Double Lung Transplant Recipients Research Articles

Breathing by Double-Lung Recipients during Exercise

Ventilation during exercise is near-normal in double-lung transplant recipients despite lung denervation. We tested the hypothesis that denervation effects might be unmasked during exercise by exposing these patients to an expiratory load. Eight double-lung recipients and nine intact control subjects were exercised to exhaustion. Ergometer work increased 20 Watt every 2 min; expiratory threshold loading (4 cm H2O) was imposed for five to six breaths at each exercise level; ventilation and O2 consumption were measured. Transplant recipients and control subjects increased ventilation similarly for comparable fractions of maximal work. At maximal exercise, transplant recipients achieved lower work (62 versus 155 W; p < 0.001) and O2 consumption (0.88 versus 2.26 L/min; p < 0.001) than control subjects, with proportional reductions in tidal volume (1.6 versus 2.6 L; p < 0.05) and ventilation (38 versus 79 L/min; p < 0.01). Threshold loading decreased expiratory flow, breathing frequency, and minute ventilation in both groups (p < 0.05). Unlike control subjects, transplant recipients also slowed inspiratory flow (p < 0.05) and prolonged inspiration (p < 0.01), exaggerating the fall in breathing frequency and ventilation (p < 0.01). We conclude that afferent information from pulmonary receptors modulates inspiration during expiratory loading; bilateral denervation disrupts these pathways, causing double-lung recipients to inspire more slowly.

The effect of lung transplantation on the neural drive to the diaphragm in patients with severe COPD.

Little is known about the effects of lung transplantation (LT) on the neural drive to the diaphragm and on the endurance of respiratory muscles in patients with severe chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate these effects of single-lung (SLT) and double-lung transplantation (DLT). The neural drive to the diaphragm was assessed during fatiguing inspiratory threshold loading manoeuvres in six SLT recipients, six DLT recipients and seven patients with severe COPD, by using diaphragmatic surface electromyograms. During threshold loading, the patients had to generate 80% of their maximal transdiaphragmatic pressure with each breath. The endurance of inspiratory muscles was defined as the time from the beginning of a resistive breathing trial until exhaustion (t lim). In DLT recipients and even in SLT recipients (on both sides), neural activation of the diaphragm was significantly lower than in COPD patients (p < 0.05). However, no statistically significant difference in t lim was seen between LT recipients and COPD patients. The data suggest that single-lung and double-lung transplantations cause a significant decrease of the neural drive to the diaphragm, while the endurance of inspiratory muscles is well-preserved in patients with advanced chronic obstructive pulmonary disease. This may contribute to reduced sensation of inspiratory effort during ventilatory stress, thus improving the quality of life.

Aspergillus infection in single and double lung transplant recipients.

To investigate the clinical manifestations of Aspergillus infections in lung transplant recipients, we reviewed the mycology and autopsy reports of all double (DLT=93) and single (SLT=48) lung transplant recipients from November 1983 to May 1993. Positive Aspergillus cultures were identified in 22% of the recipients (DLT=21, SLT=10). Colonization alone was present in 19 recipients (DLT=16, SLT=3). Complicated Aspergillus infection included Aspergillus bronchitis (DLT=1, SLT=1), aspergilloma (SLT=2), pulmonary invasive aspergillosis (DLT=1, SLT=2), disseminated aspergillosis (DLT=1, SLT=2), empyema (DLT=1), and a retroperitoneal abscess (DLT=1). Symptoms were seen only in patients with complicated lung infections and CXR abnormalities began in the native lung of four SLT recipients. Twenty patients survived (DLT=17, SLT=3) and 11 died (DLT=4, SLT=7) of disseminated aspergillosis (SLT=2), pulmonary invasive disease (DLT=1), bronchiolitis obliterans (DLT=2, SLT=2, CMV pneumonitis (SLT=1), diffuse alveolar damage (SLT=2), and hyperacute rejection (DLT=1). Complicated infection and mortality were more common in SLTs than DLTs (P<0.05). We conclude that infection with Aspergillus is not infrequent in the lung transplantation population. Single lung recipients develop more complicated infection than double lung recipients after Aspergillus infection with native lung being a potential source of infection.

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. Finances : The average charge for lung transplant evaluation was $18,000 and for transplantation, $175,000. (J T horac C ardiovasc S urg 1995;109:60-5)

Effect of lung transplantation on diaphragmatic function in patients with chronic obstructive pulmonary disease.

To date there are no data on the effects of lung transplantation on diaphragmatic function in patients with end stage chronic obstructive pulmonary disease (COPD). It is not known whether the relation between the transdiaphragmatic pressure (PDI) and lung volume is altered in recipients after transplantation as a result of changes in diaphragmatic structure caused by chronic hyperinflation. The effect of lung transplantation on diaphragmatic strength was determined in patients with COPD and the relation between postoperative PDI and lung volume analysed. Diaphragmatic strength was assessed in eight double lung transplant recipients, six single lung transplant recipients, and in 14 patients with COPD whose lung function was similar to those of the transplant recipients preoperatively. PDI obtained during unilateral and bilateral phrenic nerve stimulation at 1 Hz (twitch PDI) at functional residual capacity (FRC) and during maximal sniff manoeuvres (sniff PDI) at various levels of inspiratory vital capacity (VCin) served as parameters for diaphragmatic strength. Sniff PDI assessed at the various VCin levels were used to analyse the PDI/lung volume relation. Lung transplantation caused a reduction in lung volume, especially in the double lung transplant recipients. As a consequence sniff PDI was higher in the double lung transplant recipients than in the patients with COPD at all levels of VCin analysed. However, sniff PDI values analysed at comparable intrathoracic gas volumes were not reduced in the patients with COPD when compared with those who underwent lung transplantation. Bilateral twitch PDI values were similar in the patients with COPD and in the lung transplant recipients. In the single lung transplant recipients unilateral twitch PDI values were similar on the transplanted and the non-transplanted side. The relation between PDI and lung volume was similar in the patients with COPD and in the lung transplant recipients. In patients with COPD lung transplantation leads to an increase the maximal sniff induced PDI values by placing the diaphragm in a more favourable position for pressure generation. Since patients with COPD and postoperative lung transplant recipients showed similar PDI/lung volume relations, this suggests that chronic pulmonary hyperinflation does not cause major functional alterations of the diaphragm.

Pulmonary retransplantation for obliterative bronchiolitis:: Intermediate-term results of a North American–European series

An international series of pulmonary retransplantation was updated to identify the predictors of survival in the intermediate-term after reoperation for obliterative bronchiolitis. The study cohort included 32 patients with end-stage obliterative bronchiolitis who underwent retransplantation in 15 North American and European centers between 1988 and 1992. Five types of retransplantation procedures were done, including repeat ipsilateral single lung transplantation (7 patients), repeat contralateral single lung transplantation (8 patients), repeat double lung transplantation (3 patients), double lung transplantation after a previous single lung transplantation (3 patients), and single lung transplantation after a previous double lung or heart-lung transplantation (11 patients). The mean interval between transplants was 564 ± 51 days (range 187 to 1589 days). Postoperative follow-up was 100% complete and the average follow-up in surviving patients was 678 ± 63 days. Actuarial survival was 72%, 53%, 50%, 41%, and 33% at 1, 3, 6, 12, and 24 months, respectively. Survival did not differ according to the age, preoperative diagnosis, ambulatory or ventilator status, or cytomegalovirus serologic status of the recipient before reoperation. Life-table and Cox proportional hazards analysis identified the type of retransplantation procedure and the year of reoperation as significant ( p < 0.05) predictors of postoperative survival. Actuarial survival was significantly better in patients without an old, retained contralateral graft after retransplantation and in patients who underwent reoperation between 1990 and 1992, as opposed to between 1988 and 1989. Infection was the most common cause of death at all time intervals after retransplantation, although all deaths beyond 2 years resulted from obliterative bronchiolitis of the second graft. Most surviving patients are in a satisfactory clinical condition, with a mean forced expired volume in 1 second of 59% ± 13% of predicted (repeat double lung transplant recipients) or 41% ± 6% of predicted (repeat single lung transplant recipients). We conclude that pulmonary retransplantation for obliterative bronchiolitis is associated with significantly worse survival than after primary lung transplantation. The absence of an old contralateral graft after retransplantation and reoperation after 1989 are important predictors of survival. Additional data and follow-up are required to determine the merit of pulmonary retransplantation for obliterative bronchiolitis. (J THORACCARDIOVASCSURG1994;107:755-63)

Comparative outcome of heart-lung and lung transplantation for pulmonary hypertension

Despite the development of several lung transplantation procedures, the most advantageous for pulmonary hypertension remains controversial. Between 1986 and February 1992, 30 patients with end-stage primary pulmonary hypertension (n = 24), chronic pulmonary embolism (n = 4), and hystiocytosis X (n = 2) underwent heart-lung (n = 21), double lung (n = 8), or single lung (n = 1) transplantation. Indications for double lung transplantation were similar to those for heart-lung transplantation, and the preoperative clinical and hemodynamic parameters were not significantly different between the two groups. There were no intraoperative deaths, but two reoperations were needed for pleural hematoma. Five early deaths were related to graft failure (two heart-lung transplantations), mediastinitis (one heart-lung transplantation), multiorgan failure (one double lung transplantation), and aspergillosis (one double lung transplantation). There was a similar improvement in early (days 0 and 2) and late (6 months postoperatively) right-sided hemodynamic function in patients undergoing heart-lung and double lung transplantation. Three double lung transplant recipients had early and reversible left ventricular-failure. The early postoperative course of the one patient who had single lung transplantation was characterized by severe pulmonary edema, left ventricular failure, and persistent desaturation and later on by moderate pulmonary hypertension and an important ventilation/perfusion mismatch. The pulmonary function results were also similar in the heart-lung and double lung transplantation groups. The overall projected 2- and 4-year survivals were 49% and 41%, respectively, and were not significantly different between the heart-lung and double lung recipients. Results demonstrate that heart-lung and double lung transplantation are equally effective in obtaining early and durable right-sided hemodynamic and respiratory improvement and similar respiratory function. In patients with pulmonary hypertension, double lung transplantation should be preferred to single lung transplantation because of the critical postoperative course and the uncertain long-term results of single lung transplantation.

Long-term functional results after bilateral lung transplantation

Between February 1988 and January 1992, 61 patients have undergone bilateral lung transplantations (42 heart-lung and 19 double-lung) in Bordeaux. The underlying diseases were primary or secondary hypertension (20), emphysema (22), or other diseases including cystic fibrosis, pulmonary fibrosis, silicosis, and sarcoidosis (19). Actuarial survival for double-lung and heart-lung transplant recipients was 66% and 72% at 1 year and 57% and 53% at 3 years, respectively. Forty-two patients were still alive 6 months after operation, and we studied their pulmonary function at the short and long term. All parameters except arterial carbon dioxide tension had improved dramaticaly at 6 months ( p < 0.0001). Vital capacity, forced expiratory volume in 1 second, and forced expiratory flow rate between 25% and 75% of vital capacity were at 79% ± 3%, 92% ± 5%, and 105% ± 8% of the predicted values, respectively. Arterial oxygen tension was 88 ± 3 mm Hg. Nine months after operation, a slight decrease in forced expiratory volume in 1 second and forced expiratory flow rate between 25% and 75% of vital capacity appeared but values remained more than 75% predicted. This was related to the occurrence of obliterative bronchiolitis in 6 patients (14%). At 9 months, flow rates and oxygen tension of these 6 patients were highly different from those of patients free of obliterative bronchiolitis ( p < 0.0002 for flow rates and p < 0.01 for oxygen tension). Only 1 patient required retransplantation. The others are living an almost normal life. Our results are discussed in view of the published reports on single-lung transplantation. Short-term results of bilateral lung transplantation are thus excellent and maintained on a long-term basis. Therefore, in our opinion, bilateral lung transplantation is the therapy of choice for pulmonary hypertension and emphysema.

Prospective Assessment of a Standardized Pathologic Grading System for Acute Rejection in Lung Transplantation

Using the recent standardization of the pathologic definitions for acute lung rejection, we prospectively evaluated 66 consecutive bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB) specimens in 32 patients after lung transplantation. Clinical indications for bronchoscopies were surveillance (n = 44), rejection (n = 18), and infection (n = 4). Bronchoalveolar lavages were obtained from the right middle lobe or lingula in single lung transplant and from both sites in double lung transplant recipients. Cytosmears for differential cell counts were performed and 400 to 500 cells were counted. Five to eight TBB specimens were taken from two different lobes and stained with hematoxylin-eosin, elastic trichrome, and silver methenamine. Sixty-four of 66 sets of biopsy specimens were satisfactory, but 3 were eliminated because of presence of cytomegalovirus cytopathic changes. Of the remaining 61, rejection was presented in 45 (74 percent): grade 1 in 23 (38 percent), grade 2 in 19 (31 percent), and grade 3 in 3 (5 percent). In 30 of 42 (71 percent) surveillance biopsy specimens, rejection was present, grade 1 in 18 (43 percent) and grade 2 or 3 in 12 (28 percent). In TBBs performed for clinical suspicion of rejection, 15 of 18 TBB specimens (83 percent) showed rejection, grade 1 in 5 (28 percent) and grade 2 or 3 in 10 (55 percent). Of four biopsies performed for suspicion of infection, one was normal and three showed rejection in addition to infection. These three were eliminated from further analysis due to the limitation of the Lung Rejection Study Group criteria in distinguishing rejection from infection. Of the 45 episodes of rejection, 24 (53 percent) occurred during the first 3 months posttransplantation, 8 (18 percent) between 3 and 6 months and 13 (29 percent) after 6 months. Percentage of BAL lymphocytosis was significantly elevated in grade 2 or 3 rejection (28 +/- 4) when compared with grade 1 (15 +/- 3) or grade 0 (10 +/- 3) (p < 0.001). Bronchoalveolar lavage lymphocytosis also correlated with severity of rejection (r = 0.6). We conclude that according to the standardized criteria of the Lung Rejection Study Group, acute lung rejection occurs more frequently than clinically suspected early and late after transplantation and that BAL lymphocytosis correlates with the presence and severity of histologically proven rejection.

Pulmonary transplantation

Between November 1983 and March 1991, we performed 50 single and 40 double lung transplants in 82 recipients. Early deaths occurred in six (13 %) single and in eight (21 %) double lung transplant recipients. Late deaths occurred in 11 (28%) single and in one (3%) double lung recipients. Twenty-three of 37 (62%) single and 17 of 24 (71%) double lung transplant recipients have survived at least 1 year after the operation. In patients surviving at least 3 months after the operation (36 of 47 single lung transplant [77%] and 28 of 37 double lung transplant recipients [76%]), significant improvement occurred in arterial blood gases, pulmonary function tests, and exercise capacity. During our initial experience, airway anastomotic complications were the main cause of early morbidity and mortality. With newer surgical techniques and improved perioperative care, airway complications are now uncommon. Infectious complications, either bacterial (Pseudomonas cepacia) or viral (cytomegalovirus), are now the main cause of early mortality. Chronic rejection in the form of obliterate bronchiolitis has become a frequent cause of late morbidity. (J Thorac Cardiovasc Surg 1992;103:295—306)

Maximal Exercise Testing in Single and Double Lung Transplant Recipients

Patients with end-stage pulmonary and pulmonary vascular disease can now be offered single-lung (SLT), double-lung (DLT), or heart-lung (HLT) transplantation. Long-term survival with greatly improved pulmonary function has been reported with all three procedures. Little has been reported of the exercise capacity after transplantation. This report documents Stage 1 exercise test results in six SLT (five males and one female; age 50.7 +/- 4.4; FEV1.0 75.5 +/- 6.7% of predicted) and seven DLT (three males and four females; age 37.3 +/- 6.7; FEV1.0 85.1 +/- 10.3% of predicted) recipients, early (3 months) and late (1 to 2 yr) following transplantation. The results show low work rates and VO2max in both SLT and DLT recipients at 3 months after transplant. Heart rate and minute ventilation did not appear limiting. There was no significant improvement when retested 1 to 2 yr after transplant. At 3 months, VO2max was 46% of predicted for SLT and 50% of predicted for DLT recipients. It is concluded that considerable exercise limitation persists after transplantation and does not appear to improve with time. These limitations are similar for both SLT and DLT and are not related to ventilation. The results may suggest chronic muscle deconditioning after long-term pretransplant debilitation.

Role of CMV pneumonia in the development of obliterative bronchiolitis in heart-lung and double-lung transplant recipients

Obliterative bronchiolitis (OB) is the main cause of late mortality after lung transplantation. Cytomegalovirus infection has been associated with late graft failure. The aim of this study was to determine whether the development of OB was related to CMV pretransplant serological status and to CMV infections. The study group comprised 36 lung transplant recipients (27 HLT and 9 DLT) who survived more than 4 months, of whom 47% developed OB (defined by the persistence of an unexplained obstructive disease: FEV1/VC < 0,7). OB occurred more frequently: (1) in seronegative recipients with seropositive donors (8/9) than in seropositive recipients (7/19) or seronegative well-matched recipients (2/8); and (2) in patients who experienced CMV pneumonia (11/16) and CMV recurrence (11/16). Since matching seronegative recipients is the best way to prevent CMV infection, we believe that seronegative grafts must be reserved for seronegative recipients.

Right and left ventricular performance after single and double lung transplantation

Twelve single lung and nine double lung transplant recipients were studied before transplantation and at 3 months and 1 year after transplantation with serial right and left ventricular radionuclide angiograms. The resting right ventricular ejection fraction increased in the double lung recipients from 31% ±5% before transplantation to 43% ± 11% at 3 months after transplantation (p < 0.05) and then remained stable to 1 year. The single lung recipients also demonstrated a significant rise in ejection fraction from 25% ± 11% before transplantation to 36% ± 12% at 3 months after transplantation. Again, this remained stable to 1 year. The exercise right ventricular ejection fraction also showed a significant posttransplantation rise in the double lung recipients (p < 0.005) that remained stable to 1 year. In the single lung recipients a trend was seen for a rise in the exercise right ventricular ejection fraction that did not reach statistical significance by 1 year after transplantation. Neither group had a significant change in rest or exercise left ventricular ejection fraction. The systemic blood pressure increased significantly by 1 year after transplantation in both groups. The heart rate increase with exercise at 3 months after transplantation was significantly greater in the single lung group (42 ± 13 beats/min) than in the double lung group (14 ± 13 beats/min) (p < 0.005). These data indicate that a significant improvement in right ventricular function occurs after single and double lung transplantation.

Donor Selection for Single and Double Lung Transplantation: Chest Size Matching and Other Factors Influencing Posttransplantation Vital Capacity

In six single lung transplant (SLT) and six double lung transplant (DLT) recipients, the relationships of the recipient's posttransplantation vital capacity (posttx VCR) to the recipient's predicted normal vital capacity (pred VCR) and the donor's predicted normal vital capacity (pred VCD) were investigated. After left SLT the left posttx VCR was correlated with the left predicted VCD (r = 0.83; p less than 0.05); however, no correlation was found between these after DLT. In contrast, there was a tendency toward correlation between the posttx VCR and the predicted VCR after DLT (r = 0.75; p less than 0.1), but no such trend was apparent after SLT. These results suggest that posttx VCR depends primarily on predicted VCD after SLT and on pred VCR after DLT. Therefore, in donor-recipient size matching for lung transplantation a donor with a pred VCD greater than the pred VCR should be chosen for a left SLT recipient, whereas a donor with a pred VCD near the pred VCR would be suitable for a DLT recipient.

Respiratory Failure Caused by Adiaspiromycosis

Adiaspiromycosis is a rare pulmonary disorder caused by the fungus Emmonsia crescens (or Chrysosporium parvum var crescens). According to the amount of inhaled conidia, man may develop symptomatic disease. After reaching the alveoli, the adiaconidia do not multiply or disseminate, but will induce a granulomatous inflammatory reaction that may lead to fatal respiratory failure. Up to now, only five cases of disseminated pulmonary infection have been documented. This work describes the occurrence, in Brazil, of two further cases of symptomatic disease with diffuse interstitial infiltrates and severe functional impairment. Possible massive infestation during activities in closed and stuffy environments is suggested. The specific diagnosis was troublesome and could not be made by cultures, skin tests or bronchoalveolar lavage. Both patients were successfully treated, but a spontaneous resolution of the process is seriously considered.

Cardiopulmonary Exercise Testing after Single and Double Lung Transplantation

The cardiopulmonary response to exercise was investigated in six single and six double lung transplant recipients using a three-minute incremental work rate protocol on a cycle ergometer. Maximum VO2 averaged 44.2 +/- 9.2 percent and 48.5 +/- 5.0 percent of predicted maximal VO2 in the single and double lung transplant groups, respectively. No evidence of ventilatory limitation to exercise was found in either group. Circulatory factors that may have limited exercise capacity included anemia and submaximal heart rates. There was a strong correlation between VO2/kg at venous blood lactate level of 2.2 mEq/L and vital capacity/body surface area in the single, but not in the double, lung recipients. Maximum VO2 in these lung transplant recipients was comparable to previously published values in heart-lung transplant recipients. The factors that limit maximum exercise capacity after lung transplantation deserve further study.

Cardiac innervation after double lung transplantation

Double lung transplantation has been successfully introduced for patients with end-stage pulmonary disease and preserved cardiac function. An advantage of this operation compared with heart-lung transplantation is retention of the recipient's heart. The operative dissection, however, may lead to interruption of sympathetic and parasympathetic pathways to the heart and consequent denervation of the native heart. The cardiac innervation of seven double lung transplant recipients was investigated by the heart rate response to carotid sinus massage, the Valsalva maneuver, intravenous injection of atropine, and exercise. Five single lung and two heart-lung transplant recipients were studied for comparison. Of the seven double lung transplant recipients, three had abnormal responses to carotid sinus massage, six to the strain phase of the Valsalva maneuver, and five to the release phase of the Valsalva maneuver. Three of six double lung transplant recipients tested had no response to intravenous injection of atropine, and five of seven patients had an abnormal recovery of heart rate after maximal exercise. No patient had a normal response to all interventions, and three patients had responses compatible with complete cardiac denervation. It is concluded that cardiac denervation may occur after double lung transplantation, most likely caused by surgical interruption of sympathetic and parasympathetic pathways during dissection of the recipient's trachea.