Tacrolimus (FK 506) in clinical cardiac transplantation: a five-year experience.
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Adult↗
Biomedical subjects
B P Griffith
Publications and source records attributed to B P Griffith.
Prediction of mortality in patients awaiting cardiac transplantation: increased risk of sudden death in ischemic compared to idiopathic dilated cardiomyopathy.
A major problem in cardiac transplantation is the death of candidates due to the increasing shortage of donors and the consequent longer waiting periods. To determine whether clinical markers for death could be identified in these patients, 168 adult candidates with heart failure (NYHA class III and IV) listed between August 1987 and December 1989 were analyzed. There were 104 patients with ischemic cardiomyopathy (ISCM) and 64 with idiopathic dilated cardiomyopathy (IDCM). Transplantation was performed in 93 patients (55%). Actuarial 1 year survival was 61% in the ISCM group and 78% in the IDCM group (P = NS). Freedom from sudden death at one year was significantly lower in the ISCM group (73%) than in the IDCM group (96%) (P < 0.01). The rate of patients who did not die from terminal myocardial failure was 83% in the ISCM group and 81% in the IDCM group (P = NS). There were no significant differences between the two groups in right atrial, pulmonary artery, and pulmonary wedge pressures, transpulmonic pressure gradient, pulmonary vascular resistance, cardiac index, and ejection fraction. We conclude that candidates for cardiac transplantation with ISCM are at higher risk for sudden death during the first year on the waiting list than patients with IDCM. These results warrant consideration of aggressive arrhythmia control measures, including an automatic implantable defibrillator, to "bridge" these high risk patients to transplantation.
Actuarial Analysis↗
Daily serum interleukin-6 monitoring in multiple organ transplantation with or without liver allografts.
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Acute Disease↗
Chimerism and thoracic organ transplantation.
Current nonspecific immunosuppression for thoracic organ transplantation is limited by infection, end-organ toxicity, malignancy, and failure to completely control rejection. Donor-specific transplantation tolerance after bone marrow transplantation and the creation of mixed chimerism is a promising means for achieving drug-free allograft acceptance. This review explores bone marrow transplantation as a method for tolerance induction, the superior clinical characteristics of mixed chimerism, and recent developments that enhance marrow engraftment, minimize graft-versus host disease, and avoid lethal conditioning of the recipient. The importance of microchimerism in clinical transplantation and clinical trials aimed at augmentation of this phenomenon are reviewed.
Animals↗
Medical compliance and its predictors in the first year after heart transplantation.
BACKGROUND: Although poor medical compliance is a major risk factor for morbidity and mortality after heart transplantation, no prospective data are available on rates of noncompliance with each component of the posttransplantation regimen. Little is known about the impact of health history, sociodemographic, or perioperative psychosocial variables on long-term compliance. METHODS: Compliance in eight domains was examined in a cohort of 101 heart recipients followed through the first year after transplantation. Patients received detailed interviews at 2, 7, and 12 months after transplantation. Additional corroborative information was obtained from family member interviews and nurse evaluations. Potential predictors of noncompliance were obtained from medical record reviews and from initial patient interviews. Predictors pertained to cardiac-related history, psychiatric history, sociodemographic variables, and perioperative psychosocial status (psychologic adaptation, social supports, coping strategies). RESULTS: Although degree of noncompliance varied across timepoints, rates of persistent noncompliance during the year were as follows: 37% (exercise); 34% (monitoring blood pressure); 20% (medications); 19% (smoking); 18% (diet); 15% (having blood work completed); 9% (clinic attendance); and 6% (heavy drinking). Compliance in most areas worsened significantly (p < 0.05) over time. Background health-related and sociodemographic characteristics showed no significant influence on any area of posttransplantation compliance. Perioperative psychosocial characteristics were strong and significant predictors of noncompliance. CONCLUSIONS: Pretransplantation screening for background and demographic variables may have limited utility for compliance outcomes. Strategies to improve compliance should focus on psychosocial risk factors pertaining to early psychologic reactions to transplantation, the quality of family relationships, and patients' styles of coping. These risk factors are each potentially modifiable through appropriate educational and supportive interventions.
Adolescent↗
High-resolution fluorescent particle-tracking flow visualization within an intraventricular axial flow left ventricular assist device.
Flow visualization is typically applied in blood pump development to both confirm the design expectations and identify regions that may be predisposed to blood element deposition and trauma. Rotary pumps, in particular, place high demands on the technique chosen to visualize the flow given the limited visual accessibility of the flow path and the high impeller speeds. Fluorescent image-tracking velocimetry currently is used at the University of Pittsburgh Medical Center to visualize flow accurately inside of these pumps both qualitatively and quantitatively. Flow patterns under steady conditions within an intraventricular axial flow, left ventricular assist pump (prototype No. 7, SUN Medical Technology Research Corporation, Nagano, Japan) were investigated using this technique. The flow fields at the impeller-stator interface and at the pump outlet were given specific attention. This allowed the assessment of the fluid dynamics throughout the hydrodynamic design limits of the pump.
Biomechanical Phenomena↗
Prolonged survival of hamster-to-rat pulmonary xenografts by tacrolimus (FK506) and cyclophosphamide.
BACKGROUND: Severe shortage of donor organs in clinical lung transplantation prompted us to investigate the potential use of pulmonary xenografts. The purpose of this study was to determine whether an immunosuppressive regimen of tacrolimus (FK506) and cyclophosphamide would prolong the survival of hamster-to-rat pulmonary xenografts. METHOD: Left lung transplantation was done with male Golden Syrian hamsters used as donors and inbred male Lewis rats as recipients. Control animals (n = 10) received no immunosuppressive drugs whereas experimental animals (n = 6) were treated with tacrolimus and cyclophosphamide. Tacrolimus was administered intramuscularly at a dosage of 2 mg/kg per day on postoperative days 0 to 4, followed by 1 mg/kg per day on days 5 to 29 and 0.5 mg/kg per day on days 30 to 99. Cyclophosphamide (8 mg/kg per day) was administered orally from the day before transplantation to day 8. After transplantation the animals were monitored by chest radiography. Recipient animals were killed at timed intervals (days 60 and 100) and when the chest radiograph showed complete opacification of the transplanted lung. At necropsy, pulmonary xenografts were examined histologically for evidence of rejection, which was graded on a scale of 0 (no rejection) to 4 (severe rejection). Antihamster lymphocytotoxic antibody titer was also measured in recipient animals after transplantation. RESULTS: Pulmonary xenografts in the control animals had a median [correction of medium] survival time of 3 days, whereas the median survival in treated animals was more than 74 days. All pulmonary xenografts in control animals had severe rejection on day 3 after transplantation, whereas those in the treated animals had no rejection on days 60 and 100. The lymphocytotoxic antibody titers in control animals increased from 1:16 before operation to 1:4096 on day 3 (p < 0.01). In the treated animals, the lymphocytotoxic antibody titer on day 21 was 1: 8, which was not different from the preoperative value (1:16). CONCLUSION: These results indicate that a combination of tacrolimus and a short course of cyclophosphamide prolongs the survival of pulmonary xenografts in a hamster-to-rat model.
Animals↗
Automated echocardiographic measures of right ventricular area as an index of volume and end-systolic pressure-area relations to assess right ventricular function.
BACKGROUND: On-line determination of right ventricular (RV) volume to assess its function is clinically difficult. Echocardiographic automated border detection measures of left ventricular (LV) cavity area have been shown to reflect changes in volume, and pressure-area relations have been used to estimate LV contractility. The potential for RV cavity area to estimate changes in volume and to assess RV function, however, has not been evaluated. Accordingly, the objective of this study was to determine the relation between echocardiographic automated border-detected RV cross-sectional area and true volume and to assess the potential for end-systolic pressure-area relations to estimate RV function in an isovolumically contracting isolated canine heart preparation. METHODS AND RESULTS: Eight excised dog hearts with both right and left intraventricular balloons were perfused in an ex vivo apparatus in which both ventricular volumes were controlled independently. RV area data from the level of the left midventricular short-axis plane and pressure data were recorded on a computer through a customized hardware and software interface with the ultrasound system. RV volumes were varied from 9.4 +/- 3.9 to 43.8 +/- 6.9 mL at each of three different LV volume ranges (low range, 12.5 +/- 3.8 mL; medium range, 23.9 +/- 5.6 mL; and high range, 37.5 +/- 5.4 mL). The variation of RV area during isovolumic contraction, which we called deformational area change, was considerable (1.49 +/- 0.68 cm2 mean +/- SD) but did not change significantly with changing RV and LV volumes. Linear regression analysis correlated the maximum, minimum, and mean automated border-detected RV area during isovolumic contraction with absolute volume. A predominantly linear relation was observed, with the group mean r = .98 (y = 0.16x + 0.97; SEE = 0.21 cm2). The effect of LV volume on RV area-volume relation was a significant parallel downward shift (P < .05) by increases in LV volume. End-systolic pressure-area and pressure-volume relations using simultaneously RV pressure were both highly linear and covaried with changing LV volume. CONCLUSIONS: Echocardiographic automated border-detected RV area reflects changes in RV volume under a constant LV volume, and the derived end-systolic pressure-area relation has potential for on-line assessment of RV function.
Animals↗
Left atrial thrombus after lung transplantation.
We report on a 16-year-old boy who developed a thrombus at the left atrial suture line after undergoing a bilateral sequential single lung transplantation. The diagnosis was made by transesophageal echocardiogram.
Adolescent↗
Transesophageal echocardiography to evaluate patients with severe pulmonary hypertension for lung transplantation.
The surgical approach to lung transplantation for patients with severe pulmonary hypertension will be dependent on the primary disease and specific cardiac anatomy. To determine the safety and utility of transesophageal echocardiography in the management of patients with severe pulmonary hypertension who are being evaluated for lung transplantation, we studied 48 consecutive patients, aged 38 +/- 11 years, with pulmonary artery systolic pressure of 70 mm Hg or greater. All patients previously underwent left and right heart catheterization, transthoracic echocardiography, and radionuclide ventriculography. Transesophageal echocardiography was tolerated well by all patients. Additional data that significantly altered surgical therapy was found in 12 of 48 patients (25%): proximal pulmonary artery thrombi (3), patent foramen ovale with significant right to left shunting (2), atrial septal defect (2), double-outlet right ventricle (2), ventricular septal defect (2), and exclusion of atrial septal defect (1). These findings were confirmed surgically in all patients except 3, who died awaiting transplantation. Transesophageal echocardiography is useful in the evaluation of patients with severe pulmonary hypertension.
Adult↗
Lung reduction as bridge to lung transplantation in pulmonary emphysema.
We present a case of bridging to lung transplantation by means of laser ablation of emphysematous bullae in a lung transplant candidate. The patient underwent successful left single-lung transplantation 17 months after lung reduction. He is now well 3 months after transplantation.
Humans↗
Solid tumors after heart transplantation: lethality of lung cancer.
BACKGROUND: Prolonged nonspecific immunosuppression after solid-organ transplantation is associated with an increased risk of certain cancers. This study examined the development of solid-organ tumors after cardiac transplantation. METHODS: Thirty-eight solid tumors were identified in 36 (5.9%) of 608 cardiac transplant recipients who survived more than 30 days. Two patients had two types of skin tumors (basal cell and squamous cell). The tumors included the following types: skin (15), lung (10), breast (1), bladder (2), larynx (2), liver (1), parotid (1), testicle (1), uterus (2), melanoma (2), and Merkel's cell (1). Four immunosuppression regimens based on cyclosporin A or FK 506 were used during this period. RESULTS: There was no association between the incidence of solid tumors and the use of lympholytic therapy. After the diagnosis of tumor was made, the actuarial 2-year survival rates of recipients with skin, lung, and other solid tumors were 71%, 22%, and 23%, respectively. Eight of 10 patients with lung cancer were in stage IIIA or higher at the time of diagnosis. CONCLUSION: Skin and lung tumors are the most frequent solid tumors in heart transplant recipients. Skin tumors (except Merkel's cell carcinoma and melanoma) usually have a benign course, whereas lung and other tumors developing in cardiac transplant recipients carry a poor prognosis. Advanced disease stage at the time of diagnosis is responsible for the dismal outcome of recipients in whom solid tumors develop. Close postoperative tumor surveillance after cardiac transplantation is warranted.
Actuarial Analysis↗
Endobronchial management of benign, malignant, and lung transplantation airway stenoses.
Since 1991, we have managed 57 patients with benign (10), malignant (23), or lung transplantation (24) airway obstructions using silicone stenting and debridement (manual/neodymium:yttrium-aluminum garnet laser). Ten patients with benign lesions (4 intubation, 4 inflammatory, 1 malacia, 1 bronchial fistula) had 4 T tubes, 3 Y stents, 3 bronchial stents, and 1 straight tracheal stent placed. Eight of 10 patients (80%) received symptomatic relief with the stents in place for up to 43 months. Twenty-three patients with malignant strictures (18 lung, 5 metastatic) had 26 stents inserted (13 Y stents, 12 bronchial, 1 T tube) of which 16 required combined debridement and stenting. Four stents required repositioning. three hospital deaths were due to unrelated causes. Of 20 discharged patients, 6 remain alive at 2 to 10 months, whereas 14 patients who died of progressive disease obtained effective palliation for 10.5 +/- 5.6 months. Significant bronchial anastomotic complications developed in 24 of 212 lung transplants (11.3%). Thirty-one stents were placed in 19 of the patients; 5 patients were managed with laser debridement alone. Of the 19 patients receiving stents, 3 required only temporary stents (6 to 15 days), 11 patients needed long-term stents (40 to 507 days), and 5 patients died with their stents in place functioning well. All patients received symptomatic relief with stenting. There were no procedure-related deaths and one bronchial laceration during attempted stent placement. Early, aggressive treatment of benign and malignant tracheobronchial strictures with endoscopic debridement and stenting is safe and well tolerated, and effectively palliates airway obstruction. Repositioning of stents frequently may be required in the transplant population.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Clinical trial of tacrolimus versus cyclosporine in lung transplantation.
BACKGROUND: A prospective clinical trial was undertaken to compare the efficacy of tacrolimus (FK 506) versus cyclosporine as the primary immunosuppressive agent after lung transplantation. METHODS: Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease. RESULTS: One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p = 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05). CONCLUSIONS: This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.
Acute Disease↗
Extracorporeal membrane oxygenation as an adjunct treatment for primary graft failure in adult lung transplant recipients.
Primary graft failure is a catastrophic event in lung transplantation. Failure is characterized by profound abnormalities of gas exchange that are frequently unresponsive to alterations in mechanical ventilation. This condition can be fatal and, if less severe, is usually associated with significant permanent damage to the allograft. We report the use of extracorporeal membrane oxygenation as a means to support lung transplant recipients with severe graft failure. Since 1991, extracorporeal membrane oxygenation has been used on 17 occasions for the temporary support of 16 adult lung transplant recipients. All patients met or exceeded standard National Institutes of Health guidelines for institution of extracorporeal membrane oxygenation. Nine double lung, six single lung, and one heart-lung recipients were supported for 1 to 12 days (mean 4.6 +/- 2.2 days). Extracorporeal membrane oxygenation was instituted early, within 7 days of transplantation, in ten patients. Eight early patients (80%) were successfully weaned from extracorporeal membrane oxygenation. Seven of ten (70%) patients were long-term survivors, and five of the seven had normal lung function. In comparison, there were no survivors among six recipients placed on extracorporeal membrane oxygenation for late (> or = 7 days) graft dysfunction. Extracorporeal membrane oxygenation is a lifesaving adjunct in recipients with acute graft failure after lung transplantation. Ischemia-reperfusion injury and acute graft dysfunction after lung transplantation can be successfully reversed with early aggressive intervention.
Adult↗
Infections and pathologic factors in the donor lung.
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Anti-Bacterial Agents↗
Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation.
Infection and rejection remain the greatest threats to the survival of pulmonary allograft recipients. Furthermore, a relationship may exist between these events, because the occurrence of one may predispose to the other. By using multivariate analysis for repeated events, we analyzed the risk factors for bacterial, fungal, and viral infection, grade II or greater acute rejection, and death among 239 lung transplant recipients who received 250 allografts between January 1988 and September 1993. A total of 90 deaths, 491 episodes of acute rejection, and 542 infectious episodes occurred during a follow-up of 6 to 71 months. The hazard or risk patterns of death, infection, and rejection each followed an extremely high risk during the first 100 days after transplantation, a second modest risk period at 800 to 1200 days, and a lower constant risk. Infection and graft failure manifested by diffuse alveolar damage were the major causes of early death (< 100 days), whereas infection and chronic rejection were primary causes of later death after pulmonary transplantation. By multivariate analysis, cytomegalovirus mismatching risk for primary infection was the most significant risk factor for death, rejection, and infection. Absence of cytomegalovirus prophylaxis was also a risk factor for early and late death and late infection. Survival of recipients who received cytomegalovirus prophylaxis was significantly improved. Immunosuppression based on cyclosporine versus FK 506 was a risk factor for late death and late infection. Graft failure manifested by diffuse alveolar damage/adult respiratory distress syndrome was a significant risk for death late after transplantation. These data suggest the following: (1) The hazard for death, infection, and rejection after pulmonary transplantation appears biphasic; (2) lower survival is associated with ischemia-reperfusion lung injury represented by diffuse alveolar damage/adult respiratory distress syndrome; (3) cytomegalovirus mismatch, absence of cytomegalovirus prophylaxis, and development of cytomegalovirus disease are significant threats for death, rejection, and infection after pulmonary transplantation; (4) prevention of cytomegalovirus disease should improve survival by decreasing the prevalence of infection and rejection.
Adolescent↗
Critical issues in pediatric lung transplantation.
Forty children (aged 1 to 18 years, 27 female and 13 male) have undergone heart-lung (21), double lung (17), and single lung (2) transplant procedures at our center from 1985 through April 1994. The indications for transplantation have been diverse, primary pulmonary hypertension (10), cystic fibrosis (11), congenital heart disease (10), arteriovenous malformation (3), emphysema (1), graft-versus-host disease (1), rheumatoid lung (1), cardiomyopathy (1), desquamative interstitial pneumonitis (1), and Proteus syndrome (1). The actuarial 1-year survival was 73% (mean follow-up 2 years). One-year actuarial survival for disease groups ranged from 60% for cystic fibrosis to 90% for congenital heart disease. We have identified six issues critical to the patient and programatic survival of pediatric lung transplantation. Our experience and management strategies in these areas are reviewed. Cytomegalovirus: Cytomegalovirus disease developed in six of eight patients with cytomegalovirus mismatching (donor +/recipient-) and in seven of 32 patients who survived more than 30 days (23%). All but cytomegalovirus donor -/recipient- patients were treated with ganciclovir for 4 weeks after transplantation. Obliterative bronchiolitis: Obliterative bronchiolitis developed in seven of 32 (25%) patients who survived more than 30 days. Obliterative bronchiolitis was manifest within the first posttransplantation year as a rapid decline in small airway function. Aggressive augmentation of immunosuppression has been used with little success. Posttransplantation lymphoproliferative disease: Posttransplantation lymphoproliferative disease developed in five of 32 (15%) patients who survived more than 30 days developed. One patient died (17% mortality) despite retransplantation. In four patients the disease resolved with reduction in immunosuppression alone, and one required the addition of interferon alfa. Cystic fibrosis: We have changed our management strategies to avoid triple drug immunosuppression, perioperative blood and bronchial cultures, aggressive antimicrobial therapy, and exclusion of patients with panresistant organisms; this has resulted in elimination of infectious mortalities thus far in the pediatric cystic fibrosis group. Airways: In 21 heart-lung recipients with tracheal anastomoses we have had no airway complications. The double and single lung transplant recipients accounted for 34 bronchial and one tracheal anastomoses. Three (9%) bronchial stenoses developed. Two were treated with silicone stents and one with balloon dilation.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗