Lung and heart-lung transplantation

This report is a brief summary on current events related to lung and heart-lung transplantation. Eleven patients have undergone transplantation of the heart and both lungs at Stanford University. The ages ranged from 22–45, the average age being about 36 years, and included were four females and seven males. The diagnosis was primary pulmonary hypertension in three and Eisenmenger syndrome-congenital heart disease with pulmonary hypertension-in eight. Eight patients are living and well, two to more than 24 months after transplantation of the heart and both lungs. All these patients were discharged and are fully rehabilitated, which is an important consideration. There have been three operative deaths, one was secondary to two previous operations that made our operation much too long, another was secondary to the use of intravenous cyclosporine, and the third was related to the poor maintenance of the donor lung. Three of the eleven patients were catheterized following the transplant from six months to a year after transplantation, and the pulmonary artery pressure and pulmonary vascular resistance were absolutely normal in all three of these individuals. Of course the plan is to go ahead with further catheter studies at yearly intervals in all of the patients. The last patient underwent transplantation in January, 1983. I think no matter how effective or how ingenious the medical staff is with artificial organs, it will be a long time before these early results of transplantation of the heart and both lungs can be matched by any types of artificial organ implants. Supported in part by a grant (HL 13108) from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, and from the Dr. Ralph and Marian Falk Foundation for Medical Research Gist of a Lecture given at the Japan Surgical Society, April 7, 1983.     

Lung and heart-lung transplantation

Unilateral lung transplantation has become a successful method for the treatment of end-stage pulmonary disease, whereas double-lung transplantation has provided benefit to patients with nonfibrotic lung disease such as emphysema and cystic fibrosis. In the past 5 years, 16 single-lung and 13 double-lung transplantations have been performed by the Toronto Lung Transplant Group in patients with end-stage lung disease. Seven perioperative and two late deaths have been recorded so far. Since the introduction of heart-lung transplantation at Stanford in 1981 and at Pittsburgh in 1982 for the treatment of Eisenmenger's syndrome and terminal pulmonary vascular disease, more than 350 combined heart-lung transplantations have been carried out throughout the world. Presently, the 2-year actuarial survival is about 62%. The long-term results have not yet reached the same level of success as those of cardiac transplantation alone. Although several factors have played a role in this difference, a prominent cause has been the lack of a reliable and simple method for pulmonary protection against prolonged ischemia. Most of the techniques proposed against ischemia can be classified as normothermic or static hypothermic cardiopulmonary preservation. The use of the normothermic method has not always been successful. For this reason, interest has now been directed toward the potential for hypothermic preservation of the heart-lung bloc and the use of free-radical scavenger therapy in the reduction of reperfusion injury.     

Lung and heart-lung transplantation

This report is a brief summary on current events related to lung and heart-lung transplantation. Eleven patients have undergone transplantation of the heart and both lungs at Stanford University. The ages ranged from 22-45, the average age being about 36 years, and included were four females and seven males. The diagnosis was primary pulmonary hypertension in three and Eisenmenger syndrome--congenital heart disease with pulmonary hypertension--in eight. Eight patients are living and well, two to more than 24 months after transplantation of the heart and both lungs. All these patients were discharged and are fully rehabilitated, which is an important consideration. There have been three operative deaths, one was secondary to two previous operations that made our operation much too long, another was secondary to the use of intravenous cyclosporine, and the third was related to the poor maintenance of the donor lung. Three of the eleven patients were catheterized following the transplant from six months to a year after transplantation, and the pulmonary artery pressure and pulmonary vascular resistance were absolutely normal in all three of these individuals. Of course the plan is to go ahead with further catheter studies at yearly intervals in all of the patients. The last patient underwent transplantation in January, 1983. I think no matter how effective or how ingenious the medical staff is with artificial organs, it will be a long time before these early results of transplantation of the heart and both lungs can be matched by any types of artificial organ implants.     

Cyclosporine in heart and heart-lung transplantation

At Stanford University Medical Center from January 1968 until January 1984, 288 patients received 313 heart transplants. The immunosuppressive regimen before December 1980 consisted of azathioprine and prednisone, with or without rabbit antithymocyte globulin. After that time cyclosporine replaced azathioprine. In 92 recipients of 95 heart allografts, the 1- and 3-year survival rates were 82% and 65% to 70% respectively. In the 3 years from March 1981 to March 1984, successful heart-lung transplantation was accomplished in 13 of 19 recipients, using cyclosporine-based immunosuppression. Survival ranged from 1 to 38 months. While it is true that cyclosporine has improved survival in heart transplant recipients, has allowed successful heart-lung transplantation to be performed, has shortened intensive care unit and total hospital stays and therefore hospital costs, and has allowed easier management of rejection and infection, several disconcerting problems have not yet been resolved. These include hypertension that is difficult to control and renal dysfunction in all patients, and the fact that cellular and humoral rejection still occurs, as manifested by graft atherosclerosis, bronchiolitis obliterans and classic acute rejection. Better understanding and application of cyclosporine immunosuppression will undoubtedly minimize both cyclosporine- and non-cyclosporine-related postoperative complications and will improve survival even further.     

Pregnancy and heart-lung transplantation.

The purpose of this study was to report a single center's experience of 5 new pregnancies following heart-lung transplantation. These 5 pregnancies gave rise to 4 live births. Vaginal delivery occurred at a mean of 38 +/- 1 weeks of amenorrhea (range, 37-39 weeks) and the mean birth weight was 3,143 +/- 757 grams (range, 2,270-3,990 grams). Mean maternal forced expiratory volume in 1 second (%) before, during (sixth month), and after (1 year) pregnancy was 87 +/- 18, 87 +/- 22, and 88 +/- 17, respectively (p = NS). In conclusion, pregnancy after heart-lung transplantation can be associated with a good prognosis for mother and child.     

Allogeneic heart-lung transplantation in mice

Using a simpler technique for mouse heart and lung transplantation, a histological comparison was made between groups of syngeneic and allogeneic transplants. The initial high postoperative mortality encountered was due to technical difficulty and as the operative technique improved, mortality lessened. While direct palpation of the abdomen is the key means in the detection of graft rejection, there is no practical determination of such graft rejection other than histological clarification. Doppler tracing also is not a sensitive method for detecting rejection. The transplantation technique in this study compares the time of rejection of heart and lung transplants more legitimately.     

Recipient selection for heart-lung transplantation

Cardiac transplantation has emerged as a standard mode of clinical therapy for end-stage heart failure, while heart-lung transplantation is still an experimental rather than a standard mode of clinical therapy for end-stage heart and lung disease. Since clinical application of heart-lung transplantation began in March 1981, there has been continual improvement in donor care, surgery, post-operative management, and the diagnosis and treatment of lung and heart rejection. According to our 6-year clinical experience, both patients with Eisenmenger's physiology and patients with primary pulmonary hypertension are considered suitable candidates for heart-lung transplantation. In the future, our recipient population will include small children and patients with cystic fibrosis. Suitable candidates must have good liver and kidney function, and freedom from previous major pulmonary emboli, systemic diseases, and previous thoracic surgery. Patients must maintain their functional and emotional status to pass successfully the difficult postoperative period. Proper donor and recipient selection in connection with improved heart-lung preservation has resulted in excellent operative survival (100%) following the last ten operations, and only the lack of suitable donors can limit the number of heart-lung transplantations in the future.     

Improved survival after heart-lung transplantation

Sixty-two patients underwent 65 heart-lung transplant operations before April 1989. Thirty of these patients (operated on March 1981 to February 1986) were given cyclosporine and prednisone for immunosuppression. These 30 patients (group 1) are compared with the 32 most recent patients (group 2) treated with cyclosporine, prednisone, and azathioprine. Patient characteristics (group 1 versus group 2) were similar including age (mean 32 versus 26 years) and indication for operation (51% versus 38%, primary pulmonary hypertension; 46% versus 45%, Eisenmenger complex; 3% versus 17%, other). The perioperative (in-hospital) mortality rate was 35% in group 1 versus 16% in group 2. Obliterative bronchiolitis developed in 12 (63%) of 19 hospital survivors in group 1 from 2 months to 49 months postoperatively (mean 12 months). This complication has developed in five (20%) of the 25 hospital survivors in group 2 from 3 to 13 months postoperatively (mean 8 months). Overall, 24 of the 30 patients in group 1 died (infection in eight, obliterative bronchiolitis in five, graft coronary artery disease in two, other causes in nine). Eight of the 32 patients in group 2 died (infection in six, other cases in two). Survival rates for group 1 patients were 60% at 1 year, 50% at 2 years, 43% at 3 years, and 25% at 5 years. Survival rates for group 2 patients were 73% at 1 year, 73% at 2 years, and 65% at 3 years (p less than 0.05). When group 2 patients were compared with 134 patients undergoing heart transplantation during the same time period, there was no difference in survival. Routine bronchoscopic surveillance in the more recent group of patients has led to the earlier detection of rejection and infection. In combination with decreased perioperative mortality and augmented immunosuppression, this had led to improved survival in our more recent heart-lung transplant recipients. In addition, the earlier recognition of infection and rejection has led to a decrease in severity of obliterative bronchiolitis.     

Late-onset chylothorax after heart-lung transplantation

Chylothorax has rarely been reported after heart and lung transplantation. We describe a case of a bilateral chylothorax that occurred in a 53-year-old man 4 months after heart-lung transplantation and review the three additional reports in the literature of chylothorax after heart transplantation. Chyle drainage may cause compromise of the transplant patient. The good nutritional status of our recipient, however, allowed conservative therapy with chest tube drainage and enteral low-fat diet, without the need for surgical intervention. We concluded that chylothorax can presents late after lung transplantation and that conservative treatment should be considered in patients with good nutritional status.     

Operative technique for heart-lung transplantation

Combined heart and lung transplantation has now been carried out in 17 patients at Stanford University Hospital. The emphasis on the management of donors is upon thorough tracheobronchial toilet and ensuring an absence of significant cardiopulmonary disease. The most important aspects of the recipient operation are to remove the heart and lungs without injury to the phrenic, vagus, or recurrent laryngeal nerves and to ensure hemostasis. This is best effected if the heart and lungs are removed separately. The operative technique for both the donor and recipient is described.     

Surgical management of heart-lung transplantation

Using cyclosporin A, long-term survival after heart-lung transplantation became possible. The drug blocks the immune system more selectively and leaves the tracheal wound healing unimpaired. Since 1981, 501 clinical cases have been collected by the registry of the International Society for Heart Transplantation. Candidates for heart-lung transplantation reveal signs of irreversible heart and lung diseases that may have been caused by cardiac lesions (valvular diseases, Eisenmenger reaction due to congenital malformations) or by pulmonic disorders (primary pulmonary hypertension, emphysema, fibrosis). The standard surgical procedure, which combines donor and recipient tracheas, right atria, and aortas, makes three anastomoses necessary. Immunosuppressive regimen includes cyclosporin A (blood trough levels of 300 to 500 ng/mL), azathioprine (1 to 2 mg/kg), and rabbit antithymocyte globulin (1 to 4 mg immunoglobulin G/kg). After the first two postoperative weeks, rabbit antithymocyte globulin is replaced by methylprednisolone (0.3 to 0.1 mg/kg; 500 mg are given intravenously after opening the aortic cross-clamp; 3 x 125 mg on postoperative day 1). After heart-lung transplantation an extreme variety of problems may evolve. Early postoperative complications (within the first postoperative month) comprise acute isolated lung rejection, multiorgan failure, and bacterial pneumonia. Diagnosis of acute lung rejection proves difficult; it includes clinical signs, chest radiographic appearances, and cytoimmunological monitoring. Transbronchial lung biopsies are of similar value for precise diagnosis as are endomyocardial specimens after heart transplantation. Late postoperative complications (after 1 postoperative month) comprise viral pneumonia, fungal infection, tuberculosis, and chronic obliterative bronchiolitis.(ABSTRACT TRUNCATED AT 250 WORDS)     

General surgical complications in heart and heart-lung transplantation

One hundred forty-three patients underwent cardiac transplantation from 1980 to 1985; 122 received a heart, 19 received a heart-lung, and two received a heart-liver transplant. All patients received immunosuppression with prednisone and cyclosporine. General surgical complications have developed since transplantation in 40 patients (28%). Of these, 17 patients have required surgery: exploratory laparotomy (10 patients), inguinal or ventral herniorrhaphy (two patients), repair of false aneurysm of the femoral artery (two patients), repair of lymphocele of the groin (two patients), and incision and drainage of a perirectal abscess (one patient). Of the 10 patients who required laparotomy, three underwent sigmoid resection for a perforated sigmoid diverticulum (all survived), two underwent small bowel resection for perforation (both died), two had free intraperitoneal air with no site of perforation found (one died), one underwent a cholecystostomy and one a cholecystectomy for acute calculous cholecystitis (one died), and one underwent an elective pyloroplasty for gastric outlet obstruction secondary to vagus nerve injury during heart-lung transplantation and survived. All patients who underwent elective surgery survived. Six patients died without operation and at autopsy were found to have unrecognized general surgical complications including pancreatitis (three patients), cecal ulceration with sepsis (two patients), and jejunal perforation secondary to peritoneal dialysis (one patient). Eleven other patients had severe abdominal pain and five had gastrointestinal hemorrhage not requiring operation. Proper management of these patients includes early and aggressive diagnosis of conditions requiring operative intervention, strict attention to surgical technique, and careful titration of dose of immunosuppressive drugs. The 28% incidence of general surgical complications associated with heart and heart-lung transplantation emphasizes the role of the general surgeon in the management of these complex patients.     

Renal complications following lung and heart-lung transplantation

As survival improves after lung and heart-lung transplants, the long term detrimental impact of current management on renal function becomes more apparent as the number of non-renal solid organ transplant recipients on renal transplant waiting lists increases. Progressive chronic kidney disease (CKD) is a significant cause of morbidity and mortality in the transplant population. In this review we discuss the specific problems prior to lung or heart-lung transplant that predispose to CKD, as well as potential renal complications encountered during the peri- and post-transplant period. Significant acute and chronic nephrotoxicity is caused by calcineurin inhibitors (CNI). Mechanisms to decrease CNI exposure exist but have yet to be adopted in routine clinical care. Modifiable risk factors and the current screening and management approach taken at our institution are described. Pediatric nephrologists should be involved from an early stage. Future work will need to focus on identifying more accurate measures of renal function, given the limitations of current glomerular filtration rate estimation equations in a population where nutritional status may rapidly change post transplant. Multicentre studies of CNI minimisation strategies are required to guide future therapy that aims to minimise CKD development and progression in this vulnerable population.     

Ganciclovir prophylaxis after lung and heart-lung transplantation

Abstract Cytomegalovirus (CMV) infection causes both acute and chronic allograft damage. The aim of this study was to analyze the utility of ganciclovir in preventing CMV infection in pulmonary allografts. Thirty five consecutive lung (LTX) and heart-lung (HLTX) transplant patients were studied from 1990 to 1996 CMV prophylaxis was started in January 1995. Recipients with CMV-positive serology received ganciclovir on postoperative days (POD) 7–28. Acyclovir was given on POD 29–90. Recipients with CMV-negative serology received ganciclovir on POD 7–90 if the serology of the donor was positive. CMV was demonstrated by rapid cell vial culture and/or detecting CMV-specific antigens in bronchoalveolar lavage (BAL) samples. The time point of the first BAL fluid specimen exhibiting CMV was estimated using the Life Table method. BAL samples of all the recipients without ganciclovir treatment became positive for CMV, whereas two of the 11 patients with ganciclovir administration remained negative. Ganciclovir significantly ( P < 0.05) delayed but did not absolutely prevent CMV infection after LTX and HLTX.