Pulmonary Function after Heart-Lung Transplantation Using Larger Donor Organs 1- 3
K. SCOTT LLOYD, PETER BARNARD, VENESSA A. HOLLAND, GEORGE R NOON, and E. CLINTON LAWRENCE
Introduction
A stable restrictive pulmonary defect after heart-lung transplantation previously has been attributed to the use of small donor lungs and/or to an inability to generate normal negative pleural pressures after surgery (1). One study has suggested that lung elasticity remained normal after transplantation but that the lungs operate at lower lung volumes than before transplantation (1, 2). Other possibilities include changes in chest wall compliance or mismatch between recipient thoracic volume and donor lung volume. Because of limited donor availability, exact donor-to-recipient size matching has not always been possible. Many of our patients are women, and the majority of the donors are men. As a result, larger men have often served as donors for smaller women because of the constraints of the donor pool. Using larger donor organs raised the question of what determines final lung volumes in heart-lung transplant recipients. If the recipient chest cavity is the primary determinant of final function, how do larger donor lungs adapt and do they function poorly in smaller recipients? Todetermine whether post-transplantation lung volumes are more dependent on donor lung size or on recipient chest wall characteristics, seven heartlung transplant recipients wereevaluated preoperatively and and postoperatively in the pulmonary function laboratory. Methods Patient Population Seven patients with end-stage pulmonary or cardiopulmonary disease successfully transplanted at The Methodist Hospital between 1985 and 1989made up the study group. All patients were maintained on an immunosuppressive regimen of cyclosporin A (eYA) administered twice daily, azathioprine (1.0to 1.5 mg/kg), and prednisone (0.1 to 0.2 mg/kg/ day) with trough serum levels of CYA main1026
SUMMARY Restrictive pulmonary function after heart-lung transplantation (HLT)has been attributed to the use of smaller donor lungs and/or an Inability to generate normal negative pleural pressures. Pleural pressure generation depends on both the size of the recipient thoracic cage and its neuromuscular Integrity. To determine whether lung volumes after heart-lung transplantation are more dependent on donor lung size or on recipient chest wall characteristics, seven HLTrecipients were evaluated before and after transplantation. Postoperative values Initially (average, 2 months), 6, and 12 months after transplantation were compared with predicted lung volumes for the recipient and donor organs. TLC dropped from a mean of 5.2 ± 0.5 L preoperatively to 3.7 ± 0.3 L (p < 0.05) 2 months after HLT, but It Improved with time and ultimately was not different from preoperative values. The predicted TLCof the HLTdonor organs weresignificantly larger than those of the recipient's predicted TLC, with a mean of 6.9 ± 0.4 versus 5.3 ± 0.3 L (p < 0.05). Oleo, arterial Po 2 , and Pco 2 did not change after surgery. Within limits, larger donor lungs appear to adapt to the constraints of the recipient chest and may be used with clinical success, without apparent adverse effects. AM REV RESPIR DIS 1990; 142:1026-1029
tained at 200 to 300 ug/dl as measured by a RIA of serum using a Sandoz monoclonal antibody kit. Of heart-lung transplant recipients, the preoperative diagnosis was primary pulmonary hypertension in three patients, Eisenmenger's complex in two patients, and bronchiolitis obliterans and cystic fibrosis in one patient each (table 1). All patients were receiving supplemental oxygen prior to transplantation with severe activity limitations, New York Heart Association Class III to IV.
Donor Population Donor characteristics were recorded at the time of organ procurement after brain death was confirmed and consent for organ donation obtained. Heart-lung grafts were harvested with core blood cooling using cardiopulmonary bypass then stored in iced saline until implantation. Pulmonary Function Tests Survivors were evaluated at various intervals in the pulmonary function laboratory, ranging from 6 months preoperatively to 12 months postoperatively. Predicted lung volumes for both donor and recipients were calculated using the formulas of Morris and coworkers (3, 4), Goldman and Becklake (5), Polgar and Promadhar (6), and Boren and colleagues (7). Donor lung volumes were calculated based on height, weight, sex, age, and race characteristics. One patient (Patient 1) had preoperative TLC determined byplanimetry according to the methods of Harris and coworkers (8).
Expiratory flow parameters were determined on a rolling seal spirometer (PK Morgan, Kent, UK), which was linked to a computer for computations (Medical Graphics, St. Paul, UK). Functional residual capacity (FRC) was determined with a computerassistedbody plethysmograph (Medical Graphics). Diffusion capacity (OLeo) was measured using the single-breath carbon monoxide technique (9). Arterial blood gas measurements while breathing room air were obtained with each laboratory visit and analyzed with an ABL-3 blood gas analyzer (Radiometer, Copenhagen, Denmark).
Statistical Analysis TLC, FVC, and FEV 1 were compared as both absolute values and as percentages of predicted for both donors and patients. Preoperative and initial (average, 2 months; range, 1 (Received in originalform November 20, 1989 and in revised form May 23, 1990) 1 From the Departments of Medicine and Surgery, The Methodist Hospital and Baylor College of Medicine, Houston, Texas. 2 Supported in part by research grants from the McKelvey Funds of The Methodist Hospital, the Alkek Transplant Research Fund, and the Cullen Trust for Health Care. Computational assistance was provided by the CLINFO Project funded by the Division of Research Resources Grant No. RR00350 from the National Institutes of Health. 3 Correspondence and requests for reprints should be addressed to E. Clinton Lawrence, M.D., Director of Lung Transplantation, Sharp Memorial Hospital, San Diego, CA 92123.
1027
,,uLM0 NARY FUNCTION AFTER HEART·WNG TRANSPLANTATION
TABLE 1 COMPARISON OF RECIPIENT AND DONOR CHARACTERISTICS -~------
-
Patient No.
Recipient Height . inches Age. yr Race Sex Diagnosis [)OnOr Height. inches Age. yr Race Sex Diagnosis
2
3
4
5
6
7
Mean
67 35 W F 1° PHT
64 34 W F 1° PHT
62 42 W F 1° PHT
61 21 W F CHDI2° PHT
68 22 W M CF
68 37 W F CHD/2° PHT
61 17 W F
64.4 29.7
1.2 3.6
80
72 24 W M Head trauma
70 20 W M GSW to head
70 30 W M MVA
64 15 W F Head trauma
72 36 W M Brain tumor
70 20 W M GSW to head
74 20 W M GSW to head
70.3' 23.6
1.2 2.7
Definition of abbreviations: 1° PHT = primary pulmonary hypertension ; CHD/2° PHT = cong enital heart disease and secondary pulmonary hypertens ion (Eisenmenger's complex); CF fibroSis; BO - bronchiofttls obliterans ; GSW = gunshot wound; MVA = motor vehicle accident. , p < 0.05, donor versus recipient.
to 5 months), 6-, and 12-month postoperative values were compared for each patient. Valueswere compared using Student's paired t test, with a p value less than 0.05 being considered significant. Data storage and statistical analysis were performed on the CLINFO Project Data System of the Baylor College of Medicine.
Results
The donor and recipient characteristics in our transplantation group are shown in table 1. Recipients had a mean age of 29.7 yr at the time of transplantation, Six were white women and one was a white man. Recipients 1 through 3 were transplanted for primary pulmonary hypertension, Recipients 4 and 6 had Eisenmenger's complex, Recipient 5 had cystic fibrosis, and Recipient 7 had idiopathic bronchiolitis obliterans. Except for the severeairway obstruction in Patients 5 and 7, all recipients had essentially normal pulmonary function tests, preoperatively.
8
Donors were slightly younger, with a mean age of 23.6 yr. Six of the seven donors were men and all were white. Donors were taller, with a mean height of 70.3 inches compared with 64.4 inches for recipients (P < 0.05). In figure I, comparing donor-to-recipient predicted TLC, it can be seen that four of the seven recipients received significantly larger donor organs, ranging from 135 to 179070 of their TLC for these four donor-recipient pairs. In general, larger patients received larger donor organs. After heart-lung transplantation, all patients symptomatically and objectively improved. Twomonths after transplantation, TLC fell to a mean of 3.7 ± 0.3 L compared with a pretransplant value of 5.2 ± 0.5 L (P < 0.05) (figure 2). Subsequently, TLC gradually increased, and by 12months after transplantation it was no different from preoperative TLC (figure 2). Similar changes were noted for
± SEM
= cystic
FVC. Thus, initial postoperative lung volumes demonstrated a new restrictive defect, which showed gradual resolution after transplantation. The course of a typical heart-lung transplant recipient's improvement over time is shown in figure 3; note the stability in TLC and FVC between 7 and 12 months. For each patient, stable postoperative lung volumes more closely approximated recipient preoperative volumes than donor predicted volumes (table 2). For those four surviving patients not severely obstructed preoperatively, the mean TLC, FVC, and FEV 1 more closely approximated recipient preoperative lung volumes than donor predicted values (figure 4). Donor predicted volumes were statistically different when compared with preoperative and postoperative lung volumes of the recipients (figure 4), with the exception of residual volumes, which were no different (data not shown). There was no overall difference be-
•
5
7
6
5
.. i
...
1Il
~
3
3
::J
~
4
2
3
2 Initial
Pre
o0~--'-~2~3~....J4~-::5~6~-::7~~8~9 Recipient Predicted TLC (liters) Fig. 1. Comparisons of donor-predicted TLC and recipient·predicted TLC.
6 mos
12 mas
Post
TLe Fig. 2. Changes in mean TLC initially (average, 2 months), 6, and 12 months alter cardiopulmonary transplantation . Values are mean ± SEM . Asterisks indicate p < 0.05 compared with pretransplant values.
Pre 1
2
3
4
5
6
7
8
9 10 11 12
Months Fig. 3. Improvement in TLC and FVC with time after cardiopulmonary transplantation (Patient 1)in comparison with preoperative values . Closed circles = TLC; open squares = FVC.
1028
LLOYD, BARNARD. HOLLAND. NOON. AND LAWRENCE
TABLE 2 STATIC LUNG VOLUMES BEFORE AND AFTER TRANSPLANTATION Patient No.
2 Preoperative FVC. L FEV" L RV, L TLC. L Postoperative , 12 months FVC, L FEV" L RV, L L Donor-predicted FVC, L FEV,. L RV, L TLC, L
nc,
3
4
5
6
7
4.00 3.42 1.01 5.01
2.68 2.20 2.36 5.04
2.85 2.25 1.80 4.70
2.11 1.56 1.79 3.95
1.55 0.89 5.26 6.95
3.42 2.17 1.84 5.52
1.31 0.43 4.31 5 .93
3.43 2.71 1.46 4.91
2.27 2.15 1.18 3.45
(2.55)* (2.08) (1.11) (3.66)
2.49 2.28 1.53 3.96
4.22 3.93 2.19 6.69
3.90 3.39 1.60 5.63
1.69 1.32 1.83 3.75
5.81 4.80 1.90 7.70
5.59 4.68 1.69 7.25
5.38 4.44 1.86 7.10
3.77 3.17 1.00 4.86
5.52 4.21 1.69 6.96
5.62 4.54 1.41 6.56
6.20 5.10 1.97 8.20
• 6 months' values for Patient 3.
tween preoperative and postoperative values for POz, Pco., and DLco in the heartlung transplant recipients while at rest (see table 3). Interestingly, the DLeo remained low after transplantation despite absence of clinical rejection or infection. Blood Po.Ievels varied, with some values higher than anticipated while breathing room air; the explanation for this finding is unclear. Of the transplant recipients, three (Patients 1, 3, and 7) developed evidence of obstructive ventilatory defects several months after transplantation; airflow obstruction developed 22 months after transplantation in Patient 1, 7 months after transplantation in Patient 3, and 15 months after transplantation in Patient 7. Bronchiolitis obliterans was documented histologically in Patients 1 and 3, with Patient 3 dying of complications of treatment for this process. Patients 1 and 7 have stabilized with increased immunosuppression. Each of these three patients received lungs with substan-
tially larger predicted TLC (135, 154, and 179070 of recipient predicted values, respectively). Discussion
After transplantation, all heart-lung transplantation patients showed evidence of restrictive pulmonary defects, which improved with time towards more normal parameters. Final postoperative function did not differ significantly from pretransplant values. Theodore and coworkers (1) noted a similar course in their patients, with a final preoperative-to-postoperative TLC ratio of 1.0. They attributed this to good donor-recipient matching or possibly to adaptation of the donor organs to the constraints of the recipient chest cavity. Our data support the latter view as most of our donor organs were clearly from larger donors, even though larger recipients received proportionately larger organs. Although we cannot exclude the possibility that the actual lung volumes of some or of all donors were less than predicted, our study clearly , shows that larger donors may be used
with clinical success, with postoperative function not being significantly different from preoperative function. Whether the new lungs are simply operating at lower lung volumes because of the size constraint of a small chest or because there is actual loss of alveolar lung units in modeling to a smaller chest is unknown. Patients 5 and 7 showed marked reduction in residual volume compared with preoperative values because of the obstructive nature of their underlying diseases. A case report by the Minnesota group would also suggest that chest volumes return to normal after transplantation in the hyperexpanded chest (10). Our Patient 7 had the largest organ mismatch, and one must wonder whether this contributed to a functional obstructive defect postoperatively. The defect appears to have stabilized on increased immunosuppression, supporting a clinical diagnosis of bronchiolitis obliterans (lIB) as either a chronic form of rejection or a recurrence of the original disease in the graft organ. Nonetheless, reduced elastic recoil from larger donor lungs remains a potential problem, but the exact degree of mismatch required to lead to measurable problems is not known. The transplanted larger lung operating at low lung volumes would be one explanation for a low DLeo postoperatively, but postoperative DLeo was also low in patients receiving nearly perfectly size-matched lungs (Patients 4 and 5). There may be actual loss of lung units after transplantation through regional atelectasis and closure of poorly ventilated alveoli. Alternatively, loss of units could occur through the process of rejection, which virtually all patients experience at some point in the postoperative period (14). Gas exchange was well preserved in all groups as would be expected for equivalent loss of ventilation and perfusion units together. Ischemia and infection could conceivably cause ir-
TABLE 3 GAS EXCHANGE BEFORE AND AFTER TRANSPLANT Preoperative Patient No. TLC
FVC
FEV,
Fig. 4. Mean donor-predicted lung volumes in comparison with mean recipient preoperative lung volumes and mean postoperative lung volumes 12 months after transplantation . Values are mean ± SEM . Asterisks indicate p < 0.05 compared to other values. Dotted bars = donor; open bars = pre-op: closed bars = post-op.
1 2 3' 4 5 6 7
PAo, (mmHg)
120 92 60 51 51 72 84
pco, (mmHg)
Postoperative (12 months) DLco (%pred)
PAo, (mmHg)
29
66
38
126 (72) 115 98 105
26 34 46 34 56
• 6 months' value for Patient 3.
57 63 56 56 42
68
pco, (mmHg)
39 27 (32) 36 41 38 38
OLeo (%pred)
76 49 (56) 58 45 95
1029
pULMONARY FUNCTION AFTER HEART·WNG TRANSPLANTATION
reparable lung tissue damage. Although
all donor organs had acceptable ischemia times less than 4 h, any ischemic injury may cause loss of gas exchange units. Infections, particularly cytomegalovirus pneumonia, could further damage the transplanted lungs. Indeed, Yousem and coworkers (15) described parenchymal and pleural fibrosis in several of their long-term surviving heart-lung transplant patients in which the ischemia times were less than 4 h for all donor organs. Glanville and colleagues (2) noted postoperative maximal inspiratory pressures (PImax) to be reduced and to correlate well with the postoperative restrictive defect. Unfortunately, these measurements were not available in our patients. The effects of chest surgery on postoperative pulmonary function have been measured in the past, including the limitation of different incision types on respiratory function (16-18). In general, all of the . defects were restrictive in nature, with improvement in time towards normal. Our patients showed improvement in lung volumes with time after surgery although some mild stable restriction persisted. A decrease in lung compliance cannot be ruled out as contributing to this observation; however, a previous study in which lung compliance was measured did not detect a postoperative decrease (2). Volume mismatch leading to suboptimallength tension arrangements of the respiratory muscles has been proposed by Glanville and colleagues (2) as a possible mechanism of apparent postoperative muscle weakness. Chronic immunosuppressant with corticosteroids may also contribute to the low postoperative inspiratory capacity. Assuming that both lung compliance and respiratory muscle strength are preserved in our patient population, one might have expected the lung volumes to lie between donor and recipient volumes after transplantation. Theoretically, the larger organs operating at a lower lung volume should be able to reach a larger volume per unit of negative intrathoracic pressure generated by the respiratory
muscles. Potential explanations on the limits of lung expansion include a loss of lung compliance occurring with lung transplantation and/or lung volumes greater than the native TLC of the recipient, creating adverse length-tension arrangements of the respiratory muscle system. Alternatively, an adaptation of the donor organs to the recipient chest over time might occur, with the lungs actually adopting compliance characteristics similar to those of the native organ, possibly through selective loss of lung units through a process of modeling. Quite likely, more than one of these processes actually contributes to the limitation on post-transplantation lung expansion. Further studies regarding these processes will be needed to determine the exact role of each in the adaptation response. The three of our patients with the best pulmonary function 12 months after transplantation (patients 4, 5, and 6) were also the ones with the closest donorrecipient lung size match. Although another three of our patients (Patients 1, 3, and 7) have developed obstructive lung disease consistent with bronchiolitis obliterans (proved in Patients 1 and 3), a similar incidence of bronchiolitis obliterans has been found in institutions employing smaller donor lungs (12). While we believe that larger donor lungs may be successfully transplanted, at this time we would prefer to use lungs with predicted TLC no greater than 120 percent of that TLC predicted for the recipient. A related study by Otulana and colleagues (19) would support this approach. Only with an increased donor pool through greater public awareness will such close matching be possible. Acknowledgment The writers thank Ms. Jackie Warren and Ms. Lisa Conway for their expert secretarial assistance in preparation of the manuscript. References 1. Theodore J, Jamieson SW, Burke CM, et al. Physiologic aspects ofthe human heart-lung transplantation. Chest 1984; 86:349-57. 2. GlanvilleAR, Theodore J, Harvey J, Robin ED.
Elastic behavior of the transplanted lung. Am Rev Respir Dis 1988; 137:308-12. 3. Morris JF, Koski A, Johnson LC. Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 1971; 103:57-67. 4. Morris JF, TempleWF, Koski A. Normal values for the ratio of one-second forced expiratory volume to forced vital capacity. Am Rev Respir Dis 1973; 108:1000-3. 5. Goldman HI, Becklake MR. Respiratory function tests: normal values at median altitudes and the prediction of normal results. Am Rev Tuberc 1959; 79:457. 6. Polgar G, Promadhar V. Pulmonary function testing in children: techniques and standards. Philadelphia: W.B. Saunders, 1971. 7. Boren HG, Kory RC, Syner JC. The Veterans Administration-Army Cooperative Study of Pulmonary Function. The lung volume and its subdivisions in normal men. Am J Med 1966;41:96-114. 8. Harris TR, Pratt PC, Kilburn KH. Total lung capacity measured by roentgenograms. Am J Med 1971; 50:756-63. 9. Burrows B, Kasik JE, Niden AH, Barclay WR. Clinical usefulness of the single breath pulmonary diffusion capacity test. Am Rev Respir Dis 1961; 84:789-806. 10. Hertz MI, Bonser RS, Jamieson SW,Tashjian J, Halvorsen RA. Reversiblehyperinflation in emphysema. Chest 1989; 96:421-2. 11. Glanville AR, Baldwin JC, Burke CM, Theodore J, Robin ED. Obliterative bronchiolitis after heart-lung transplantation: apparent arrest byaugmented immunosuppression. Ann Intern Med 1987; 107:300-4. 12. Burke CM, Morris AJ, Dawkins KD, et al. Late airflow obstruction in heart-lung transplant recipients. J Heart Transplant 1985; 4:437-40. 13. Burke CM, Glanville AR, Theodore J, Robin ED. Lung immunogenicity, rejection, and obliterative bronchiolitis. Chest 1987; 92:547-9. 14. Lawrence EC, Holland AV, Young JB, et al. Dynamic changes in soluble interleukin-2 receptor levelsfollowinglung or heart-lung transplantation. Am Rev Respir Dis 1989; 140:789-96. 15. Yousem SA, Burke CM, Billingham ME. Pathologic pulmonary alterations in long-term human heart-lung transplantation. Hum Patho11985; 16:911-23. 16. Johnson We. Postoperative ventilatory performance: dependence upon surgical incision. Am Surg 1975; 41:615-9. 17. Pecora DV. Predictability of effectsof abdominal'and thoracic surgery upon pulmonary function. Ann Surg 1969; 170:101-8. 18. Zin WA, Marina PR, Caldeira BSC, Wellington VC, Auler JOC, Saldiva PHN. Expiratory mechanics before and after uncomplicated heart surgery. Chest 1989; 95:21-8. 19. Otulana BA, Mist BA, Scott JP, Wallwork J, Higenbottam T. The effect of recipient lung size on lung physiology after heart-lung transplantation. Transplantation 1989; 48:625-9.
K. SCOTT LLOYD, PETER BARNARD, VENESSA A. HOLLAND, GEORGE R NOON, and E. CLINTON LAWRENCE
Introduction
A stable restrictive pulmonary defect after heart-lung transplantation previously has been attributed to the use of small donor lungs and/or to an inability to generate normal negative pleural pressures after surgery (1). One study has suggested that lung elasticity remained normal after transplantation but that the lungs operate at lower lung volumes than before transplantation (1, 2). Other possibilities include changes in chest wall compliance or mismatch between recipient thoracic volume and donor lung volume. Because of limited donor availability, exact donor-to-recipient size matching has not always been possible. Many of our patients are women, and the majority of the donors are men. As a result, larger men have often served as donors for smaller women because of the constraints of the donor pool. Using larger donor organs raised the question of what determines final lung volumes in heart-lung transplant recipients. If the recipient chest cavity is the primary determinant of final function, how do larger donor lungs adapt and do they function poorly in smaller recipients? Todetermine whether post-transplantation lung volumes are more dependent on donor lung size or on recipient chest wall characteristics, seven heartlung transplant recipients wereevaluated preoperatively and and postoperatively in the pulmonary function laboratory. Methods Patient Population Seven patients with end-stage pulmonary or cardiopulmonary disease successfully transplanted at The Methodist Hospital between 1985 and 1989made up the study group. All patients were maintained on an immunosuppressive regimen of cyclosporin A (eYA) administered twice daily, azathioprine (1.0to 1.5 mg/kg), and prednisone (0.1 to 0.2 mg/kg/ day) with trough serum levels of CYA main1026
SUMMARY Restrictive pulmonary function after heart-lung transplantation (HLT)has been attributed to the use of smaller donor lungs and/or an Inability to generate normal negative pleural pressures. Pleural pressure generation depends on both the size of the recipient thoracic cage and its neuromuscular Integrity. To determine whether lung volumes after heart-lung transplantation are more dependent on donor lung size or on recipient chest wall characteristics, seven HLTrecipients were evaluated before and after transplantation. Postoperative values Initially (average, 2 months), 6, and 12 months after transplantation were compared with predicted lung volumes for the recipient and donor organs. TLC dropped from a mean of 5.2 ± 0.5 L preoperatively to 3.7 ± 0.3 L (p < 0.05) 2 months after HLT, but It Improved with time and ultimately was not different from preoperative values. The predicted TLCof the HLTdonor organs weresignificantly larger than those of the recipient's predicted TLC, with a mean of 6.9 ± 0.4 versus 5.3 ± 0.3 L (p < 0.05). Oleo, arterial Po 2 , and Pco 2 did not change after surgery. Within limits, larger donor lungs appear to adapt to the constraints of the recipient chest and may be used with clinical success, without apparent adverse effects. AM REV RESPIR DIS 1990; 142:1026-1029
tained at 200 to 300 ug/dl as measured by a RIA of serum using a Sandoz monoclonal antibody kit. Of heart-lung transplant recipients, the preoperative diagnosis was primary pulmonary hypertension in three patients, Eisenmenger's complex in two patients, and bronchiolitis obliterans and cystic fibrosis in one patient each (table 1). All patients were receiving supplemental oxygen prior to transplantation with severe activity limitations, New York Heart Association Class III to IV.
Donor Population Donor characteristics were recorded at the time of organ procurement after brain death was confirmed and consent for organ donation obtained. Heart-lung grafts were harvested with core blood cooling using cardiopulmonary bypass then stored in iced saline until implantation. Pulmonary Function Tests Survivors were evaluated at various intervals in the pulmonary function laboratory, ranging from 6 months preoperatively to 12 months postoperatively. Predicted lung volumes for both donor and recipients were calculated using the formulas of Morris and coworkers (3, 4), Goldman and Becklake (5), Polgar and Promadhar (6), and Boren and colleagues (7). Donor lung volumes were calculated based on height, weight, sex, age, and race characteristics. One patient (Patient 1) had preoperative TLC determined byplanimetry according to the methods of Harris and coworkers (8).
Expiratory flow parameters were determined on a rolling seal spirometer (PK Morgan, Kent, UK), which was linked to a computer for computations (Medical Graphics, St. Paul, UK). Functional residual capacity (FRC) was determined with a computerassistedbody plethysmograph (Medical Graphics). Diffusion capacity (OLeo) was measured using the single-breath carbon monoxide technique (9). Arterial blood gas measurements while breathing room air were obtained with each laboratory visit and analyzed with an ABL-3 blood gas analyzer (Radiometer, Copenhagen, Denmark).
Statistical Analysis TLC, FVC, and FEV 1 were compared as both absolute values and as percentages of predicted for both donors and patients. Preoperative and initial (average, 2 months; range, 1 (Received in originalform November 20, 1989 and in revised form May 23, 1990) 1 From the Departments of Medicine and Surgery, The Methodist Hospital and Baylor College of Medicine, Houston, Texas. 2 Supported in part by research grants from the McKelvey Funds of The Methodist Hospital, the Alkek Transplant Research Fund, and the Cullen Trust for Health Care. Computational assistance was provided by the CLINFO Project funded by the Division of Research Resources Grant No. RR00350 from the National Institutes of Health. 3 Correspondence and requests for reprints should be addressed to E. Clinton Lawrence, M.D., Director of Lung Transplantation, Sharp Memorial Hospital, San Diego, CA 92123.
1027
,,uLM0 NARY FUNCTION AFTER HEART·WNG TRANSPLANTATION
TABLE 1 COMPARISON OF RECIPIENT AND DONOR CHARACTERISTICS -~------
-
Patient No.
Recipient Height . inches Age. yr Race Sex Diagnosis [)OnOr Height. inches Age. yr Race Sex Diagnosis
2
3
4
5
6
7
Mean
67 35 W F 1° PHT
64 34 W F 1° PHT
62 42 W F 1° PHT
61 21 W F CHDI2° PHT
68 22 W M CF
68 37 W F CHD/2° PHT
61 17 W F
64.4 29.7
1.2 3.6
80
72 24 W M Head trauma
70 20 W M GSW to head
70 30 W M MVA
64 15 W F Head trauma
72 36 W M Brain tumor
70 20 W M GSW to head
74 20 W M GSW to head
70.3' 23.6
1.2 2.7
Definition of abbreviations: 1° PHT = primary pulmonary hypertension ; CHD/2° PHT = cong enital heart disease and secondary pulmonary hypertens ion (Eisenmenger's complex); CF fibroSis; BO - bronchiofttls obliterans ; GSW = gunshot wound; MVA = motor vehicle accident. , p < 0.05, donor versus recipient.
to 5 months), 6-, and 12-month postoperative values were compared for each patient. Valueswere compared using Student's paired t test, with a p value less than 0.05 being considered significant. Data storage and statistical analysis were performed on the CLINFO Project Data System of the Baylor College of Medicine.
Results
The donor and recipient characteristics in our transplantation group are shown in table 1. Recipients had a mean age of 29.7 yr at the time of transplantation, Six were white women and one was a white man. Recipients 1 through 3 were transplanted for primary pulmonary hypertension, Recipients 4 and 6 had Eisenmenger's complex, Recipient 5 had cystic fibrosis, and Recipient 7 had idiopathic bronchiolitis obliterans. Except for the severeairway obstruction in Patients 5 and 7, all recipients had essentially normal pulmonary function tests, preoperatively.
8
Donors were slightly younger, with a mean age of 23.6 yr. Six of the seven donors were men and all were white. Donors were taller, with a mean height of 70.3 inches compared with 64.4 inches for recipients (P < 0.05). In figure I, comparing donor-to-recipient predicted TLC, it can be seen that four of the seven recipients received significantly larger donor organs, ranging from 135 to 179070 of their TLC for these four donor-recipient pairs. In general, larger patients received larger donor organs. After heart-lung transplantation, all patients symptomatically and objectively improved. Twomonths after transplantation, TLC fell to a mean of 3.7 ± 0.3 L compared with a pretransplant value of 5.2 ± 0.5 L (P < 0.05) (figure 2). Subsequently, TLC gradually increased, and by 12months after transplantation it was no different from preoperative TLC (figure 2). Similar changes were noted for
± SEM
= cystic
FVC. Thus, initial postoperative lung volumes demonstrated a new restrictive defect, which showed gradual resolution after transplantation. The course of a typical heart-lung transplant recipient's improvement over time is shown in figure 3; note the stability in TLC and FVC between 7 and 12 months. For each patient, stable postoperative lung volumes more closely approximated recipient preoperative volumes than donor predicted volumes (table 2). For those four surviving patients not severely obstructed preoperatively, the mean TLC, FVC, and FEV 1 more closely approximated recipient preoperative lung volumes than donor predicted values (figure 4). Donor predicted volumes were statistically different when compared with preoperative and postoperative lung volumes of the recipients (figure 4), with the exception of residual volumes, which were no different (data not shown). There was no overall difference be-
•
5
7
6
5
.. i
...
1Il
~
3
3
::J
~
4
2
3
2 Initial
Pre
o0~--'-~2~3~....J4~-::5~6~-::7~~8~9 Recipient Predicted TLC (liters) Fig. 1. Comparisons of donor-predicted TLC and recipient·predicted TLC.
6 mos
12 mas
Post
TLe Fig. 2. Changes in mean TLC initially (average, 2 months), 6, and 12 months alter cardiopulmonary transplantation . Values are mean ± SEM . Asterisks indicate p < 0.05 compared with pretransplant values.
Pre 1
2
3
4
5
6
7
8
9 10 11 12
Months Fig. 3. Improvement in TLC and FVC with time after cardiopulmonary transplantation (Patient 1)in comparison with preoperative values . Closed circles = TLC; open squares = FVC.
1028
LLOYD, BARNARD. HOLLAND. NOON. AND LAWRENCE
TABLE 2 STATIC LUNG VOLUMES BEFORE AND AFTER TRANSPLANTATION Patient No.
2 Preoperative FVC. L FEV" L RV, L TLC. L Postoperative , 12 months FVC, L FEV" L RV, L L Donor-predicted FVC, L FEV,. L RV, L TLC, L
nc,
3
4
5
6
7
4.00 3.42 1.01 5.01
2.68 2.20 2.36 5.04
2.85 2.25 1.80 4.70
2.11 1.56 1.79 3.95
1.55 0.89 5.26 6.95
3.42 2.17 1.84 5.52
1.31 0.43 4.31 5 .93
3.43 2.71 1.46 4.91
2.27 2.15 1.18 3.45
(2.55)* (2.08) (1.11) (3.66)
2.49 2.28 1.53 3.96
4.22 3.93 2.19 6.69
3.90 3.39 1.60 5.63
1.69 1.32 1.83 3.75
5.81 4.80 1.90 7.70
5.59 4.68 1.69 7.25
5.38 4.44 1.86 7.10
3.77 3.17 1.00 4.86
5.52 4.21 1.69 6.96
5.62 4.54 1.41 6.56
6.20 5.10 1.97 8.20
• 6 months' values for Patient 3.
tween preoperative and postoperative values for POz, Pco., and DLco in the heartlung transplant recipients while at rest (see table 3). Interestingly, the DLeo remained low after transplantation despite absence of clinical rejection or infection. Blood Po.Ievels varied, with some values higher than anticipated while breathing room air; the explanation for this finding is unclear. Of the transplant recipients, three (Patients 1, 3, and 7) developed evidence of obstructive ventilatory defects several months after transplantation; airflow obstruction developed 22 months after transplantation in Patient 1, 7 months after transplantation in Patient 3, and 15 months after transplantation in Patient 7. Bronchiolitis obliterans was documented histologically in Patients 1 and 3, with Patient 3 dying of complications of treatment for this process. Patients 1 and 7 have stabilized with increased immunosuppression. Each of these three patients received lungs with substan-
tially larger predicted TLC (135, 154, and 179070 of recipient predicted values, respectively). Discussion
After transplantation, all heart-lung transplantation patients showed evidence of restrictive pulmonary defects, which improved with time towards more normal parameters. Final postoperative function did not differ significantly from pretransplant values. Theodore and coworkers (1) noted a similar course in their patients, with a final preoperative-to-postoperative TLC ratio of 1.0. They attributed this to good donor-recipient matching or possibly to adaptation of the donor organs to the constraints of the recipient chest cavity. Our data support the latter view as most of our donor organs were clearly from larger donors, even though larger recipients received proportionately larger organs. Although we cannot exclude the possibility that the actual lung volumes of some or of all donors were less than predicted, our study clearly , shows that larger donors may be used
with clinical success, with postoperative function not being significantly different from preoperative function. Whether the new lungs are simply operating at lower lung volumes because of the size constraint of a small chest or because there is actual loss of alveolar lung units in modeling to a smaller chest is unknown. Patients 5 and 7 showed marked reduction in residual volume compared with preoperative values because of the obstructive nature of their underlying diseases. A case report by the Minnesota group would also suggest that chest volumes return to normal after transplantation in the hyperexpanded chest (10). Our Patient 7 had the largest organ mismatch, and one must wonder whether this contributed to a functional obstructive defect postoperatively. The defect appears to have stabilized on increased immunosuppression, supporting a clinical diagnosis of bronchiolitis obliterans (lIB) as either a chronic form of rejection or a recurrence of the original disease in the graft organ. Nonetheless, reduced elastic recoil from larger donor lungs remains a potential problem, but the exact degree of mismatch required to lead to measurable problems is not known. The transplanted larger lung operating at low lung volumes would be one explanation for a low DLeo postoperatively, but postoperative DLeo was also low in patients receiving nearly perfectly size-matched lungs (Patients 4 and 5). There may be actual loss of lung units after transplantation through regional atelectasis and closure of poorly ventilated alveoli. Alternatively, loss of units could occur through the process of rejection, which virtually all patients experience at some point in the postoperative period (14). Gas exchange was well preserved in all groups as would be expected for equivalent loss of ventilation and perfusion units together. Ischemia and infection could conceivably cause ir-
TABLE 3 GAS EXCHANGE BEFORE AND AFTER TRANSPLANT Preoperative Patient No. TLC
FVC
FEV,
Fig. 4. Mean donor-predicted lung volumes in comparison with mean recipient preoperative lung volumes and mean postoperative lung volumes 12 months after transplantation . Values are mean ± SEM . Asterisks indicate p < 0.05 compared to other values. Dotted bars = donor; open bars = pre-op: closed bars = post-op.
1 2 3' 4 5 6 7
PAo, (mmHg)
120 92 60 51 51 72 84
pco, (mmHg)
Postoperative (12 months) DLco (%pred)
PAo, (mmHg)
29
66
38
126 (72) 115 98 105
26 34 46 34 56
• 6 months' value for Patient 3.
57 63 56 56 42
68
pco, (mmHg)
39 27 (32) 36 41 38 38
OLeo (%pred)
76 49 (56) 58 45 95
1029
pULMONARY FUNCTION AFTER HEART·WNG TRANSPLANTATION
reparable lung tissue damage. Although
all donor organs had acceptable ischemia times less than 4 h, any ischemic injury may cause loss of gas exchange units. Infections, particularly cytomegalovirus pneumonia, could further damage the transplanted lungs. Indeed, Yousem and coworkers (15) described parenchymal and pleural fibrosis in several of their long-term surviving heart-lung transplant patients in which the ischemia times were less than 4 h for all donor organs. Glanville and colleagues (2) noted postoperative maximal inspiratory pressures (PImax) to be reduced and to correlate well with the postoperative restrictive defect. Unfortunately, these measurements were not available in our patients. The effects of chest surgery on postoperative pulmonary function have been measured in the past, including the limitation of different incision types on respiratory function (16-18). In general, all of the . defects were restrictive in nature, with improvement in time towards normal. Our patients showed improvement in lung volumes with time after surgery although some mild stable restriction persisted. A decrease in lung compliance cannot be ruled out as contributing to this observation; however, a previous study in which lung compliance was measured did not detect a postoperative decrease (2). Volume mismatch leading to suboptimallength tension arrangements of the respiratory muscles has been proposed by Glanville and colleagues (2) as a possible mechanism of apparent postoperative muscle weakness. Chronic immunosuppressant with corticosteroids may also contribute to the low postoperative inspiratory capacity. Assuming that both lung compliance and respiratory muscle strength are preserved in our patient population, one might have expected the lung volumes to lie between donor and recipient volumes after transplantation. Theoretically, the larger organs operating at a lower lung volume should be able to reach a larger volume per unit of negative intrathoracic pressure generated by the respiratory
muscles. Potential explanations on the limits of lung expansion include a loss of lung compliance occurring with lung transplantation and/or lung volumes greater than the native TLC of the recipient, creating adverse length-tension arrangements of the respiratory muscle system. Alternatively, an adaptation of the donor organs to the recipient chest over time might occur, with the lungs actually adopting compliance characteristics similar to those of the native organ, possibly through selective loss of lung units through a process of modeling. Quite likely, more than one of these processes actually contributes to the limitation on post-transplantation lung expansion. Further studies regarding these processes will be needed to determine the exact role of each in the adaptation response. The three of our patients with the best pulmonary function 12 months after transplantation (patients 4, 5, and 6) were also the ones with the closest donorrecipient lung size match. Although another three of our patients (Patients 1, 3, and 7) have developed obstructive lung disease consistent with bronchiolitis obliterans (proved in Patients 1 and 3), a similar incidence of bronchiolitis obliterans has been found in institutions employing smaller donor lungs (12). While we believe that larger donor lungs may be successfully transplanted, at this time we would prefer to use lungs with predicted TLC no greater than 120 percent of that TLC predicted for the recipient. A related study by Otulana and colleagues (19) would support this approach. Only with an increased donor pool through greater public awareness will such close matching be possible. Acknowledgment The writers thank Ms. Jackie Warren and Ms. Lisa Conway for their expert secretarial assistance in preparation of the manuscript. References 1. Theodore J, Jamieson SW, Burke CM, et al. Physiologic aspects ofthe human heart-lung transplantation. Chest 1984; 86:349-57. 2. GlanvilleAR, Theodore J, Harvey J, Robin ED.
Elastic behavior of the transplanted lung. Am Rev Respir Dis 1988; 137:308-12. 3. Morris JF, Koski A, Johnson LC. Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 1971; 103:57-67. 4. Morris JF, TempleWF, Koski A. Normal values for the ratio of one-second forced expiratory volume to forced vital capacity. Am Rev Respir Dis 1973; 108:1000-3. 5. Goldman HI, Becklake MR. Respiratory function tests: normal values at median altitudes and the prediction of normal results. Am Rev Tuberc 1959; 79:457. 6. Polgar G, Promadhar V. Pulmonary function testing in children: techniques and standards. Philadelphia: W.B. Saunders, 1971. 7. Boren HG, Kory RC, Syner JC. The Veterans Administration-Army Cooperative Study of Pulmonary Function. The lung volume and its subdivisions in normal men. Am J Med 1966;41:96-114. 8. Harris TR, Pratt PC, Kilburn KH. Total lung capacity measured by roentgenograms. Am J Med 1971; 50:756-63. 9. Burrows B, Kasik JE, Niden AH, Barclay WR. Clinical usefulness of the single breath pulmonary diffusion capacity test. Am Rev Respir Dis 1961; 84:789-806. 10. Hertz MI, Bonser RS, Jamieson SW,Tashjian J, Halvorsen RA. Reversiblehyperinflation in emphysema. Chest 1989; 96:421-2. 11. Glanville AR, Baldwin JC, Burke CM, Theodore J, Robin ED. Obliterative bronchiolitis after heart-lung transplantation: apparent arrest byaugmented immunosuppression. Ann Intern Med 1987; 107:300-4. 12. Burke CM, Morris AJ, Dawkins KD, et al. Late airflow obstruction in heart-lung transplant recipients. J Heart Transplant 1985; 4:437-40. 13. Burke CM, Glanville AR, Theodore J, Robin ED. Lung immunogenicity, rejection, and obliterative bronchiolitis. Chest 1987; 92:547-9. 14. Lawrence EC, Holland AV, Young JB, et al. Dynamic changes in soluble interleukin-2 receptor levelsfollowinglung or heart-lung transplantation. Am Rev Respir Dis 1989; 140:789-96. 15. Yousem SA, Burke CM, Billingham ME. Pathologic pulmonary alterations in long-term human heart-lung transplantation. Hum Patho11985; 16:911-23. 16. Johnson We. Postoperative ventilatory performance: dependence upon surgical incision. Am Surg 1975; 41:615-9. 17. Pecora DV. Predictability of effectsof abdominal'and thoracic surgery upon pulmonary function. Ann Surg 1969; 170:101-8. 18. Zin WA, Marina PR, Caldeira BSC, Wellington VC, Auler JOC, Saldiva PHN. Expiratory mechanics before and after uncomplicated heart surgery. Chest 1989; 95:21-8. 19. Otulana BA, Mist BA, Scott JP, Wallwork J, Higenbottam T. The effect of recipient lung size on lung physiology after heart-lung transplantation. Transplantation 1989; 48:625-9.
