concentrations. Nevertheless, studies published in the 1960s and early 1970s found that approximately 20% of patients receiving maintenance digoxin therapy demonstrated signs or symptoms of toxicity at some point in their clinical course.1,2 In a prospective clinical trial, Beller et al3 reported that 17% of patients receiving maintenance digoxin or digitoxin therapy who required hospitalization showed definite evidence of toxicity, and another 4% had probable toxicity. These results are similar to the estimate of overt digoxin or digitoxin toxicity in hospitalized patients in the Boston Collaborative Drug Surveillance Program, which reported an incidence of 13% in 1972.4 The marked variability JUNE 4, 1992

TABLE I Laboratory

Diagnosis

Data and Mortality Patients (n)

in 219

Patients

Digoxin Level (ng/mL)

With Discharge

Diagnosis

Serum BUN (mg/dL)

of Digoxin

Intoxication

Serum

Serum

Creatinine

Potassium (mEq/liter)

(mg/dL) -+ 2*

Deaths+ (n)

Definite

43

4.1

f 2*

42 f 21*

2.5

4.7 + 1*

2

Possible

133

3.4

2 1

41 -t 33

2.4 i 2

4.6 t

1

9

Nontoxic

43

1.7 + 1*

28 + 20*

1.6 f l*

4.1 -c 1*

0

*p < 0.05 between definitely toxic vs nontoxic groups. tNine of 11 deaths resulted from causes other than digoxin intoxication. BUN = blood urea nitrogen. Adapted with permission from Am HeartJ.g. L

in digoxin bioavailability from manufacturer to manufacturer also resulted in episodes of increased toxicity due to a hospital’s change in formulation or vendor; one medical ward, for example, reported 15 concurrent casesof digitalis toxicity in a 30-bed unit.5 The introduction in 1969 of a sensitive radioimmunoassay for serum digoxin concentrations, and its widespread acceptance and availability, has made this technique useful in the assessment of suspected digitalis toxicity.627Nevertheless, considerable overlap of serum concentrations exists between populations of patients with and without clinical signs and symptoms of digoxin toxicity. Also, there is only a poor correlation between the ventricular response rate at rest and serum digoxin concentrations in patients with atria1 fibrillation who are taking digoxin. Other testshave been proposed to aid in the diagnosis of digitalis toxicity, such as a patient’s response to the ultra-short-acting cardiac glycoside acetyl-strophanthidin,8 but this approach is regarded as too dangerous for routine clinical use. Nevertheless, the general impression is that the incidence of digitalis toxicity has fallen since the availability of the digoxin assays.This is due in part to the development of newer classes of drugs for the treatment of both supraventricular arrhythmias and CHF, and to the recognition of important drug interactions between digoxin and other commonly used cardiovascular agents, such as quinidine. A large prospective epidemiologic study by Mahdyoon et a1,gwho examined 994 patients admitted to a large urban teaching hospital with the diagnosis of CHF, supports this. Of this group, 56% were receiving maintenance digoxin, but only 4 patients (0.8%) were classified as definitely being digoxin toxic, and another 16 (4.0%) were classified as possibly digoxin toxic. The diagnosis of digitalis toxicity was based on the presence of both symptoms and electrocardiographic signs consistent with digoxin toxicity, a serum digoxin concentration of at least 1 ng/mL, and, importantly, a close time correlation between resolution of evidence of toxic-

I

ity and drug withdrawal or administration of antidigoxin F(ab) fragments.g Mahdyoon et al9 also retrospectively analyzed mortality due to digoxin intoxication in 219 patients discharged from the hospital over an &year period with the diagnosis of digitalis toxicity while receiving maintenance digoxin therapy (i.e., excluding those patients who had accidentally or with suicidal intent consumed large quantities of digoxin). Earlier studies of mortality in patients diagnosed with digoxin intoxication are difficult to evaluate due to the absence of serum level data in most cases,or to reliance on criteria that were too nonspecific to allow a conclusive diagnosis of toxicity. In the study reported by Beller et a1,3 the mortality rate was 41% in patients with “definite” intoxication (although only rarely due to digitalis toxicity per se) and only 17% in digitalized patients not showing signs or symptoms of digoxin toxicity. In marked contrast, Mahdyoon et al9 demonstrated a mortality rate of 4.6% in patients with documented digoxin toxicity, as classified by their rather rigorous criteria. As shown in Table I, of the 11 deaths in the 2 groups of patients originally classified as “digoxin toxic” prior to retrospective analysis of their medical records, only 2 patients were thought to have definitely died of digoxin toxicity.g Thus, the true mortality rate was probably < 1%. This is consistent with the low mortality rate for digoxin toxicity reported in the Boston Collaborative Drug Surveillance Program.4 Other serious manifestations of digoxin toxicity in the retrospective trial by Mahdyoon et al9 were also uncommon and treated effectively with standard therapy. Although 33% of the definitely toxic patients demonstrated second- or third-degree atrioventricular (AV) block, only 5% required a temporary pacemaker. Reasons for the low incidence of digoxin toxicity and the low morbidity and mortality rates observed in the recent trial by Mahdyoon et a1,9compared with older studies, are changes in patients’ characteristics and in the management of patients given A SYMPOSIUM:

CONGESTIVE

HEART

FAILURE

1090

1ASl.E II Factors Intoxication Renal

Associated

With Increased

Risk for Digitalis

insufficiency

Type and severity Electrolyte

of underlying

abnormalities

cardiac

(especially

disease 1 K+, 1 Mg?+,

i Ca2+ serum

levels)

Hypothyroidism Advanced

pulmonary

Pharmacokinetic verapamil, Pharmacodynamic sympatholytic

disease

interacbons and amiodarone) interactlons agents)

with other (especially

drugs (especially

qumidine,

with sympathomimetic

and

long-term digitalis therapy. In the 1971 prospective trial by Beller et al,3 >70% of the patients had coronary artery disease and 60% had had a previous myocardial infarction; in the 1990 study by Mahdyoon et al, 9 these numbers were 35% and 20%, respectively. In past studies, hypokalemia had often been implicated as a major complicating factor contributing to serious morbidity in patients receiving long-term digoxin therapy. In a 1978 study by Lehmann et al, lo the incidence of digitalis toxicity was 13% in > 4,600 cardiology admissions and was considered life-threatening in nearly half. Most of the more serious arrhythmias-ventricular tachycardia, ventricular fibrillation, accelerated junctional rhythms, and advanced AV nodal blockwere found in hypokalemic patients (i.e., potassium 2 ng/mL, the wide overlap between patients with and without toxicity limits the ability of the serum digoxin concentration to confirm (or deny) toxicity’s existence. Only a temporal correlation with drug withdrawal, or a prompt termination of the arrhythmia after administration of F(ab) fragment of antidigoxin antibodies, is confirmatory. JUNE

4, 1992

Atrium and atrioventricular node: In patients in sinus rhythm, cardiac glycosides often slow the heart rate, usually as a result of decreased adrenergic tone. This is due partly to enhanced cardiac performance and partly to a direct drug effect to increase baroreceptor responsiveness. Toxic digoxin concentrations may lead to sinus arrest or sinus exit block, however, due to a direct drug effect on the sinoatrial node.22 Although atria1 tissue is not affected by therapeutic digoxin concentrations, higher serum levels may lead to increased automaticity and a decline in conduction velocity. The effect of cardiac glycosides in slowing AV nodal conduction and prolonging nodal refractoriness is largely mediated by enhanced parasympathetic and decreased adrenergic tone. At toxic levels, however, digoxin appears to act directly to prolong the AV nodal refractory period. This effect, along with increased vagal tone, may lead to advanced AV junctional conduction block. Also, junctional pacemakers may begin to discharge at increasing frequency, resulting in a nonparoxysmal, automatic AV junctional tachycardia. This is often recognized clinically as a paradoxic regularization of ventricular rate in chronic atria1 fibrillation. Other supraventricular arrhythmias include AV nodal reentrant tachycardias and tachycardias that originate from enhanced atrial automaticity. Although paroxysmal atrial tachycardia with block (“PAT with block”) is associated with digitalis toxicity, there are no features of this arrhythmia that clearly distinguish whether it is due to digitalis intoxication.23 AV junctional block of varying degrees, along with increased ventricular automaticity, are the most common manifestations of digoxin toxicity, occurring in 30-40% of patients with recognized digoxin toxicity. 9,24Although first-degree AV block is often a simple indication of digitalis effect, higher degrees of AV block are evidence of digoxin toxicity. Second-degree AV block typically has a Wenckebach periodicity, whether or not the patient is in sinus rhythm or automatic atria1 tachycardia. Mobitz type II second-degree AV block due to digoxin intoxication alone is rare. Third-degree AV block should be distinguished electrocardiographically from apparent AV dissociation due to an accelerated idioventricular or AV junctional pacemaker. Purkinje fibers and ventricular muscle: The toxic manifestations of cardiac glycosides in ventricular tissue are primarily due to enhanced automaticity and triggered activity. Ventricular arrhythmias are uncommon, however, in young patients with healthy hearts even after suicidal ingestion of

a large quantity of digoxin. This suggests that in older patients with underlying heart disease, enhanced Purkinje fiber [email protected] in digitalis toxicity may be exacerbated by ischemia, fiber stretch, or other injury. The degree of diastolic depolarization observed with cardiac glycoside intoxication also increases with ventricular rate and drug level. A second contributing mechanism includes spontaneous depolarizations triggered by previous action potentials, or “delayed after-depolarizations.” These may be related to a transient decrease in membrane potential late in phase 3 or early in phase 4 that reaches threshold and depolarizes the ventricle. The likelihood that an after-depolarization will reach threshold is enhanced by hypokalemia or hypercalcemia and may be induced by catecholamines and digitalis glycosides in isolated Purkinje fibers. Although triggered activity is a plausible explanation for many digitalis-induced ventricular arrhythmias, it has not been proven in humans.25 The most common manifestation of digitalis toxicity is an increase in the frequency of ventricular premature beats of any morphology, with either fixed or varying coupling intervals to preceding supraventricular beats. As noted, bidirectional and fascicular tachycardias may occur and are very suggestive of digitalis toxicity. Ventricular fibrillation is rarely the first electrophysiologic manifestation of digitalis toxicity. Again, although there is no one electrocardiographic abnormality that is pathognomonic of digoxin toxicity, the combination of enhanced automatic&y and impaired conduction (e.g., AV block accompanied by an accelerated junctional pacemaker) is highly suggestive of toxicity even in patients with serum levels of l-2 ng/mL.

EXTRACARDIAC MANIFESTATIONS The noncardiac manifestations of digitalis toxicity are nonspecific but highly prevalent in patients with known or suspected digoxin toxicity (Table III). Most patients experience fatigue and often anorexia is an early complaint, followed by nausea and occasionally vomiting due to central effects of these drugs. A somewhat more specific, if uncommon, complaint is visual symptoms, particularly halos around bright objects and changes in color perception, in addition to more common neurologic manifestations such as headache, neuralgic pain, and confusion. A SYMPOSIUM:

CONGESTIVE

HEART

FAILURE

113.G

TABLE III Intoxication

Frequency

of Symptoms

Associated

With Digoxin

Definite (%)

Possible (%)

Nontoxic (%)

Nausea

52

30

27

Vomiting

48

30

27

Anorexia

34

27

18

Dizziness

14

19

23

14

16

11

9

5

7

6

3

2

6

4

0

Diarrhea

2

2

2

Headache

0

2

0

Delirium

0

1

0

Fatigue Visual

disturbances

Syncope Abdominal

Reprinted

pain

with permission

TABLE IV Acute Digitalis Toxicity

from Am Heart J.¶

Potassium

Administration

in Suspected

Indications Serum potassium ~4.0 mEq/liter VPCs; VT SVT with AV block Serum potassium ~3.0 mEq/liter (in addition to those listed above) First-degree AV block and second-degree AV block with Wenckebach periodicity (Mobitz I) Contraindications Mobitz type II or third-degree available

AV block

if temporary

AV = atrioventricular; SIT = supraventricular prematurecomplexes; VT = ventriculartachycardia.

electrical

tachywrdia;

pacing

un-

VPCs = ventricular

FACTORS CONTRIBUTING TO INCREASED RISK OF DlGOXlN TOMCITY Electrolyte abnormalities: Changes in potas-

sium homeostasis clearly influence the action of digitalis. Cardiac glycoside binding to sarcolemmal sodium-potassium adenosine triphosphatase, (Na+,K+-ATPase), the “sodium pump,” is affected by the plasma potassium concentration.26 This is, at least in part, because the association of potassium with Na+,K+-ATPase results in dephosphorylation of the enzyme, including a conformational change that reduces the likelihood that a cardiac glycoside will successfully bind to and inhibit this enzyme. Potassium is also a necessary cofactor for sodium pump cycling. Severe hypokalemia ( 100 beats/min should be monitored closely and tally or with suicidal intent is usually characterized treated actively, at least in some patients. by diminished AV conduction or by sinoatrial exit Potassium: Both hypokalemia and hyperkaleblock, with little evidence of increased automaticmia may exacerbate digitalis-induced arrhythmias. ity. In patients with ischemic heart disease, valvular Hyperkalemia can occur as a consequence of heart disease or cardiomyopathies, the effects of massive digitalis overdose, usually following atdigitalis often are superimposed on preexisting tempted suicide, but rarely complicates the more abnormalities of impulse formation and conduccommon forms of digitalis toxicity in patients with tion. In addition, digoxin binding by amyloid fibrils underlying heart disease, unless advanced renal may contribute to the increased sensitivity to car- insufficiency is also present (Table I). Potassium diac glycosides that is characteristic of this cardiosalts, as noted in Table IV, are indicated for myopathy. ectopic ventricular arrhythmias, even when the In patients with underlying ischemic heart dis- serum potassium level is within the “normal” ease and left ventricular dysfunction, the net effect range. Potassium may also improve digitalisof digitalis administration on myocardial oxygen induced AV block in the presence of hypokalemia, consumption is the result of two opposing actions although it should be given cautiously, with concurof this class of drugs: an increase in contractility, rent cardiac monitoring. A SYMPOSIUM:

CONGESTIVE

HEART FAILURE

1136

Recently, final results were reported from a multicenter prospective trial of the use of F(ab) Intoxication fragments for treatment of acute, life-threatening Gaultier et al (1978)* Antman et al (1990)t Pretreatment digitalis toxicity,32 and from an observational surSerum Potassium Patients Deaths Patients Deaths veillance study of experience with antidigoxin F(ab) (mEq/liter) (n) % (n) % (n) (n) antibody fragment preparations following Food 6.4 10 9 90 8 1 12.5 fragments given to 150 patients with severe digoxin *Data from previous trial of conventional treatment by Gaultier M, Bismuth C. L’intoxication digitalique. Rev Prat 1978;28:4579. or digitoxin intoxication. Patients ranged in age iTreated with F(ab) fragments. Reprinted with permission from Circulation.32 from neonates treated only hours after birth to 94 I I years. The median digoxin concentration before Digoxin-specific F(ab) fragments: The wide- administration of the antidote was 8.0 ng/mL. As spread availability of F(ab) fragments of high- shown quantitatively in Figure 1, this was associaffinity, polyclonal, digoxin-specific antibodies (Di- ated with high-degree AV block or severe ventricugibind, Burroughs Wellcome Co.) provides the lar arrhythmias, including ventricular fibrillation clinician with a means of rapidly and selectively (in 33%) and asystole (11%). The median serum reversing digoxin toxicity with little risk of adverse creatinine level was 2.8 mg/dL in adults, and 5 effects. The use of F(ab) fragments, as opposed to patients were receiving long-term hemodialysis intact IgG molecules, results in rapid clearance of therapy; 40% had normal renal function, and 90% the antibody fragment-digitalis complex, and also of patients had a complete or partial response to reduces the immunogenicity of this sheep protein. F(ab) fragments of antidigoxin antibodies, with few Digoxin-specific F(ab) fragments also have a large adverse effects. Failure to respond (10%) was most volume of distribution and result in rapid, and often attributed to inadequate dosing, moribund effectively irreversible, removal of digitalis from clinical status before F(ab) fragment administramyocardial and other tissue-binding sites. Several tion, or the likely absence of digitalis toxicity as the thousand patients with life-threatening digoxin or cause of the patient’s symptoms. The most promidigitoxin toxicity have now been treated, most nent adverse effect, seen in 4% of patients, was successfully and with few adverse effects.32,33 A few rapid development of hypokalemia, presumably patients have now been treated more than once for due to sodium pump reactivation in skeletal muscle suicidal digitalis overdose. To date, no evidence of and other tissues following dissociation of digitalis serum sickness or serious reaction to the injection from its binding site on Na+,K+-ATPase. Table V of this foreign (sheep) protein has been observed. lists the results of treatment with F(ab) antibody TABLE Digitalis

V Relation of Pretreatment

Hyperkalemia

to Outcome

in

150 oatients Refractory VT VF High grade AV block 51 t:WJ 0 Hyperkalemia

Res’ponse 133 (90%)

No Response 15 (10%)

I

1146

THE AMERICAN

JOURNAL

OF CARDIOLOGY

VOLUME

69

JUNE

4, 1992

FIGURE l. Clinical response to F(ab) fragment treatment in 150 patients with Me-threatening digRails itioxkatlon. VT = ventrkular tachycardla; VF = ventricular fibrfllation; AV = atrioventricular. (Reprinted wRh permission from Citwlati0n.q

fragments versus conventional treatment of digitalis poisoning in patients who had become hyperkalemic. Importantly, the mean time to an initial response was 19 minutes after initiation of the F(ab) fragment infusion, with a complete response obtained within 88 minutes on average. No allergic phenomena were witnessed in this study.32 In an observational surveillance study covering the first 2 years of postmarketing experience with F(ab) fragments of antidigoxin antibodies, information was received by the manufacturer (Burroughs Wellcome Co.) on 717 adult treatments, estimated to be about 15% of all treatments administered during this period. 34 Figure 2 shows the age distribution of those individuals diagnosed as having digitalis toxicity who were prescribed the F(ab) fragment preparation. The increased number of treated women >70 years of age reflects the increased survival rate of women in this age group, but it also may reflect the tendency of many clinicians to prescribe at a constant dose (e.g., 0.125 or 0.25 mg/day), which would lead to higher digoxin concentrations in women due to their lower lean body mass and lower absolute glomerular filtration rate. Most patients who received antidigoxin F(ab) fragments in this observational study were demographically and clinically similar to those reported in the retrospective study of Mahdyoon et a1.9 Most patients had some degree of renal impairment and most were normokalemic. The median digoxin serum concentration at the time of diagnosis of digitalis intoxication was 4.2 ng/mL, similar to that reported by Mahdyoon et al9 in a similar patient population (Table I). The type and frequency of arrhythmias are shown in Figure 3 for patients with and without underlying heart disease. The re-

sponse rate was not as high as that reported in the prospective trial,9 presumably due in large part to the much more heterogeneous patient population in the postmarketing tria1.34 The nonresponse rate was 14% in patients who developed suspected digoxin toxicity while receiving maintenance doses of the drug, 20% in patients who were receiving loading doses of digoxin or who were in the hospital during development of suspected digoxin toxicity, and 15% in patients with heart disease who had ingested a single large overdose. Importantly, there were no nonresponders in the group of patients without underlying heart disease who had ingested a single large dose. The reasons for the absence of any response to F(ab) fragments in some cases of suspected digoxin toxicity were again similar to those described for nonresponders in the prospective trial by Mahdyoon et a19: inadequate dosing, moribund clinical status, or incorrect diagnosis.34 The postmarketing surveillance trial also provides a better assessment of the complications likely to be seen in the treatment of suspected digitalis toxicity in clinical practice.34 These data were discussed in greater depth in a recent symposium.35A1 The number of adverse events associated with F(ab) fragment administration was low (7%) and included allergic-type responses,36 possible recrudescence of digitalis toxicity, and other events, such as worsening of CHF symptoms due to the abrupt withdrawal of the cardiac glycoside’s inotropic effects. Interestingly, the abrupt onset of hypokalemia, which occurred more frequently in the prospective trial of patients following massive ingestion of digoxin or digitoxin, was not observed in this patient population. Only 6 of 717 patients (0.8%) had probable allergic reactions to F(ab)

150-

143

FIGURE 2. Distribution by age and gender of 717 patients receiving F(ab) fragments of antkliioxin antibodies In a postmarketi% surveillance study. (Reprinted with permission from I Am Co// cartfi0l.J”)

>13-30

>30-40

>40-50

>50-60

>60-70

>70-80

>80-90

>90

Age (years)

A SYMPOSIUM:

CONGESTIVE

HEART FAILURE

1150

antibody fragments, characterized by pruritic rash and flushing or facial swelling, all of which responded to symptomatic treatment.j6 There was a greater likelihood (5%) of an allergic response if a patient had a history of allergy or asthma; in patients with no history of allergy or asthma the incidence of allergic response was 0.3%. Recrudescent digitalis toxicity occurred in 2.8% of patients receiving F(ab) fragments, with recurrent symptoms developing most commonly within 3 days of therapy.34 The most common reason was inadequate dosing, based on the full neutralizing dose calculated using the formula and nomogram in the product’s approved labelling. Interestingly, 18% of the patients studied were restarted on digitalis therapy at a median of 7 days after administration of F(ab) fragments. In 2 patients who were prescribed digoxin for ventricular rate control in chronic atria1 fibrillation 1 day and 4 days after F(ab) antidigoxin antibody fragment administration, the drug was initially ineffective in slowing ventricular response, presumably due to persistent, effective neutralizing antibody levels not yet excreted. Neither this observational surveillance study

nor any prospective trial to date has addressed the utility of F(ab) fragments of antidigoxin antibodies for diagnosing digoxin intoxication. No clinical trials are under way to evaluate the utility and safety of F(ab) antidigoxin fragments in the diagnosis and treatment of suspected digitalis toxicity of mild-to-moderate severity. This is in part due to the low incidence of digoxin toxicity in digitalized patients, as already noted. Nevertheless, the unique specificity of the antibody preparation and its good safety record in more seriously intoxicated patients make a case for its administration to patients with suspected moderate degrees of digitalis intoxication. A few patients have received the preparation more than once, usually in the setting of reported suicidal ingestion, without incident. There are too few data, however, to comment on its safety when administered to a given patient on > 1 occasion, as would likely occur with routine diagnostic use. A more attractive approach, feasible with currently available recombinant DNA technology, would be to develop a nonallergenic F(ab) fragment with “framework” regions of human immune specificity that could be used without fear of patient sensitization.

50

UY E al ‘Z x

6 E % b a

FlGuRE3,tsekted~of d&ttalts lntoxkatiam h 717 Welnapantmarke4tl~suwelBancastudy oftheuseofF(ab)fragmants afantidigoxin antibodk, by prewwe+(dosedbars)orabsome (open bars) of heart dls-.(Repmnd-W sh from IAm Co/i cardror.~)

25

n=18 236 Bradycardia or atrioventricular block

1166

THE AMERICAN

n=5 137

JOURNAL

Ectopy

A-

n=ll 256 Bradycardia or atrioventricular block with ectopy

OF CARDIOLOGY

VOLUME

n=33 Extracardiac signs only

69

JUNE 4, 1992

6%

n=2 16 None

The potential immunogenicity of the present F(ab) formulation and its relatively high cost ($1,140.00 as of August 1991 in a representative hospital) argue against its routine use in the diagnosis of suspected digoxin intoxication. If the clinician’s index of suspicion for digoxin toxicity is sufficiently high, and the observed cardiac arrhythmia sufficiently serious to warrant a major intervention, such as insertion of a temporary pacemaker, administration of F(ab) fragments of antidigoxin antibodies would be indicated. If an electrocardiographic abnormality is due to digoxin toxicity, most patients should show some response within 20-40 minutes after beginning a 40 mg infusion. If a response is observed, the full neutralizing dose of F(ab) fragments should be given to prevent recrudescent toxicity. Digoxin could then be safely reinstituted at a lower dose, if indicated, within several days. Antiarrhythmics: The drugs most useful for treatment of digitalis-induced ventricular arrhythmias, aside from F(ab) fragments of antidigoxin antibodies and potassium, are lidocaine and phenytoin, each of which has little effect on the sinus node or on sinoatrial, AV, or His-Purkinje conduction. Phenytoin may occasionally improve sinoatria1 or AV conduction. Both quinidine and procainamide depress AV and sinoatrial conduction and may exhibit proarrhythmic effects in the presence of digitalis-toxic arrhythmias. Quinidine also reduces tissue binding and renal clearance of digoxin, thus altering both volume of distribution and elimination half-life. Beta blockers may also exacerbate AV conduction disturbances due to digitalis, but they are clearly effective in decreasing catecholamine-induced automaticity and in shortening the refractory period of atria1 and ventricular muscle while slowing conduction velocity. Use of an ultra-short-acting l3 blocker, such as esmolol, may be appropriate initially, when the possibility of worsening AV block or a negative inotropic effect exists, particularly in severely ill patients. Electrical cardioversion: In the absence of severe digitalis-induced arrhythmias, direct current cardioversion is safe, particularly if lower energy levels are used. Electrical cardioversion is potentially hazardous in severe arrhythmias with advanced digitalis toxicity and should be avoided if other measures are available and effective. Binding resins and hemodialysis: Selected cardisc glycosides such as digitoxin, which undergo some enterohepatic circulation, may be trapped by binding resins during transit through the gut lumen. Both cholestyramine and colestipol can re-

duce serum digitoxin concentrations by this means, but the decrease is not of sufficient magnitude or rapidity to affect life-threatening toxicity. Hemodialysis is ineffective both in the case of digitoxin toxicity, due to its extensive binding by serum proteins, and in the treatment of digoxin toxicity, due to that drug’s large volume of distribution. It could be used to control life-threatening hyperkalemia if digoxinspecific F(ab) fragments were unavailable. CONCLUSION As the role of digitalis glycosides becomes better defined in the modern pharmacotherapy of cardiovascular disease, and with the availability of an accurate and reliable digoxin assay, both the incidence and mortality of digitalis intoxication have declined markedly over the past 2 decades. Nevertheless, the documentation of digitalis toxicity in most clinical settings remains difficult, due to the varied and nonspecific nature of the signs and symptoms of digitalis intoxication. The development and widespread availability of F(ab) fragments of antidigoxin antibodies provide the clinician with a useful and effective therapy for patients with potentially life-threatening digitalis-induced toxic rhythm disturbances. REFERENCES I. Hmwitz N, Wade OL. Intensive hospital monitoring of adverse reaction to drugs. Br Med J 1969;1:531-536. 2. Ogilvie RI, Ruedy .I. Adverse drug reactions during hospitalization. Can Med Awe J 1967;97:[email protected] 3. BeIler GA, Smith TW, Abehnann m Haber E, Hood WB. Digitalis intoxication: a prospective clinical study with serum level correlations. N [email protected] J Med 1971;284:989-997. 4. Boston CoUaborative Drug SurveilIance Program. Relation between digoxin arrhythmia and ABO blood groups. Circulation 1972;45:352-357. 1. Danon A, Horowitz .I, Ben-Zvi 2. An outbreak of digoxin intoxication. Clin Phamcol

i%r

1977;21:643-646.

6. Smith TW, Butler VP Jr, Haber E. Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay. N Engl J Med 1969;281:12121216. 7. Holt DW. Plasma digoxin measurement and the assessment of extracardiac symptoms of toxicity. Br J Clin Phamacoi 1979;7:428P-429P. 8. Klein MD, Lawn B, Barr I. Comparison of serum digoxin level measurement with acetyl strophanthidm tolerance testing. Circulation 1977;49:1053-1062. 9. Mahdyoon H. Bat&ma G, Rosman H, Goldstein S, Gheorghiade M. The evolving pattern of digoxin intotication: observations at a large urban hospital from 1980 to 1988. Am Heart .I 1990;120:1189-1194. l0. Lehmann HU, Witt E, Temmen L. Lebensbedrohliche Digitalisintoxikationen mit und ohne sahxetische Zasatztherapie. Dtsch Med Wochemchr 1978; 103:1566-1571. 1L Shapiro W. Correlative studies of serum digitalis levels and the arrhythmias of digitalis intoxication. Am J Cardiol1978;41:8S2-859. 12. Weintraub M, Karch F, Morgan JP, Trabert MA, Sorensen & Becker LA, Lasagna L. Digoxin-prescribing. JA&zl 1979;242%5-448. 13. Pedoe HDT. Digoxin prescribing in general practice, 1967-1977. Lancet 1978;2:931-933.

14. Duhme DW, Greenblatt DJ, Koch-Weser J. Reduction of digoxin toxicity associated with measurement of serum levels. Ann Intern Med 1974;80:516-519. 15. Smith TW, Haber E. Digoxin intoxication: the relationship of clinical Presentation to serum digoxin c¢ration. J Clin Znveti 1970;49:&77-2386. 16. Moss AJ, Davis HT, Canard DL, DeCamiIkla JJ, Odoroff CH. Digitalisassociated cardiac mofiality after myocardial infarction. Ctiufatin 1981;64:[email protected] 1156.

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17. Bigger JT, Fleiss JL RolnitzJ.. IM, Merab JP. Fcrrick KJ. Effect of digitalis treatment on survival after acute myowrdial infarction. Am J Ckliol lY8%55:62u,.30. l8. Ryan TJ, Bailey KR: ~McCabe CH, I.uk S, Fisher LD, Mock MB, Killip T. The efTccts of digitalis on survival in high risk patients with coronary anery disease. Cinxlution lY83;67:735-742. 19.Madsen EB. Gipin E, Henning II, Ahnvc S, LcWiiter M, Mum J, Shahetai R, Collins D, Ross J Jr. Prognostic importance of digitalis after acute mywardial infarction. J Am Co/l C:nrdL,I 1984;3:tXld89. 20. Byington R. Goldstein S, BHAT Resarch Group. hwxiation of digitalis thcrdpy with mortality in survivors of acute myocardial infarction: observation of the Beta-Blocker Heart Attack Trial. JAm Coil Curdio/ 1985;6:97~9’)82. 21 Mullcr JE, Turi ZG, Stone PH, Rude RI:, Raabc DS, Jaffcc AS, Gold HK. Gus&on N, Poole WK. Pauamani E, Smith TW, Braunwald E. The MILIS Study Group. Digoxin therapy and mortality after myocardial infarction: experience in the .MILIS study. NEnglJMuf 198($14:265-271. 22 Dhingra RC, Amat-Y-Leon F, Wyndham C. The electrophysiological effcc& of ouabain on sinus node and atrium in man. / Ciin Invesr 1975$6:555562. 23. Lawn B, By&t NF, Levine HD. Paroxysmal attial tachycardia with block. Cimhlirm 1Ytx1;21:12%l43. 24. Friedman PI., Antman EM. Elutrocardiogrdphic manifestations of digitalis toxicity. Disturbances of sinus impulse formation and conduction. In: Smith TW, cd. Digitalis Glycosidcs. Orlando, FL Grune L Stratton, 1986:241215. 25. Fisch C, Knocbcl SB. Accelerated junctional e.scape: a clinical manifestation of “triggered” automaticity. In: Zipcs DP, Jalife J, eds. Cardiac Electrophysiolw and Arrhythmias. New York: Grune & Stratton, 1985~467. 26. Kelly RA. Cardiac glyccsides and congestive heart failure. Am J Cardiol 199Qfl5:IOE-1% 27. Klausen T, Kjcldscn K, Norgaard A. Effects of dcnervation on sodium, potauium, and [Hlouabain hinding in muscles of normal and potassium depleted rats. / !$x+f (L.ond)1983:345:12~134. 2S.Smirh TW, Braunwald E. Kelly RA Management of congestive heart failure. In: Braunwald E, ed. Heart Disease, 4th cd. Philadelphia: WB Saunders. 1902. 29. Whang R, Qci TO, Watanabe A. Frequency of h~magnexmla in hospitalized patients receiving digitalis.An+ Intern Med 1985;145:655456. 30. Vogel R, Kirch D, LcFree M, Frlschknett J. Steele P. ElTects of digitalis on resting and isometric exercise mywardial perfusion in patients with cornnary artcv disease and left ventricular dpfunction. Circular~m 1!?77;56:355350. 3L Craulord MH. LcWinter MM, O‘Rourke RA. Combined propranolol and digoxin therapy in angina pcctoris. Am Inrem Med lY75;83:440-455. 32. Antman EM. Wcnger TL Butler VP Jr, Iiabcr I 70 years of age. Dr. Kelly, what are your thoughts about this? Dr. Kelly: The most immediate issue that comes to mind is that of lean body mass. Most patients are given a common dose of digoxin, and due to the lower lean body mass and lower glomerular filtration rate in women, steady-state serum drug levels would bc higher, thus predisposing to toxicity. Dr. Creage~ How often is hyperkalemia observed in nonsuicidal digoxin-toxic patients? (h. [email protected] It is very unusual. Generally, you will not see it in patients with serum digoxin levels of 3-4 ng/mL; you will see it at levels of 8-10 ng/mL. Actually, hypokalemia-not hyperkalcmia-is more common in patients who have not taken a suicidal overdose. Dr. Gheorghiade: Patients with severe heart failure and a low cardiac output may have an JUNE

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unexpectedly high serum potassium in the presence of a relatively low serum digoxin concentration. Factors like prerenal azotemia and diabetes mellitus increase the likelihood of its occurrence.5 Dr. Kelly: If these patients have metabolic acidosis, they will also become hyperkalemic. REFERENCES 1. Mahdyoon H, Rosman HS, Mermiges DN, Gheorghiade M. Digitalis into& cation or intrinsic conduction system disease. Hmy Fonl Hasp Med .I 1989;37:43.

2. Mauskopf JA, Wenger TL. Cost-effectiveness analysis of the use of digoxin immune F(ab) (ovine) for treatment of dioxin toxicity. Am J Cardiol 1991;68: 1709-1714. 3. Antman EM, Wenger TL, Butler VP Jr, Haber E, Smith TW. Treatment of 150 cases of lie-threatening digitalis intoxication with digoh-specific F(ab) antibody fragments: fmal report of a multicenter shady. Circulation 1990;81:17441752. 4. Hickey AR, Wenger TL, Carpenter VP, T&on HH, Hlatky MA, Furberg CT, Kirkpatrick CH, Strauss HC, Smith TW. Digoxin immune F(ab) therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study. JAm Coil CardA 1991;17:59&598. 5. Chakko SC, Frutchey J, Gheorghiade M. Life-threatening hyperkalemia in severe heart failure. Am HeatiJ 1989;117:108~1091.

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Recognition and management of digitalis toxicity.

The most important step in the management of toxicity due to any of the cardiac glycosides is its recognition. Despite the development of an accurate ...
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