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We reviewed all tissue specimens from 163 transplant patients (108 double lung transplant [DLT], 55 single lung transplant [SLT]) between November 1983 and January 1994 for abnormalities indicating bronchiolitis obliterans organizing pneumonia (BOOP) and found 17 cases (14 DLT and 3 SLT). Of the three SLTs, BOOP was diagnosed by open lung biopsy (OLB) in two and one was found at autopsy. Of the 14 DLTs, BOOP was diagnosed by transbronchial biopsy (TBB) specimens (9), OLB specimens (2), autopsy (1), TBB and OLB specimens (1), and OLB specimens and autopsy (1). BOOP was found between 1 and 43 months posttransplantation; time of survival from diagnosis was between 2 and 36 months with 9 patients presently alive. Concurrent pathologic diagnosis at the time of BOOP findings were as follows: acute rejection (7) (grade 1 [4] and grade 2 [3]), BO and grade 1 rejection (2), BO and grade 2 rejection (2), BO and Aspergillus infection (1), acute alveolar injury (1), acute alveolar injury and pulmonary embolus (1), acute rejection (grade 1) and Burkholderia cepacia pneumonia (1). No other pathologic diagnosis was found in 1 patient. In total, 11 of 17 patients (65%) had associated acute rejection. Of the 17 patients, 7 subsequently developed BO and 3 had BO before the finding of BOOP. Death occurred in 8 patients (5 DLT and the 3 SLT) between 2 and 6 months after the diagnosis. We conclude that BOOP is an important complication after lung transplantation; it was present in 13% of DLTs and 5% of SLTs. BOOP was most often associated with acute rejection.

Damage to the phrenic nerve, either unilaterally or bilaterally, is a well-documented complication of cardiac operation, but less commonly reported after lung transplantation.A retrospective review of 185 single and sequential single lung transplant procedures was performed at The Toronto Hospital. Objective confirmation (fluoroscopy or ultrasound) of diaphragmatic paralysis was found in 6 patients. Paralysis was unilateral in 5 patients (all were left sided) and bilateral in 1 patient.The average length of ventilation was 8.2 +/- 9.2 days with an average intensive care unit stay of 11.2 +/- 10.6 days. Mean duration in the hospital was 37.5 +/- 11.1 days. The average length of intensive care unit stay and hospitalization were compared with all other sequential single transplantations performed from approximately the time of the first documented case of diaphragmatic paralysis. Intensive care unit stay and hospitalization for the other (no diaphragmatic paralysis) transplant recipients were significantly shorter (5.3 +/- 2.7 and 29.1 +/- 12.9 days, respectively; p0.05). One patient required noninvasive ventilatory assistance via bilevel positive airway pressure in the hospital. One other patient used bilevel positive airway pressure in the hospital and overnight for 6 months after discharge. All patients obtained acceptable lung function and were ambulatory upon discharge from the hospital.Clinically detectable diaphragmatic paralysis is an infrequent complication of lung transplantation and is associated with longer intensive care unit stay and hospitalization, but is not associated with significant adverse outcomes.

Cardiopulmonary bypass has been widely used in the management of isolated single and double lung transplantations. Although there are certain clear-cut preoperative indications for cardiopulmonary bypass, in many patients the decision to use this modality is based on the hemodynamic consequences of intraoperative pulmonary artery clamping. We have performed 109 isolated lung transplantations. In 69 patients (38 single lung transplantations and 31 double lung transplantations) cardiopulmonary bypass was initiated only on the basis of intraoperative hemodynamics. We have analyzed preoperative data From these 69 patients to determine whether an intraoperative requirement for cardiopulmonary bypass can be predicted. Of 38 single lung transplantations, 12 necessitated cardiopulmonary bypass (all patients had restrictive lung disease). No patients with obstructive lung disease who underwent single lung transplantation required cardiopulmonary bypass (p

Malnutrition is a documented problem in some types of endstage lung disease (ESLD). Recently, isolated lung transplants have successfully reversed the respiratory failure of patients suffering from ESLD. In this study, we compare the preoperative and postoperative nutritional states of lung transplant recipients using weight-to-height ratios, anthropometric measurements, subjective global assessment, and biochemical blood values. Patients with emphysema, cystic fibrosis, and other types of bronchiectasis, but not patients with pulmonary fibrosis or pulmonary hypertension, were malnourished preoperatively. All groups had normal biochemical profiles. Caloric intake of patients with cystic fibrosis and bronchiectasis was increased above predicted basal energy expenditure levels. By six months to one year postoperatively, all groups of malnourished patients had significantly improved their nutritional status. Emphysema patients improved nutrition by maintaining preoperative caloric intake levels--however, both cystic fibrosis and bronchiectasis patients were able to achieve the same goal with significantly decreased caloric intakes. We conclude that malnourished ESLD patients receiving isolated lung grafts are able to achieve normal nutrition within one year posttransplant. Since this occurs in all cases with a reduced, or at best maintained, caloric intake, more study is needed to elucidate the factors that contribute to ESLD malnutrition.

End-stage lung disease has been treated successfully by lung transplantation (LTXP) at our institution since 1983. We report on the renal function of 30 LTXP recipients who were followed for at least 6 months (mean, 39 months; range, 6-60 months). All patients received quadruple immunosuppressive therapy including cyclosporine A, with a trough serum level (RIA) between 150 and 250 ng/ml for the first 6 months between 125 and 150 mg/ml after 6 months. The mean serum creatinine (SeCr) increased from a baseline value of 75 +/- 3.5 to 182 +/- 13.9 microM at the end of the follow-up. The greatest change in SeCr occurred within the first 6 months post LTXP. Fifteen of 30 patients who were initially normotensive required at least one antihypertensive medication post LTXP. By the end of the follow-up, 9 patients had SeCr > 200 microM. Two patients in this institution have progressed to end-stage renal disease requiring dialytic therapy. CsA nephrotoxicity has emerged as a major source of morbidity in the lung transplant population. Nephrotoxicity occurs early, and there does not appear to be any trend toward reversibility despite a lowering of the dose. Renal parenchymal injury may be progressive, despite an apparent plateau of the SeCr in some patients.

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 T horac C ardiovasc S urg 1992;103:295—306)

Between March 1988 and March 1991, 17 patients underwent bilateral lung transplantation for end-stage lung disease caused by cystic fibrosis. There were 11 male and six female patients. Ages ranged from 19 to 41 years (mean age 28 years). Preoperative mean arterial oxygen tension with the patient breathing room air was 54 +/- 6 mm Hg; forced vital capacity, 1.8 +/- 0.7 L; forced expiratory volume in 1 second, 0.9 +/- 0.3 L; and 6-minute walk test, 506 +/- 44 m. Immunosuppression consisted of cyclosporine, azathioprine, and prednisone. Induction immunosuppression was obtained with Minnesota antilymphocyte globulin. All patients received perioperative antibiotics according to sputum cultures and sensitivities. There were six operative deaths, four of which resulted from bacterial infection. Two patients required a second transplantation, one receiving a single lung and one undergoing bilateral lung replacement. Significant functional improvement was observed in all survivors. At 3 months follow-up, mean arterial oxygen tension on room air was 95 +/- 6 mm Hg (p less than 0.01); forced vital capacity, 3 +/- 0.8 L (p less than 0.01); forced expiratory volume in 1 second, 2.6 +/- 0.9 L (p less than 0.01); and 6-minute walk test, 678 +/- 47 m (p less than 0.01). The actuarial survival rate was 66% at 3 months and 58% at 6, 12, and 24 months. The most frequent cause of morbidity and mortality was acute pneumonia resulting from Pseudomonas cepacia. For patients with respiratory failure caused by cystic fibrosis, bilateral lung transplantation is an effective treatment option associated with significant functional improvement.

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.

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 less than 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 less than 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 less than 0.005). These data indicate that a significant improvement in right ventricular function occurs after single and double lung transplantation.

SUMMARY Therapeutic challenges in the management of lung transplant recipients abound. Every new (and often seemingly niggling) symptom should be carefully considered as it may be the prelude to a life-threatening infection or rejection episode; the minor, but unexplained, abnormality in a laboratory result may be the precursor to a major drug reaction. Constant vigilance is critical, but most emerging crises can be successfully addressed, and the ultimate rewards are immeasurable.

Between November 1983 and August 1989, we performed single-lung transplantation for end-stage pulmonary fibrosis in 20 patients. Nine patients (45 percent) who survived for more than one year form the basis of this report. Before surgery, the nine survivors had severe restrictive lung disease, with a mean (+/- SD) vital capacity (VC) of 43 +/- 9 percent, a forced expiratory volume in one second (FEV1) of 50 +/- 9 percent, and a single-breath diffusing capacity (DLCO) of 36 +/- 9 percent of predicted values. One year after transplantation, the patients' VC had reached 69 +/- 10 percent, FEV1 79 +/- 15 percent, and DLCO 62 +/- 16 percent of predicted values. Relative perfusion to the transplanted lung rose from 63 +/- 14 percent (three days after surgery) to 77 +/- 7 percent within three months and stayed constant or increased slightly thereafter. Before surgery, despite supplemental oxygen at flow rates varying from 1 to 9 liters per minute, none of the patients could exercise beyond stage 1/2 (2.7 km [1.7 miles] per hour, 5 percent grade) on a modified Bruce treadmill-exercise protocol. All eight patients tested one year or more after transplantation achieved at least stage 1 (2.7 km [1.7 miles] per hour, 10 percent grade), and usually a higher stage, without supplemental oxygen. Arterial oxygen tension returned to normal values in most patients (87 +/- 13 mm Hg), and supplemental oxygen, which all patients required before surgery, was no longer needed by any patient after transplantation. We conclude that in carefully selected patients with end-stage pulmonary fibrosis, single-lung transplantation is an effective treatment.

We have had success with en bloc double lung transplantation in the management of selected patients with end-stage parenchymal pulmonary disease. Airway complications have been more prevalent in our own experience with double lung transplantation than in reports of combined heart-lung transplantation from other centers. Between November 1986 and March 1989, 16 patients underwent double lung transplantation. Allografts were preserved by topical hypothermic immersion in 12 patients and by pulmonary artery flush with cold crystalloid solution in the most recent four patients. Thirteen patients underwent tracheal anastomosis and the most recent three patients underwent bilateral bronchial anastomoses. Fatal ischemic necrosis of the donor trachea and both main bronchi developed in three patients. Preterminal airway ischemia developed in a patient who had systemic sepsis. Partial anastomotic dehiscence, which went on to form fibrous strictures necessitating endoscopic placement of silicone rubber airway stents, developed in two additional patients. Two other patients had late strictures and required subsequent placement of bifurcation stents. There was no relationship between development of airway complications and gas exchange in the donor lungs, lung ischemic time, early postoperative gas exchange, early postoperative mean pulmonary artery pressure, or frequency of early postoperative rejection. Severe postoperative hypotension occurred in five of eight patients with airway complications and in three of eight patients without airway complications.

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.

Since the first edition of this textbook, technical advances in surgical approach and intraoperative management, combined with increasing experience in medical care of transplant recipients, have led to much-improved outcomes for lung transplant recipients. This increased experience in the care of the recipients has led both to changes in indications for specific surgeries and to improved criteria for choosing appropriate transplant candidates.

Invasive aspergillosis is a major cause of morbidity and mortality in lung transplant recipients (LTR), occurring in up to 15% of patients post-transplant. The 14% aspergillus incidence at the Cleveland Clinic Foundation prompted institution of universal prophylaxis with oral itraconazole (ICZ) in 1997. We report our experience with two protocols of ICZ administration in non-cystic fibrosis LTR and the interaction with cyclosporine (CSA).Group 1 patients (n=12) were administered ICZ capsules in a fasting or fed state, with or without a histamine-2 (H-2) receptor antagonist or proton pump inhibitor. Group 2 patients (n=12) received the same protocol as group I, but in a fed state with a carbonated beverage (cola) to increase acidity in the stomach to enhance absorption of ICZ. The ICZ dose was 200 mg/d, given as one daily dose. A historical control group (n=10) did not receive chemoprophylaxis with ICZ. CSA daily doses, dose intervals, concentration, cost, and random ICZ levels were documented over a 4-month period of time and compared using generalized estimating equations.The daily CSA mg/kg/d dose decreased over time in all three groups, but no differences were found between the three groups. The CSA dosing interval over time was significantly prolonged in group 2 compared to group 1 or the control group (por =0.003). Over time, there was no difference in CSA concentration between all groups. There was no difference in cost over time between the three groups; however, the mean cost of CSA therapy was significantly lower in group 2 compared to the control group (p=0.025). Group 2 administered ICZ with cola had greater random blood concentrations of ICZ (p=0.019).ICZ capsules administered in a fed state with a cola resulted in greater random levels of ICZ, a decrease in cost/d of CSA, and a prolongation of CSA dosing interval. Although daily CSA dosage trended lower in group 2, it did not reach statistical significance. We believe these changes in CSA dosing over time reflect increased absorption of ICZ and recommend verifying ICZ absorption with an itraconazole level, especially when CSA intervals are not prolonged.

Abdominal complications are recognized as a common complication of solid organ transplantation. These complications can range from gastritis with minor morbidity to viscus perforation and death. This study addresses specifically colonic complications in lung transplant patients to highlight their high incidence and significant morbidity and mortality in this population.Data was obtained from a prospectively gathered database on 210 patients who underwent isolated lung transplantation between February 1, 1990, and July 10, 2000 at the Cleveland Clinic Foundation. Chronic diarrhea without a specific colonic lesion and infectious diarrheas except for CMV disease was excluded from the analysis.Twenty-seven of the 210 transplant recipients (13 percent) developed a colonic complication. The sex distribution of complications was 14 males and 13 females. The colonic complications noted were diverticulitis (9), CMV colitis (5), colon cancer/precancerous polyps (4), post transplant lymphoproliferative disorder (4), megacolon (4), colon rupture (2). One patient had concurrent CMV colitis and diverticulitis. Documented perforations occurred in seven patients and surgical resection was required in 11 patients. Of the 27 patients, 10 died and nine of the deaths were directly attributable to the colonic complication.Colonic complications are common post lung transplant and result in excessive morbidity and mortality in this population. Strategies to reduce this risk should be put in place in lung transplant centers.

This study describes the central nervous system (CNS) events after lung transplantation.A chart review of all lung transplant recipients (LTR) to collect the clinical and neuroimaging data for CNS events defined as seizures, severe headaches, confusion, or stroke.Twenty-six patients of 100 LTRs from 1990 through 1995 had a CNS event; more than one event occurred in 5 patients for a total of 32 events. Severe headache was most common, occurring in 14 patients, followed by seizures in 10, stroke in 5, and confusion in 3. The CNS event was related to infection in three of the 26 patients. Of all evaluations performed, magnetic resonance imaging (MRI) identified the most abnormalities, the most common being white matter changes consistent with cyclosporine toxicity. Cyclosporine levels were elevated in slightly more than half of the patients. Hypomagnesemia was present in three of 10 patients with seizures. Prognosis for recovery from these complications was good, with only five patients having ongoing problems with headaches, one requiring long term anticonvulsant therapy, three having minor or no limitations from stroke and no long-term problems with confusion. One patient with seizures resulting from an aspergilloma died.CNS events occur commonly in LTRs, mostly related to cyclosporine toxicity or infection. MRI identifies more abnormalities than computed tomography. These events were not consistently associated with documented high cyclosporine levels and hypomagnesemia. In spite of significantly abnormal MRIs, the functional outcome is favorable.

Background Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term lung allograft viability. The diagnosis often occurs after significant organ dysfunction is present, and BOS is often unresponsive to standard immunosuppressive agents. We have observed bronchodilator responses (BRs) at low lung volumes in many of our patients who have developed BOS. We therefore assessed whether BR could predict the development of BOS. Methods We conducted a retrospective review of the clinical and pulmonary function laboratory records of 146 patients who underwent transplantation between March 1983 and November 1993. BR was defined as 25% or more increase in forced expiratory flow at 50% of vital capacity or 30% or more increase in forced expiratory flow at 75% of vital capacity. BOS was defined according to recently published FEV 1 criteria. Bronchiolitis obliterans was defined histologically according to criteria of the Lung Rejection Study Group. Results Of the total population, 52 were excluded because of death or insufficient information. BRs of the small airways were seen in 31 patients (33%), 25 of whom developed BOS (83%). Approximately half of those with BR who developed BOS had evidence of acute rejection in the month prior to the onset of BR. Two thirds (four of six) of patients with BR not developing BOS had acute rejection in the previous month. The sensitivity of BR in predicting BOS was 51% with a specificity of 87%. The positive predictive value was 81%. Conclusions BR appears to be useful as an early marker of BOS. The development of BR in selected patients should lead to closer monitoring and possibly a trial of augmented immunosuppression to arrest the establishment of BOS.

Between November 1983 and August 1993, The Toronto Lung Transplant Program performed 153 transplantations in 144 recipients: 53 single-lung transplantations (SLT) and 100 double-lung transplantations (DLT). Thirty-eight open lung biopsies (OLBs) were done in 32 (22% of all recipients): 19 in SLT (36% of SLT) 12 in DLT (12% of DLT), and 1 in a patient who had a SLT and then a double retransplantation. Six recipients underwent OLB twice: 1 DLT, 3 SLT, and 2 who had OLB both before and after retransplantation. Indication for 11 early OLBs (or = 45 days postoperative) was persistent parenchymal infiltrates. Indications for 27 late OLBs (45 days postoperative) included progressive radiologic disease with clinical findings or progressive loss of pulmonary function (18), persistent poor graft function (3), mass or nodules (3), persistent infiltrates without functional loss (2), and persistent lymphocytosis in bronchoalveolar lavage (1). Open lung biopsy confirmed a previous clinical or pathologic diagnosis in 11, suggested a diagnosis in 2, yielded nonspecific information in 16, and provided different diagnosis in 9. New diagnosis that changed therapy was made in 1 of 11 early OLBs and in 8 of 27 late OLBs. These 9 diagnoses included in SLTs: bronchiolitis obliterans (2), bronchiolitis obliterans organizing pneumonia (1), malignant lymphoma (1), and chronic vascular rejection (1) in SLT, and bronchiolitis obliterans organizing pneumonia (3) and Burkholderia cepacia infection (1) in DLT. We conclude that OLB is of little value in the perioperative period but yields useful information in approximately 30% of patients when performed late.

After early experience with perioperative bleeding in sequential single-lung transplant recipients, aprotinin was introduced in an attempt to reduce this complication and the attendant morbidity. Records of sequential single-lung transplantations (n = 33) performed between January 1989 and November 1991 were reviewed to assess the impact of aprotinin on perioperative blood loss and blood product requirements. Recipients were divided according to whether or not they required cardiopulmonary bypass. In patients requiring cardiopulmonary bypass (n = 15), mean estimated postoperative blood loss was 3,000 +/- 500 mL in those who did not receive aprotinin (n = 4) compared with 1,177 +/- 253 mL in those who received aprotinin (n = 11) (p0.05). An average of 8.0 +/- 0.7 units of packed red blood cells were administered to patients not receiving aprotinin compared with 3.1 +/- 0.7 units to those who received aprotinin (p0.05). Requirements for fresh frozen plasma were similar in each group. There were no differences in blood loss or blood product replacement in the group not undergoing cardiopulmonary bypass (n = 18). Therefore, we conclude that aprotinin decreases postoperative blood loss and blood product requirements in patients undergoing sequential single-lung transplantation under cardiopulmonary bypass.

Between November 1983 and September 1992, The Toronto Lung Transplant Program performed 131 lung transplantations in 122 recipients; 53 single lung transplantations and 78 double lung transplantations. Forty-five patients died, 25 (47%) in the single lung transplantation and 20 (25%) in the double lung transplantation groups. We retrospectively reviewed the hospital charts of all deceased recipients and the postmortem reports of the 35 patients (20 single lung transplantations and 15 double lung transplantations) who had autopsies. Preoperative single lung transplantation diagnoses included pulmonary fibrosis, (n = 17) obstructive disease (n = 6) and vascular disease (n = 2). Preoperative diagnosis of double lung transplantation included pulmonary fibrosis (n = 2), obstructive disease (n = 6), septic lung disease (n = 9), and vascular disease (n = 3). The most common cause of death in single lung transplantation was infection. Five patients died of bronchiolitis obliterans, and five more had bronchiolitis obliterans lesions present at autopsy that were not a direct cause of death. Diagnosis of primary disease was made in 23 of 25 single lung transplantations antemortem and 2 of 25 at autopsy. Autopsy diagnoses were disseminated Aspergillus and cytomegalovirus infection. In double lung transplantations, infection was also the primary cause of death; in three other patients, airway dehiscence preceded infection. Bronchiolitis obliterans was the second most common cause of death and was also present in four patients dying of infection. All double lung transplantation diagnoses were made antemortem. We concluded that infection and then bronchiolitis obliterans are the primary causes of death after lung transplantation. Although infection is a major cause both early and late after transplantation, bronchiolitis obliterans is an important factor in transplantation only late after the operation.

Cardiopulmonary bypass has been widely used in the management of isolated single and double lung transplantations. Although there are certain clear-cut preoperative indications for cardiopulmonary bypass, in many patients the decision to use this modality is based on the hemodynamic consequences of intraoperative pulmonary artery clamping. We have performed 109 isolated lung transplantations. In 69 patients (38 single lung transplantations and 31 double lung transplantations) cardiopulmonary bypass was initiated only on the basis of intraoperative hemodynamics. We have analyzed preoperative data from these 69 patients to determine whether an intraoperative requirement for cardiopulmonary bypass can be predicted. Of 38 single lung transplantations, 12 necessitated cardiopulmonary bypass (all patients had restrictive lung disease). No patients with obstructive lung disease who underwent single lung transplantation required cardiopulmonary bypass (p0.001). For single lung transplantations, 6-minute walk, the arterial desaturation/oxygen requirements on exercise, and the right ventricular ejection fraction were all significantly different between the cardiopulmonary bypass and noncardiopulmonary bypass groups (p0.001). Of 31 double lung transplantations, 10 patients required cardiopulmonary bypass (seven had bronchiectasis, two had obstructive lung disease, and one had restrictive lung disease). For obstructive lung disease, no preoperative parameters predicted cardiopulmonary bypass. In conclusion, cardiopulmonary bypass is not necessary for most patients undergoing lung transplantation (in the absence of an absolute preoperative indication). Obstructive lung disease rarely necessitates cardiopulmonary bypass. In single lung transplantations, the subsequent requirement for cardiopulmonary bypass can be predicted from preoperative cardiopulmonary performance. For double lung transplantations, the requirement for cardiopulmonary bypass is usually dependent on unpredictable intraoperative factors.

It is common to assign an upper age limit for potential lung transplant recipients. The influence of age on LTX outcome is, however not, documented. A review of our first 103 LTXs, 51 single LTXs and 52 double LTXs, includes 31 recipients aged 50-63 years (mean 55.3 +/- 3.9); 19 received single LTX, and 12 received double LTX. Indications for LTX in those aged greater than 50 included proportionately more patients with emphysema and interstitial lung disease. Actuarial survivals in those aged less than 50 at 12, 36, and 60 months were 68%, 60%, and 55%, and in those aged greater than 50 was 70%, 61%, and 61%, respectively. The causes of death reflect a tendency of younger patients to die from graft rejection and older patients to die from sepsis. Acute rejection more than 6 weeks posttransplant and chronic rejection were less frequent in older patients (P < 0.05). The 6-minute walk and modified Bruce protocol tests, the incidence of CMV pneumonitis, and the late post-LTX renal function were not related to age. In conclusion, in carefully selected candidates in their sixth and seventh decades, LTX is an acceptable operation for end-stage lung disease. The tendency of older patients to a lower incidence of late allograft rejection (acute or chronic) may reflect decreased immunological responsiveness with age.

Twenty-four isolated double lung transplants (LTXs) have been performed in 22 patients with cystic fibrosis, with a follow-up of 4 to 47 months. Prior to LTX, all patients were colonized with Pseudomonas aeruginosa, and ten patients were also colonized with Pseudomonas cepacia. Both organisms were specifically sought before LTX. All patients who grew P cepacia before LTX did so after LTX. Five additional patients only grew this bacterium after LTX. There was no difference between those who grew P cepacia and those who did not in terms of data before LTX for age, weight, pulmonary function, and 6-min walk. After LTX, 7 of the 15 patients who had ever grown P cepacia died. No patient who grew only P aeruginosa died. The median survival in the subgroup with P cepacia was 28 days. Five of the seven died as a direct result of P cepacia pneumonia and sepsis. One died of cyclosporin A (cyclosporine) neurotoxicity with concurrent P cepacia pneumonia, and one died at the time of a retransplant for graft failure (associated with three bouts of P cepacia pneumonia and cytomegalovirus). Four of seven had not grown this bacterium before LTX. There were no perioperative factors, including antibiotic choices, that distinguished survivors and nonsurvivors. Overall 1-year survival is about 70 percent (15/22). Fourteen bouts of P cepacia pneumonia occurred in 12 patients. Four empyemas, one lung abscess, one suppurative pericarditis, and five cases of sinusitis were also due to this bacterium. In conclusion, P cepacia is responsible for excess morbidity and mortality after LTX. This organism is particularly lethal if isolated for the first time after LTX. Factors predicting its acquisition in this setting are unknown. While it is possible that the facial sinuses may act as an unrecognized reservoir or that patients or equipment provide a source, further study into the epidemiology of this organism is necessary to improve the survival of colonized patients undergoing LTX.

Study Objective To ascertain the incidence, types, morbidity, and mortality of infectious episodes in isolated lung transplant recipients. Design Retrospective chart review of patients who have undergone transplants over a six-year period in one institution. Patients Twenty-three single and 17 double lung transplants followed up between 2 and 68 months. Results Fifty-one episodes of infection occurred in the group with a slight predominance in the double lung transplants. The 32 episodes of bacterial infection constituted the largest group of infection and more than half of these were pneumonias. Organisms identified were predominantly Gram negative. While bacterial processes made up the bulk of infections, fatalities were rare. Viral and fungal infections were less common, but more often fatal. Of six cases of viral pneumonitis, two were fatal; two of five cases of invasive fungal infection were also fatal. Overall, six patients died of infection. Conclusion Our findings support previous reports from heart-lung centers documenting a high rate of infectious complications, particularly pneumonia, in recipients of lung grafts. In our experience, bacterial infections are the most common (two of three infections), but have the lowest mortality. Efforts should be directed toward establishing effective prophylaxis programs and early detection of infection.

Between March 1988 and March 1991, 17 patients underwent bilateral lung transplantation for end-stage lung disease caused by cystic fibrosis. There were 11 male and six female patients. Ages ranged from 19 to 41 years (mean age 28 years). Preoperative mean arterial oxygen tension with the patient breathing room air was 54 +/- 6 mm Hg; forced vital capacity, 1.8 +/- 0.7 L; forced expiratory volume in 1 second, 0.9 +/- 0.3 L; and 6-minute walk test, 506 +/- 44 m. Immunosuppression consisted of cyclosporine, azathioprine, and prednisone. Induction immunosuppression was obtained with Minnesota antilymphocyte globulin. All patients received perioperative antibiotics according to sputum cultures and sensitivities. There were six operative deaths, four of which resulted from bacterial infection. Two patients required a second transplantation, one receiving a single lung and one undergoing bilateral lung replacement. Significant functional improvement was observed in all survivors. At 3 months follow-up, mean arterial oxygen tension on room air was 95 +/- 6 mm Hg (p less than 0.01); forced vital capacity, 3 +/- 0.8 L (p less than 0.01); forced expiratory volume in 1 second, 2.6 +/- 0.9 L (p less than 0.01); and 6-minute walk test, 678 +/- 47 m (p less than 0.01). The actuarial survival rate was 66% at 3 months and 58% at 6, 12, and 24 months. The most frequent cause of morbidity and mortality was acute pneumonia resulting from Pseudomonas cepacia. For patients with respiratory failure caused by cystic fibrosis, bilateral lung transplantation is an effective treatment option associated with significant functional improvement.

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 obliterative bronchiolitis has become a frequent cause of late morbidity.

The course of 52 isolated single and double lung transplant recipients who survived more than 2 weeks was reviewed to determine the incidence of cytomegalovirus (CMV) infection. In this group 22 patients were seromatched: 11 donor-recipient pairs were seronegative and 11 were seropositive. Of the remaining 30, 13 were donor-positive, recipient-negative and 17 were donor-negative, recipient positive. Diagnosis of CMV infection was made in the event of (1) seroconversion, (2) clinical symptoms consistent with CMV plus a fourfold rise in CMV titer, (3) isolation of CMV from tissue or body fluid by shell vial monoclonal antibody technique. CMV pneumonitis was diagnosed when shell vial culture from bronchoalveolar lavage fluid was positive in the appropriate clinical setting even if cytopathic changes were not yet present. Clinical CMV infection did not develop in any of the 22 seromatched pairs, and none of the seronegative pairs seroconverted. Of 17 recipient-positive, donor-negative pairs, CMV pneumonitis developed in two; one died. Of 13 recipient-negative, donor-positive pairs, seven seroconverted and pneumonitis developed in two but they did not die. The most recent 10 mismatched pairs received hyperimmune globulin prophylaxis, but this did not prevent the development of infection or clinical disease. Morbidity and mortality were greater in the seromismatched groups than in seromatched groups although this difference could not be directly related to CMV infection in most cases. Our experience suggests that both seronegative and seropositive recipients who receive a mismatched graft, but not the usual high-risk seropositive matched pairs, are at significant risk of clinical CMV disease after isolated single and double lung transplantation.

Single lung transplantation has recently been applied with success in patients with obstructive lung disease. Such patients were previously managed by bilateral pulmonary transplantation. Between November 1986 and January 1990, 18 patients underwent transplantation for obstructive lung disease in our center. Eleven double lung transplants and seven single lung transplants were performed in patients having a mean age of 43.4 and 44.1 years, respectively. Operative death occurred in two of 11 double lung transplantations and one of seven single lung transplantations. Each patient underwent preoperative and 3-month postoperative pulmonary function tests, arterial blood gas analyses, nuclear lung scans, and 6-minute walk tests. There was no difference in the preoperative values for any of these parameters. Double lung recipients had significantly higher forced expiratory volume in 1 second and forced vital capacity than single lung recipients. However, the ratios of forced expiratory volume in 1 second to vital capacity were not different. Arterial oxygen and carbon dioxide tension were not different between the two procedures. Whereas double lung transplantations caused a slight preponderance of perfusion to the right lung, the transplanted lung in single lung recipients received a mean of 79.5% +/- 12.3% of predicted flow and only 61.6% +/- 5.0% of predicted ventilation. Three-month 6-minute walk distances were markedly improved in both groups, with double lung recipients achieving 573.0 +/- 44.7 m in comparison with the 528.0 +/- 43.0 m achieved by the single lung recipients. Single lung transplantation is a satisfactory option in patients with obstructive lung disease and might offer significant advantages to the older patient population, in which risk of double lung transplantation is high.

Six patients with end-stage pulmonary vascular disease received right SLTs. Though patients generally had difficult early postoperative courses, four of the six have survived from 3 to 23 months and have achieved good recovery of right ventricular function and good functional results. SLT is a viable option in selected patients with severe pulmonary hypertension even when right ventricular function is severely impaired.

Lung transplantation has evolved from an intellectual curiosity to a viable therapeutic option in a selected number of patients with end-stage lung disease. The indications for single lung, double lung, or heart-lung transplantation at major North American transplant centers are presented, the selection criteria are discussed, and the standard preoperative evaluation is outlined. Utilizing these guidelines, a 1-year actuarial survival following each of these procedures of greater than 60% can be expected.

Transplantation is now a treatment option in patients with end-stage pulmonary and pulmonary vascular disease. This article describes the outcome of single and double lung transplants performed by the Toronto Lung Transplant Group. Specifically reported are mortality, cause of death, pulmonary physiology, arterial blood gases, and exercise performance. Where possible, these results are compared with results of heart-lung transplantation from other centers.

Therapeutic challenges in the management of lung transplant recipients abound. Every new (and often seemingly niggling) symptom should be carefully considered as it may be the prelude to a life-threatening infection or rejection episode; the minor, but unexplained, abnormality in a laboratory result may be the precursor to a major drug reaction. Constant vigilance is critical, but most emerging crises can be successfully addressed, and the ultimate rewards are immeasurable.

Single lung transplantation has been attempted in humans since 1963, but it was uniformly unsuccessful until the early 1980s (Chapter 45). These poor early results could be attributed to several factors, including technical problems resulting in bronchial dehiscence, poor donor lung preservation, infection, and inadequate immunosuppression. Probably equally important in the early failures was the selection of inappropriate patients. Most of those transplanted were desperately ill, debilitated patients with end-stage obstructive lung disease and malignancy.

We have achieved repeated success with unilateral lung transplantation for pulmonary fibrosis and have developed an en bloc, double-lung transplant procedure for patients with advanced lung disease of an obstructive or infective nature. Six such procedures have now been performed for end-stage emphysema, and all recipients are alive and well 5 to 15 months later. A seventh transplant for primary pulmonary hypertension was unsuccessful. All recipients were judged to have a life expectancy of 12 to 18 months on the basis of the degree of disability and the documented rate of disease progression. We feel the double-lung procedure is more appropriate than the combined heart-lung transplant for patients requiring replacement of both lungs when right heart function is adequate or deemed recoverable. With this procedure, the recipient is able to retain his or her own heart, avoiding the liabilities associated with cardiac transplantation. Furthermore, the donor heart is available for a separate recipient, and this sharing of the heart and lungs greatly increases the supply of transplantable lungs for patients with end-stage lung disease. Ischemia of the donor airway has been a source of complication, including the one death to date, but this appears to be a surmountable problem.

Discussed are the mean-square response exceedance characteristics of a single-tuned system to amplitude modulated noise. The results bear on the accuracy of spectral estimates of nonstationary data, and subsequently, relate directly to the design, analysis, and testing of structural systems in environments as gusts, earthquakes, and ignition transients. For noise correlated as an exponentially damped cosine, the nonstationary response may exceed its stationary value by a factor in excess of two. A time-varying shaping filter explanation is offered for this behavior. For white noise, such exceedances do not occur.

This paper concerns the mean-square response of a single-degree-of-freedom system to amplitude modulated random noise. The formulation is developed in terms of the frequency-response function of the system and generalized spectra of the nonstationary random excitation. Both the unit step and rectangular step functions are used for the amplitude modulation, and both white noise and noise with an exponentially decaying harmonic correlation function are considered. The time-varying mean-square response is shown not to exceed its stationary value for white noise. For correlated noise, however, it is shown that the system mean-square response may exceed its stationary value.

Pleural complications occurred in 30 (22%) of 138 patients after 53 single and 91 double lung transplants between September 1986 and February 1993. These were defined for the purpose of this study as pneumothorax persisting beyond the first 14 postoperative days, recurrent pneumothorax, or any other pleural process that necessitated diagnostic or therapeutic intervention. Overall, a higher pleural complication rate was seen in double lung transplantation (25 of 30) than in single lung transplantation (5 of 30) with no differences noted in the frequency among preoperative diagnostic groups (p > 0.05). Pneumothorax was the most frequent complication, affecting 14 of 30 patients, with 6 of 14 cases occurring after transbronchial biopsy. All pneumothoraces in single (n = 4) and double lung transplantation (n = 10) resolved spontaneously or with chest tube thoracostomy. One patient required placement of a Clagett window after open lung biopsy and another required thoracotomy and pleural abrasion after transbronchial biopsy. Parapneumonic effusion was observed in 4 of 30 double lung transplantations with spontaneous resolution in all cases. Empyema affected 7 of 30 patients and occurred exclusively in the double lung transplant group. Sepsis developed in three of the patients with this complication and they subsequently died. The risk of empyema was independent of preoperative diagnosis (p > 0.05). Of interest, all patients with cystic fibrosis (n = 3) with complicating empyema had Pseudomonas cepacia in the pleural fluid. Other miscellaneous complications included subpleural hematoma, chylothorax, and hemothorax. The latter two necessitated thoracic duct and bronchial artery ligation, respectively. In summary, a significant proportion of lung transplant recipients will have pleural space complications. The vast majority of these will resolve spontaneously or with conservative procedures. These complications were not related to preoperative diagnosis nor associated with a significant prolongation of hospital stay (p > 0.05). Empyema is the only pleural space complication associated with increased patient mortality and, as such, is an important clinical marker for those at risk for sepsis and death.

We describe the simultaneous occurrence of Mycobacterium tuberculosis and lymphocytic interstitial pneumonitis in a 54-year-old man. Two drugs were used to treat the tuberculosis, and the patient had clinical improvement but persistent laboratory and chest roentgenographic abnormalities.