John M. Armitage

Obliterative bronchiolitis after lung and heart-lung transplantation: An analysis of risk factors and management

With a prevalence of 34% (55/162 at-risk recipients) and a mortality of 25% (14/55 affected recipients), obliterative bronchiolitis is the most significant long-term complication after pulmonary transplantation. Because of its importance, we examined donor-recipient characteristics and antecedent clinical events to identify factors associated with development of obliterative bronchiolitis, which might be eliminated or modified to decrease its prevalence. We also compared treatment outcome between recipients whose diagnosis was made early by surveillance transbronchial lung biopsy before symptoms or decline in pulmonary function were present versus recipients whose diagnosis was made later when symptoms or declines in pulmonary function were present. Postoperative airway ischemia, an episode of moderate or severe acute rejection (grade III/IV), three or more episodes of histologic grade II (or greater) acute rejection, and cytomegalovirus disease were risk factors for development of obliterative bronchiolitis. Recipients with obliterative bronchiolitis detected in the preclinical stage were significantly more likely to be in remission than recipients who had clinical disease at the time of diagnosis: 81% (13/15) versus 33% (13/40); p < 0.05). These results indicate that acute rejection is the most significant risk factor for development of obliterative bronchiolitis and that obliterative bronchiolitis responds to treatment with augmented immunosuppression when it is detected early by surveillance transbronchial biopsy.

Acute myocardial dysfunction and recovery: A common occurrence after coronary bypass surgery

To evaluate whether acute myocardial dysfunction was common in the early postoperative period, serial hemodynamic measurements and radionuclide evaluation of ventricular function were performed before and after operation in 24 patients undergoing elective coronary bypass surgery. All patients had uncomplicated surgery, and no patient sustained an intraoperative infarction. In 96% of patients, significant depression in right and left ventricular ejection fraction was seen postoperatively, reaching a nadir at 262 +/- 116 min after coronary bypass. Left ventricular ejection fraction was 58 +/- 12% preoperatively and 37 +/- 10% at trough. Right ventricular function displayed a similar pattern. These findings were also associated with depressed cardiac and left ventricular stroke work index despite maintenance of adequate ventricular filling pressures and mean arterial pressure. The depression in ventricular function was partially reversible within 8 to 10 h after surgery. Left ventricular ejection fraction had increased to 55 +/- 13% at 426 +/- 77 min after coronary bypass and showed complete recovery within 48 h. Left ventricular end-systolic and end-diastolic volume index increased significantly postoperatively, but recovery in left ventricular ejection fraction was mostly due to decreases in end-systolic volume index (50 +/- 22 ml at trough and 32 +/- 16 ml at recovery). Depressed myocardial function was independent of bypass time, number of grafts placed, preoperative medications or core temperatures postoperatively. Postoperative therapy with pressors or inotropic agents delayed but did not prevent the occurrence of postoperative ventricular dysfunction. Despite improvements in operative techniques and methods of myocardial protection, postoperative left ventricular dysfunction continues to be common in patients undergoing cardiopulmonary bypass surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative pulmonary hemodynamics and early mortality after orthotopic cardiac transplantation: The Pittsburgh experience

The influence of preoperative transpulmonary pressure gradient (TPG) and pulmonary vascular resistance (PVR) on early post-transplant mortality was evaluated in 425 orthotopic transplant recipients. The overall 30-day post-transplant mortality rate was 12.5%; the majority of the deaths (52.8%) were due to primary allograft failure. The 0- to 2-day mortality rate was threefold higher in patients with severe preoperative pulmonary hypertension (TPG > or = 15 mm Hg or PVR > or = 5 Wood units), whereas the 3- to 7-day and 8- to 30-day mortality rates were similar. Early post-transplant mortality (0 to 2 days and 8 to 30 days) was also significantly higher (15.9% vs 3.9% and 9.9% vs 2.8%, respectively; p < 0.05) in women compared with men. Women with severe preoperative pulmonary hypertension had higher (p < 0.05) 0- to 2-day post-transplant mortality than comparable men. According to univariate analysis, recipients with preoperative TPG > or = 15 mm Hg had a significantly higher 30-day postoperative mortality rate, irrespective of their level of PVR. Furthermore, patients with severe preoperative pulmonary hypertension who underwent transplantation between 1980 and 1987 had a higher 0- to 2-day post-transplant mortality rate compared with patients operated on after that time. Multiple logistic regression analysis identified female recipient sex and preoperative TPG but not preoperative PVR, era of transplantation, or recipient age as significant (p < 0.001 and p < 0.01, respectively) independent predictors of early post-transplant mortality.

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.

A decade of lung transplantation.

OBJECTIVE The experience accrued at the University of Pittsburgh between March 1982 and December 1992 in the various forms of lung transplantation, including heart-lung, double lung, and single lung, is discussed. SUMMARY BACKGROUND DATA Heart-lung (n = 97) was the most commonly performed operation followed by double lung (n = 80) and single lung (n = 68). Major indications included primary pulmonary hypertension (n = 76), obstructive lung disease (n = 57), Eisenmengers syndrome (n = 42), cystic fibrosis (n = 32), and retransplantation (n = 13). Since May 1991, 115 procedures have been performed and heart-lung transplantation has decreased from 61% to 15% of the cases with a corresponding doubling in double lung from 24% to 43% and single lung from 15% to 42%. RESULTS The 1-, 2-, and 5-year survival rates in all 232 recipients were 61%, 55%, and 44%, respectively. The actuarial survival rate was significantly better for those 107 recent recipients compared to the 125 early recipients (70% vs. 61%). Overall, the 63 single (70%) and 74 double (65%) lung procedures were more successful than heart-lung transplantation (53%). Recently, however, lung transplantation has been associated with an improvement in the survival rate from 48% to 72%. The survival rate has also improved from 53% to 77% for single lung transplant recipients. The causes of death in 106 recipients included infection (n = 40), early allograft dysfunction (n = 23), obliterative bronchiolitis (n = 13), and inoperative bleeding (n = 10). Poor outcomes also included technical problems (n = 6), lymphoma (n = 4), acute rejection (n = 3), diaphragmatic paralysis (n = 2), multisystem organ failure (n = 2), stroke (n = 2), liver failure (n = 1), and airway dehiscence (n = 1). CONCLUSIONS The long-term outlook for lung transplant recipients has improved. There appears to be significant conservation of organs with single lung and double lung transplantation, finding greater acceptance for diseases once exclusively treated by heart-lung transplantation alone. The improved long-term outlook will be dependent upon better treatment for chronic rejection of the airways that histologically is defined by obliterative bronchiolitis.

Chronic mechanical circulatory support: Rehabilitation, low morbidity, and superior survival

Because of donor scarcity, 12 (39%) of a series of 31 Novacor left ventricular assist system recipients required mechanical circulatory support for an average of 125 days before transplantation (range, 61 to 303 days). Ten received a heart transplant and all survived to discharge. Two died of infection before transplantation after 93 and 303 days of support. Significant reductions were noted from preimplantation values of right and left cardiac filling pressures. Right ventricular ejection fraction and cardiac index increased. The 4-month actuarial freedom from infection during support was 75%. Three patients benefited from chronic outpatient housing for 5, 18, and 131 days, respectively, with improvements in quality of life measures. Ten chronically supported patients participated in an intensive rehabilitative exercise program resulting in an improvement of New York Heart Association class from IV to I in 9 patients. Mean oxygen consumption, which was 10 mL.kg-1.min-1 30 days after implantation (mean exercise time, 10 minutes) had risen to 15 mL.kg-1.min-1 before transplantation (mean exercise time, 16 minutes). This series suggests that long-term circulatory support is compatible with low morbidity, significant physical and hemodynamic rehabilitation, and an outpatient setting.

A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation.

We have conducted a unique prospective randomized study to compare the effect of FK506 and cyclosporine (CsA) as the principal immunosuppressive agents after pulmonary transplantation. Between October 1991 and March 1993, 74 lung transplants (35 single lung transplants [SLT], 39 bilateral lung transplant [BLT]) were performed on 74 recipients who were randomly assigned to receive either FK or CsA. Thirty-eight recipients (19 SLT, 19 BLT) received FK and 36 recipients (16 SLT, 20 BLT) received CsA. Recipients receiving FK or CsA were similar in age, gender, preoperative New York Heart Association functional class, and underlying disease. Acute rejection (ACR) was assessed by clinical, radiographic, and histologic criteria. ACR was treated with methylprednisolone, 1 g i.v./day, for three days or rabbit antithymocyte globulin if steroid-resistant. During the first 30 days after transplant, one patient in the FK group died of cerebral edema, while two recipients treated with CsA died of bacterial pneumonia (1) and cardiac arrest (1) (P = NS). Although one-year survival was similar between the groups, the number of recipients free from ACR in the FK group was significantly higher as compared with the CsA group (P < 0.05). Bacterial and viral pneumonias were the major causes of late graft failure in both groups. The mean number of episodes of ACR/100 patient days was significantly fewer in the FK group (1.2) as compared with the CsA group (2.0) (P < 0.05). While only one recipient (1/36 = 3%) in the group treated with CsA remained free from ACR within 120 days of transplantation, 13% (5/38) of the group treated with FK remained free from ACR during this interval (P < 0.05). The prevalence of bacterial infection in the CsA group was 1.5 episodes/100 patient days and 0.6 episodes/100 patient days in the FK group. The prevalence of cytomegaloviral and fungal infection was similar in both groups. Although the presence of bacterial, fungal, and viral infections was similar in the two groups, ACR occurred less frequently in the FK-treated group as compared with the CsA-treated group in the early postoperative period (< 90 days). Early graft survival at 30 days was similar in the two groups, but intermediate graft survival at 6 months was better in the FK group as compared with the CsA group.

Cardiac rhythm disturbances early after orthotopic heart transplantation: Prevalence and clinical importance of the observed abnormalities

To precisely define the incidence, type and consequences of cardiac arrhythmias early after heart transplantation, 25 cardiac transplant recipients were monitored continuously for 728 days from the day of surgery to discharge or death. A subset of 15 patients had sinus node function studies with overdrive suppression performed weekly at the time of endomyocardial biopsy. Results revealed sinus bradycardia in 10 patients (40%) and junctional bradycardia in 6 (24%). Supraventricular tachycardia in the form of atrial tachycardia, atrial fibrillation and atrial flutter occurred in 11 patients (44%). Ventricular tachycardia occurred in 15 patients (60%) and was nonsustained in all. Cardiac pacing for 1,403 h was used in nine patients with a pulse rate less than 50 beats/min; seven recovered and permanent pacing was instituted in two. In the subgroup that had sinus node function studies, seven patients were identified with clinical bradyarrhythmia; each had abnormal sinus node recovery time (greater than 1,400 ms) and abnormal corrected sinus node recovery time (greater than 525 ms) in at least one study. These seven patients also had a significantly prolonged ischemic time (236 +/- 26 versus 159 +/- 68 min, p less than 0.01). In conclusion, cardiac arrhythmias, particularly ventricular tachycardia and bradyarrhythmia, occur more commonly early after orthotopic heart transplantation than has previously been reported. Sinus node dysfunction due to prolonged organ ischemic time, antiarrhythmic drug use or surgical trauma, alone or in combination, may contribute to these arrhythmias.

Indications for and results of single, bilateral, and heart-lung transplantation for pulmonary hypertension.

The indications for single, bilateral, and heart-lung transplantation for patients with pulmonary hypertension remain controversial. We retrospectively analyzed the results from 11 single, 22 bilateral, and 24 heart-lung transplant procedures performed between January 1989 and January 1993 on 57 consecutive patients with pulmonary hypertension caused by primary pulmonary hypertension (n = 27) or Eisenmengers syndrome (n = 30). Candidates with a left ventricular ejection fraction less than 35%, coronary artery disease, or Eisenmengers syndrome caused by surgically irreparable complex congenital heart disease received heart-lung transplantation. All other candidates received single or bilateral lung transplantation according to donor availability. Although postoperative pulmonary artery pressures decreased in all three allograft groups, those in single lung recipients remained significantly higher than those in bilateral and heart-lung recipients. The cardiac index improved significantly in only the bilateral and heart-lung transplant recipients. A significant ventilation/perfusion mismatch occurred in the single lung recipients as compared with bilateral and heart-lung recipients because of preferential blood flow to the allograft. Graft-related mortality was significantly higher and overall functional recovery as assessed by New York Heart Association functional class was significantly lower at 1 year in the single as compared with bilateral and heart-lung recipients. Thus bilateral lung transplantation may be a more satisfactory option for patients with pulmonary hypertension with simple congenital heart disease, absent coronary arterial disease, and preserved left ventricular function. Other candidates will still require heart-lung transplantation.

Effect of Cardiopulmonary Bypass on Early Graft Dysfunction in Clinical Lung Transplantation

The records of 100 lung transplant recipients (13 heart-lungs, 45 double-lungs, and 42 single-lungs) from September 1990 through April 1992 were reviewed to determine the role of cardiopulmonary bypass (CPB) in early graft dysfunction. Fifty-five patients requiring CPB (CPB group) for 186 +/- 54 minutes were compared with the 45 patients without CPB (no-CPB group). All of the heart-lung and en-bloc double-lung transplantations were performed under CPB, with pulmonary vascular lung disease the principal diagnosis, resulting in a significantly younger age population in the CPB group. All other donor- and recipient-related factors matched well in both groups. Of 38 bilateral single-lung transplantations, CPB was used in 18. In double-lung and heart-lung recipients gas exchange of the allografts was evaluated by the arterial/alveolar oxygen tension ratios at nine intervals during the first 72 hours. The mean arterial/alveolar oxygen tension ratio in the CPB group was 0.48 +/- 0.19, significantly lower than in the no-CPB group with 0.60 +/- 0.22 (p = 0.025). All patients had radiographic interpretation and scoring of pulmonary infiltrates from chest roentgenograms taken within 12 hours after reperfusion. The CPB group had more severe pulmonary infiltrates than the no-CPB group (p = 0.034). Prolonged intubation defined as 7 days or longer occurred significantly more often (29/55) in the CPB group than in the no-CPB group (8/45) (p = 0.003). Actuarial graft and patient survival at 1 month was better in the no-CPB group than in the CPB group (42/45 versus 44/55 [p = 0.05] and 43/45 versus 45/55 [p = 0.033], respectively).(ABSTRACT TRUNCATED AT 250 WORDS)