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Biomedical subjects

R E Michler

Publications and source records attributed to R E Michler.

At least 163 records · Page 9Linked to original sources
PubMed1986

Reversal of cardiac transplant rejection without massive immunosuppression.

Although cyclosporine has decreased the severity of acute cardiac transplant rejection, most centers have continued to use high-dose intravenous steroids to treat acute rejection. To minimize the morbidity of antirejection therapy, acute rejection episodes in 37 cardiac transplant recipients were treated prospectively with only a boost of oral prednisone. Cyclosporine was continued at the same maintenance dose while oral prednisone was increased to 100 mg/day for 3 days, then rapidly tapered over 1 week to the maintenance dose. Seventy-six of 85 acute rejection episodes (90%) showed histologic resolution of mycocyte necrosis on repeat biopsy. Three acute rejection episodes (3.5%) resolved only after "rescue therapy" with intravenous steroid, and an additional three episodes (3.5%) required the combination of intravenous steroid and rabbit antithymocyte globulin to effect resolution. In addition, three acute rejection episodes (3.5%) resulted in graft loss. This was fatal in two patients and one patient underwent successful retransplantation. Oral steroid therapy alone is adequate therapy for most acute rejection episodes in cyclosporine-treated heart transplant recipients, and low infectious morbidity and mortality has been associated with this antirejection protocol.

Adolescent↗
PubMed1985

Technique for primate heterotopic cardiac xenotransplantation.

Heterotopic cardiac transplantation in the primate is a valuable method for the evaluation of immuno-suppressive regimens. This report describes our technique for heterotopic transplantation of cardiac grafts into the neck of baboons. Preliminary experience with cross-genus cardiac transplantation in the nonhuman primate is discussed.

Animals↗
PubMedDate not supplied

Immature host for xenotransplantation.

The overall shortage of appropriate donor organs has prompted transplant physicians and surgeons to consider using organs from other nonhuman species. The shortage of appropriate human donor hearts for newborn recipients is especially severe. Presently, the pig appears to be the most appropriate source for organs. Humans and baboons uniformly develop high titers of complement-fixing (IgM) anti-pig xenoantibodies, resulting in complement-mediated hyperacute rejection (HAR) of pig organs transplanted into mature baboons within minutes to hours. In contrast, newborn humans and baboons do not have high titers of anti-pig IgM xenoantibody, and consequently pig cardiac xenografts transplanted into newborn baboons do not undergo HAR. Rather, these organs are rejected at days 3 to 4 by a distinctive immunologic process that involves natural killer cells and macrophages. With the addition of cyclosporine-based triple immunosuppression, this process is reduced and graft life is prolonged to 6 to 7 days. This therapy, however, is not sufficient to prevent the induced humoral response to the graft, and the organs are rejected by antibody- and complement-dependent mechanisms. Future treatment strategies to reduce this humoral response must incorporate immunodepletion columns, soluble complement-inhibiting agents, and additional anti-B lymphocyte agents. These strategies, in conjunction with the use of transgenic pig organs that express human membrane-bound complement regulatory proteins or reduced xenoantigenic epitopes could further prolong graft life. Clinical trials are being formulated that would utilize pig organs as a "bridge," sustaining a newborn human in need of a heart transplant until an appropriate donor is located.

Animals↗
PubMedDate not supplied

Left ventricular assist device options in pediatric patients.

Left ventricular assist devices can be successfully used in the pediatric population if currently available devices are used appropriately. To highlight their management strategies, the authors' experience with pediatric left ventricular assist devices is reviewed, with case studies documenting options for device use. A retrospective study was conducted for all patients supported at the authors' institutions. Nine pediatric patients received devices during this time, with ages ranging from 12 days to 15 years. There was considerable size differences in our patients, with weights ranging between 2.5 and 73 kg. Either the Abiomed BVS 5000 (Abiomed Cardiovascular, Inc, Danvers, MA) or the Biomedicus centrifugal pump (Bio-Medicus, Inc, Eden Prairie, MN) were used for all patients. Patients were supported for an average of 5 days (range 1-11 days). Eight patients were successfully weaned from the device, with four undergoing transplant. Four patients were discharged and are long-term survivors, and one is still recovering post transplant. Neurologic sequelae were the most common complications in these patients, with four patients having events. Pediatric ventricular assist devices are limited because of size considerations, although current devices can be successfully used for bridging to recovery or transplantation. New devices are needed to meet the flow and size characteristics for pediatric patients. Successful use of assist devices, as has been recognized in adults, is possible in pediatric patients if these requirements are met.

Adolescent↗
PubMedDate not supplied

Predictors of survival after repeat heart transplantation. The Registry of the International Society for Heart and Lung Transplantation, and Contributing Investigators.

To examine factors potentially predictive of outcome after repeat heart transplantation, data were analyzed for 449 recipients of second allografts reported to the registry of the International Society for Heart and Lung Transplantation and a matched group of 421 primary transplant recipients. Survival was markedly decreased in repeat transplantation patients (1 year actuarial survival rate, 48% vs 79%; p less than 0.001). Univariate analysis showed no impact on survival of recipient age or gender, ischemic time, or transplant center experience. Accelerated coronary artery disease as the cause of allograft failure, longer interval between transplants, lack of preoperative mechanical assistance, and second transplantation after 1985 were predictive of increased survival after repeat transplantation. An "ideal candidate" defined by these predictive variables had a 1-year survival rate of 64%. In addition to the International Society for Heart and Lung Transplantation registry, a multicenter data base was developed with data for 125 repeat transplant recipients and 1325 primary transplant recipients at 13 transplant centers in the United States. In this group of patients the 1-year survival rate was greater than that in the International Society for Heart and Lung Transplantation registry (60% vs 48%), and the impact of the predictive variables listed previously was decreased. The incidence of rejection, infection, and accelerated coronary artery disease was not different between secondary and primary allograft recipients. Nonskin malignancies occurred more frequently in repeat transplantation patients (8% vs 4%; p less than 0.05). Recipients of second allografts were more likely to have major surgical complications, had a higher level of sensitization to HLA antigens, and were more likely to have a positive donor-specific crossmatch (17% vs 2%). A trend toward improved survival was noted in patients with repetition in the second donor of mismatched HLA antigens present in the first donor (1-year survival rate of 68% vs 47%; p = 0.06). We conclude that longer interval between transplants, accelerated coronary artery disease as cause of allograft loss, and lack of preoperative mechanical assistance are predictive of longer survival after repeat transplantation. Nonetheless, the "ideal candidate" for repeat transplantation has an anticipated survival rate significantly less than that expected for primary transplant recipients.

Adult↗
PubMedDate not supplied

Present status of human cardiac allografts and prospects for xenografts.

Cardiac allotransplantation is no longer experimental. It is the standard by which all other methods of cardiac replacement must be judged. The dramatic improvement in survival and the quality of life of cardiac transplant recipients reflects many factors including refined criteria for patient and donor selection, as well as the clinical introduction of cyclosporine. Current contraindications to the procedure include: 1) age greater than 65 years, 2) active infection, 3) active malignant neoplastic disease, 4) recent pulmonary embolus or infarction, 5) irreversible renal or hepatic failure, and 6) fixed elevation of pulmonary vascular resistance. The introduction of cyclosporine has been accompanied by an increase in the 1 year survival. While the use of cyclosporine has not decreased the incidence of rejection episodes, it has dramatically decreased their severity. In addition, the incidence and severity of infectious complications, as well as the length of hospitalization, have been decreased with the introduction of cyclosporine. Despite the progress made, several problems remain in the management of transplant recipients. Chronic cyclosporine therapy has been associated with a disturbingly high incidence of hypertension and renal impairment, and a low, yet significant, incidence of malignant neoplasms. However, the most significant obstacle to successful clinical cardiac transplantation is the scarcity of donor organs. Many centers now report that the mortality rate for patients awaiting transplantation exceeds the mortality associated with the procedure itself. Donor scarcity has led to renewed interest in the development of mechanical cardiac devices and investigation into cross-species transplantation (xenotransplantation).

Bacterial Infections↗
PubMedDate not supplied

Role of the carrier solution in cyclosporine pharmacokinetics in the baboon.

Although numerous investigational models have demonstrated the potent immunosuppressive properties of cyclosporine, the effectiveness of any given dosage may vary with the metabolism of the animal, the route of administration, and the carrier solution of the drug. We investigated the pharmacokinetics of intramuscular cyclosporine administration in the baboon using three carriers: polyoxethylated castor oil (Cremophor), a mixture of octanoic and decanoic acids (Miglyol), and olive oil. Cyclosporine prepared in Cremophor, Miglyol, or olive oil was injected intramuscularly into the hindlegs of baboons. Specimens for cyclosporine assay were obtained 2, 4, 6, 12, 18, and 24 hours after single intramuscular injection of 10 mg/kg or 15 mg/kg. In addition, weekly, then monthly, levels were obtained on animals receiving daily intramuscular injections following heterotopic heart xenografts. Attempts at oral administration proved unreliable and were discontinued. Cyclosporine assay was performed on stored serum using the RIA-KIT (Sandoz Pharmaceuticals Corporation, East Hanover, N.J.). Cremophor provides a more bioavailable form of cyclosporine than Miglyol when administered intramuscularly. (Area under curve = 7776 +/- 1437 for Cremophor 15 mg/kg vs 1837 +/- 726 for Miglyol 15 mg/kg; 2579 +/- 694 for Cremophor 10 vs 1123 +/- 393 for Miglyol 10.) Long-term daily intramuscular administration of Cremophor provides a sustained drug serum trough level with wide variability between individual animals (80 to 825 ng/ml). Toxicity was limited to injection site inflammation. There was no biochemical evidence of renal toxicity; however, some animals did demonstrate early histologic changes of cyclosporine effect.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMedDate not supplied

Natural antipig xenoantibody is absent in neonatal human serum.

BACKGROUND: Discordant xenotransplantation represents an attractive alternative to allotransplantation in light of the current shortage of donor organs suitable for heart allotransplantation. Unfortunately, discordant xenotransplantation is still limited by hyperacute rejection, a process thought to be mediated by natural antixenodonor antibodies. On the basis of our previous findings that cytotoxic natural xenoantibodies are immunoglobulin M in nature and that natural immunoglobulin M xenoantibodies are barely detectable in neonatal baboon serum, we postulated that immunoglobulin M xenoantibodies may be absent from newborn human serum. METHODS: Neonatal human sera were obtained from the cord blood of normal term infants and pooled. Pooled adult human sera were used as a control. A whole cell enzyme-linked immunosorbent assay and a complement-mediated cytotoxicity assay were performed to determine the binding and cytotoxicity of these xenoantibodies to pig aortic endothelial cells and pig lymphocytes. RESULTS: Neonatal human sera did not show binding of immunoglobulin M xenoantibodies to pig aortic endothelial cells or lymphocytes. However, low level binding of immunoglobulin G xenoantibodies was detected to pig endothelial cells and lymphocytes. In contrast, adult human sera showed significant binding of both natural immunoglobulin M and G xenoantibodies to pig aortic endothelial cells and lymphocytes. In addition, adult human immunoglobulin M xenoantibodies bound with similar avidity to both cultured adult and neonatal pig aortic endothelial cells. Although neonatal human sera were not cytotoxic to target cells, adult sera were cytotoxic to both pig aortic endothelial cells and pig lymphocytes. Our findings indicate that neonatal human sera lack natural antipig immunoglobulin M xenoantibodies, and therefore, neonatal human serum is not cytotoxic to pig endothelial cells or lymphocytes. Like adult pig endothelial cells, neonatal pig endothelial cells may also express similar membrane xenoantigens recognized by natural immunoglobulin M xenoantibodies. CONCLUSIONS: The absence of cytotoxic natural immunoglobulin M xenoantibodies in the neonate suggests that discordant xenotransplantation may be feasible in the neonate.

Adult↗
PubMedDate not supplied

Experience with heart transplantation for cardiac tumors.

BACKGROUND: Primary cardiac tumors are rare clinical entities. Benign tumors are often amenable to surgical excision, whereas malignant tumors are seldom resectable. Five patients have been reported to undergo orthotopic heart transplantation for inoperable primary cardiac tumors. We review the clinical course of these five patients and present our institutional experience with three patients who underwent orthotopic heart transplantation as primary therapy for unresectable cardiac tumors. METHODS: Retrospective chart review and telephone interview, when possible, were used to gather historical and clinical course data. RESULTS: Of the eight patients who underwent orthotopic heart transplantation for primary cardiac neoplasms, four had malignant tumors (three sarcomas, one lymphoma) and four had locally invasive neoplasms (three fibromas, one pheochromocytoma). For those patients in whom cardiectomy resulted in surgical margins free of tumor (six of eight), orthotopic heart transplantation provided long-term survival (range 14 to 78 months) without tumor recurrence despite therapeutic immunosuppression. The only death in this group, at 6.2 years after operation, was unrelated to tumor recurrence. The patients with tumor identified at the surgical margins died of metastatic disease at 14 and 15 months after the operation in spite of adjuvant chemotherapy. CONCLUSIONS: An awareness by clinicians of the presenting clinical picture of these tumors is warranted in view of the potential for cure by resection or transplantation. Patients with benign primary cardiac tumors appear to benefit from the complete resection afforded by cardiectomy and transplantation. The role of transplantation for patients with malignant tumors remains unclear. Additional studies and continued follow-up with serial echocardiography is necessary to further ascertain the role of heart transplantation in the management of patients with primary cardiac tumors.

Adult↗