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Current expectations in cardiac transplantation
Current expectations in cardiac transplantation One hundred thirty cardiac transplant procedures have been performed at Stanford University in 124 patients. Four major developments have contributed to increased survival over the past 3 1/ 2 years (60 patients): (I) transvenous graft biopsy for diagnosis of rejection, (2) antihuman thymocyte globulin of rabbit origin (RATG), (3) immunologic monitoring, and (4) cardiac retransplantation. Right ventricular endomyocardial biopsy is performed every 5 to 7 days for 4 to 6 weeks (830 biopsies in 78 patients without serious morbidity). RATG is given over the first 9 days (total 49 mg. immunoglobulin G per kilogram). Half-lives (P/2) of circulating rabbit globulin (RG) are calculated by radioimmune assay. Slow Ph correlates directly with delayed rejection, decreased severity of rejection, and increased survival. RATG is reinstituted for acute rejection and as long-term therapy to reduce toxic maintenance prednisone doses. Its administration is individually modulated by serum RG levels. No serious toxicity has occurred. The primary immunologic monitoring assay is measurement of circulating T-lymphocytes by sheep e-rosette formation. Depression to less than lO percent of normal occurs within 6 days. Subsequent rejection episodes are heralded by exponential T-cell rises I to 3 days before abnormal graft biopsy. This assay detects early efferent immune response and permits earlier and more efficient immunosuppression. Two indications for retransplantation exist: intractable recurrent rejection and accelerated graft atherosclerosis. Five patients have undergone graft replacement, three successfully. These advances have contributed to present survival rates of 66, 63, and 58 percent I, 2, and 3 years after transplantation (90 percent rehabilitation). More extended application in selected patients is warranted.
William A. Baumgartner, M.D., Bruce A. Reitz, M.D., Charles P. Bieber, M.D., Philip E. Oyer, M.D., Norman E. Shumway, M.D., and Edward B. Stinson, M.D., Stanford, Calif.
Clinical cardiac transplantation remains a challenging project with many complex problems yet unsolved. In recent years (1974 to 1976), however, the level of success in terms of survival and rehabilitation has improved significantly in comparison to previous experience at Stanford University Medical Center. Over-all survival rates during this 3 year interval are 66, 63, and 58 percent at I, 2, and 3 years postoperatively, respectively. Four major developments appear to have contributed to these current statistics. The purpose of this report is to define and clarify progress achieved in these From the Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. 94305. Supported in part by Public Health Service Research Grant RR 70 from the General Clinical Research Centers, Division of Research Resources, and by National Heart, Lung and Blood Institute Research Grant HL 13108. Read at the Third Annual Meeting of The Samson Thoracic Surgical Society, Colorado Springs, Colorado, June 4-7, 1977. Address for reprints: Edward B. Stinson, M.D., Associate Professor of Cardiovascular Surgery, Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. 94305.
0022-5223/78/0475-0525$00.60/0 © 1978 The C. V. Mosby Co.
four areas. Each is considered separately in the subsections below.
Transvenous endomyocardiaI biopsy Since the initial clinical application of transvenous endomyocardial biopsy to cardiac transplantation in 1972,1 this technique has become an increasingly important clinical tool for the diagnosis of cardiac graft rejection and monitoring of the efficacy of treatment. The procedure is performed percutaneously under local anesthesia and requires only 10 to 15 minutes. After cannulation of the right internal jugular vein with a cardiac catheterization sheath by the Seldinger technique, a specially designed biopsy forceps is passed through the sheath and advanced to the apex of the right ventricle; 2 to 3 mm. specimens are obtained from multiple sites (Fig. I). By virtue of the Seldinger technique, cardiac biopsy can be carried out safely on a repetitive basis. Altogether, 830 biopsies have been performed in 78 patients by the cardiac surgical house staff. Complications have consisted of premature ventricular contractions in approximately 20 525
526 Baumgartner et al,
Fig . 1. Plain chest x-ray film demonstrating the biopsy forceps in the apex of the right ventricle . (From Caves, P. K., Stinson , E. B., Billingham, M . E. , and Shumway , N. E.: Heart & Lung, 4:69 , January-February, 1975. Published by The C . V. Mosby Company.)
The Journal of Thoracic and Cardiovascular Surgery
percent , supraventricular arrhythmias in 3 percent , pneumothorax in 0.4 percent, and the necessity to perform a venous cutdown on the internal jugular vein to retrieve a broken bioptome in one patient. Accurate diagnostic information has been available in more than 95 percent of biopsy specimens . Graft biopsy is performed routinely every 5 to 7 days postoperatively for 4 to 6 weeks. It is utilized for initial diagnosis of rejection, for assessment of treatment, and for correlative analysis of other potentially useful indices of host immune response. " Application of the biopsy procedure during periods of clinical instability is advantageous because it permits more conservative use of antirejection therapy, directed entirely by objective histologic evaluation of biopsy specimens . Because morphologic changes indicative of rejection (Fig. 2) usually develop before clinical manifestations, such as atrial arrhythmias, decreased electrocardiographic voltage , or abnormal diastolic gallop sounds , treatment can be initiated prior to the evolution of irreversible structural graft damage. This important feature is the reason for the frequency of performance of cardiac biopsies. At the present time biopsy remains the most sensitive and specific index available for early detection of the acute rejection process.
Antihuman thymocyte globulin of rabbit origin (RATG)
Fig. 2. Early rejection. There is cellular edema with myofibrillar separation and scant mononuclear infiltrate in both the endocardium and myocardium . (Hematoxylin and eosin. Original magnification x I 20.)
Clinical use of this immunosuppressive agent was initiated in October, 1973, and the agent has since been used in 60 patients. RATG is produced in our unit by methods similar to those described by Davis and colleagues. " Recipients receive intramuscularly a total of 49 mg. of immunoglobulin G per kilogram in divided doses over the first 9 days, beginning immediately before transplantation. Subsequently, RATG is reinstituted for acute rejection in a similar dosage. RATG has also been incorporated into long-term maintenance immunosuppression for those patients who require, for prevention of recurrent rejection, toxic doses of prednisone resulting in osteoporosis, muscle wasting , serious infection, or other signs of severe hyperadrenocorticism. This strategy permits a reduction in prednisone dosage to tolerable levels ("steroidsparing effect") and is integrated with immunologic assays (see below) and cardiac biop sy for quantitative regulation . This type of regimen has been applied successfully to four long-term patients. The efficacy of rabbit as compared to horse ATO for immunosuppression after heart transplantation in our institution has been previously documented ." It has also been shown that the patients recei ving ATO can be
Volume 75
527
Cardiac transplantation
Number4 April, 1978
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Fig. 3. Progressive prolongation of half-life of serum rabbit globulin with repeated courses of rabbit antithymocyte globulin (RATG). characterized according to the kinetics of elimination of rabbit globulin (RG) from their sera. In the early postoperative period, half-lives (Tlh) of circulating RG are calculated by a radioimmune assay by means of a modified Farr technique." A prolonged Tlh (mean 11.4 ± 1.6 days) correlates directly with decreased frequency and severity of rejection episodes, delayed onset to first rejection episode, and increased survival," whereas a short Ph (mean 1.57 ± 0.25 days) is associated with directionally opposite effects. No serious toxicity has occurred with use of intramuscular RATG, whether given in one or multiple courses. Intramuscular administration in the thigh does cause local inflammation and pain with development of both lymphocytic and leukocytic infiltrates, and associated local myocytolysis at the microscopic level. In terms of muscle function, patients sustain mild difficulty with ambulation but regain full strength with vigorous physical therapy after cessation of the injections. However, because of the local toxicity associated with intramuscular RATG, we are presently modifying its preparation to permit intravenous administration.
Immunologic monitoring Since October, 1973, when RATG was first employed as an immunosuppressive agent at our Center, Tlh of circulating RG has been used to modulate immunosuppressive therapy on an individual basis. As noted earlier, a short serum Tlh is related to a short rejection onset time, increased frequency of rejection, and decreased survival. As the significance of these data became apparent, those patients with short RG Tih were treated more vigorously with intravenous corticosteroids and increased frequency of RATG injections.
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Fig. 4. Correlation of all rejection episodes recorded in 24 consecutive recipients to rises in the circulating T-cell (rosette) level. For all episodes r = 0.99; for the initial episode (open circles) r, = 0.82. Triangles refer to the false positive T-cell rises not associated with defined rejection episodes. This experience revealed that prolongation of serum RG Tlh developed concurrently with repeated courses of RATG. For instance, Patient 74 required retransplantation for intractable, recurrent acute rejection episodes, and he exhibited progressive prolongation of serum RG Tlh from a minimum of 1.5 days to a maximum of 12.7 days after his second operation (Fig. 3). Postoperatively, this patient had no proved rejection episodes. Since prolonged RG Tlh is a favorable feature in terms of immunosuppressive control and a decrease in the required frequency of RATG administration, the advantage of progressive lengthening of TV2 with repeat RATG courses is self-evident. We6 have demonstrated previously that levels of circulating T-Iymphocytes measured by sheep e-rosette formation? reflect host immune responses. There exists a close correlation between the postoperative date of significant (+3 S.D.) rises in the T-cell fraction of peripheral blood lymphocytes and the time to onset of the initial rejection episode diagnosed by direct graft biopsy (r = 0.82, P < 0.001) (Fig. 4). This correlation is reliable only during the first 30 postoperative days, after which an apparent increase in the number of false positive T-lymphocyte rises occurs. A primary goal in the early postoperative period, therefore, is to depress the fraction of peripheral T-Iymphocytes to values less than 10 percent of normal by I week. If daily measurements of e-rosette-forming cells indicate
The Journal of
528 Baumgartner et at.
Thoracic and Cardiovascular Surgery
c.1968-1970 01971-1973 .1974-1977
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Fig. 5. Survival of recipients of cardiac transplants divided into three groups according to the date of operation. Standard errors of the mean survival are shown at each point.
that this targeted response is not being achieved, both dosage and frequency of RATG administration are increased. There is an exponential rise in the circulating T-lymphocyte fraction I to 3 days prior to confirmation of rejection by biopsy. This exponential rise can occur during the end of the initial course of RATG or following its discontinuation. During this critical time period of T-lymphocyte rebound, considered to represent activation of the efferent limb of the immune response, injections of RATG are reinstituted in order to prevent full expression of the rejection process. Frequent monitoring by cardiac biopsy is continued, and other immunosuppressive agents are not added if the results of biopsy remain normal. Again, this maneuver is designed to minimize administration of intravenous corticosteroids. Presently, however, there is insufficient experience to document the long-term effectiveness of this type of prophylactic immunosuppression. One limitation of this mode of therapy is its dependence on a relatively slow rise ofT-lymphocyte fraction. When the slope of rise is excessively steep, biopsy specimens obtained at the time of reinstitution of RATG are usually abnormal. It is therefore necessary to administer intravenous methylprednisolone and actinomycin D, the standard form of treatment for severe, initial rejection episodes. 8
Cardiac retransplantation We have identified two indications for cardiac retransplantation: (I) accelerated graft atherosclerosis" and (2) intractable, recurrent, acute rejection episodes.
Five patients have required retransplantation of the heart, two for the former reason and three for the latter. Currently, two of these recipients are surviving (Cases 74 and 99) 33 and 14 months after operation, respectively. Both of them underwent retransplantation because of recurrent rejection of the first graft. 10 A third patient lived 16 months following retransplantation for accelerated graft atherosclerosis, dying of a presumed arrhythmia and moderate coronary atherosclerosis. Retransplantation is contemplated for any patient who requires excessive immunosuppression for repetitive acute rejection episodes during the first 2 months after transplantation and who has clinical signs of severe graft failure during such rejection episodes. Active infection or advanced functional deterioration of extracardiac organ systems contraindicates retransplantation. Long-term survivors are evaluated at yearly intervals by cardiac catheterization and coronary arteriographic studies in order to detect coronary arterial atherosclerosis. This late postoperative complication of cardiac transplantation has been previously described in de-' tail. 9, II If progression to critical occlusive disease is demonstrated and there are no contraindicating factors, retransplantation is recommended. A program for control of graft atherosclerosis was instituted in 1970 on the basis of its hypothetical pathogenesis, as described by Griepp." This hypothesis, as well as the previous findings of Kincaid-Smith" in renal transplantation, suggests that efforts directed toward prevention of graft intravascular microthrombi by combined treatment with dipyridamole and warfarin sodium and reduction of plasma lipid levels should retard the development of accelerated atherosclerotic lesions. Since institution of this prophylactic regimen, the incidence of graft atherosclerosis has been significantly reduced;'! This complication, therefore, no longer constitutes a barrier to long-term survival after heart transplantation.
Summary Survival after cardiac transplantation has improved significantly over the past 3112 years at our Center as compared to previous experience (Fig. 5). Currently, survival rates for 60 patients who have had heart transplantation since late in 1973 (program year mean survival ±S.E.) are 66 percent (±6.6 S.E.), 63 percent (±7.0) and 58 percent (±8.2) 1,2, and 3 years after operation, respectively. In this report the major reasons for this successful trend have been summarized. These consist of transvenous endomyocardial biopsy for diagnosis and management of graft rejection, use of RATG,
Volume 75
Cardiac transplantation
Number 4
529
April,1978
immunologic monitoring for early detection of impending rejection, and cardiac retransplantation in selected cases. The present expectations for survival and rehabilitation after heart transplantation are fully comparable to the current results of renal transplantation from unrelated donors.!' These considerations support the inclusion of cardiac transplantation as a realistic therapeutic alternative in the management of patients with advanced heart disease irremediable by standard forms of treatment.
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REFERENCES Caves PK, Schulz WP, Dong E, Stinson EB, Shumway NE: New instrument for transvenous cardiac biopsy. Am J Cardiol 33: 264, 1974 Caves PK, Billingham ME, Stinson EB, Shumway NE: Serial transvenous biopsy of the transplanted human heart. Lancet 1: 821, 1974 Davis RC, Glasgow AH, Williams LF Jr, et al: Trial of rabbit antihuman ALG in cadaver kidney transplantation. Transplant Pro 3: 766, 1971 Bieber CP, Griepp RB, Oyer PE, Wong J, Stinson EB: Use of rabbit antithymocyte globulin in cardiac transplantation. Relationship of serum clearance rates to clinical outcome. Transplantation 22: 478, 1976 Bieber CP, Lydick E, Griepp RB, David LA, Oyer PE, Stinson EB: Radioimmune assay of heterologous serum gamma globulin in patients receiving rabbit antihuman thymocyte globulin. Transplantation 20: 393, 1975 Bieber CP, Lydick E, Griepp RB, Oyer PE, David LA, Stinson EB: Relationships of rabbit ATG serum clearance rates to circulating T-cell levels, rejection onset and survival in cardiac transplantation. Transplant Proc 9: 1031, 1977 Bentwich Z, Douglas SO, Skultelsky E, et al: Sheep red cell binding to human hymphocytes treated with neuraminidase. Enhancement of T cell binding and identification of a subpopulation of B cells. J Exp Med 137: 1532, 1973 Griepp RB, Stinson EB, Bieber CP, Reitz BA, Copeland JG, Oyer PE, Shumway NE: Human heart transplantation. Current status, Ann Thorac Surg 22: 17I, 1976 Kosek JC, Bieber CP, Lower RR: Heart graft arteriosclerosis. Transplant Proc 3: 512, 1971 Copeland JG, Griepp RB, Bieber CP, Billingham ME, Schroeder JS, Hunt S, Mason J, Stinson EB, Shumway NE: Successful retransplantation of the human heart. J THoRAc CARDJOVASC SURG 73: 242, 1977 Griepp RB, Wexler L, Stinson EB, et al: Coronary arteriography following cardiac transplantation. JAMA 221: 147, 1972 Griepp, RB, Stinson EB, Bieber CP, Rietz BA, Copeland JG, Oyer PE, Shumway NE: Control of graft arteriosclerosis in human heart transplant recipients. Surgery 81: 262, 1977 Kincaid-Smith P: Modification of the vascular lesions of
rejection in cadaveric renal allografts by dipyridamole and anticoagulants. Lancet 2: 920, 1969 14 The thirteenth report of the Human Renal Transplant Registry. Transplant Proc 9: 9, 1977
Discussion DR. JOHN E. CONNOLLY Irvine, Calif.
The instrument used to obtain biopsy specimens from the endocardium, which I believe was devised by Dr. Caves, is an ingenious tool and very helpful in cardiac transplantation. I do not think that this instrument has been as widely employed by other heart transplantation teams as it has at Stanford, perhaps because of the possibility of sampling errors. However, the authors have used this technique many times, 830 times in 78 patients. Such repeated biopsies should obviate the possibility of error that might occur with an occasional or single biopsy. I would like to ask the authors about the possible danger of puncturing the right ventricle during biopsy. We have all seen transvenous pacer leads perforate the right ventricle. I would think that this might be a danger with repeated biopsies and might even result in cardiac tamponade. Does the instrument have any other use, such as retrieving plastic venous catheters that sometimes break off from peripheral veins and pass into the right ventricle or retrieving embedded transvenous pacemaker wires? Regarding the use of antihuman thymocyte rabbit globulin, I do not think we know yet how much of an advance this agent will be in transplantation. It certainly has an effect on organ rejection. Some leaders in transplantation, such as Dr. Najarian, are very excited about its ultimate prospects. On the other hand, its critics feel it may just be pushing the calendar back with ultimate irreversible rejection occurring later. Thus the value of the agent is still widely debated. To date I am not aware of any control series with rabbit globulin on the transplantation of any organ. Such a study would be helpful. The authors have performed retransplantation in five cases. I believe this approach makes sense, because certain death is the other alternative. Only about four other centers currently are performing heart transplantation. The results from Dr. Shumway's group obviously are unique and pioneering. It seems to me that they are able to get better results because of their large body of superbly qualified personnel who have the time to "crash" treat all aspects of infections. They are able to employ higher doses of suppressive drugs and cope with the resultant lifethreatening infections. Their 3 year results are very exciting, and I hope that the 5 year curves of survival will be as significantly ahead of their previous 5 year survival rates as are the 3 year results. If their enthusiastic expectations are realized, other centers will undoubtedly re-enter this field. DR. BA U MG A R TN ER (Closing) I would like to thank Dr. Connolly for his remarks. To answer his question concerning the risks of cardiac
The Journal of
530 Baumgartner et al.
Thoracic and Cardiovascular Surgery
biopsy, there are some minor complications with the use of the biopsy forceps. In about 20 percent of the cases there are ventricular premature contractions. Actually, sometimes these contractions are of benefit because they indicate that the forceps is in the right ventricle. At no time have any lifethreatening arrhythmias developed. There is also about a 0.4 percent chance of a pneumothorax developing. To my knowledge there has been no puncture of the right ventricle by the surgical house staff. However, this has occurred in the hands of our cardiology colleagues on two occasions. In both situations the tamponade was controlled by
pericardiocentesis. The biopsy forceps has not been used for retrieval of migrating catheters at our institution although this certainly would be fairly easy to do for someone experienced with the use of this forceps. In closing, I would like to draw your attention to one point that was not emphasized in the talk: The vast majority of our patients, including our longest surviving patient, who is alive 7.4 years after transplantation, have returned to some form of employment. I believe this is an important aspect of our program.
William A. Baumgartner, M.D., Bruce A. Reitz, M.D., Charles P. Bieber, M.D., Philip E. Oyer, M.D., Norman E. Shumway, M.D., and Edward B. Stinson, M.D., Stanford, Calif.
Clinical cardiac transplantation remains a challenging project with many complex problems yet unsolved. In recent years (1974 to 1976), however, the level of success in terms of survival and rehabilitation has improved significantly in comparison to previous experience at Stanford University Medical Center. Over-all survival rates during this 3 year interval are 66, 63, and 58 percent at I, 2, and 3 years postoperatively, respectively. Four major developments appear to have contributed to these current statistics. The purpose of this report is to define and clarify progress achieved in these From the Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. 94305. Supported in part by Public Health Service Research Grant RR 70 from the General Clinical Research Centers, Division of Research Resources, and by National Heart, Lung and Blood Institute Research Grant HL 13108. Read at the Third Annual Meeting of The Samson Thoracic Surgical Society, Colorado Springs, Colorado, June 4-7, 1977. Address for reprints: Edward B. Stinson, M.D., Associate Professor of Cardiovascular Surgery, Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. 94305.
0022-5223/78/0475-0525$00.60/0 © 1978 The C. V. Mosby Co.
four areas. Each is considered separately in the subsections below.
Transvenous endomyocardiaI biopsy Since the initial clinical application of transvenous endomyocardial biopsy to cardiac transplantation in 1972,1 this technique has become an increasingly important clinical tool for the diagnosis of cardiac graft rejection and monitoring of the efficacy of treatment. The procedure is performed percutaneously under local anesthesia and requires only 10 to 15 minutes. After cannulation of the right internal jugular vein with a cardiac catheterization sheath by the Seldinger technique, a specially designed biopsy forceps is passed through the sheath and advanced to the apex of the right ventricle; 2 to 3 mm. specimens are obtained from multiple sites (Fig. I). By virtue of the Seldinger technique, cardiac biopsy can be carried out safely on a repetitive basis. Altogether, 830 biopsies have been performed in 78 patients by the cardiac surgical house staff. Complications have consisted of premature ventricular contractions in approximately 20 525
526 Baumgartner et al,
Fig . 1. Plain chest x-ray film demonstrating the biopsy forceps in the apex of the right ventricle . (From Caves, P. K., Stinson , E. B., Billingham, M . E. , and Shumway , N. E.: Heart & Lung, 4:69 , January-February, 1975. Published by The C . V. Mosby Company.)
The Journal of Thoracic and Cardiovascular Surgery
percent , supraventricular arrhythmias in 3 percent , pneumothorax in 0.4 percent, and the necessity to perform a venous cutdown on the internal jugular vein to retrieve a broken bioptome in one patient. Accurate diagnostic information has been available in more than 95 percent of biopsy specimens . Graft biopsy is performed routinely every 5 to 7 days postoperatively for 4 to 6 weeks. It is utilized for initial diagnosis of rejection, for assessment of treatment, and for correlative analysis of other potentially useful indices of host immune response. " Application of the biopsy procedure during periods of clinical instability is advantageous because it permits more conservative use of antirejection therapy, directed entirely by objective histologic evaluation of biopsy specimens . Because morphologic changes indicative of rejection (Fig. 2) usually develop before clinical manifestations, such as atrial arrhythmias, decreased electrocardiographic voltage , or abnormal diastolic gallop sounds , treatment can be initiated prior to the evolution of irreversible structural graft damage. This important feature is the reason for the frequency of performance of cardiac biopsies. At the present time biopsy remains the most sensitive and specific index available for early detection of the acute rejection process.
Antihuman thymocyte globulin of rabbit origin (RATG)
Fig. 2. Early rejection. There is cellular edema with myofibrillar separation and scant mononuclear infiltrate in both the endocardium and myocardium . (Hematoxylin and eosin. Original magnification x I 20.)
Clinical use of this immunosuppressive agent was initiated in October, 1973, and the agent has since been used in 60 patients. RATG is produced in our unit by methods similar to those described by Davis and colleagues. " Recipients receive intramuscularly a total of 49 mg. of immunoglobulin G per kilogram in divided doses over the first 9 days, beginning immediately before transplantation. Subsequently, RATG is reinstituted for acute rejection in a similar dosage. RATG has also been incorporated into long-term maintenance immunosuppression for those patients who require, for prevention of recurrent rejection, toxic doses of prednisone resulting in osteoporosis, muscle wasting , serious infection, or other signs of severe hyperadrenocorticism. This strategy permits a reduction in prednisone dosage to tolerable levels ("steroidsparing effect") and is integrated with immunologic assays (see below) and cardiac biop sy for quantitative regulation . This type of regimen has been applied successfully to four long-term patients. The efficacy of rabbit as compared to horse ATO for immunosuppression after heart transplantation in our institution has been previously documented ." It has also been shown that the patients recei ving ATO can be
Volume 75
527
Cardiac transplantation
Number4 April, 1978
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120
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Fig. 3. Progressive prolongation of half-life of serum rabbit globulin with repeated courses of rabbit antithymocyte globulin (RATG). characterized according to the kinetics of elimination of rabbit globulin (RG) from their sera. In the early postoperative period, half-lives (Tlh) of circulating RG are calculated by a radioimmune assay by means of a modified Farr technique." A prolonged Tlh (mean 11.4 ± 1.6 days) correlates directly with decreased frequency and severity of rejection episodes, delayed onset to first rejection episode, and increased survival," whereas a short Ph (mean 1.57 ± 0.25 days) is associated with directionally opposite effects. No serious toxicity has occurred with use of intramuscular RATG, whether given in one or multiple courses. Intramuscular administration in the thigh does cause local inflammation and pain with development of both lymphocytic and leukocytic infiltrates, and associated local myocytolysis at the microscopic level. In terms of muscle function, patients sustain mild difficulty with ambulation but regain full strength with vigorous physical therapy after cessation of the injections. However, because of the local toxicity associated with intramuscular RATG, we are presently modifying its preparation to permit intravenous administration.
Immunologic monitoring Since October, 1973, when RATG was first employed as an immunosuppressive agent at our Center, Tlh of circulating RG has been used to modulate immunosuppressive therapy on an individual basis. As noted earlier, a short serum Tlh is related to a short rejection onset time, increased frequency of rejection, and decreased survival. As the significance of these data became apparent, those patients with short RG Tih were treated more vigorously with intravenous corticosteroids and increased frequency of RATG injections.
100
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Fig. 4. Correlation of all rejection episodes recorded in 24 consecutive recipients to rises in the circulating T-cell (rosette) level. For all episodes r = 0.99; for the initial episode (open circles) r, = 0.82. Triangles refer to the false positive T-cell rises not associated with defined rejection episodes. This experience revealed that prolongation of serum RG Tlh developed concurrently with repeated courses of RATG. For instance, Patient 74 required retransplantation for intractable, recurrent acute rejection episodes, and he exhibited progressive prolongation of serum RG Tlh from a minimum of 1.5 days to a maximum of 12.7 days after his second operation (Fig. 3). Postoperatively, this patient had no proved rejection episodes. Since prolonged RG Tlh is a favorable feature in terms of immunosuppressive control and a decrease in the required frequency of RATG administration, the advantage of progressive lengthening of TV2 with repeat RATG courses is self-evident. We6 have demonstrated previously that levels of circulating T-Iymphocytes measured by sheep e-rosette formation? reflect host immune responses. There exists a close correlation between the postoperative date of significant (+3 S.D.) rises in the T-cell fraction of peripheral blood lymphocytes and the time to onset of the initial rejection episode diagnosed by direct graft biopsy (r = 0.82, P < 0.001) (Fig. 4). This correlation is reliable only during the first 30 postoperative days, after which an apparent increase in the number of false positive T-lymphocyte rises occurs. A primary goal in the early postoperative period, therefore, is to depress the fraction of peripheral T-Iymphocytes to values less than 10 percent of normal by I week. If daily measurements of e-rosette-forming cells indicate
The Journal of
528 Baumgartner et at.
Thoracic and Cardiovascular Surgery
c.1968-1970 01971-1973 .1974-1977
..J
«
> > a:
=> en
60
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40
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= 0.005
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0..
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Fig. 5. Survival of recipients of cardiac transplants divided into three groups according to the date of operation. Standard errors of the mean survival are shown at each point.
that this targeted response is not being achieved, both dosage and frequency of RATG administration are increased. There is an exponential rise in the circulating T-lymphocyte fraction I to 3 days prior to confirmation of rejection by biopsy. This exponential rise can occur during the end of the initial course of RATG or following its discontinuation. During this critical time period of T-lymphocyte rebound, considered to represent activation of the efferent limb of the immune response, injections of RATG are reinstituted in order to prevent full expression of the rejection process. Frequent monitoring by cardiac biopsy is continued, and other immunosuppressive agents are not added if the results of biopsy remain normal. Again, this maneuver is designed to minimize administration of intravenous corticosteroids. Presently, however, there is insufficient experience to document the long-term effectiveness of this type of prophylactic immunosuppression. One limitation of this mode of therapy is its dependence on a relatively slow rise ofT-lymphocyte fraction. When the slope of rise is excessively steep, biopsy specimens obtained at the time of reinstitution of RATG are usually abnormal. It is therefore necessary to administer intravenous methylprednisolone and actinomycin D, the standard form of treatment for severe, initial rejection episodes. 8
Cardiac retransplantation We have identified two indications for cardiac retransplantation: (I) accelerated graft atherosclerosis" and (2) intractable, recurrent, acute rejection episodes.
Five patients have required retransplantation of the heart, two for the former reason and three for the latter. Currently, two of these recipients are surviving (Cases 74 and 99) 33 and 14 months after operation, respectively. Both of them underwent retransplantation because of recurrent rejection of the first graft. 10 A third patient lived 16 months following retransplantation for accelerated graft atherosclerosis, dying of a presumed arrhythmia and moderate coronary atherosclerosis. Retransplantation is contemplated for any patient who requires excessive immunosuppression for repetitive acute rejection episodes during the first 2 months after transplantation and who has clinical signs of severe graft failure during such rejection episodes. Active infection or advanced functional deterioration of extracardiac organ systems contraindicates retransplantation. Long-term survivors are evaluated at yearly intervals by cardiac catheterization and coronary arteriographic studies in order to detect coronary arterial atherosclerosis. This late postoperative complication of cardiac transplantation has been previously described in de-' tail. 9, II If progression to critical occlusive disease is demonstrated and there are no contraindicating factors, retransplantation is recommended. A program for control of graft atherosclerosis was instituted in 1970 on the basis of its hypothetical pathogenesis, as described by Griepp." This hypothesis, as well as the previous findings of Kincaid-Smith" in renal transplantation, suggests that efforts directed toward prevention of graft intravascular microthrombi by combined treatment with dipyridamole and warfarin sodium and reduction of plasma lipid levels should retard the development of accelerated atherosclerotic lesions. Since institution of this prophylactic regimen, the incidence of graft atherosclerosis has been significantly reduced;'! This complication, therefore, no longer constitutes a barrier to long-term survival after heart transplantation.
Summary Survival after cardiac transplantation has improved significantly over the past 3112 years at our Center as compared to previous experience (Fig. 5). Currently, survival rates for 60 patients who have had heart transplantation since late in 1973 (program year mean survival ±S.E.) are 66 percent (±6.6 S.E.), 63 percent (±7.0) and 58 percent (±8.2) 1,2, and 3 years after operation, respectively. In this report the major reasons for this successful trend have been summarized. These consist of transvenous endomyocardial biopsy for diagnosis and management of graft rejection, use of RATG,
Volume 75
Cardiac transplantation
Number 4
529
April,1978
immunologic monitoring for early detection of impending rejection, and cardiac retransplantation in selected cases. The present expectations for survival and rehabilitation after heart transplantation are fully comparable to the current results of renal transplantation from unrelated donors.!' These considerations support the inclusion of cardiac transplantation as a realistic therapeutic alternative in the management of patients with advanced heart disease irremediable by standard forms of treatment.
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REFERENCES Caves PK, Schulz WP, Dong E, Stinson EB, Shumway NE: New instrument for transvenous cardiac biopsy. Am J Cardiol 33: 264, 1974 Caves PK, Billingham ME, Stinson EB, Shumway NE: Serial transvenous biopsy of the transplanted human heart. Lancet 1: 821, 1974 Davis RC, Glasgow AH, Williams LF Jr, et al: Trial of rabbit antihuman ALG in cadaver kidney transplantation. Transplant Pro 3: 766, 1971 Bieber CP, Griepp RB, Oyer PE, Wong J, Stinson EB: Use of rabbit antithymocyte globulin in cardiac transplantation. Relationship of serum clearance rates to clinical outcome. Transplantation 22: 478, 1976 Bieber CP, Lydick E, Griepp RB, David LA, Oyer PE, Stinson EB: Radioimmune assay of heterologous serum gamma globulin in patients receiving rabbit antihuman thymocyte globulin. Transplantation 20: 393, 1975 Bieber CP, Lydick E, Griepp RB, Oyer PE, David LA, Stinson EB: Relationships of rabbit ATG serum clearance rates to circulating T-cell levels, rejection onset and survival in cardiac transplantation. Transplant Proc 9: 1031, 1977 Bentwich Z, Douglas SO, Skultelsky E, et al: Sheep red cell binding to human hymphocytes treated with neuraminidase. Enhancement of T cell binding and identification of a subpopulation of B cells. J Exp Med 137: 1532, 1973 Griepp RB, Stinson EB, Bieber CP, Reitz BA, Copeland JG, Oyer PE, Shumway NE: Human heart transplantation. Current status, Ann Thorac Surg 22: 17I, 1976 Kosek JC, Bieber CP, Lower RR: Heart graft arteriosclerosis. Transplant Proc 3: 512, 1971 Copeland JG, Griepp RB, Bieber CP, Billingham ME, Schroeder JS, Hunt S, Mason J, Stinson EB, Shumway NE: Successful retransplantation of the human heart. J THoRAc CARDJOVASC SURG 73: 242, 1977 Griepp RB, Wexler L, Stinson EB, et al: Coronary arteriography following cardiac transplantation. JAMA 221: 147, 1972 Griepp, RB, Stinson EB, Bieber CP, Rietz BA, Copeland JG, Oyer PE, Shumway NE: Control of graft arteriosclerosis in human heart transplant recipients. Surgery 81: 262, 1977 Kincaid-Smith P: Modification of the vascular lesions of
rejection in cadaveric renal allografts by dipyridamole and anticoagulants. Lancet 2: 920, 1969 14 The thirteenth report of the Human Renal Transplant Registry. Transplant Proc 9: 9, 1977
Discussion DR. JOHN E. CONNOLLY Irvine, Calif.
The instrument used to obtain biopsy specimens from the endocardium, which I believe was devised by Dr. Caves, is an ingenious tool and very helpful in cardiac transplantation. I do not think that this instrument has been as widely employed by other heart transplantation teams as it has at Stanford, perhaps because of the possibility of sampling errors. However, the authors have used this technique many times, 830 times in 78 patients. Such repeated biopsies should obviate the possibility of error that might occur with an occasional or single biopsy. I would like to ask the authors about the possible danger of puncturing the right ventricle during biopsy. We have all seen transvenous pacer leads perforate the right ventricle. I would think that this might be a danger with repeated biopsies and might even result in cardiac tamponade. Does the instrument have any other use, such as retrieving plastic venous catheters that sometimes break off from peripheral veins and pass into the right ventricle or retrieving embedded transvenous pacemaker wires? Regarding the use of antihuman thymocyte rabbit globulin, I do not think we know yet how much of an advance this agent will be in transplantation. It certainly has an effect on organ rejection. Some leaders in transplantation, such as Dr. Najarian, are very excited about its ultimate prospects. On the other hand, its critics feel it may just be pushing the calendar back with ultimate irreversible rejection occurring later. Thus the value of the agent is still widely debated. To date I am not aware of any control series with rabbit globulin on the transplantation of any organ. Such a study would be helpful. The authors have performed retransplantation in five cases. I believe this approach makes sense, because certain death is the other alternative. Only about four other centers currently are performing heart transplantation. The results from Dr. Shumway's group obviously are unique and pioneering. It seems to me that they are able to get better results because of their large body of superbly qualified personnel who have the time to "crash" treat all aspects of infections. They are able to employ higher doses of suppressive drugs and cope with the resultant lifethreatening infections. Their 3 year results are very exciting, and I hope that the 5 year curves of survival will be as significantly ahead of their previous 5 year survival rates as are the 3 year results. If their enthusiastic expectations are realized, other centers will undoubtedly re-enter this field. DR. BA U MG A R TN ER (Closing) I would like to thank Dr. Connolly for his remarks. To answer his question concerning the risks of cardiac
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Thoracic and Cardiovascular Surgery
biopsy, there are some minor complications with the use of the biopsy forceps. In about 20 percent of the cases there are ventricular premature contractions. Actually, sometimes these contractions are of benefit because they indicate that the forceps is in the right ventricle. At no time have any lifethreatening arrhythmias developed. There is also about a 0.4 percent chance of a pneumothorax developing. To my knowledge there has been no puncture of the right ventricle by the surgical house staff. However, this has occurred in the hands of our cardiology colleagues on two occasions. In both situations the tamponade was controlled by
pericardiocentesis. The biopsy forceps has not been used for retrieval of migrating catheters at our institution although this certainly would be fairly easy to do for someone experienced with the use of this forceps. In closing, I would like to draw your attention to one point that was not emphasized in the talk: The vast majority of our patients, including our longest surviving patient, who is alive 7.4 years after transplantation, have returned to some form of employment. I believe this is an important aspect of our program.