M Zenati, AJ Duncan, GJ Burckart, M Schaper, SA Yousem, BP Griffith, and D Casarotto. 1991. “Immunosuppression with aerosolized cyclosporine for prevention of lung rejection in a rat model.” Eur J Cardiothorac Surg, 5, 5, Pp. 266-71; discussion 272.Abstract
The efficacy of local delivery of aerosol cyclosporine (CsA) for prevention of lung rejection was compared with the intramuscular route (IM) in a fully allogeneic rat model (BN/LEW) of lung transplantation (LTx). Control rats (group 1, n = 6) received no CsA after LTx. Rats in group 2 (n = 10) received 4 doses of CsA in olive oil (25 mg/kg) intramuscularly starting on postoperative day (POD) 0. Group 3 (n = 9) was treated with aerosolized CsA for 3 h/day for 7 days starting on POD 0. All animals were sacrificed on POD 6. Transplanted lungs were graded histologically in a blind manner on a 0-4 scale. Control animals all showed grade 4 rejection. i.m. CsA therapy reduced lung rejection with a rejection grade of 1.8 +/- 0.35 (mean +/- SD) but was associated with a 50% incidence of pneumonia. Aerosol CsA provided better control of rejection with a rejection grade of 1.2 +/- 0.4 (group 3 vs. group 2: P less than 0.05 Wilcoxon) and none of these animals had penumonia. Trough blood levels of CsA were significantly lower in the group treated with aerosolized CsA when compared with the IM group (P less than 0.05). Therefore we conclude that: (1) aerosol CsA is effective in preventing lung allograft rejection following lung transplantation in rats, and (2) local delivery of aerosol CsA is superior to the i.m. route because better control of rejection is achieved with a lower systemic delivery of CsA.
RD Dowling, M Zenati, GJ Burckart, SA Yousem, M Schaper, RL Simmons, RL Hardesty, and BP Griffith. 1990. “Aerosolized cyclosporine as single-agent immunotherapy in canine lung allografts.” Surgery, 108, 2, Pp. 198-204; discussion 204-5.Abstract
Current systemic immunosuppressive regimens are unable to prevent lung allograft rejection consistently and are associated with significant morbidity and death. Acute rejection has occurred in 40% and chronic rejection in 50% of our lung recipients. We hypothesized that regional immunotherapy with aerosolized cyclosporine would prevent or reduce lung allograft rejection while allowing for low systemic drug delivery. In a canine model of unilateral lung allotransplantation, aerosolized cyclosporine was delivered directly to the allograft. Acute rejection was prevented or reduced in all treated recipients. All control animals had severe acute rejection. Intragraft cyclosporine concentration was high and systemic drug delivery was low, as evidenced by low whole-blood cyclosporine levels and low tissue cyclosporine levels in skeletal muscle. Ninety-five percent of whole-blood trough cyclosporine levels were less than 150 ng/ml. Aerosolized cyclosporine was able to prevent or reduce acute pulmonary rejection and resulted in minimal systemic drug delivery.
RD Dowling, N Baladi, M Zenati, JS Dummer, RL Kormos, JM Armitage, SA Yousem, RL Hardesty, and BP Griffith. 1990. “Disruption of the aortic anastomosis after heart-lung transplantation.” Ann Thorac Surg, 49, 1, Pp. 118-22.Abstract
Disruption of the aorta at the anastomotic site occurred in 4 of 66 consecutive heart-lung transplant recipients and was associated with a 100% mortality. In 3 of these patients, Candida either was cultured from the suture line or was seen in the wall of the aorta at postmortem examination. In 2 of these 3 patients, cultures of material from the donor trachea taken at the time of explanation grew Candida species. Two patients were seen with sudden massive hemorrhage on postoperative day 26 and postoperative day 28. One patient experienced acute decompensation due to right ventricular outflow tract obstruction on postoperative day 30, and the remaining patient was seen 7 months postoperatively with obstruction of both the left main bronchus and the right pulmonary artery caused by extrinsic compression by an aortic pseudoaneurysm. A high index of suspicion should be maintained when transplanting lungs containing Candida species, as we believe there is substantial evidence of donor transmission of the fungal agents. We now include amphotericin B in our antibiotic prophylactic regimen in an attempt to prevent fungal infection because previous treatment has been uniformly unsuccessful. Furthermore, we wrap both the trachea and the aorta with omentum to lessen the likelihood of mediastinal spread of infection to the aortic suture line.
SA Yousem, JM Curley, J Dauber, I Paradis, H Rabinowich, A Zeevi, R Duquesnoy, R Dowling, M Zenati, and R Hardesty. 1990. “HLA-class II antigen expression in human heart-lung allografts.” Transplantation, 49, 5, Pp. 991-5.Abstract
Long-term survival in heart-lung transplantation has ben hindered by the development of bronchiolitis obliterans (OB), which is believed to be a manifestation of chronic rejection of the lung. Since HLA-class II antigens are involved in the rejection response, the distribution of the class II products HLA-DR, HLA-DQ, and HLA-DP were studied in normal lung, and in transplanted lung with and without OB, utilizing frozen-section immunohistochemical techniques. All three allelic products are usually expressed on the epithelial, endothelial, and mesenchymal components of the lung. Sequential transbronchial biopsies from 4 recipients before and concurrent with the diagnosis of OB were stained with serial dilutions of monoclonal antibodies to assess the level of expression of the above class II products. Increased levels of HLA-DR and HLA-DP antigens may be seen on the bronchial and bronchiolar epithelium during OB, but the changes are subtle and complicated by many other variables. Additional studies are needed to confirm these preliminary results.
M Zenati, RD Dowling, JS Dummer, IL Paradis, VC Arena, JM Armitage, RL Kormos, RL Hardesty, and BP Griffith. 1990. “Influence of the donor lung on development of early infections in lung transplant recipients.” J Heart Transplant, 9, 5, Pp. 502-8; discussion 508-9.Abstract
Infection of the lung allograft is the greatest cause of morbidity and mortality after heart-lung transplantation. To better understand the pathogenesis of these infections, we compared the results from cultures of the donor tracheas with the type and prevalence of early intrathoracic infections in the recipients. In the last 37 recipients, intrathoracic infections occurred within 2 weeks of operation in 16 (43%). Organisms isolated from the donor tracheal cultures were different from those associated with early infections, except for three of four recipients with heavy growth of Candida in donor tracheal cultures, in whom fatal invasive candidiasis developed caused by the same species of Candida isolated from the donor culture. Comparisons were made between recipients with (n = 16) and without early infection (n = 21) for age of donors and recipients, ischemic time, length of donor stay in an intensive care unit, donor arterial oxygen pressure, duration of recipient intubation, sterile donor tracheal culture or culture with presence of mouth flora, bacterial pathogens, or Candida, method of lung preservation, and antibiotic prophylaxis of donor. The only factor significantly associated with the onset of early infection was the presence of mouth flora in the donor tracheal culture (p = 0.004, Fisher's exact test, two sided). Multiple logistic regression was performed to test the additional contribution of other covariates after adjusting for the presence of mouth flora. None of the other covariates contributed to the occurrence of early infection. Recipients with early infection had a significantly lower survival compared with those without early infection (p = 0.04) by the Kaplan-Meier survival analysis.(ABSTRACT TRUNCATED AT 400 WORDS)
M Zenati, SA Yousem, RD Dowling, KL Stein, and BP Griffith. 1990. “Primary graft failure following pulmonary transplantation.” Transplantation, 50, 1, Pp. 165-7.
E Russo, M Zenati, D Morelli, M Beduschi, D Casarotto, D Marelli, and D Casarotti. 1990. “[Psycho-affective and relational aspects of children with congenital cardiopathy].” Pediatr Med Chir, 12, 1, Pp. 81-4.Abstract
The psychological and relational problems present in pediatric patients with congenital cardiac anomalies and in their families are reviewed based on an analysis of the current literature and on the personal experience of the authors. The need for all caretakers, especially the cardiologist and the cardiac surgeon, to be aware of these critical aspects is emphasized. The psychological experience of the patient and of his family is thoroughly addressed. Moreover, the complex relationship that developed between the family and the physician as a result of the family's expectations, requests and unconscious projections are discussed.
BP Griffith and M Zenati. 1990. “The pulmonary donor.” Clin Chest Med, 11, 2, Pp. 217-26.Abstract
This article discusses the Pittsburgh experience with the pulmonary donor and provides guidelines for the maintenance and selection of appropriate donor lungs. Criteria for the selection of the pulmonary donor include absence of radiographic abnormality, minimal ventilation-perfusion mismatch, and an absence of identifiable infection. Because early thoracic infections result in a high mortality, donors are excluded if white cells, fungi, or bacteria are noted in samples obtained from tracheal aspirates or bronchoscopic examination. A number of techniques for the procurement of donor lungs are currently satisfactory and include core cooling with the use of cardiopulmonary bypass and different hypothermic pulmonary artery flush solutions. Other clinical preservation techniques are discussed, including autoperfusion and the use of blood-based pulmoplegia and University of Wisconsin storage solution. Because so much of the outcome following pulmonary allografting is based on the quality of the donor lungs, much of the future direction in pulmonary transplantation must be directed toward a continuing investigation of better methods for selection and maintenance of the donor and ex vivo preservation.
RD Dowling, M Zenati, AW Pasculle, SA Yousem, BP Griffith, and RL Hardesty. 1989. “Experimental donor-transmitted pneumonia in a model of canine orthotopic unilateral lung allotransplantation.” Curr Surg, 46, 6, Pp. 464-7.
J Hsu, BP Griffith, RD Dowling, RL Kormos, JS Dummer, JM Armitage, M Zenati, and RL Hardesty. 1989. “Infections in mortally ill cardiac transplant recipients.” J Thorac Cardiovasc Surg, 98, 4, Pp. 506-9.Abstract
A total of 351 cardiac transplantations performed between June 1, 1980, and Sept. 30, 1987, were reviewed to determine if infectious complications were more frequent in those patients requiring preoperative intravenous inotropic support, placement of an intraaortic balloon pump, or mechanical support with a left ventricular assist device or total artificial heart. One hundred forty-nine transplants (45%) were performed in these mortally ill patients. There was no statistically significant difference between patients with and without infection within each support group for the following: the number of in-patient days awaiting a donor heart, the number of days receiving support, the percent of patients with preoperative tracheal intubation, the length of the operation, and the percent of patients requiring reoperation for bleeding. The need for invasive methods of support (intraaortic balloon pump, left ventricular assist device, or total artificial heart) in patients awaiting heart transplantation increases the prevalence of perioperative nonviral infection. Preoperative mechanical support with a left ventricular assist device or total artificial heart significantly increases the risk of infection-related mortality.
M Zenati, RD Dowling, SA Yousem, RL Hardesty, BP Griffith, and D Casarotto. 1989. “[New trends in combined transplantation of the heart and lungs].” G Ital Cardiol, 19, 10, Pp. 913-22.Abstract
Heart-lung transplantation is a surgical alternative for patients with end-stage lung disease with associated right heart failure. While the procedure is very promising, the morbidity and mortality remain high. The current understanding of the proper selection of candidates, procurement and preservation of donor organs, operative procedure and postoperative care continues to evolve. At the University of Pittsburgh, 70 heart-lung transplantations have been performed since 1982. Early infection and chronic rejection are the major factors influencing survival. Early (less than 2 weeks) intrathoracic infection occurred in 43% of heart-lung transplant recipients, with pneumonia being the most frequent infection. The incidence of pneumonia in heart-lung transplant recipients is twice that in a comparable group of heart recipients. Subclinical pneumonitis in the donor lung, abnormal muco-ciliary clearance and altered allogenic response in the transplanted lung are significant factors associated with the increased incidence of early infections. Chronic rejection, manifested as bronchiolitis obliterans, has occurred in 54% of heart-lung transplantation recipients. Infection caused by cytomegalovirus, Epstein-Barr virus and Pneumocystis carinii have been shown to increase the incidence of bronchiolitis obliterans, as have episodes of acute rejection. Recent reports of a 61% 2-year survival rate represent a substantial improvement over earlier trials. With a better understanding of the pathogenesis of infection in the transplanted lung as well as improved immunosuppressive agents, further improvements in survival can be expected.
M Zenati, RD Dowling, JM Armitage, RL Kormos, JS Dummer, RL Hardesty, and BP Griffith. 1989. “Organ procurement for pulmonary transplantation.” Ann Thorac Surg, 48, 6, Pp. 882-6.Abstract
Selection of suitable donors is critical to the success of clinical pulmonary transplantation. Requirements for lung donors, management before explantation, and methods of preservation were reviewed for the 70 heart-lung, eight double-lung, and two single-lung transplantations performed at the University of Pittsburgh since 1982. Careful observation of trends of hyperoxygenation studies, chest roentgenograms, and Gram stain and culture results of tracheal secretions, as well as findings on bronchoscopy, can help identify which lungs not only have adequate function but are acceptable for transplantation. In spite of the rigid criteria used, 76% of tracheal cultures from donors deemed acceptable grew organisms. The presence of oropharyngeal flora has been shown to correlate with the development of early intrathoracic infections in the recipient. Prophylactic broad-spectrum antibiotic treatment of the donor is desirable to treat microbial contamination that could cause focal injury to the donor lung and predispose to infection in the recipient. Acceptance of less than ideal donors is ill-advised even though rejection of such donors conflicts with the current shortage of organs.
L Brahimi, L Bacha, K Kozlowski, R Massen, and M Zenati. 1988. “Acro-mesomelic dysplasia--a new type. Report of two siblings.” Pediatr Radiol, 18, 1, Pp. 67-9.Abstract
Two siblings who represent a new type of acro-mesomelic dysplasia are reported. The unique pattern of the acro-mesomelic hypoplastic/dysplastic changes allows us to designate them as a new syndrome.
M Zenati, D Morelli, A Fabbri, and D Casarotto. 1988. “[Elements for an analysis of psychosocial indicators and psychological intervention in heart transplantation].” G Ital Cardiol, 18, 6, Pp. 479-84.Abstract
It is now accepted that cardiac transplantation is a viable therapeutic alternative for patients with end-stage heart disease. The most recent data offer a favourable short and medium term prognosis. Retrospective studies suggest that transplantation is associated with a good quality of life and tolerance of the side effects of the medication. Even if cardiac transplantation does not appear to be associated with serious psychological morbidity, it is important to assess the recipient's anxiety, depression, body image and his subjective quality of life, including satisfaction with his family and marital life, to prevent postoperative psychologic distress and enhance the patient's coping abilities. The family is the patient's chief buffer against stress but it is also under stress and needs to be aided through this process. The psychosocial themes that appear prominently at the different stages of the transplant process are somewhat predictable. These can be used to help the patient and family anticipate stress and deal with these issues in a way that enhances mastery of a difficult situation. The heart transplant team faces difficult ethical issues regarding patient selection and informed consent. Public input on these issues is needed, especially since more patients elect to receive heart transplants and the donor supply is likely to remain the same, thereby making donor hearts less available to those who could derive benefit from them.
D Casarotto, A Fabbri, A Motta, M Rebonato, M Zenati, and G Consolaro. 1985. “[Cardiac failure due to isolated pulmonary sequestration. Description of a clinical case in the neonatal period].” G Ital Cardiol, 15, 7, Pp. 725-8.Abstract
Pulmonary Sequestration is a congenital anomaly rarely seen in the pediatric age. Clinical manifestations commonly appear with a respiratory symptomatology and less frequently with cardiac signs especially in the case of an associated congenital heart disease. In the presented case, isolated Pulmonary Sequestration manifested itself as a congestive heart failure, and a diastolic overloading of the left ventricle. After surgical removal of the Sequestration was demonstrated a normalization of both clinical and haemodynamic findings.