Transplantation of hearts after arrest and resuscitation. Early and long-term results.

Transplant surgeons are reluctant to use hearts that have undergone cardiopulmonary resuscitation for cardiac arrest because of the fear of poor early and late cardiac function. A policy of minimizing contraindications to use of donor hearts has led to the unique opportunity of assessing the effects of donor arrest and successful cardiopulmonary resuscitation on early and late cardiac function in pediatric heart transplantation. A number of 140 infants and children undergoing transplantation from birth to 17 years of age were studied retrospectively and divided into two groups on the basis of cardiopulmonary resuscitation status. Group 1 (72 patients) received donor hearts that were not subjected to cardiopulmonary resuscitation; group 2 (68 patients) received donor hearts that had cardiopulmonary resuscitation for a mean of 18.8 +/- 14.6 minutes, the longest period of time being 60 minutes. Mean ischemic times were almost identical in the two groups: 4.43 +/- 2.0 hours (cardiopulmonary resuscitation) versus 4.5 +/- 2.1 hours (no cardiopulmonary resuscitation). Early cardiac function was assessed on the basis of the number of days the recipient was supported by the ventilator, days receiving dopamine, days receiving isoproterenol, and the amount of inotropic agents required after the operation. The groups did not differ. Parameters of systolic function included fractional shortening, posterior wall thickening, and maximum velocity of change in left ventricular posterior wall dimension during systole. Diastolic function was measured on the basis of left ventricular end-diastolic volume, left ventricular mass, and maximum velocity of change in left ventricular posterior wall dimension during diastole. Both systolic and diastolic function were measured and analyzed from M-mode echocardiography at 1 week, 1 month, 6 months, 1 year, and 2 years after the operation. There were no statistically significant differences in graft function between the two groups in any of the echocardiographic parameters studied, even at 2 years. No group differed from ranges of normal. Our results suggest that hearts undergoing cardiopulmonary resuscitation for periods of up to 60 minutes can be used safely without evidence of deterioration of early or late cardiac function.

Prolonged survival of orthotopically transplanted heart xenograft in infant baboons.

Orthotopic concordant xenotransplantation in a juvenile primate model was examined. Eighteen donor rhesus monkeys weighing 2.4 to 3.8 kg (mean 2.9 kg) were matched with juvenile baboons, aged 9 to 19 months (mean 12.7 months) and weighing 3.2 to 4.8 kg (mean 3.9 kg), using ABH blood type and mixed lymphocyte culture. Rhesus monkey hearts were orthotopically transplanted without immunosuppression into six control baboons (group I). In five baboons (group II), 4 mg/kg per day of antilymphocyte globulin was administered for 3 days before the operation and 5 days after the operation. Splenectomy was also performed, and 18 mg/kg per day of FK 506 was administered orally. Intravenous methotrexate, methylprednisolone, or both were used as rescue therapy. Seven baboons (group III) received the same immunosuppression as those in group II, but an intravenous dose of methotrexate (0.1 to 5 mg) was given twice weekly to suppress the proliferative response as monitored by in vitro immunologic assays. Baboons in group I had a mean survival of 8 days; all died as a result of classic cellular rejection. Baboons in group II had a mean survival of 48.4 days (p < 0.05 versus group I). Two died during rescue therapy for rejection, and three died of cytomegalovirus infection. Two group II baboons showed mild rejection at autopsy. Baboons in group III had a mean survival of 127 days, and one baboon was still alive after 286 days. Two died of cytomegalovirus infection, one of toxoplasmosis, one of Klebsiella pneumoniae, one of massive micropulmonary embolism, one of renal failure aggravated by ganciclovir. Only two of the baboons that died showed rejection (estimated as mild) at autopsy. The baboon still alive at 286 days had no rejection on myocardial biopsy on the two hundred forty-fourth postoperative day. FK 506 coupled with low-dose maintenance methotrexate and splenectomy has produced prolonged host survival in this xenotransplantation model. Results suggest that concordant xenotransplantation would be a suitable biologic bridge to allotransplantation.

Methotrexate as rescue/adjunctive immunotherapy in infant and adult heart transplantation.

Methotrexate may be a useful adjunct to more conventional immunosuppression in heart transplantation, but experience is limited. We report our findings in 18 patients aged 19 days to 64 years, who were treated with methotrexate. Five patients were less than 1 year of age; 11 patients were over 16 years of age. Indications could be divided in two groups. Seven patients were treated with methotrexate as rescue therapy for unresolving acute grade 3 rejection or for early recurrence after one rejection episode that had been treated with steroids and antilymphocyte serum. All infants were treated with methotrexate for life-threatening rejection. Methotrexate was given as an adjunct to conventional treatment in six patients for mild rejection, which occurred while steroids were being decreased or in patients with relative contraindications to high-dose steroids. One grade 3b rejection could not be reversed with methotrexate and led to the patient's death 3 months later. One grade 1b rejection only temporarily improved and was actually reversed with high-dose steroids after 4 months. All other rejections were rapidly reversed with the use of methotrexate. Tolerance of methotrexate has been very good with transient leukopenia in four patients, with ulcerative stomatitis in one patient, and with transient elevation of liver enzymes in two patients. We conclude that methotrexate is a valuable rescue/adjunctive immunotherapeutic agent that is capable of altering heart rejection with considerable safety and efficacy.

Male donor into female recipient increases the risk of pediatric heart allograft rejection.

Sixty-one infants and children, 12 years old or younger, who received an orthotopic cardiac allograft between November 1985 and December 1989 were analyzed for the incidence of rejection. Rejection was diagnosed non-invasively within the first 3 months and during the first year. Rejection episodes were diagnosed by signs and symptoms according to previously reported criteria. Multiple regression analysis with recipient age, donor age, donor-recipient weight ratio, number of HLA mismatches, sex of the recipient, sex-encoded minor tissue antigen incompatibility (H-Y: female recipients receiving male donor organ), graft ischemic time, lowest cyclosporine level during the first 2 postoperative weeks, and prophylactic use of OKT3 showed that H-Y was the only significant contributing factor for rejection at 3 months and 1 year (r = 0.308, p < 0.02; r = 0.308, p < 0.02; respectively). Patients were divided into two groups: group 1, 45 patients who were H-Y compatible (male and female recipients receiving female donor hearts); and group 2, 16 patients who were H-Y incompatible (female recipients with male hearts). Patients in group 2 had significantly more episodes of graft rejection than did patients in group 1 by 3 months and by 12 months after heart transplantation (3 months: 2.75 +/- 1.48 versus 1.67 +/- 1.41, p < 0.05; 1 year: 4.80 +/- 1.87 versus 2.59 +/- 1.93, p < 0.01; respectively). There were six grafts lost due to rejection in group 2 (6/15, 37.5%) and 7 grafts lost (7/45, 15.5%) in Group 1 (not significant). Heart transplantation with H-Y incompatibility resulted in a significantly greater incidence of rejection episodes.

Utilization of pediatric donors salvaged by cardiopulmonary resuscitation.

The efficacy of using infant donors with an extended cardiopulmonary resuscitation (CPR) history was investigated. Eight heart transplantations with donors who had no or minimal (less than 10 minutes) history of CPR (group A) and seven heart transplantations with donors with extended CPR history (35 to 125 minutes; mean, 59 minutes; group B) were compared for peak myosin levels after transplantation, and systolic and diastolic cardiac function in the first week after transplantation. All donor hearts had normal hemodynamics in the early postoperative period. No significant differences were found between the groups with regard to age of donors, age of recipients, donor heart ischemic time, and cardiac function in the first week after transplantation. In group B, peak myosin levels were 1.4, 4.6, 7.0, 11.3, 14.8, 20.2, and 21.3 ng/ml. These values were significantly (p < 0.05) higher than those in group A but represented only minimal myocardial damage when compared with the values in previous myocardial infarction studies. Although donors with a history of protracted CPR had higher efflux of myosin light chains perioperatively, hemodynamic recovery suggests that use of pediatric donor heart grafts after prolonged CPR is safe and efficacious.

Prolonged preservation of human pediatric hearts for transplantation: correlation of ischemic time and subsequent function.

Ninety-one infants and children, aged 0 days to 12 years, who received 93 hearts from donors aged 2 days to 24 years between November 1985 and September 1990 were retrospectively studied. Forty-three children were less than 1 month of age; 31 children were between 1 month and 6 months of age, and 19 children were between 6 months and 12 years of age. The donor heart ischemic time ranged from 51 minutes to 8 hours 17 minutes (mean, 4 hours 2 minutes). Fifty-one hearts had an ischemic time of less than 4 hours (group 1), and 42 hearts, more than 4 hours (group 2). No significant difference was noted in the age of donor or recipient or in donor/recipient weight ratio. No correlation was found between ischemic time and number of primary graft failures between groups. Inotropic support was required for 3.9 +/- 3.3 and 5.2 +/- 3.7 days for group 1 versus group 2 (not significant). Ventilator status was the same between the groups. A significant decrease of posterior wall movement in diastole (p < 0.01) occurred among patients of group 2 at 1 week after transplantation, but no difference was found between groups at 2 weeks, 1 month, and 3 months after operation. Posterior wall movement of group 2 heart grafts recovered completely by week 2. No difference was noted in the fractional shortening between the groups; but in both groups, fractional shortening significantly increased from week 1 to week 2. We conclude that ischemic times up to nearly 8 1/2 hours are well tolerated by donor hearts used in pediatric transplantation.

Successful transplantation of hearts harvested 30 minutes after death from exsanguination.

The donor pool for heart transplants is severely limited. Unfortunately, many trauma patients who might be donors die of exsanguination before their organs can be used. We tested whether hearts "dead" for one half hour after exsanguination could be used as heart transplants in 8 lambs (mean weight, 8 kg). Four lambs were exsanguinated by severing the subclavian artery while simultaneously infusing intravenous saline solution to mimic resuscitation attempts. All animals died. Thirty minutes after hypotensive arrest and death, simulating the time needed to secure donation permission, the heart was harvested, perfused with 250 mL of cold cardioplegia containing 200,000 units of streptokinase to dissolve intravascular clots, and stored in iced saline solution for a mean of 1.5 hours while 4 recipient lambs were prepared for operation. After bypass and recipient heart excision, the "dead" donor heart was transplanted orthotopically. The heart was reperfused with low flow (25 mL/min), low pressure (30 mm Hg), low hematocrit (hematocrit, 0.08 to 0.12) blood supplemented with prostaglandin E1 and nifedipine for 15 minutes, followed by full flow rewarming for 45 minutes. All hearts resumed normal contractions. All animals were weaned from bypass without inotropes. Pressures a half hour after bypass were (in mm Hg): aorta, 80 +/- 10; pulmonary artery, 20 +/- 5; right atrium, 9 +/- 5; and left atrium, 9 +/- 2. We conclude that hearts "dead" for one half hour after exsanguination are capable of being reanimated and used successfully as donor organs. With further development, this method could potentially greatly expand the donor heart pool.

Aggressive peritoneal dialysis for treatment of acute kidney failure after neonatal heart transplantation.

Many infants with hypoplastic left heart syndrome are now treated with heart transplantation. Preoperative or postoperative systemic/renal hypoperfusion occurs frequently, however, resulting in perioperative kidney failure. Of 45 neonates undergoing heart transplantation at our institution, we report on 10 (22%) who required postoperative peritoneal dialysis. Patients' age at transplantation ranged between 1 and 31 (mean, 16.7) days, average weight was 2912 (range, 2140 to 3664) gms. Peritoneal dialysis was started at a mean of 51 hours after transplantation for treatment of anuria (5 patients, 50%), oliguria (3 patients, 30%), fluid overload or hyperkalemia (1 patient each, 10%) and continued for a mean of 101 +/- 90.5 (range, 33 to 270) hours. The value for blood urea nitrogen fell from 46.7 +/- 15.6 mg/dl to 14.3 +/- 10.5 mg/dl, and serum creatinine levels decreased from 2.4 +/- 1.0 mg/dl to 0.6 +/- 0.3 mg/dl throughout peritoneal dialysis. All patients continued to receive cyclosporine during dialysis. Hyperglycemia developed in four patients. Five of 10 patients had ongoing sepsis during dialysis, but only one died while on dialysis (10%). Two patients died late, after peritoneal dialysis was discontinued. Follow-up ranges from 2 months to 5 years. At most recent follow-up, mean creatinine level was 0.5 +/- 0.1 mg/dl. We conclude that aggressive peritoneal dialysis may result in high salvage rates with low morbidity, without the need to discontinue cyclosporine in the setting of neonatal heart transplantation and acute kidney failure.

Real-time monitoring of the endomyocardial biopsy site with pediatric transesophageal echocardiography.

We studied the feasibility of transesophageal echocardiography to guide endomyocardial biopsies in five heart transplant patients and two baboons with heart transplantations. The patients were 1 month to 1.5 years old with weight range of 2.9 to 9.5 kg. The two juvenile baboons weighed 6.6 and 7 kg. Transesophageal echocardiography was performed uneventfully in all cases with the use of sedation and anesthesia, which were necessary for catheterization. The combination of four-chamber and short-axis views easily identified the exact location of the bioptome within the heart, views that fluoroscopic imaging could not provide. Transesophageal echocardiography proved to be a safe and useful tool for guiding the endomyocardial biopsy procedure. With further refinement endomyocardial biopsy with only transesophageal echocardiography guidance could become the routine method for endomyocardial biopsies in infants, particularly when there are abnormalities of heart situs or position.

Changes in left ventricular mass with rejection after heart transplantation in infants.

Thirty-three infants who underwent successful heart transplantation before 6 months of age were studied to evaluate subacute changes in left ventricular mass (LVM) and its correlation to a history of rejection episodes. LVM and left ventricular wall mass (LVWM) and their percentage of predicted normal values were analyzed by means of M-mode echocardiography. LVM (as a percentage of predicted normal for body surface area) at 1 week, 1 month, and 3 months after transplantation was 103.2% +/- 24.5%, 137.3% +/- 36.0%, and 138.6% +/- 32.0%, respectively. Values for the wall mass were 82.1% +/- 23.0%, 111.3% +/- 35.7%, and 104.6% +/- 30.4%. After 1 and 3 months, both LVM and LVWM were significantly (p less than 0.01) increased from the values in the first week. The patients were subdivided on the basis of a history of rejection. There were six patients without a rejection episode within 1 month (group 1), 17 patients with one rejection episode (group 2), and 10 patients with two or more episodes (group 3). LVM at 1 month was 104.5% +/- 27.7% for group 1, 142.5% +/- 27.7% for group 2 (p less than 0.05), and 148.9% +/- 31.3% for group 3 (p less than 0.05). LVWM at 1 month was 83.4% +/- 24.6%, 114.8% +/- 35.3%, and 122.2% +/- 36.2% (groups 1 through 3, respectively). Thus an increase in posttransplant LVM may signify a rejection episode. Heart transplantation in infancy increases LVM and LVWM (septum and posterior wall); the degree of thickening of septum correlates well with rejection episodes.