lISA lACC Vol. 5, No.5 May 1985:118A-123A

Treatment of 63 Severely -Toxic Patients With -Specific Fragments

THOMAS L. WENGER, MD,* VINCENT P. BUTLER, Jr., MD,t EDGAR HABER, MD, FACC,:\: THOMAS W. SMITH, MD, FACC § Research Triangle Park, North Carolina, New York, New York and Boston, Massachusetts

Sixty-three patients with life-threatening digitalis intox­ istration of Fab fragments. Unbound and, therefore, ication were treated with purified fragments of digoxin­ active digoxin serum concentrations decreased to un­ specific (Fab) obtained from sheep. Twenty­ detectable levels within minutes after administration of eight patients developed as the result of digitalis the fragments. In all patients who had elevated serum ingestion in a suicide attempt,S ingested a large amount potassium concentrations caused by massive digitalis of digoxin accidentally and 30 developed toxicity in the toxicity, treatment with the Fab fragments reversed the course of treatment for underlying heart disease. The . There were no obvious adverse reactions dosage of digoxin-specific Fab was calculated to be equl­ to treatment. Potentially life-threatening digitalis intox­ molar to the amount of cardiac glycoside in the patient's ication can be rapidly and safely reversed by treatment body. with purified digoxin-specific Fab fragments. Digitalistoxicitywas completelyreversed in most cases, o Am Coli Cardio! 1985;5:1l8A-123A) with onset of effect usually within 30 minutes of admin-

Digitalis intoxication is among the most common adverse concentrations in body fluids and also to reverse digitalis drug reactions in clinical medicine . Severe episodes may be toxicity in human beings (I ). The serum digoxin radioim­ fatal, particularly in patients with advanced cardiac disease munoassay employing these antibodies was first reported in or in patients who have ingested massive doses of digitalis 1969 (2). Intravenous use of the antibodies to reverse ex­ accidentally or with suicidal intent. Treatment of digitalis perimentally induced digoxin toxicity was demonstrated in intoxication has been limited by the absence of a specific dogs in 1971 (3). The mechanism by which they reverse antagonist and by the fact that standard therapeutic modal­ toxicity appears to be by binding digoxin in extracellular ities are of limited effectiveness when toxicity is severe. fluid, causing a decrease in the effective free extracellular The need to improve treatment of digitalis toxicity stimu­ drug concentration. A concentration gradient is thus created lated interest in finding a specific means for reversing the that promotes release of digoxin from receptor sites. effect of this group of drugs . Use of these whole heterologous antibodies , derived ini­ tially from rabbits and subsequently from sheep, was limited Development of Antigen-Binding by the known incidence of immediate and delayed hyper­ Fragments (Fab) sensitivity when such foreign proteins are administered to human beings. Advances in the knowledge of antibody Antibodies to digoxin were successfully produced in 1967 structure and purification methods during the 1960s and with the hope that they could be used to measure digoxin early 19705 allowed modification of these antibodies to ren­ der them less immunogenic. Digestion of the antibody with From the *Department of Clinical Research, Burroughs Wellcome papain yields two antigen-binding fragments (Fab), each Company , Research Triangle Park, North Carolina, tthe Department of Medicine, College of Physicians and Surgeons, Columbia University, New having a mass of 50,000 daltons, and one crystalline frag­ York, New York, tthe Cardiac Unit, Massachusetts General Hospital, the ment (Fe) from each gamma-G globulin molecule (mass = Cardiovascular Division, §Brigham and Women's Hospital and Harvard 150,000 daltons) (4). Digoxin-specific Fab can be isolated Medical School, Boston, Massachusetts . This study was supported in part by Grants HLl9259, 10608 and 18003 from the National Heart, Lung, and purified by passing papain-digested hyperimmune an­ and Blood Institute, National Institutes of Health, U.S. Public Health imal serum through a column containing a digitalis glycoside Service, Bethesda. Maryland . attached to an inert support matrix (5). This process is re­ Address for reprints: Thomas L. Wenger, MD, Department of Clinical Research, Burroughs Wellcome Company, 3030 Comwallis Road, Re­ ferred to as immunoadsorption and is closely analogous to search Triangle Park, North Carolina 27709. affinity chromatography. Only the digoxin-binding frag-

©1985 by the American College of Cardiology 0735-1097/85/.$3 .30 lACC Vol. 5. No.5 WENGER ET AL. 119A May 1985:11 8A-123A DIGOXIN FAB TREATMENT OF DIGITALIS TOXICITY

ments adhere to the column, from which they are eluted as purifed digoxin-specific Fab. Methods This purified Fab eluate has numerous advantages over The design of the multicenter trial has been described whole antibody. The smaller size of these fragments permits previously (13) . Briefly, this was a study in 20 geograph­ them to distribute more rapidly and into a larger distribution ically distributed medical centers in the United States in volume within the body (6), resulting in more rapid and which digoxin-specific Fab fragments were given in an un­ effective reversal oftoxicity (7,8). They also can be excreted blinded fashion to patients with potentially life-threatening rapidly by glomerular filtration (6) in contrast to the whole cardiac rhythm disturbances or hyperkalemia, or both, caused antibody, which is degraded slowly by the reticuloendothe­ by digoxin or digitoxin intoxication. These patients had lial system. Elimination of the antigenic determinants and failed conventional therapeutic efforts to treat digitalis tox­ complement-binding site of the Fe portion renders the Fab icity or, in a few cases , were judged unlikely to respond to portion less immunogenic than intact antibody (6). In ad­ standard measures because of massive intoxication. dition , the smaller size of the fragments, their more rapid Digoxin-specific Fab fragm ents derived from sheep were excretion and the absence of other protein impurities further administered intravenously, generally over a 15 to 30 minute reduce the antigenicity of the preparation. period . The dosage of Fab fragments was calculated to be The ability of digoxin-specific antibodies and antibody equimolar to the amount of digoxin in the patient's body . fragments to reverse toxicity in experimental preparations Estimates of total digoxin load were derived from the med­ in vitro and in intact animals has been amply demonstrated. ical history or from determinations of serum digoxin con­ In erythrocytes with established digoxin-induced inhibition centrations, or both . of sodium and potassium transport, the inhibition was re­ Therapy with digoxin-specific antibody fragments was versed by subsequent incubation with digoxin antibody and considered effective if life-threatening cardiac antibody fragments (9 ,10). Digoxin induce s an increase in resolved over an accelerated time course, that is, within developed tension in isolated guinea pig atrial muscle strips. minutes to a few hours after treatment. In addition, evidence The addition of digoxin antibody fragments reverses this was sought for resolution of hyperkalemia caused by tox­ effect and restores muscle tension to pre-digoxin levels (10). icity-induced inactivation of the cellular Na + -K + adeno sine Addition of toxic levels of digoxin to canine Purkinje fibers triphosphatase (ATPase) pump . Total and free plasma dig­ in a tissue bath can cause electrical inexcitabilty. When oxin concentrations were determined when possible. digoxin antibodies are added to the bath , membrane char­ To assess safety, skin testing and intravenous challenge acteristics return to normal (II). Also, prolongation ofrabbit with a small dose of purified digoxin-specific antibody frag­ atrioventricular node effective and functional refractory pe­ ments were undertaken along with standard laboratory tests . riods and conduction time caused by digoxin are rapidly Patients were observed carefully for immediate and delayed reversed by digoxin antibodies (II). hypersensitivity reactions. Clinical circumstances some­ Intact animal studies ofdigoxin toxicity have shown that times limited the ability to collect data from laboratory tests. lethal doses of digoxin in control dogs can be reversed after the onset of toxic rhythm disturbances by digoxin antibodies (3) and antibody fragments (7) . When an adequate neu­ Results tralizing dose is given, advanced toxicity can be reversed, Patients. After informed con sent was given by the pa­ and this occurs more rapidly with Fab fragments than with tient or a responsible relative, 63 patients received digoxin­ the whole antibody (7). The inotropic effects of digoxin are specific antibody fragments .Fifty-nine had digoxin toxic ity also reversed with more rapid reversal using Fab fragments and 4 had digitoxin toxicity . Thirty-seven were male, 25 than with whole antibody (8), but this occurs over a slower were female and I was a true hermaphrodite. The mean age time course than does reversal. These in vitro was 50.6 years (range 3.5 days to 85 years) . and in vivo studies clearly demon strate the ability of dig­ Twenty-eight patients ingested massive amounts of dig­ oxin-specific antibodies and antibody fragments to reverse italis with suicidal intent. Seventeen of these were patients the toxic and inotropic effects of digoxin, and also dem­ receiving long-term digitalis therapy , whereas the other II onstrate the advantage of the purified digoxin-specific Fab had no underlying heart disease . An additional five patients, portion over the intact garnma-G globulin antibody. previously in good health, ingested large amounts ofdigoxin On the basis of these experimental findin gs , digoxin­ as a result of error or accident. Toxicity occurred in 30 specific Fab fragments were prepared in a form suitable to patients as a result of error, accident or misadventure in an treat patients suffering from severe and potentially life­ effort to treat their underlying heart disease. threatening digitalis intoxication. The first patient treated in Manifestations of digitalis toxicity included nausea and this trial was described in 1976 (12) . Experience with the vomiting in 37 patients, hyperkalemia in 29 patients, second first 26 patients was reported in 1982 (13). The present or third degree in 41 patients, high article summarizes our experience to date. grade ventricular ectopic activity in 46 patients, ventricular 120A WENGER ET AL. lACC VoL 5. No.5 DIGOXIN FAB TREATMENT OF DIGITALIS TOXICITY May 1985:118A-123A

in 41 patients, in 23 pa­ of Fab fragments less than one-tenth the amount calculated tients and ventricular asystole in I patient. to be needed . Both of these patients died before an adequate Previous attempts to reverse digitalis toxicity included dose was given . An additional three patients were excluded ventricular pacing in 39 patients, direct current cardiover­ because they received their digoxin-specific antibody frag­ sion in 15 patients and administration of in 16 ments after they were already agonal (which we defined as patients, in 34 patients and in 23 pa­ no functioning ventricular rhythm for longer than 5 minutes tients . Twenty-four patients required closed chest cardiopul­ before initiation of digoxin antibody fragments, or resus­ monary resuscitation. citation efforts discontinued and death pronounced less than Serum digoxin concentrations of patients at the time of 15 minutes after administration of a therapeutic dose) . Two entry into the study ranged from 2.4 to greater than 100 other patients were excluded because they did not have clear ng/rnl, with an average concentration of greater than 14.1 evidence of digitalis toxicity. One of these was a patient ng/ml (in cases where the pretreatment serum digoxin con­ receiving therapeutic doses of digoxin who took a suicidal centration was reported only as greater than a stated amount, overdose of furosemide; he was also agonal before antibody that stated amount was used to calculate the mean). All but fragments were administered. The second patient had ven­ 9 ofthe 63 patients had serum digoxin concentrations greater tricular arrhyth mias and a history of digoxin use, but no than 5 ng/ml. The administered dose of digoxin-specific other clinical evidence in favor of the diagnosis of digitalis antibody fragments averaged 520 mg (range 4.0 to 1,600). toxicity. This patient had no response to the antibody frag­ Twenty of the patients in this study had normal renal ments and a pretreatment serum digoxin concentration mea­ function before Fab administration . Thirty-one patients had surement returned from the laboratory later in the day showed evidence of abnormal renal function. Renal function was a low therapeutic concentration. not reported in 12. The mean (± SO) blood urea nitrogen Ofthe remaining 56 patients , digitalis toxicity responded and creatinine levels in those patients with abnormal renal to digoxin-specific antibody fragment therapy in 53 . In one function were 43 ± 20 mg/IOO ml (n = 28) and 2.7 ± of these patients. recovery was followed by a return of toxic 1.2 mg/IOO ml (n = 30), respectively. manifestations due to a lack of sufficient supply of Fab Clinical response. Our overall experience is summa­ fragments . This patient received about half the dose ex­ rized in Figure I . Seven of these 63 patients who received pected to neutralize the amount of digoxin believed to be digoxin-specific antibody fragments were excluded from the in the patient's body. However, his suicidal ingestion was evaluation of efficacy. Two of these patients received doses massive (25 mg) and he ultimately died from digoxin-in­ duced ventricular fibrillation before more antibody frag­ ments could be obtained. Toxicity resolved completely in the other 52 patients including the 4 patients with digitoxin Figure 1. Flow diagram summarizing the clinical experience in toxicity. 63 patients given digoxin-specific antibody fragments. In each ofthe three patients who showed no response to the digoxin-specific antibody fragments, the diagnosis of 63 patients I digitalis toxicity was uncertain. Two of these patients had an elevated serum digoxin concentration, but also had very Exclusion - 7 patients 2: Inadequate dose severe underlying heart disease and documented severe ven­ 2: Wrong diagnosis tricular arrhythmias before the serum digoxin concentration 3: Agonal : Ventricular Fibrtlla - tion or asystole >5 min prior became elevated. A third patient developed a prolonged to Fab or death pronounced < 15 min .pFab episode of ventricular fibrillation after a combined digoxin and tricyclic antidepressant overdose. She was successfully Inclusion- resuscitated to a regular rhythm with complete heart block, 56 patients I but without return of brain function . Digoxin antibody frag­ ments were then administered but had no effect on her heart No Response - 3 patients IPositive Response- I block, which in retrospect was considered most likely to be 53 patient s 1: Muitiple ; diagnosis of digitalis toxicity due to the tricyclic overdose. uncertain Time course of response . Patients usually responded to 2: Severe underl ying heart disease. diagno sis of digitalis the antibody fragments within 30 minutes ofadministration. to xicit y uncertain Recrudescence of The onset of response was probably affected by such factors toxicity - 1 patient as the speed of administration of the antibody fragments, i- No more drug the amount of Fab fragments given in relation to the amount available. patient expired of digoxin ingested and other less well defined factors . In­ fants and young children sometimes responded within minutes. Resolution of Toxicity- The response of an adult patient is shown in Figure 2. I 52 patients I He was given 520 mg of digoxi n-specific antibody fragments JACC Vol. 5, No.5 WENGER ET AL. l21A May 1985:118A-123A DIGOXIN FAB TREATMENT OF DIGITALIS TOXICITY

160 150 w (/J 140 z 200 ~ z 0 I 1:>.. 0 a. 130 ~ ~ '[)..a... ,./Total (/J a: '-u.. w ~ '-Q a:~ 120 z , , a: E w '0.., , «0. 110 o , ...J8. Z '0-, :::J 0= o 100 (),E a: zg' z~ 90 ... x- w 0 > 80 o ,./Fab Infusion 15 I1ll11.I ~ :::J 5 f IIIII a: w 5pm 7pm 9pm 11 pm lam 30m 5am (/J 2 /Free TIME

Figure 2. Change in ventricularresponserate of a patient in atrial -10 0 10 50 fibrillation with a serum digoxin concentration of 4.7 ng/m!. The patient received 520 mg of digoxin-specific Fab between4: 45 and HOURS 5: 15 PM. The onset of effect was rapid, with complete response Figure 3. Time course of serum digoxinconcentration beforeFab 1 occurring within 3 / 2 hours. administration (e), total serum digoxin concentration after treat­ ment (0) and free serum digoxin concentrations after treatment (.). Administration of digoxin-specific Fab fragments was started at0 hours.(Adapted fromRef. 12,withpermission of thepublishers.) after three episodes of requiring di­ rect current cardioversion. This patient also manifested ven­ tricular ectopic beats, , nausea and vomit­ posttreatment level (usually obtained about 4 hours after ing, a serum potassium concentration of 6.2 mEq/liter and start of treatment) was 4.4 mEq/liter (p < 0.01). In all a serum digoxin concentration of 4.7 ng/m!. No episodes patients who had elevated serum potassium concentrations, of ventricular tachycardia occurred after the Fab fragments treatment with digoxin antibody fragments reversed the hy­ were given. He averaged two ventricular ectopic beats/min perkalemia. Some of these patients received other treatment until treatment with the antibody fragments, after which for hyperkalemia before administration of the antibody frag­ ventricular ectopic activity completely resolved. As can be ments. There was no relation between pretreatment hyper­ seen in Figure 2, his ventricular response was 90 beats/min kalemia and outcome (Fig. 4). There were no significant before Fab was administered. During Fab infusion, the ven­ changes in other laboratory variables measured. tricular rate increased to 120 beats/min, indicating partial Adverse reactions. There were no obvious reactions to reversal of digoxin effects on atrioventricular conduction. Fab treatment in any of the patients in this tria!. One patient Response was complete by 3 '12 hours after Fab administration. had slight erythema at the site of skin testing, but no sys­ Laboratory evaluation. Laboratory evidence for bind­ temic reaction to the therapeutic dose. Several patients de­ ing of digoxin or digitoxin by digoxin-specific antibody veloped fever at various times after administration of the fragments was seen in the postadministration serum drug antibody fragments, but in no case was the timing or the concentrations. In all six patients in whom it was measured, clinical setting suggestive of a Fab-induced or endotoxin­ the concentration of free and, therefore, active digoxin or induced fever. In all febrile patients, clear evidence of in­ digitoxin decreased to zero or near zero within I to 2 minutes fection existed. There was no evidence of renal deterioration after administration of the antibody fragments. Total serum caused by antibody fragment therapy. No acute hypersen­ digoxin concentration increased rapidly after administration sitivity reaction or delayed serum sickness was seen in any of the antibody fragments to values typically 10- to 20-fold of the patients. higher than pretreatment levels. Essentially, all of this dig­ Six patients had clinical evidence of some degree of im­ oxin was bound to the antibody fragments and was, there­ paired ventricular function several hours to 1 day after fore, pharamacologically inactive. A typical serum digoxin treatment. Although withdrawal of the inotropic support of response to administration ofdigoxin-specific antibody frag­ digoxin may have added to their preexisting low cardiac ments is shown in Figure 3. output state, numerous adjustments in fluid volume, diuretic Serum potassium concentration, The mean potassium drug and vasodilator therapy, as well as the frequent oc­ concentration before treatment with antibody fragments was currence of occurring about the time of treat­ 5.5 mEq/liter (range 2.4 to 10.3). In 31 patients for whom ment in this group, make assessments of causality impos­ serum potassium concentrations were known both before sible. In contrast, most patients responded to digoxin antibody and after Fab administration, the average pretreatment po­ treatment with obvious improvement in their hemodynamic tassium concentration was 5.8 mEq/liter and the average state coincident with resolution of refractory arrhythmias. 122A WENGER ET AL. lACC VoL 5. No.5 DIGOXIN FAB TREATMENT OF DIGITALISTOXICITY May 1985:118A-123A

9.0 al. (14),38 patients from our study were excluded from the analysis in Figure 4. Nine patients lacked a pretreatment serum potassium concentration determination, 23 patients 8.0 • •• developed toxicity in the course ofclinical management with ';"" • digitalis and diuretic drugs and 6 patients died more than 4 ~ 7.0 • • ::E .. • days after ingestion of digitalis. By comparing the outcome ::) •• a: • of the patients of Bismuth et al. with our results, it is evident UJ • ~~ .. I that digoxin-specific antibody fragments had a pronounced z '" 6.0 ... • UJE r effect on survival in our patients. ::E- •• • • ~ I • Response time. As suggested by the large volume of UJ • a: II • I-:- 5.0 distribution of Fab fragments compared with the intact garnma­ UJ I 0: 0. •• G globulin molecule in baboons (6), and in keeping with • • other experimental studie s in animals, clinical response to 4.0 • I • digoxin-specific antibody fragments has been reasonably rapid in almost all cases. One would expect response time t• 3.0 l...---I__--'- ----'__....L- _ to be even faster with more rapid administration or use of SURVIVED EXPIRED SURVIVED EXPIRED LBISMUTH·GAULTIERJ L FAB TREATMENT ~ a larger dose of Fab fragments . On the other hand, admin­ istration of a larger dose subjects the recipient to a larger Figure 4. Serum potassiumconcentration before treatment (stan­ and more prolonged antigenic stimulus and greater exposure dard therapy or Fab administration) versus patient outcome. De­ picted on the left of the figure is the experienceof Bismuth et al. to potentially coadministered impurities, such as bacterial (14) from 91 patients using standard therapy for digitalis toxicity. endotoxins that might arise in processing of the Fab frag­ Results from the present study are depicted on the right of the ments. Such impurities are minimized by the manufacturing fi gure. Patients from the present study were excluded from this process, and detailed sterility and pyrogenicity testing is analysis if they lacked a pretreatmentserum potassium concentra­ done before clinical use. Where speed of action is essential tion determination, if they developed toxicity in the course of clinical management with both digitalis and diuretic drugs or if to the life of the patient, bolus administration of an ample they died more than 4 days after ingestion of digitalis. neutralizing dose seems a reasonable way to accelerate the effect. Safety of ovine Fab. From the inception of this effort Discussion to develop a specific therapeutic agent for digitalis intoxi­ Our clinical experience to date confirm s and extends the cation, special attention was given to the potential problems data previously reported in 1982 (13). Treatment of digoxin associated with intravenous use of heterologous antibody and digitoxin toxicity with digox in-specific antibody frag­ fragments in human beings . Thu s far, there has been no ments is rapid and appears to be safe. The antibody frag­ evidence ofacute hypersensitivity or delayed serum sickness ments had no demonstrable effects other than reversal of after use of ovine Fab fragments. We do not yet have any the action of digitalis. experience with reexposure to purified digoxin-specific Fab Relation of pretreatment potassium concentration to fragments. outcome. Digitalis toxicity can cause a net loss of potas­ Elimination of Fab fragments. Although the toxic and sium from cells by inactivating the cell membrane Na + -K + pharmacologic actions of digoxin are neutralized by binding ATPase pump. When toxicity is severe, serum potassium to the antibody fragment whether or not this digo xin-Fab concentration rises . A clear relation between hyperkalemia fragment complex is removed from the body, elimination and fatal outcome was demonstrated in patients who ingested of both digoxin and the antibody fragments is a matter of large amounts of digitalis accidentally or with suicidal intent concern. If the digoxin-Fab complex remains for a pro­ and who received standard therapy for their toxicity (14). longed period in the body , immune degradation of the het­ Bismuth et al. (14) reviewed 91 episodes of acute digitalis erologous Fab might lead to re-release of free digoxin over at the Paris Control Center. They excluded a period of a few days, with possible recrude scence ofovert patients who were receiving therapy with diuretic drugs toxicity . at the time of ingestion and those who died more than 4 In patients with good renal function , the digo xin-Fab days after the ingestion. Their results are summarized in complex appears to be elim inated fairly rapidly by glomer­ Figure 4. ular filtration, usually with a half-life of about 16 to 20 In the present study, no correlation existed between po­ hours. We were unable to obtain adequate serum samples tassium concentration before treatment and outcome. In fact, in patients with severe renal impairment to define the half­ most of the patients with hyperkalemia survived as a result lives of elimination of either digo xin or the Fab fragments of treatment with digoxin antibody fragments. To compare in such patients. However, with the exception of one patient the results of our study with the experience of Bismuth et who received an inadequate Fab dose, we did not observe lACC Vol. 5. No.5 WENGER ET AL. 123A May 1985:1IBA-I23A DIGOXIN FAD TREATMENT OF DIGITALIS TOXICITY

any recurrence of toxicity after response to the antibody 5. Smith TW. Discussion paper: use of antibodies in the study of the fragments. Many of our patients with abnormal renal func­ mechanism of action of digitalis . Ann NY Acad Sci 1974;242:731-6. tion had excellent responses to antibody fragment treatment. 6. Smith TW , Lloyd BL, Spicer N, Haber E. Immunogenicity and ki­ netics of distribution and elimination of sheep digoxin-specific IgG Experience with these Fab fragments in patients without and Fab fragments in the rabbit and baboon. Clin Exp Immunol renal function is insufficient to permit comment. 1979;36:384-96. Once the antibody fragments have been given, it is not 7. Lloyd BL, Smith TW. Contrasting rates of reversal of digoxin toxicity possible to follow the patient 's serum digoxin concentration by digoxin-specificIgG and Fab fragments. Circulation 1978;58:280-3. using routine radioimmunoassay methods (12,15). An ac­ 8. Ochs HR, Vatner SF, Smith TW. Reversal of inotropic effects of digoxin by specific antibodies and their Fab fragments in the conscious curate determination of total digoxin concentration can be dog. J Phannacol Exp Ther 1978;207:64-71. obtained by first boiling the serum, but this measure does 9. Gardner 10, Kiino DR. Swartz 11, Butler VP Jr. Effects of digoxin­ not reflect the concentration of free and, therefore , active specific antibodies on accumulation and binding of digoxin by human digoxin in the body. Free digoxin concentrations can be erythrocytes. J Clin Invest 1973;52:1820-33. measured by equilibrium dialysis (12). 10. Curd J, Smith TW, Jaton JC, Haber E. The isolation of digoxin­ The presence of digoxin-specific antibody fragments in specific antibody and its use in reversing the effects of digoxin . Proc Natl Acad Sci USA 1971;68:2401-6. the patient's blood also complicates the process of repeat II. Mandel WJ, BiggerJT Jr, Butler VP Jr. The electrophysiologic effects administration of digoxin in these patients. Elimination of of low and high digoxin concentrations on isolated mammalian car­ Fab fragments from the body may require a week or longer, diac tissue: reversal by digoxin-specific antibody. J Clin Invest depending, as noted, on renal function , after which redi­ 1972;51:1378-87. gitalization and use ofstandard serum digoxin concentration 12. Smith TW , Haber E, Yeatman L, Butler VP Jr. Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. assays for follow-up study can be instituted as needed . N Engl J Med 1976;294:797-800. Further experience. The digoxin antibody fragments 13. Smith TW , Butler VP Jr, Haber E, et al. Treatment of life-threatening used in this study were supplied by Wellcorne Research digitalis intoxication with digoxin-specific Fab antibody fragments: Laboratories, United Kingdom. Additional experience with experience in 26 cases. N Engl J Med 1982;307:1357-62. this material in other countries and with digoxin-specific 14. Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic im­ antibody fragments made by others support our conclusions. plications. Clin Toxico! 1973;6:153-62. A total of 40 such patients treated worldwide has been 15. Gibb I, Adams PC, Pamham AJ, Jennings K. Plasma digoxin: assay reported (15-23), with apparent good response and no evi­ anomalies in Fab-treated patients. Br J Clin PhannacoI1983;16:445-7. dence of hypersensitivity or other adverse reactions . If fur­ 16. Hess T. Stucki P, Barandun S, Scholtysik G, Riesen W. Treatment ther experience confirms the safety of the clinical use of of a case of lanatoside C intoxication with digoxin-specific F(ab')2 antibody fragments. Am Heart J 1979;98:767-71. digoxin-specific antibody fragments, their use might be ex­ 17. Hess T, Stucki P, Barandun S, Scholtysik G, Riesen W. Antibody panded to first line therapy for any patient who requires treatment of digoxin intoxication in a patient with renal failure. Dtsch definitive treatment. Use of digoxin-specific Fab fragments Med Wochenschr 1979;104:1273-7. for both diagnostic and therapeutic purposes in patients in 18. Hess T, Dubach HV, Scholtysik G, Riesen W. Suicidal digoxin poi­ whom the diagnosis of digitalis toxicity is uncertain must soning: conventional treatment and antibody therapy. Klin Woch­ enschr 1982;60:401-5. await further evidence supporting their safety and usefulness 19. Bouffard Y, Bui Xuan B, Roux H, Perrot 0, Bouletreau P, Pontal in this setting. PG. Digitoxin intoxication: treatment with antidigoxin antibody Fab fragments. Nouv Presse Med 1982;11:2928. References 20. Dornan Y, Bismuth C, Schennann JM, et al. Digitoxin toxicity: re­ I. Butler VP Jr, Chen JP. Digoxin-specific antibodies. Proc Natl Acad versability of ventricular fibrillation with antidigoxin antibody fab Sci USA 1967;57:71-8. fragments. Nouv Presse Med 1982;11:3827-30. 2. Smith TW, Butler VP Jr, Haber E. Determination of therapeutic and 21. Hess T, Riesen W, Scholtysik G, Stucki P. Digitoxin intoxication toxic serum digoxin concentrations by radioimmunoassay . N Engl J with severe thrombocytopenia : reversal by digoxin-specific antibodies. Med 1969;281:[ 212-6. Eur J Clin Invest 1983;13:159-63. 3. Schmidt DH, Butler VP Jr. Reversal of digoxin toxicity with specific 22. Ye Z. Deng N, Jin M, et al. Using digoxin antibody as a specific antibodies. J Clin Invest !971;50:1738-44. treatment for severedigitalis intoxication. Chin J Cardiol 1983;II :242- 5. 4. Nisonoff A. Enzymatic digestion of rabbit gamma globulin and an­ 23. Smolarz A, Roesch E, Lenz H, Neubert P, Abshagen U. Report on tibody and chromatography of digestion products. Methods Med Res the treatment of 16 cases of severe glycoside poisoning with sheep 1964;10:131-41. antidigoxin fragments (Fab). Z KardioI1984;73:l13-9.