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Determinants of operative risk in human heart transplantation
Determinants of Operative Risk in Human Heart Transplantation RANQALL EDWARD EUGENE 04Vlp A. NORFAN
The world experience with cardiac transplantation now extends over three years and includes more than 170 operations. Although most patients have died within the first few months after operation, a significant minority have survived one to two years after transplantation. Through 1970, twenty-six patients have received heart transplants at Stanford. Over-all survival is 45 per cent at six months, 38 per cent at twelve and eighteen months, and 30 per cent at two years. Although few lives are shortened by the performance of cardiac transplantation (average survival of sixteen patients selected for transplantation at Stanford for whom no donor became available was thirty days), a substantial saving in donor organs as well as medical resources could be effected by selecting only those patients for operatiop whose chances of surviving a significant period of time are good. This communication represents an attempt to characterize those patients who are likely to benefit most from heart transplantation. Material and Methods Recipients. Through 1970, twenty-six patients received heart grafts at Stanford. Twenty-three were male and three were female. Nineteen had end-stage arteriosclerotic heart disease, five bad a primary cardiomyopathy, and two patients were in cardiogenic shock after a recent myocardial infarction. All patients had class IV disability (New York Heart Association classification). Donors. Al! cardiac donors were included in four diagnostic categories : intracranial hemorrhage, blunt trauma to the head, gunshot wound of the head, and
From the Divisions of Cardiovascular Surgery and Cardiology, Stanford University School of Medicine, Stanford, California. This work was sup ported by US Public Health Ssrvica Grants HE 08696 and HE ,l3108. and USPHS Research Grant, FR 70, General Clinical Research Centers Branch. Presented at the Forty-Second Annual Meeting of the Pacific Coast Surgical Association, Mexico City, Mexico, February 14-18. 1971. l By invitation. t Established Investigator. American Heart Association.
192
B. GRIEPP, MD,* Stanford, California 8. STINSON, MD,* Stanford, California DONG, Jr, MD,++ Stanford, California CLARK, MD,* Stanford, California E. SHUMWAY, MD, Stanford, California
brain tumor [I 1. The average age was twenty-eight years. Nineteen were male and seven were female. A diagnosis of irretrievable loss of brain function was made by a referring neurosurgeon or neurologist in each case. After transfer to the Stanford neurosurgical service, total absence of cortical and brainstem function was certified by a panel of three senior staff neurosurgeons and neurologists. Tissue Typing. ABO blood group compatibility as well as a negative crossmatch between recipient serum and donor lymphocytes was assured in all cases. Preoperative tissue typing was performed in all but one case, but because of the desperate straits of most recipients, no donor organ was not used because of poor histocompatibility match. Eight donor-recipient pairs were mismatched for three antigens, ten for two antigens, five for one antigen, and two were compatible for all antigens tested [Z]. Operative Technic. A detailed description of the operative technic has been reported elsewhere [Sl. The recipient is placed on cardiopulmonary bypass after central cannulation of the venae cavae and aorta. The heart is excised by severing the atria in a plane just posterior to the bases of both atria1 appendages, and by cutting the great vessels just above the semilunar valves. The posterior walls of both atria containing the entrances of the two venae cavae and the pulmonary veins are left in situ. The donor heart is excised by severing the two cavae and the great vessels at the pericardial reflexions, and the pulmonary veins at their entrances into the left atrium. The left atrium is opened by interconnecting the pulmonary vein orifices. The right atrium is opened with a lateral incision extending from the inferior vena cava to the base of the right atria1 appendage. The superior vena cava is tied Off.
After excision, the heart is immediately cooled by immersing it in cold saline solution. The heart is implanted by anastomosing the left atria, the right atria, aortas, and pulmonary arteries. During performance of the anastomoses, the heart is cooled with a drip of iced saline solution in the pericardial sac. After a short period of support, the heart is weaned from cardiopulmonary bypass, the cannulas are removed, and the chest
me Amerk*n
lournal
of Surgery
Human
Operative technic, The recipient heart has been exFigure 1A. cised leaving behind the posterior walls of both atria. Cannufas are in place in the ascending aorta and superior and inferior venae cavao. The donor heart is prebared by interconnecting the pulmonary vein orifices and by opening the right atrium with a lateral incision.
is closed. Figure 1 illustrates the essential features of operative and cannulation technic. Immunosuppression. Maintenance immunosuppression is begun at the time of surgery with azathioprine, corticosteroids, and antilymphocyte globulin. During the first two months after operation, acute rejection episodes. occurred at a frequency of one episode per twenty-one patient days. These episodes were treated an average of 3.4 days with an average of 2,800 mg of methylprednisolone and 510 pg of actinomycin D as well as by systemic heparinization [43. Antilymphocyte globulin is discontinued two to six months after surgery. Average long-term maintenance doses of immunosuppressive drugs are azathioprine 2 mg/kg/day, and prednisone 0.4 mg/kg/day. Patient Groups. Figures 2 and 3 document the incidence of acute rejection and infections in the four months after operation. The occurrence of both phenomena is maximal during the first two months after operation and results in the majority of deaths during this time. (Table I.) On reviewing the causes of mortality in our series, three distinct patient groups emerged : Group I. Three patients died within seventy-two hours of operation secondary to severe pulmonary hypertension and right ventricular failure. Group 11. Nine patients died of infection or rejection within the first two months after operation. Group III. Thirteen patients were discharged from the hospital in good health one to four months after operation. The one death after a cerebrovascular accident was
Volume 122, August 1971
Heart
Operative technic. Figure IS. The anastomoses are tompleted and the cannulas have been removed. A pacemaker wire is sewn to the right ventricle.
RtISiDF’ERATM:
DAYS
Incidence of acute rejection Figure 2. four months after heart transplantation.
TABLE
I
Transplantation
episodes
in the first
Causes of Death aft&r Heart Transplantation
Cause
Number of Deaths
Daysof Survival
Infection
7
Acute rejection Chronic rejection
3 3
15, 46, 59, 54, 60, 61, 127 10, 39, 46 136, 281, 624
Right heart failure Cerebrovascular accident
3 1
24
1, 1, 3
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12
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16
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Montha Rxto&mitive
Figure 3.
Incidence of infectious months after heart transplantation.
&yS
_
episodes in the first four
apparently unrelated to cardiac transplantation and this patient is not included in the three groups, Preoperative Factors. The following factors were surveyed from each patient’s preoperative data: (1) patient’s age; (2) known duration of heart disease ; (3) known duration of severe heart disease (class IV disability) ; (4) number of HL-A antigen mismatches; (5) preoperative pulmonary artery mean pressure; (6) preoperative pulmonary vascular resistance ; (7) preoperative left atria1 pressure ; (8) preoperative cardiac index; (9) preoperative bilirubin ; (10) preoperative blood urea nitrogen. Means for each of these factors were then determined for each patient group, and the significance for the difference of the means was ascertained by the Student t test. Differences referred to as significant within the text refer to those which have less than 5 per cent probability of occurring by chance (p < .06). Results
Table II summarizes the significant differences between the three groups. The patients in group I differed from those in both groups II and III by having a higher average pulmonary artery mean pressure (55 versus 40 and 38 mm Hg, respectively), as well as a higher average pulmonary vascular resistance (11.6 versus 3.7 and 4.1 resistance units, respectively). The patients in group II, all of whom died during the initial hospitalization period, differed from those in group III, all of whom were discharged, only by slightly greater average age (fifty-two versus forty-seven years), and a longer duration of knoivn cardiovascular disease (8.4 versus 4.3 years). No differences were found among the three groups with respect to duration of severe cardiac disease or to histocompatibility matching as measured by number of HGA antigen mismatches. The severity of left ventricular dys-
194
Figure 4. Survival of groups I, II, and Ill calculated fife table method.
TABLE II
by the
Average Value by Group of Preoperative Factors Group Factor
I
II
III
55
40
38
Group I significantly different from groups II and III: Pulmonary artery mean pressure (mm Hg) Pulmonary vascular resistance* (units)
11.5
3.7
4.1
Group II significantly different from group III: Age (yr) Duration of disease (yr)
45 7.2
52 8.4
47 4.3
No significant difference between any group: HL-A antigen mismatches (number) Duration of class IV disability (mo) Cardiac index (L/min/MI) Left atrial pressures (mm Hg) Preoperative bilirubin (mg 96.) Preoperative BUN (mg %)
1.6 9.0 1.2 32 1.7 15
2.3 8.4 1.9 28 1.6 35
1.8 6.4 1.7 27 1.3 22
Pulmonary vascular resistance = pulmonary artery mean pressure minus pulmonary artery wedge mean pressure (mm Hg) divided by cardiac output (L/min). l
function as measured by left atria1 mean pressure and cardiac index was similar in all three groups. Preoperative levels of bilirubin and blood urea nitrogen did not differ significantly among the three groups. Figure 4 documents the postoperative survival of the three groups as determined by the standard life table method [5]. By definition, all patients in groups I and II had died by two months. For those patients who survived this period, however, patient survival was 84 per cent at six months, and 76 and 60 per cent at one and two years, respectively.
The
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Human Heart Transplantation
Comments
Several conclusions can be drawn from this survey. First, severely elevated pulmonary vascular resistance joins intercurrent infection as an absolute contraindication to cardiac transplantation. The normal right ventricle of the grafted heart is unable to work at near systemic pressures which are present in the lesser circulation of these patients. Progressive failure of the graft and death of the patient result. In more moderate degrees of elevated pulmonary vascular resistance, however, the graft can temporarily adapt itself to an elevated pulmonary artery pressure. Moreover, cardiac catheterization one year after operation has shown that in most cases of moderately elevated pulmonary vascular resistance, the resistance returns to normal levels by one year after operation [6]. At present we believe that any patient whose pulmonary vascular resistance is less than 5 units and whose mean pulmonary artery pressure is less than 40 mm Hg does not face an increased risk of right ventricular failure postoperatively. Transplantation is absolutely contraindicated if the pulmonary vascular resistance is greater than 10 units or the pulmonary artery mean pressure is greater than 50 mm Hg. Patients whose values are between these two cutoff points mu,st be considered on an individual basis for transplantation. It is not surprising that patients who are younger and whose disease is of shorter duration fare better after transplantation than do older patients whose disease is more chronic. Resistance to infection probably represents one of the primary differences between these two groups. In patients who have received cardiac transplants we have observed that infection tends to occur with greater frequency among the older patients, and that once contracted, infections are more difficult to eradicate [7]. In this small series of patients no effect of tissue matching was seen in postoperative survival. This may be because of the small sample size, or may reflect the inability of present tissue typing methods to accurately quantitate tissue incompatibility. Recent studies have suggested that the antigens present in tissue cells, such as renal cells, may not be detected routinely by white cell typing methods [8]. In any case the relative paucity of donor organs coupled with the extremely limited life span of patients who are candidates for heart transplantation make tissue typing a somewhat academic issue at present. Thirty-eight per cent of patients selected for transplantation in this center
Volume 122, August 1971
TABLE III
1. 2. 3. 4. 5. 6.
Optimal Conditions in a Candidate for Cardiac Transplantation Age is forty to fifty years. Duration of disease is less than five years. Pulmonary artery mean pressure is less than 40 mm Hg. Pulmonary vascular resistance is less than five units. Renal and hepatic dysfunction secondary to cardiac decompensation is not severe. There is no evidence of active infection.
have died before a donor who was ABO-compatible became available. If white cell matching were an additional requirement, it is unlikely that more than 10 per cent of these patients would have survived until a compatible donor was found. It is particularly encouraging that the severity of left ventricular dysfunction, both as measured by hemodynamic criteria and by its secondary effect on renal and hepatic function, does not prejudice the outcome of heart transplantation. Thus, severe congestive heart failure or a low cardiac output do not contraindicate operation. Table III summarizes the characteristics of the optimal candidate for cardiac transplantation. He should be relatively young and should have been sick for less than five years ; he must be free of severe pulmonary vascular occlusive disease and ongoing infection ; and he should not have more than moderate secondary dysfunction of the liver or kidneys. Based on our recent experience, we believe that if a candidate fits these criteria, his chances of surviving at least one year after operation are greater than 50 per cent. For the patient who fits the foregoing criteria and for whom no alternative methods of medical or surgical therapy are available and death seems imminent within weeks, cardiac transplantation is recommended without reservation. In less optimal situations each patient must be carefully evaluated on an individual basis. In the patient who is obviously a poor operative risk, despite the fact that his prognosis is grave without transplantation, it is perhaps wise not to engender unrealistic hopes by offering a new heart to a patient who has little chance of long-term survival. Summary
In the past two and a half years twenty-six patients have received heart transplants at Stanford. Over-all survival is 45 per cent at six months, 38 per cent at twelve and eighteen months, and 30 per cent at two years. Analysis of mortality
195
Griepp
et al
after operation allows separation of these patients into three groups. Three patients died within seventy-two hours of operation, all secondary to markedly elevated pulmonary vascular resistance resulting in progressive right heart failure (group I). Nine patients died in the hospital within two months of operation of infection or rejection (group II). Thirteen patients were discharged in satisfactory condition one to four months after operation (group III). One patient died in the early postoperative period from a cerebrovascular accident apparently unrelated to transplantation. Patients in group I differed significantly from those in groups II and III in having a higher pulmonary artery mean pressure and a higher calculated pulmonary vascular resistance. Patients in group II differed from those in group III with respect to age and the duration of known heart disease. No differences were found between the three groups with respect to number of HL-A antigen mismatches, duration of severe heart disease, cardiac index, mean left atria1 pressur’e, or preoperative bilirubin or blood urea nitrogen levels. Follow-up study of the thirteen patients who survived the immediate postoperative period shows 84 per cent survival at six months, 75 per cent at twelve and eighteen months, and 60 per cent at two years. For patients with end-stage myocardial insufficiency, heart transplantation in appropriately selected cases offers a substantial probability for return to normal activity.
1. Griepp RB, Stinson EB, Clark DA, Dong E Jr, Shumway NE: The cardiac donor. (Sorg Gynec Obstet, in press). 2. Bodmer W, Tripp M, Bodmer J: Application of fluorochromatic cytotoxicity assay to human leukocyte typing, p 341. Histocompatibility Testing (Curtoni ES, Mattiuz PL, Tosi RM, ed). Copenhagen, Ejnar Munksgaards Forlag, 1967. 3. Stinson EB, Dong E Jr, lben AB, Shumway NE: Cardiac transplantation in man. III. Surgical aspects. Amer J Surg 118: 182, 1969. 4. Griepp RB, Stinson EB, Dong E Jr, Clark DA, Shumway NE: Acute rejection of the allografted human heart: diagnosis and treatment. (Ann Thorac Surg, in press). 5. Cutler SJ, Ederer F: Maximum utilization of the life table method in analyzing survival. J Chron Dis 8: 699, 1958. 6. Griepp RB, Stinson EB, Dong E Jr, Clark DA, Shumway NE: Hemodynamic performance of the transplanted human heart. (Surgery, in press). 7. Stinson EB, Bieber CP, Griepp RB, Clark DA, Shumway NE, Remington JS: Infectious complications following cardiac transplantation in man. Ann Int Med 74: 22, 1971. 8. Kountz SL, Cochrum KC, Perkins HA, Douglas KS, Belzer FO: Selection of allograft recipients by leukocyte and kidney cell phenotyping. Surgery 68: 69, 1970.
196
Discussion
L. KOUNTZ (San Francisco, Calif) : I wish congratulate Dr Griepp and his associates on their work for delineating those patients with end-stage cardiac failure who have the greatest chance of benefiting from cardiac transplantation during its evoluSAMUEL
to
tion. This is a most challenging problem when a new and expensive life-saving procedure becomes available, yet is still in the developmental stages. Similar problems occur with kidney transplantation, However, I agree with the authors’ conclusion that until there is a greater supply of donor organs, the procedure should be limited to patients who have the greatest chance of long-term survival. Such an approach will permit a study of other factors which are critical for success. It is worth emphasizing that the 38 per cent and 30 per cent one and two year graft survival rates, respectively, that they have achieved is not significantly different from the one and two year survival rates with cadaveric renal transplants that were achieved two years ago. In their patients in group III, however, who represented their good risks, the survival rate is greater than the national average for those receiving cadaveric renal transplants, and I wish to congratulate Dr Griepp and his co-workers on this success. Death of patients after transplantation is almost always related to infection from high doses of immunosuppressive drugs used to treat an acute rejection episode. Closer tissue matching might minimize this problem. Although the authors could show no correlation with HL-A phenotyping in their study, I would like to emphasize that none of their patients had a match equivalent to that of siblings with identical HL-A antifens in whom the rejection rate is extremely low, and the five year survival of such grafts is more than 90 per cent. This points up one of the logistic problems not only with cardiac transplantation, but also with kidney transplantation, that is, obtaining a match equal to that of HL-A-identical siblings. In my opinion, the value of tissue typing cannot be determined because the critical experiments have not yet been performed. One of the most limiting factors in the delivery of transplantation as a service is the small number of cadaveric organs offered for transplantation, Young donors have been used, in whom neurologists or neurosurgeons have diagnosed death by use of the Harvard criterion of brain death, and this is the time when an autopsy may be initiated and the organ made available. Although this concept is understood by most physicians, and some surveys indicate that it is accepted by a large segment of society, it is poorly accepted at present by the medical profession. It is my opinion that sufficient cadaveric organs will not become available for transplantation until patients demand of their
Tha Amsrlcan
Journal
of
Surlary
Human
physicians that the organs of their family be made available for transplantation. This will require the active participation in transplantation of all physicians attending patients who are dying. At the same time, research in organ preservation and resuscitation must continue to ease the logistics of organ procurement. In closing, I would like to ask one question : Since Dr Griepp and his associates have used antilymphocyte serum in the management of their patients after cardiac transplantation, and since this is reported to induce glomerulonephritis and malignant lesions, have clinical glomerulonephritis or malignant lesions occurred in any of their patients? ROBERT W. JAMPLIS (closing) : Although my experience with cardiac transplantation is nil, all of us in Palo Alto have followed Dr Shumway’s work and that of his group with great interest and considerable pride. I well remember that first Sunday in January three years ago when Dr Shumway was performing his first
Volume 122. August 1971
Heart
Transplantation
transplant procedure, just one month after Dr Barnard’s famous operation. Afterwards I complimented him on the achievement, at which point he cheerfully asked, “Who’s the second guy to fly a plane?” I think it also is significant that at the last meeting of the American Association for Thoracic Surgery he and his group were cited as the only ones in the world who had any statistics approaching those that were given by Dr Griepp, namely, a 50 per cent survival in twenty-six patients; this figure approaches that of kidney transplantation. Therefore, I believe that clinical investigation in heart transplantation by this team should continue despite the fact that we have not solved the rejection phenomenon as yet. To answer specifically Dr Kountz’ question, there have been no cases of glomerulonephritis or of malignancies in those patients who have received antilymphocyte globulin.
197
The world experience with cardiac transplantation now extends over three years and includes more than 170 operations. Although most patients have died within the first few months after operation, a significant minority have survived one to two years after transplantation. Through 1970, twenty-six patients have received heart transplants at Stanford. Over-all survival is 45 per cent at six months, 38 per cent at twelve and eighteen months, and 30 per cent at two years. Although few lives are shortened by the performance of cardiac transplantation (average survival of sixteen patients selected for transplantation at Stanford for whom no donor became available was thirty days), a substantial saving in donor organs as well as medical resources could be effected by selecting only those patients for operatiop whose chances of surviving a significant period of time are good. This communication represents an attempt to characterize those patients who are likely to benefit most from heart transplantation. Material and Methods Recipients. Through 1970, twenty-six patients received heart grafts at Stanford. Twenty-three were male and three were female. Nineteen had end-stage arteriosclerotic heart disease, five bad a primary cardiomyopathy, and two patients were in cardiogenic shock after a recent myocardial infarction. All patients had class IV disability (New York Heart Association classification). Donors. Al! cardiac donors were included in four diagnostic categories : intracranial hemorrhage, blunt trauma to the head, gunshot wound of the head, and
From the Divisions of Cardiovascular Surgery and Cardiology, Stanford University School of Medicine, Stanford, California. This work was sup ported by US Public Health Ssrvica Grants HE 08696 and HE ,l3108. and USPHS Research Grant, FR 70, General Clinical Research Centers Branch. Presented at the Forty-Second Annual Meeting of the Pacific Coast Surgical Association, Mexico City, Mexico, February 14-18. 1971. l By invitation. t Established Investigator. American Heart Association.
192
B. GRIEPP, MD,* Stanford, California 8. STINSON, MD,* Stanford, California DONG, Jr, MD,++ Stanford, California CLARK, MD,* Stanford, California E. SHUMWAY, MD, Stanford, California
brain tumor [I 1. The average age was twenty-eight years. Nineteen were male and seven were female. A diagnosis of irretrievable loss of brain function was made by a referring neurosurgeon or neurologist in each case. After transfer to the Stanford neurosurgical service, total absence of cortical and brainstem function was certified by a panel of three senior staff neurosurgeons and neurologists. Tissue Typing. ABO blood group compatibility as well as a negative crossmatch between recipient serum and donor lymphocytes was assured in all cases. Preoperative tissue typing was performed in all but one case, but because of the desperate straits of most recipients, no donor organ was not used because of poor histocompatibility match. Eight donor-recipient pairs were mismatched for three antigens, ten for two antigens, five for one antigen, and two were compatible for all antigens tested [Z]. Operative Technic. A detailed description of the operative technic has been reported elsewhere [Sl. The recipient is placed on cardiopulmonary bypass after central cannulation of the venae cavae and aorta. The heart is excised by severing the atria in a plane just posterior to the bases of both atria1 appendages, and by cutting the great vessels just above the semilunar valves. The posterior walls of both atria containing the entrances of the two venae cavae and the pulmonary veins are left in situ. The donor heart is excised by severing the two cavae and the great vessels at the pericardial reflexions, and the pulmonary veins at their entrances into the left atrium. The left atrium is opened by interconnecting the pulmonary vein orifices. The right atrium is opened with a lateral incision extending from the inferior vena cava to the base of the right atria1 appendage. The superior vena cava is tied Off.
After excision, the heart is immediately cooled by immersing it in cold saline solution. The heart is implanted by anastomosing the left atria, the right atria, aortas, and pulmonary arteries. During performance of the anastomoses, the heart is cooled with a drip of iced saline solution in the pericardial sac. After a short period of support, the heart is weaned from cardiopulmonary bypass, the cannulas are removed, and the chest
me Amerk*n
lournal
of Surgery
Human
Operative technic, The recipient heart has been exFigure 1A. cised leaving behind the posterior walls of both atria. Cannufas are in place in the ascending aorta and superior and inferior venae cavao. The donor heart is prebared by interconnecting the pulmonary vein orifices and by opening the right atrium with a lateral incision.
is closed. Figure 1 illustrates the essential features of operative and cannulation technic. Immunosuppression. Maintenance immunosuppression is begun at the time of surgery with azathioprine, corticosteroids, and antilymphocyte globulin. During the first two months after operation, acute rejection episodes. occurred at a frequency of one episode per twenty-one patient days. These episodes were treated an average of 3.4 days with an average of 2,800 mg of methylprednisolone and 510 pg of actinomycin D as well as by systemic heparinization [43. Antilymphocyte globulin is discontinued two to six months after surgery. Average long-term maintenance doses of immunosuppressive drugs are azathioprine 2 mg/kg/day, and prednisone 0.4 mg/kg/day. Patient Groups. Figures 2 and 3 document the incidence of acute rejection and infections in the four months after operation. The occurrence of both phenomena is maximal during the first two months after operation and results in the majority of deaths during this time. (Table I.) On reviewing the causes of mortality in our series, three distinct patient groups emerged : Group I. Three patients died within seventy-two hours of operation secondary to severe pulmonary hypertension and right ventricular failure. Group 11. Nine patients died of infection or rejection within the first two months after operation. Group III. Thirteen patients were discharged from the hospital in good health one to four months after operation. The one death after a cerebrovascular accident was
Volume 122, August 1971
Heart
Operative technic. Figure IS. The anastomoses are tompleted and the cannulas have been removed. A pacemaker wire is sewn to the right ventricle.
RtISiDF’ERATM:
DAYS
Incidence of acute rejection Figure 2. four months after heart transplantation.
TABLE
I
Transplantation
episodes
in the first
Causes of Death aft&r Heart Transplantation
Cause
Number of Deaths
Daysof Survival
Infection
7
Acute rejection Chronic rejection
3 3
15, 46, 59, 54, 60, 61, 127 10, 39, 46 136, 281, 624
Right heart failure Cerebrovascular accident
3 1
24
1, 1, 3
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’
4
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b
’
4
‘I’
IO
12
’
14
’
16
’
’
18
’
20
22
24
Montha Rxto&mitive
Figure 3.
Incidence of infectious months after heart transplantation.
&yS
_
episodes in the first four
apparently unrelated to cardiac transplantation and this patient is not included in the three groups, Preoperative Factors. The following factors were surveyed from each patient’s preoperative data: (1) patient’s age; (2) known duration of heart disease ; (3) known duration of severe heart disease (class IV disability) ; (4) number of HL-A antigen mismatches; (5) preoperative pulmonary artery mean pressure; (6) preoperative pulmonary vascular resistance ; (7) preoperative left atria1 pressure ; (8) preoperative cardiac index; (9) preoperative bilirubin ; (10) preoperative blood urea nitrogen. Means for each of these factors were then determined for each patient group, and the significance for the difference of the means was ascertained by the Student t test. Differences referred to as significant within the text refer to those which have less than 5 per cent probability of occurring by chance (p < .06). Results
Table II summarizes the significant differences between the three groups. The patients in group I differed from those in both groups II and III by having a higher average pulmonary artery mean pressure (55 versus 40 and 38 mm Hg, respectively), as well as a higher average pulmonary vascular resistance (11.6 versus 3.7 and 4.1 resistance units, respectively). The patients in group II, all of whom died during the initial hospitalization period, differed from those in group III, all of whom were discharged, only by slightly greater average age (fifty-two versus forty-seven years), and a longer duration of knoivn cardiovascular disease (8.4 versus 4.3 years). No differences were found among the three groups with respect to duration of severe cardiac disease or to histocompatibility matching as measured by number of HGA antigen mismatches. The severity of left ventricular dys-
194
Figure 4. Survival of groups I, II, and Ill calculated fife table method.
TABLE II
by the
Average Value by Group of Preoperative Factors Group Factor
I
II
III
55
40
38
Group I significantly different from groups II and III: Pulmonary artery mean pressure (mm Hg) Pulmonary vascular resistance* (units)
11.5
3.7
4.1
Group II significantly different from group III: Age (yr) Duration of disease (yr)
45 7.2
52 8.4
47 4.3
No significant difference between any group: HL-A antigen mismatches (number) Duration of class IV disability (mo) Cardiac index (L/min/MI) Left atrial pressures (mm Hg) Preoperative bilirubin (mg 96.) Preoperative BUN (mg %)
1.6 9.0 1.2 32 1.7 15
2.3 8.4 1.9 28 1.6 35
1.8 6.4 1.7 27 1.3 22
Pulmonary vascular resistance = pulmonary artery mean pressure minus pulmonary artery wedge mean pressure (mm Hg) divided by cardiac output (L/min). l
function as measured by left atria1 mean pressure and cardiac index was similar in all three groups. Preoperative levels of bilirubin and blood urea nitrogen did not differ significantly among the three groups. Figure 4 documents the postoperative survival of the three groups as determined by the standard life table method [5]. By definition, all patients in groups I and II had died by two months. For those patients who survived this period, however, patient survival was 84 per cent at six months, and 76 and 60 per cent at one and two years, respectively.
The
Amorhxn
Journd
of
Sui’gory
Human Heart Transplantation
Comments
Several conclusions can be drawn from this survey. First, severely elevated pulmonary vascular resistance joins intercurrent infection as an absolute contraindication to cardiac transplantation. The normal right ventricle of the grafted heart is unable to work at near systemic pressures which are present in the lesser circulation of these patients. Progressive failure of the graft and death of the patient result. In more moderate degrees of elevated pulmonary vascular resistance, however, the graft can temporarily adapt itself to an elevated pulmonary artery pressure. Moreover, cardiac catheterization one year after operation has shown that in most cases of moderately elevated pulmonary vascular resistance, the resistance returns to normal levels by one year after operation [6]. At present we believe that any patient whose pulmonary vascular resistance is less than 5 units and whose mean pulmonary artery pressure is less than 40 mm Hg does not face an increased risk of right ventricular failure postoperatively. Transplantation is absolutely contraindicated if the pulmonary vascular resistance is greater than 10 units or the pulmonary artery mean pressure is greater than 50 mm Hg. Patients whose values are between these two cutoff points mu,st be considered on an individual basis for transplantation. It is not surprising that patients who are younger and whose disease is of shorter duration fare better after transplantation than do older patients whose disease is more chronic. Resistance to infection probably represents one of the primary differences between these two groups. In patients who have received cardiac transplants we have observed that infection tends to occur with greater frequency among the older patients, and that once contracted, infections are more difficult to eradicate [7]. In this small series of patients no effect of tissue matching was seen in postoperative survival. This may be because of the small sample size, or may reflect the inability of present tissue typing methods to accurately quantitate tissue incompatibility. Recent studies have suggested that the antigens present in tissue cells, such as renal cells, may not be detected routinely by white cell typing methods [8]. In any case the relative paucity of donor organs coupled with the extremely limited life span of patients who are candidates for heart transplantation make tissue typing a somewhat academic issue at present. Thirty-eight per cent of patients selected for transplantation in this center
Volume 122, August 1971
TABLE III
1. 2. 3. 4. 5. 6.
Optimal Conditions in a Candidate for Cardiac Transplantation Age is forty to fifty years. Duration of disease is less than five years. Pulmonary artery mean pressure is less than 40 mm Hg. Pulmonary vascular resistance is less than five units. Renal and hepatic dysfunction secondary to cardiac decompensation is not severe. There is no evidence of active infection.
have died before a donor who was ABO-compatible became available. If white cell matching were an additional requirement, it is unlikely that more than 10 per cent of these patients would have survived until a compatible donor was found. It is particularly encouraging that the severity of left ventricular dysfunction, both as measured by hemodynamic criteria and by its secondary effect on renal and hepatic function, does not prejudice the outcome of heart transplantation. Thus, severe congestive heart failure or a low cardiac output do not contraindicate operation. Table III summarizes the characteristics of the optimal candidate for cardiac transplantation. He should be relatively young and should have been sick for less than five years ; he must be free of severe pulmonary vascular occlusive disease and ongoing infection ; and he should not have more than moderate secondary dysfunction of the liver or kidneys. Based on our recent experience, we believe that if a candidate fits these criteria, his chances of surviving at least one year after operation are greater than 50 per cent. For the patient who fits the foregoing criteria and for whom no alternative methods of medical or surgical therapy are available and death seems imminent within weeks, cardiac transplantation is recommended without reservation. In less optimal situations each patient must be carefully evaluated on an individual basis. In the patient who is obviously a poor operative risk, despite the fact that his prognosis is grave without transplantation, it is perhaps wise not to engender unrealistic hopes by offering a new heart to a patient who has little chance of long-term survival. Summary
In the past two and a half years twenty-six patients have received heart transplants at Stanford. Over-all survival is 45 per cent at six months, 38 per cent at twelve and eighteen months, and 30 per cent at two years. Analysis of mortality
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after operation allows separation of these patients into three groups. Three patients died within seventy-two hours of operation, all secondary to markedly elevated pulmonary vascular resistance resulting in progressive right heart failure (group I). Nine patients died in the hospital within two months of operation of infection or rejection (group II). Thirteen patients were discharged in satisfactory condition one to four months after operation (group III). One patient died in the early postoperative period from a cerebrovascular accident apparently unrelated to transplantation. Patients in group I differed significantly from those in groups II and III in having a higher pulmonary artery mean pressure and a higher calculated pulmonary vascular resistance. Patients in group II differed from those in group III with respect to age and the duration of known heart disease. No differences were found between the three groups with respect to number of HL-A antigen mismatches, duration of severe heart disease, cardiac index, mean left atria1 pressur’e, or preoperative bilirubin or blood urea nitrogen levels. Follow-up study of the thirteen patients who survived the immediate postoperative period shows 84 per cent survival at six months, 75 per cent at twelve and eighteen months, and 60 per cent at two years. For patients with end-stage myocardial insufficiency, heart transplantation in appropriately selected cases offers a substantial probability for return to normal activity.
1. Griepp RB, Stinson EB, Clark DA, Dong E Jr, Shumway NE: The cardiac donor. (Sorg Gynec Obstet, in press). 2. Bodmer W, Tripp M, Bodmer J: Application of fluorochromatic cytotoxicity assay to human leukocyte typing, p 341. Histocompatibility Testing (Curtoni ES, Mattiuz PL, Tosi RM, ed). Copenhagen, Ejnar Munksgaards Forlag, 1967. 3. Stinson EB, Dong E Jr, lben AB, Shumway NE: Cardiac transplantation in man. III. Surgical aspects. Amer J Surg 118: 182, 1969. 4. Griepp RB, Stinson EB, Dong E Jr, Clark DA, Shumway NE: Acute rejection of the allografted human heart: diagnosis and treatment. (Ann Thorac Surg, in press). 5. Cutler SJ, Ederer F: Maximum utilization of the life table method in analyzing survival. J Chron Dis 8: 699, 1958. 6. Griepp RB, Stinson EB, Dong E Jr, Clark DA, Shumway NE: Hemodynamic performance of the transplanted human heart. (Surgery, in press). 7. Stinson EB, Bieber CP, Griepp RB, Clark DA, Shumway NE, Remington JS: Infectious complications following cardiac transplantation in man. Ann Int Med 74: 22, 1971. 8. Kountz SL, Cochrum KC, Perkins HA, Douglas KS, Belzer FO: Selection of allograft recipients by leukocyte and kidney cell phenotyping. Surgery 68: 69, 1970.
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Discussion
L. KOUNTZ (San Francisco, Calif) : I wish congratulate Dr Griepp and his associates on their work for delineating those patients with end-stage cardiac failure who have the greatest chance of benefiting from cardiac transplantation during its evoluSAMUEL
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tion. This is a most challenging problem when a new and expensive life-saving procedure becomes available, yet is still in the developmental stages. Similar problems occur with kidney transplantation, However, I agree with the authors’ conclusion that until there is a greater supply of donor organs, the procedure should be limited to patients who have the greatest chance of long-term survival. Such an approach will permit a study of other factors which are critical for success. It is worth emphasizing that the 38 per cent and 30 per cent one and two year graft survival rates, respectively, that they have achieved is not significantly different from the one and two year survival rates with cadaveric renal transplants that were achieved two years ago. In their patients in group III, however, who represented their good risks, the survival rate is greater than the national average for those receiving cadaveric renal transplants, and I wish to congratulate Dr Griepp and his co-workers on this success. Death of patients after transplantation is almost always related to infection from high doses of immunosuppressive drugs used to treat an acute rejection episode. Closer tissue matching might minimize this problem. Although the authors could show no correlation with HL-A phenotyping in their study, I would like to emphasize that none of their patients had a match equivalent to that of siblings with identical HL-A antifens in whom the rejection rate is extremely low, and the five year survival of such grafts is more than 90 per cent. This points up one of the logistic problems not only with cardiac transplantation, but also with kidney transplantation, that is, obtaining a match equal to that of HL-A-identical siblings. In my opinion, the value of tissue typing cannot be determined because the critical experiments have not yet been performed. One of the most limiting factors in the delivery of transplantation as a service is the small number of cadaveric organs offered for transplantation, Young donors have been used, in whom neurologists or neurosurgeons have diagnosed death by use of the Harvard criterion of brain death, and this is the time when an autopsy may be initiated and the organ made available. Although this concept is understood by most physicians, and some surveys indicate that it is accepted by a large segment of society, it is poorly accepted at present by the medical profession. It is my opinion that sufficient cadaveric organs will not become available for transplantation until patients demand of their
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physicians that the organs of their family be made available for transplantation. This will require the active participation in transplantation of all physicians attending patients who are dying. At the same time, research in organ preservation and resuscitation must continue to ease the logistics of organ procurement. In closing, I would like to ask one question : Since Dr Griepp and his associates have used antilymphocyte serum in the management of their patients after cardiac transplantation, and since this is reported to induce glomerulonephritis and malignant lesions, have clinical glomerulonephritis or malignant lesions occurred in any of their patients? ROBERT W. JAMPLIS (closing) : Although my experience with cardiac transplantation is nil, all of us in Palo Alto have followed Dr Shumway’s work and that of his group with great interest and considerable pride. I well remember that first Sunday in January three years ago when Dr Shumway was performing his first
Volume 122. August 1971
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transplant procedure, just one month after Dr Barnard’s famous operation. Afterwards I complimented him on the achievement, at which point he cheerfully asked, “Who’s the second guy to fly a plane?” I think it also is significant that at the last meeting of the American Association for Thoracic Surgery he and his group were cited as the only ones in the world who had any statistics approaching those that were given by Dr Griepp, namely, a 50 per cent survival in twenty-six patients; this figure approaches that of kidney transplantation. Therefore, I believe that clinical investigation in heart transplantation by this team should continue despite the fact that we have not solved the rejection phenomenon as yet. To answer specifically Dr Kountz’ question, there have been no cases of glomerulonephritis or of malignancies in those patients who have received antilymphocyte globulin.
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