Maximal Exercise Testing in Single and Double Lung Transplant Recipients 1, 2
TREVOR J. WILLlAMS,3 G. ALEXANDER PATTERSON, PATRICIA A. MCCLEAN, NOE ZAMEL, and JANET R. MAURER
Introduction
Patients with end-stage pulmonary and pulmonary vascular disease can now be successfully treated by transplantation. The decade of the 1980s saw the development of successful heart-lung (HLT) (I), single-lung (SLT) (2), and doublelung (DLT) (3) transplantation. To date, the assessment of success has focused on patient survival and documentation of improved pulmonary function. Reported 2-yr actuarial survival rates are 54070 for HLT (4), 72f1Jo for DLT (5), and 62f1Jo for SLT (5). Pulmonary function, including vital capacity (VC), forced expiratory volume in one second (FEV1.0), and diffusion capacity (Dtoo), approach normal in HLT (6) and DLT (5) recipients after transplantation. Single-lung transplant recipients with restrictive lung diseases remain moderatelyrestrictedwith reduced DLco (5).The improvedpulmonary function is associated with improvement in symptoms and functional capacity. The results of formal exercise studies have been only sporadically reported following HLT, SLT, and DLT. A low maximum oxygen uptake (vo.max) of 50f1Jo of predicted has been noted in HLT recipients (7). The 6-min walk tests and the modified Bruce protocol have been used to evaluate SLT recipients (8). To date, no long-term results of maximal exercise studies have been reported in SLT or DLT recipients. This study aims to investigate the response of SLT and DLT recipients to maximum exercise, in particular to see if exerciselimitation persists despite substantial improvement in pulmonary function. Furthermore, repeat study of the patients allows assessment of improvement in exercise capacity with the passage of time. Methods Long-term survivors of SLT and DLT were studied early (3 months) and late (l to 2 yr) following transplantation. Pulmonary func-
SUMMARY Patients with end-stage pulmonary and pulmonary vascular disease can now be offered single-lung (SLT), double-lung (OLT), 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 ± 4A; FEV,., 75.5 ± 6.7% of predicted) and seven OLT (three males and four females; age 37.3 ± 6.7; FEV,., 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 VO,max in both SLTand OLTrecipients 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, VO,max was 46% of predicted for SLT and 50% of predicted for OLTrecipients. 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 OLTand are not related to ventilation. The results may suggest chronic muscle deconditioning after longAM REV RESPIR DIS 1992; 145:101-105 term pretransplant debilitation.
tion testing (including FEV i , o, VC, Dr.co, and maximal inspiratory pressure, MIP) followed by a graded maximal exercisetest (Stage 1) (9) were performed on each occasion. Pulmonary function data available from preoperative assessment were also used for comparative purposes.
Stage 1 Exercise Test Procedure Resting measurements weremade with the patient seated on a bicycle ergometer (Siemens 380;Siemens-Elema, Sweden)breathing room air through a one-way nonrebreathing circuit. The patient then commenced pedaling at 60 rpm at an initial work load of 20 W, which was incremented 20 W/min until the test was terminated by patient exhaustion or at the supervising physician's discretion. The following data were recorded continuously at rest and throughout exercise: 1. Pulse rate (electrocardiogram; ECG
monitor, Rigel Model 801R,England) 2. Respiratory rate, tidal value, and minute ventilation (ventilation monitor; P. K. Morgan, Ltd., England) 3. Blood pressure 4. Oxygen consumption (oxygen analyzer S-3Al; Amtek, Pittsburgh, PA) 5. Carbon dioxide production (carbon dioxide analyzer CD-3A, Amtek) 6. Oxygen saturation by ear oximetry (Hewlett-Packard 47201A oximeter, Waltham, MA) All data were fed on-line into a personal computer (IBM PC XT, Kent, United Kingdom) and calculations wereperformed using
physiologic test system software (P. K. Morgan Instruments, Inc., Kent, United Kingdom). Reference values were derived from Jones and Campbell (9) and Cotes (10). Maximum predicted ventilation was based on observed FEV1.o (II).
Statistical Analysis Within-group analysis was performed using a paired t test, with p < 0.01 regarded as significant. Comparison between SLTand DLT patients was performed with an unpaired t test with p < 0.05 regarded as significant. All resultsare expressed as mean ± standard deviation unless otherwise specified. Rehabilitation Program All patients participated three times weekly in rehabilitation therapy before transplant and up to 3 months after transplant. The program included treadmill, light aerobic exercises,bicycleergometer, and light weights within the patient's physical capacity. Supplemental oxygen was given to keep the Sa02 > 90070 on
(Received in original form December 4, 1990 and in revised form July 12, 1991) I From the Departments of Surgery and Medicine, University of Toronto, Ontario, Canada. 'Correspondence and requests for reprints should be addressed to Dr. Janet R. Maurer, 200 Elizabeth Street, lOEN-220Toronto, Ontario M5G 2C4, Canada. 3 Supported by the Lung Association, Metropolitan Toronto and York Region.
101
102
WILLIAMS. PATTERSON, MCCLEAN, ZAMEL, AND MAURER
UNDERLYING DISEASE IN RECIPIENT Single-lung transplant, n = 6 Idiopathic pulmonary fibrosis 6 Double-lung transplant, n = 7 Emphysema 4 a,-Antitrypsin deficiency 3 Other 1 Bronchiolitis obliterans 1 Eosinophilic granuloma 1 Bronchiectasis, cystic fibrosis 1
PATIENT DATA"
50.7 ± 4.4:1: Age 5M,1F Gender Height, cm 172.8 ± 7.5 67.8 ± 16.0 Weight, kg
REASON FOR STAGE 1 EXERCISE TEST TERMINATION
Results
Pulmonary Function (table 3) SLT recipients showed substantial improvement in FEV1.o, ve, and DLco by three months after transplant. Slightly higher values of FEV1.o, ve, and DLCO were noted when restudied at 1 to 2 yr after transplant, but these did not reach statistical significance. MIP values were normal before transplant with a slight but nonsignificant decrement after transplant. The SLT recipients remained with a mild to moderate restrictive ventilatory defect with reduced diffusion capacity. DLT recipients also showed substantially improved FEV1.0, ve, and DLCO 3 months after transplant with further statistically significant improvement by 1 to 2 yr. DLT recipients achieved nearly normal spirometry and diffusion capacity. As well, there was a significant improvement in MIP to near normal values by 3 months, which continued to improve by 1 to 2 yr.
TABLE 2
DLT (n = 7)
P Value t
37.3 ± 6.7
< 0.001
SLT (n = 6)
TABLE 4
(table 2); thus, direct comparison between these two groups should be undertaken only with caution.
TABLE 1
3M,4F 162.1 ± 7.1
< 0.025 < 0.05
51.9 ± 11.5
• At time of SLT or DLT. Unpaired I test, SLT versus DLT. Expressed as mean ± standard deviation.
t
*
exercise. Increases in the amount of exercise performed were adjusted according to tolerance by the supervising physiotherapist.
Patients
Stage 1 Exercise SLT recipients. At 3 months after transplant a maximum work rate of 80.0 ± 28.3 W (44.8070 of predicted) was achieved. At maximum work, heart rate 132.8 ± 23.6 beats/min (75% of predicted), minute ventilation 54.0 ± 16.9 L/min (61% of predicted), oxygen consumption 1,244 ± 412 mllmin (18.3 mIlkg/min or 58% of predicted), and Sao, 90.3 ± 5.7% were seen. The anaerobic threshold (AT) averaged 46.8 ± 7.4% of predicted. Exercise was terminated because of leg tiredness in four patients and breathlessness in two patients
The patients studied are part of a cohort of SLT and DLT recipients of the Toronto Lung Transplant Group. These results are part of a detailed follow-up assessment performed at 3, 6, 9, 12, 18, and 24 months and thereafter yearly in all transplant recipients. Consecutive SLT (n == 6) and DLT (n == 7) recipients who survived more than 1 yr and were transplanted November 1985 to March 1988 are reported. All SLTrecipientshad end-stage respiratory disease secondary to idiopathic pulmonary fibrosis; DLT recipients had end-stage obstructive lung disease (table I). SLTrecipients werenot comparable to DLT recipients with respect to anthropometric data
SLT, n After After OLT, n After After
=
Leg Tiredness
Dyspnea
4
2 2
6
3 months 1-2 yr = 7 3 months 1-2 yr
4
6 6
(table 4). When the same patients were retested 1 to 2 yr after transplant, no significant improvement in maximum work rate, heart rate, minute ventilation, oxygen consumption, Sao., or anaerobic threshold was seen (table 5). Termination of exercisewas due to leg tiredness in four patients and breathlessness in two patients. DLTrecipients. A maximum work rate of 65.7 ± 15.1 W (43% of predicted) was seen 3 months after transplant. A high resting heart rate of 107 ± 5 beats/min was noted. At maximum work rate, heart rate of 136 ± 12 beats/min (73% of predicted), a minute ventilation of 39.0 ± 6.9 Umin (34% of predicted), oxygen consumption of918 ± 182mllmin (17.7 mIlkg/min or 50% of predicted) with San, of 94.4 ± 4.0% were seen (table 6). The AT was 42.6 ± 3.7% of predicted. Exercise was terminated as a result of leg tiredness in six patients and breathlessness in one patient. When retested 1 to 2 yr after transplant, a significantly lower (P < 0.01)resting pulse rate was noted. No significant improvement in maximum work rate, heart rate, minute ventilation, oxygen consumption, Sao z' or AT was seen when the results were compared with those obtained at 3 months after transplantation. Termination of exercise was due to leg
TABLE 3 PULMONARY FUNCTION TESTS IN RECIPIENTS' FEV, SLT, n = 6 Pretransplant
VC
42.2 ± 7.5
48.7 ± 8.6 p
After 3 months
75.5 ± 16.8
After 1-2 yr
81.8 ± 14.6
DLT, n = 7 Pretransplant
20.3 ± 10.9
< 0.0025t
28.0 ± 13.2:1: p
P
101.4 ± 10.4
• Expressed as percentage of predicted. Mean ± standard deviation.
t p value for paired I test.
*
n = 4.
§n =
5.
IIn = 6.
44 ± 1811
71.3 ± 16.0
P < 0.004
75 ± 19 P
76.3 ± 11.5
ns
91 ± 2111
P < 0.01
P < 0.0025
=
ns
25.8 ± 13.811
< 0.025
77.9 ± 9.8 92.1 ± 9.2
=
58.5 ± 9.8
p
P
83 ± 25§ P
ns
56.6 ± 24.6
p < 0.025 After 1-2 yr
=
66.5 ± 8.0
85.1 ± 10.3
101 ± 11:1: P < 0.025
54.7 ± 6.3
P = ns
After 3 months
< 0.0025
66.2 ± 15.2
p < 0.0005t
MIP
OLeo
=
ns
P
89 ± 21
=
ns
MAXIMAL EXERCISE TESTING IN LUNG TRANSPLANT RECIPIENTS
103
TABLE 5 RESULTS OF MAXIMAL EXERCISE TESTING (STAGE 1) IN SLT (n = 6) RECIPIENTS
Work, W HR, mirr' Rest Exercise RR, rnirr' Rest Exercise VT, L Rest Exercise VE, Umin Rest Exercise V02 , mlfmin Rest Exercise vco; mlfmin Rest Exercise Sa0 2 , % Rest Exercise AT, % of predicted MV02
Early
Late
80.0 ± 28.3
83.3 ± 32.0
85.0 ± 15.5 132.8 ± 23.6
94.2 ± 15.7 131.5 ± 20.0
20.0 ± 6.2 38.7 ± 4.3
18.3 ± 4.1 32.5 ± 8.0
0.607 ± 0.212 1.411 ± 0.466
0.682 ± 0.219 1.558 ± 0.641
11.4 ± 3.8 54.0 ± 16.9
11.8 ± 1.9 53.0 ± 18.4
235 ± 71 1,244 ± 412
274 ± 60 1,180 ± 500
170 ± 63 1,135 ± 403
206 ± 44 1,232 ± 484
93.5 ± 2.9 90.3 ± 5.7 46.8 ± 7.4
92.7 ± 3.1 90.3 ± 5.0 41.0 ± 15.8
Maximum Predicted"
p Value'l
178.5
NS
< 0.05 177.0
NS NS
< 0.025 < 0.05 NS NS NS
85.8
NS NS
2,340
< 0.025 NS NS NS NS
• From reference 9. p value for paired t lest, early versus late.
t
tiredness in six patients and breathlessness in one patient.
Comparison of SLT and DLT Recipients No significant difference was seen in maximal work rate between SLT (44070 of predicted) and DLT (46% of predict-
ed) recipients at 3 months (or 1 to 2 yr) after transplant. At 3 months SLT recipients had significantly lower resting heart rates as well as higher respiratory rate and minute ventilation on exercise. When retested at 1 to 2 yr after transplant, no significant difference was seen in resting heart rate, respiratory rate on exercise, or minute ventilation on exer-
TABLE 6 RESULTS OF MAXIMAL EXERCISE TESTING (STAGE 1) IN DLT (n
Work, W Hr, rnirr' Rest Exercise RR, mln' Rest Exercise VT, L Rest Exercise VE, Umin Rest Exercise v0 2 , mlfmin Rest Exercise vco; mlfmin Rest Exercise Sa0 2 Rest Exercise AT, % of predicted MV0 2
=
7) RECIPIENTS
Maximum Predicted"
p Value t
Early
Late
65.7 ± 15.1
74.3 ± 15.1
107 ± 5 136 ± 12
93 ± 10 129 ± 19
16.1 ± 4.7 31.7±8.4
17.7 ± 8.0 30.6 ± 3.9
0.847 ± 0.198 1.269 ± 0.205
0.783 ± 0.228 1.499 ± 0.235
12.1 ± 1.8 39.0 ± 6.9
12.4 ± 2.5 45.4 ± 6.6
278 ± 53 918 ± 182
222 ± 50 963 ± 229
214 ± 31 916 ± 196
198 ± 58 1,059 ± 166
NS NS
95.1 ± 3.4 94.4 ± 4.0 42.6 ± 3.7
96.1 ± 2.5 96.4 ± 3.1 43.1 ± 18.3
NS NS NS
*
From reference 9.
t
p value for paired t test, early versus late,
152.2
NS
< 0.Q1 186
NS NS NS NS
< 0.05 93.0
NS NS
< 0.025 1,920
cise; however, a significantly higher Sao, at rest and on exercise was noted in DLT recipients.
NS
Discussion
The ultimate aim of transplantation in patients with end-stage pulmonary or pulmonary vascular disease is long-term survival and return of normal functional capacity. A previous report observed subnormal maximal oxygen consumption in HLT (7) recipients and suggested a nonpulmonary cause. This report shows that despite nearly normal spirometry and diffusion capacity in DLT recipients and a substantial improvement in these parameters in SLT recipients, exercise capacity is reduced. For SLT recipients, a maximal work rate of 44% of predicted was seen at 3 months after transplant without significant improvement (48% of predicted) when retested at 1to 2 yr after transplant. This work capacity represented an oxygen delivery of only 46% of predicted. DLT recipients fared no better with no significant improvement in maximum work capacity between 3 months (46% of predicted) and 1 to 2 yr (51 % of predicted) after transplant. Similarly, a subnormal V0 2 was observed (50% of predicted at 3 months) that did not significantly improve with time (55% of predicted at 1 to 2 yr). The suboptimal results of graded testing in most cases, however, did not reflect patient life-style after transplant. Before transplantation severe exercise limitation due to respiratory disease was present in both SLT and DLT patients such that all were impaired in their ability to complete activities of daily living (although none were bedridden). Most patients had had chronically debilitating illnesses with steadily decreasing levels of activity over 1 to 4 yr before surgery. At formal pretransplant assessment, the mean distance achieved on a 6-min walk test was 328 ± 37 m for SLT and 377 ± 41 m for DLT (12). The level of disability in most cases precluded preoperative graded exercise studies. Following transplant all DLT have resumed their predebility life-styles. All work in full-time or part-time jobs or are students. None, however, adhere to a regular exercise training program. Of SLT recipients, six of seven are able to carry out daily activities without difficulty. One has resumed full-time work. Five of the remaining six are either retired or engaged in part-time work and do not have
104
physical limitation to their usual activities. The remaining patient has developed significant chronic rejection. He functions independently without supplemental oxygen but is limited to New York Heart Association Class II to III. Our findings are particularly interesting in the DLT who despite marked improvement in lung mechanics and gas exchange after transplant have ongoing exercise limitation. The posttransplant near normal spirometry and MIP measurements tend to refute a ventilatory limitation to exercise. Both the DLT and SLT groups had a substantial ventilatory reserve at the end of exercise as they only achieved 48 and 62070 of their respective predicted maximums based on their observed preexercise FEV 1.0 values. Exercise gas exchange, although somewhat better in the DLT group (Sa0 2 95070) than the SLT group (Sao, 90070), was more than adequate to meet the O 2 delivery requirements of the work levels achieved. Maximal heart rates were low in both the DLT and SLT groups (70 and 74070 of predicted, respectively)and showed little change with time. This might suggest an inadequate cardiac output as a limiting factor to exercise. However, if the submaximal heart rates at any work load are compared with population normal rates for that level of work, the rate responses were average to high, suggesting an appropriate exerciseadaptation. There was also no indication in any patient tested of a plateauing of the heart rate suggestive of a lowering of the rate response ceiling. It is possible that the exercise limitation may be peripheral rather than central in origin. A prolonged period of severe illness and its accompanying immobility would lead to muscle deconditioning that would persist postoperatively despite restoration of near normal pulmonary function. This "deconditioning" may become the limiting factor in exercise. Reduced exercise capacity secondary to muscle deconditioning or disuse can manifest itself in two ways. Prolonged immobility makes a muscle more prone to fatigue related to anaerobic lactic acid processes, that is, less efficient H+ buffering capacity, and loss of phosphocreatine stores. These factors require an earlier onset of glycolysis and hence a low anaerobic threshold (13). Both the DLT and SLT groups showed low AT, and the predominant exercise-limiting symptom was leg fatigue.
WILLIAMS, PATTERSON, MCCLEAN, ZAMEL, AND MAURER
The other factor associated with deconditioning is the process of muscle atrophy. Usually two-leg exercise provides sufficient muscle mass for a central exercise limitation to occur, that is, cardiovascular. However, long-term disuse may result in a sufficient reduction of muscle mass to result in a peripheral limitation to exercise as is commonly seen in oneleg or one-arm exercise. Shephard and colleagues (14) have shown a significant correlation between muscle volume and Vo.max, maximal work load, and also maximal HR. The authors suggested that this last observation could be explained by decreased peripheral cardioaccelatory activity secondary to the reduced active muscle volume as well as decreased central drive due to less absolute muscular vasodilation. A recent study by Rutherford and coworkers (15) showed that significant decrements in both muscle size and strength remained up to 5 yr after full mobilization following nonmuscular lower limb trauma in seven patients. These decrements ranged from 6 to 27070 for muscle sizeand 17to 50070 for strength. They were not directly associated with the duration of immobilization, which varied from 1to 13months, and were not related to an inability to fully activate the muscles during testing. Although no measurements were made or estimated of leg volumes in these patients, the low maximum exercise capacities and heart rates, as well as the large ventilatory reserves particularly in the DLT, could suggest a deconditioning-related reduced muscle volume component. This is an area that warrants further investigation. Any initial improvement in exercisecapacity after transplantation was probably due to the continued effect of improved pulmonary physiology and physical training resulting from participation in the exercise rehabilitation program. Lack of further improvement in performance over time may be related to the absence of such a program for these patients after discharge from the structured posttransplant rehabilitation program, which usually occurs about 3 months postoperatively. One subject in the Rutherford (15) study with marked unilateral weakness participated in an intensive 3-month training program that restored the leg to nearly 100070 of its uninjured pair. The authors concluded that, unlike muscle injury, which generates new fibers, the slow recovery from immobilization-induced atrophy was probably due to the growth of mature fibers, which re-
quire a much greater stimulus than daily activity normally provides. Other studies have produced similar findings, as outlined in a recent review of this area (16). Several factors have been identified that will likely influence the degree of atrophy and the time necessary for recovery; these include age, sex, degree of disuse compared with normal usage, pretreatment, preexisting atrophy, fiber type, and muscle type (antigravity) (16). In our study, the similarity in exercise capacities of the SLT and DLT recipients is interesting in view of the considerable difference in postoperative pulmonary function. If atrophy is a significant contributor, then steps must be taken to lessen its impact. Preoperative rehabilitation is probably of limited utility because the ventilatory limitation of severe chronic obstructive pulmonary disease (and likely other end-stage lung diseases) prevents the imposition of sufficient stress to stimulate muscular development. Earlier transplantation or a much more aggressive postoperative training program may be necessary to allow these patients to achieve their full potential. If, on the other hand, exercise capacity is the same following SLT as DLT or HLT, this may have implications regarding the type of transplant chosen in a particular situation. SLT, since it has been performed successfully for several different types of end-stage disease (2, 17-19) and leads to optimal utilization of scarce donor lungs, could become the procedure of choice in most patients. Comparison of all aspects of outcome of SLT and DLT between well-matched recipient groups will help to better define the respective roles of these procedures. In conclusion, these results suggest that persistent exercise limitation after SLT and DLT is not respiratory in many instances. Prolonged illness may lead to a considerable decrement in skeletal muscle performance, which may not spontaneously recover with the return of normal activity. Continuation of a formal, more intensive rehabilitation program may result in significantly improved exercise performance. Although patients who survive SLT, DLT, and HLT are greatly improved, they still fall short of the ultimate aim of survival with normal functional capacity. References I. Reitz BA, Wallwork JL, Hunt SA, et al. Heartlung transplantation: successful therapy for patients
MAXIMAL EXERCISE TESTING IN LUNG TRANSPLANT RECIPIENTS
with pulmonary vascular disease. N Eng J Med 1982; 306:557-64. 2. Toronto lung transplant group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986; 314:1140-5. 3. Cooper JD, Patterson GA, Grossman R, Maurer J. Double lung transplantation for advanced chronic obstructive lung disease. Am Rev Respir Dis 1989; 139:303-7. 4. Dawkins KD, Jamieson SW, Hunt SA, et al. Long-term resuts and complications after combined heart and lung transplantation. Circulation 1985; 71:919-26. 5. Williams Tl, Grossman RF, Maurer JR. Longterm functional follow-up of lung transplant recipients. Clin Chest Med 1990; 11(2):347-58. 6. Burke CM, Baldwin JC, Morris AJ, et al. Twenty-eight cases of human heart-lung transplantations. Lancet 1986; 1:517-9.
7. Dawkins KD,Jamieson SW. Pulmonary function of the transplanted human lung. Annu Rev Med 1988; 37:263-9. 8. Maurer JR. Unilateral lung transplant. Pulm Perspect 1987; 4:1-3. 9. Jones NL, Campbell EJM. Clinical exercise testing, 3rd ed. Philadelphia: W. B. Saunders, 1988. 10. Cotes JE. Lung function: assessment and application in medicine, 4th ed. Oxford: Blackwell Scientific, 1979. II. Freedman S. Sustained maximum voluntary ventilation. Respir Physiol 1970; 8:230-44. 12. Williams Tf, Grossman RF, Maurer JR. Longterm functional follow-up of lung transplant recipients. Clin Chest Med 1990; 11(2):347-58. 13. Hainaut K, Duchateau J. Muscle fatigue, effects of training and disuse. Muscle Nerve 1989; 12:660-9. 14. Shephard RJ, Bouhlel E, Vanderwalle H,
105
Monod H. Muscle mass as a factor limiting physical work. J Appl Physiol 1988; 64(4):1472-9. 15. Rutherford OM, Jones DA, Round JM. Longlasting unilateral muscle wasting and weakness following injury and immobilization. Scand J Rehab Med 1990; 22:33-7. 16. Appell HJ. Muscular atrophy following immobilization; a review. Sports Med 1990;10:42-58. 17. Trulock EP, Egan TM, Kouchoukos NT, et al. Singlelung transplant for severechronic obstructive pulmonary disease. Chest 1989; 96:738-42. 18. Starnes VA, Stinson EB, Oyer PE, et al. Single lung transplantation: a new therapeutic option for patients with pulmonary hypertension. Transplant Proc 1991; 23(1):1209-10. 19. Maurer JR, Winton TL, Patterson GA, et al. Single-lung transplantation for pulmonary vascular disease. Transplant Proc 1991; 23(1):1211-2.
TREVOR J. WILLlAMS,3 G. ALEXANDER PATTERSON, PATRICIA A. MCCLEAN, NOE ZAMEL, and JANET R. MAURER
Introduction
Patients with end-stage pulmonary and pulmonary vascular disease can now be successfully treated by transplantation. The decade of the 1980s saw the development of successful heart-lung (HLT) (I), single-lung (SLT) (2), and doublelung (DLT) (3) transplantation. To date, the assessment of success has focused on patient survival and documentation of improved pulmonary function. Reported 2-yr actuarial survival rates are 54070 for HLT (4), 72f1Jo for DLT (5), and 62f1Jo for SLT (5). Pulmonary function, including vital capacity (VC), forced expiratory volume in one second (FEV1.0), and diffusion capacity (Dtoo), approach normal in HLT (6) and DLT (5) recipients after transplantation. Single-lung transplant recipients with restrictive lung diseases remain moderatelyrestrictedwith reduced DLco (5).The improvedpulmonary function is associated with improvement in symptoms and functional capacity. The results of formal exercise studies have been only sporadically reported following HLT, SLT, and DLT. A low maximum oxygen uptake (vo.max) of 50f1Jo of predicted has been noted in HLT recipients (7). The 6-min walk tests and the modified Bruce protocol have been used to evaluate SLT recipients (8). To date, no long-term results of maximal exercise studies have been reported in SLT or DLT recipients. This study aims to investigate the response of SLT and DLT recipients to maximum exercise, in particular to see if exerciselimitation persists despite substantial improvement in pulmonary function. Furthermore, repeat study of the patients allows assessment of improvement in exercise capacity with the passage of time. Methods Long-term survivors of SLT and DLT were studied early (3 months) and late (l to 2 yr) following transplantation. Pulmonary func-
SUMMARY Patients with end-stage pulmonary and pulmonary vascular disease can now be offered single-lung (SLT), double-lung (OLT), 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 ± 4A; FEV,., 75.5 ± 6.7% of predicted) and seven OLT (three males and four females; age 37.3 ± 6.7; FEV,., 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 VO,max in both SLTand OLTrecipients 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, VO,max was 46% of predicted for SLT and 50% of predicted for OLTrecipients. 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 OLTand are not related to ventilation. The results may suggest chronic muscle deconditioning after longAM REV RESPIR DIS 1992; 145:101-105 term pretransplant debilitation.
tion testing (including FEV i , o, VC, Dr.co, and maximal inspiratory pressure, MIP) followed by a graded maximal exercisetest (Stage 1) (9) were performed on each occasion. Pulmonary function data available from preoperative assessment were also used for comparative purposes.
Stage 1 Exercise Test Procedure Resting measurements weremade with the patient seated on a bicycle ergometer (Siemens 380;Siemens-Elema, Sweden)breathing room air through a one-way nonrebreathing circuit. The patient then commenced pedaling at 60 rpm at an initial work load of 20 W, which was incremented 20 W/min until the test was terminated by patient exhaustion or at the supervising physician's discretion. The following data were recorded continuously at rest and throughout exercise: 1. Pulse rate (electrocardiogram; ECG
monitor, Rigel Model 801R,England) 2. Respiratory rate, tidal value, and minute ventilation (ventilation monitor; P. K. Morgan, Ltd., England) 3. Blood pressure 4. Oxygen consumption (oxygen analyzer S-3Al; Amtek, Pittsburgh, PA) 5. Carbon dioxide production (carbon dioxide analyzer CD-3A, Amtek) 6. Oxygen saturation by ear oximetry (Hewlett-Packard 47201A oximeter, Waltham, MA) All data were fed on-line into a personal computer (IBM PC XT, Kent, United Kingdom) and calculations wereperformed using
physiologic test system software (P. K. Morgan Instruments, Inc., Kent, United Kingdom). Reference values were derived from Jones and Campbell (9) and Cotes (10). Maximum predicted ventilation was based on observed FEV1.o (II).
Statistical Analysis Within-group analysis was performed using a paired t test, with p < 0.01 regarded as significant. Comparison between SLTand DLT patients was performed with an unpaired t test with p < 0.05 regarded as significant. All resultsare expressed as mean ± standard deviation unless otherwise specified. Rehabilitation Program All patients participated three times weekly in rehabilitation therapy before transplant and up to 3 months after transplant. The program included treadmill, light aerobic exercises,bicycleergometer, and light weights within the patient's physical capacity. Supplemental oxygen was given to keep the Sa02 > 90070 on
(Received in original form December 4, 1990 and in revised form July 12, 1991) I From the Departments of Surgery and Medicine, University of Toronto, Ontario, Canada. 'Correspondence and requests for reprints should be addressed to Dr. Janet R. Maurer, 200 Elizabeth Street, lOEN-220Toronto, Ontario M5G 2C4, Canada. 3 Supported by the Lung Association, Metropolitan Toronto and York Region.
101
102
WILLIAMS. PATTERSON, MCCLEAN, ZAMEL, AND MAURER
UNDERLYING DISEASE IN RECIPIENT Single-lung transplant, n = 6 Idiopathic pulmonary fibrosis 6 Double-lung transplant, n = 7 Emphysema 4 a,-Antitrypsin deficiency 3 Other 1 Bronchiolitis obliterans 1 Eosinophilic granuloma 1 Bronchiectasis, cystic fibrosis 1
PATIENT DATA"
50.7 ± 4.4:1: Age 5M,1F Gender Height, cm 172.8 ± 7.5 67.8 ± 16.0 Weight, kg
REASON FOR STAGE 1 EXERCISE TEST TERMINATION
Results
Pulmonary Function (table 3) SLT recipients showed substantial improvement in FEV1.o, ve, and DLco by three months after transplant. Slightly higher values of FEV1.o, ve, and DLCO were noted when restudied at 1 to 2 yr after transplant, but these did not reach statistical significance. MIP values were normal before transplant with a slight but nonsignificant decrement after transplant. The SLT recipients remained with a mild to moderate restrictive ventilatory defect with reduced diffusion capacity. DLT recipients also showed substantially improved FEV1.0, ve, and DLCO 3 months after transplant with further statistically significant improvement by 1 to 2 yr. DLT recipients achieved nearly normal spirometry and diffusion capacity. As well, there was a significant improvement in MIP to near normal values by 3 months, which continued to improve by 1 to 2 yr.
TABLE 2
DLT (n = 7)
P Value t
37.3 ± 6.7
< 0.001
SLT (n = 6)
TABLE 4
(table 2); thus, direct comparison between these two groups should be undertaken only with caution.
TABLE 1
3M,4F 162.1 ± 7.1
< 0.025 < 0.05
51.9 ± 11.5
• At time of SLT or DLT. Unpaired I test, SLT versus DLT. Expressed as mean ± standard deviation.
t
*
exercise. Increases in the amount of exercise performed were adjusted according to tolerance by the supervising physiotherapist.
Patients
Stage 1 Exercise SLT recipients. At 3 months after transplant a maximum work rate of 80.0 ± 28.3 W (44.8070 of predicted) was achieved. At maximum work, heart rate 132.8 ± 23.6 beats/min (75% of predicted), minute ventilation 54.0 ± 16.9 L/min (61% of predicted), oxygen consumption 1,244 ± 412 mllmin (18.3 mIlkg/min or 58% of predicted), and Sao, 90.3 ± 5.7% were seen. The anaerobic threshold (AT) averaged 46.8 ± 7.4% of predicted. Exercise was terminated because of leg tiredness in four patients and breathlessness in two patients
The patients studied are part of a cohort of SLT and DLT recipients of the Toronto Lung Transplant Group. These results are part of a detailed follow-up assessment performed at 3, 6, 9, 12, 18, and 24 months and thereafter yearly in all transplant recipients. Consecutive SLT (n == 6) and DLT (n == 7) recipients who survived more than 1 yr and were transplanted November 1985 to March 1988 are reported. All SLTrecipientshad end-stage respiratory disease secondary to idiopathic pulmonary fibrosis; DLT recipients had end-stage obstructive lung disease (table I). SLTrecipients werenot comparable to DLT recipients with respect to anthropometric data
SLT, n After After OLT, n After After
=
Leg Tiredness
Dyspnea
4
2 2
6
3 months 1-2 yr = 7 3 months 1-2 yr
4
6 6
(table 4). When the same patients were retested 1 to 2 yr after transplant, no significant improvement in maximum work rate, heart rate, minute ventilation, oxygen consumption, Sao., or anaerobic threshold was seen (table 5). Termination of exercisewas due to leg tiredness in four patients and breathlessness in two patients. DLTrecipients. A maximum work rate of 65.7 ± 15.1 W (43% of predicted) was seen 3 months after transplant. A high resting heart rate of 107 ± 5 beats/min was noted. At maximum work rate, heart rate of 136 ± 12 beats/min (73% of predicted), a minute ventilation of 39.0 ± 6.9 Umin (34% of predicted), oxygen consumption of918 ± 182mllmin (17.7 mIlkg/min or 50% of predicted) with San, of 94.4 ± 4.0% were seen (table 6). The AT was 42.6 ± 3.7% of predicted. Exercise was terminated as a result of leg tiredness in six patients and breathlessness in one patient. When retested 1 to 2 yr after transplant, a significantly lower (P < 0.01)resting pulse rate was noted. No significant improvement in maximum work rate, heart rate, minute ventilation, oxygen consumption, Sao z' or AT was seen when the results were compared with those obtained at 3 months after transplantation. Termination of exercise was due to leg
TABLE 3 PULMONARY FUNCTION TESTS IN RECIPIENTS' FEV, SLT, n = 6 Pretransplant
VC
42.2 ± 7.5
48.7 ± 8.6 p
After 3 months
75.5 ± 16.8
After 1-2 yr
81.8 ± 14.6
DLT, n = 7 Pretransplant
20.3 ± 10.9
< 0.0025t
28.0 ± 13.2:1: p
P
101.4 ± 10.4
• Expressed as percentage of predicted. Mean ± standard deviation.
t p value for paired I test.
*
n = 4.
§n =
5.
IIn = 6.
44 ± 1811
71.3 ± 16.0
P < 0.004
75 ± 19 P
76.3 ± 11.5
ns
91 ± 2111
P < 0.01
P < 0.0025
=
ns
25.8 ± 13.811
< 0.025
77.9 ± 9.8 92.1 ± 9.2
=
58.5 ± 9.8
p
P
83 ± 25§ P
ns
56.6 ± 24.6
p < 0.025 After 1-2 yr
=
66.5 ± 8.0
85.1 ± 10.3
101 ± 11:1: P < 0.025
54.7 ± 6.3
P = ns
After 3 months
< 0.0025
66.2 ± 15.2
p < 0.0005t
MIP
OLeo
=
ns
P
89 ± 21
=
ns
MAXIMAL EXERCISE TESTING IN LUNG TRANSPLANT RECIPIENTS
103
TABLE 5 RESULTS OF MAXIMAL EXERCISE TESTING (STAGE 1) IN SLT (n = 6) RECIPIENTS
Work, W HR, mirr' Rest Exercise RR, rnirr' Rest Exercise VT, L Rest Exercise VE, Umin Rest Exercise V02 , mlfmin Rest Exercise vco; mlfmin Rest Exercise Sa0 2 , % Rest Exercise AT, % of predicted MV02
Early
Late
80.0 ± 28.3
83.3 ± 32.0
85.0 ± 15.5 132.8 ± 23.6
94.2 ± 15.7 131.5 ± 20.0
20.0 ± 6.2 38.7 ± 4.3
18.3 ± 4.1 32.5 ± 8.0
0.607 ± 0.212 1.411 ± 0.466
0.682 ± 0.219 1.558 ± 0.641
11.4 ± 3.8 54.0 ± 16.9
11.8 ± 1.9 53.0 ± 18.4
235 ± 71 1,244 ± 412
274 ± 60 1,180 ± 500
170 ± 63 1,135 ± 403
206 ± 44 1,232 ± 484
93.5 ± 2.9 90.3 ± 5.7 46.8 ± 7.4
92.7 ± 3.1 90.3 ± 5.0 41.0 ± 15.8
Maximum Predicted"
p Value'l
178.5
NS
< 0.05 177.0
NS NS
< 0.025 < 0.05 NS NS NS
85.8
NS NS
2,340
< 0.025 NS NS NS NS
• From reference 9. p value for paired t lest, early versus late.
t
tiredness in six patients and breathlessness in one patient.
Comparison of SLT and DLT Recipients No significant difference was seen in maximal work rate between SLT (44070 of predicted) and DLT (46% of predict-
ed) recipients at 3 months (or 1 to 2 yr) after transplant. At 3 months SLT recipients had significantly lower resting heart rates as well as higher respiratory rate and minute ventilation on exercise. When retested at 1 to 2 yr after transplant, no significant difference was seen in resting heart rate, respiratory rate on exercise, or minute ventilation on exer-
TABLE 6 RESULTS OF MAXIMAL EXERCISE TESTING (STAGE 1) IN DLT (n
Work, W Hr, rnirr' Rest Exercise RR, mln' Rest Exercise VT, L Rest Exercise VE, Umin Rest Exercise v0 2 , mlfmin Rest Exercise vco; mlfmin Rest Exercise Sa0 2 Rest Exercise AT, % of predicted MV0 2
=
7) RECIPIENTS
Maximum Predicted"
p Value t
Early
Late
65.7 ± 15.1
74.3 ± 15.1
107 ± 5 136 ± 12
93 ± 10 129 ± 19
16.1 ± 4.7 31.7±8.4
17.7 ± 8.0 30.6 ± 3.9
0.847 ± 0.198 1.269 ± 0.205
0.783 ± 0.228 1.499 ± 0.235
12.1 ± 1.8 39.0 ± 6.9
12.4 ± 2.5 45.4 ± 6.6
278 ± 53 918 ± 182
222 ± 50 963 ± 229
214 ± 31 916 ± 196
198 ± 58 1,059 ± 166
NS NS
95.1 ± 3.4 94.4 ± 4.0 42.6 ± 3.7
96.1 ± 2.5 96.4 ± 3.1 43.1 ± 18.3
NS NS NS
*
From reference 9.
t
p value for paired t test, early versus late,
152.2
NS
< 0.Q1 186
NS NS NS NS
< 0.05 93.0
NS NS
< 0.025 1,920
cise; however, a significantly higher Sao, at rest and on exercise was noted in DLT recipients.
NS
Discussion
The ultimate aim of transplantation in patients with end-stage pulmonary or pulmonary vascular disease is long-term survival and return of normal functional capacity. A previous report observed subnormal maximal oxygen consumption in HLT (7) recipients and suggested a nonpulmonary cause. This report shows that despite nearly normal spirometry and diffusion capacity in DLT recipients and a substantial improvement in these parameters in SLT recipients, exercise capacity is reduced. For SLT recipients, a maximal work rate of 44% of predicted was seen at 3 months after transplant without significant improvement (48% of predicted) when retested at 1to 2 yr after transplant. This work capacity represented an oxygen delivery of only 46% of predicted. DLT recipients fared no better with no significant improvement in maximum work capacity between 3 months (46% of predicted) and 1 to 2 yr (51 % of predicted) after transplant. Similarly, a subnormal V0 2 was observed (50% of predicted at 3 months) that did not significantly improve with time (55% of predicted at 1 to 2 yr). The suboptimal results of graded testing in most cases, however, did not reflect patient life-style after transplant. Before transplantation severe exercise limitation due to respiratory disease was present in both SLT and DLT patients such that all were impaired in their ability to complete activities of daily living (although none were bedridden). Most patients had had chronically debilitating illnesses with steadily decreasing levels of activity over 1 to 4 yr before surgery. At formal pretransplant assessment, the mean distance achieved on a 6-min walk test was 328 ± 37 m for SLT and 377 ± 41 m for DLT (12). The level of disability in most cases precluded preoperative graded exercise studies. Following transplant all DLT have resumed their predebility life-styles. All work in full-time or part-time jobs or are students. None, however, adhere to a regular exercise training program. Of SLT recipients, six of seven are able to carry out daily activities without difficulty. One has resumed full-time work. Five of the remaining six are either retired or engaged in part-time work and do not have
104
physical limitation to their usual activities. The remaining patient has developed significant chronic rejection. He functions independently without supplemental oxygen but is limited to New York Heart Association Class II to III. Our findings are particularly interesting in the DLT who despite marked improvement in lung mechanics and gas exchange after transplant have ongoing exercise limitation. The posttransplant near normal spirometry and MIP measurements tend to refute a ventilatory limitation to exercise. Both the DLT and SLT groups had a substantial ventilatory reserve at the end of exercise as they only achieved 48 and 62070 of their respective predicted maximums based on their observed preexercise FEV 1.0 values. Exercise gas exchange, although somewhat better in the DLT group (Sa0 2 95070) than the SLT group (Sao, 90070), was more than adequate to meet the O 2 delivery requirements of the work levels achieved. Maximal heart rates were low in both the DLT and SLT groups (70 and 74070 of predicted, respectively)and showed little change with time. This might suggest an inadequate cardiac output as a limiting factor to exercise. However, if the submaximal heart rates at any work load are compared with population normal rates for that level of work, the rate responses were average to high, suggesting an appropriate exerciseadaptation. There was also no indication in any patient tested of a plateauing of the heart rate suggestive of a lowering of the rate response ceiling. It is possible that the exercise limitation may be peripheral rather than central in origin. A prolonged period of severe illness and its accompanying immobility would lead to muscle deconditioning that would persist postoperatively despite restoration of near normal pulmonary function. This "deconditioning" may become the limiting factor in exercise. Reduced exercise capacity secondary to muscle deconditioning or disuse can manifest itself in two ways. Prolonged immobility makes a muscle more prone to fatigue related to anaerobic lactic acid processes, that is, less efficient H+ buffering capacity, and loss of phosphocreatine stores. These factors require an earlier onset of glycolysis and hence a low anaerobic threshold (13). Both the DLT and SLT groups showed low AT, and the predominant exercise-limiting symptom was leg fatigue.
WILLIAMS, PATTERSON, MCCLEAN, ZAMEL, AND MAURER
The other factor associated with deconditioning is the process of muscle atrophy. Usually two-leg exercise provides sufficient muscle mass for a central exercise limitation to occur, that is, cardiovascular. However, long-term disuse may result in a sufficient reduction of muscle mass to result in a peripheral limitation to exercise as is commonly seen in oneleg or one-arm exercise. Shephard and colleagues (14) have shown a significant correlation between muscle volume and Vo.max, maximal work load, and also maximal HR. The authors suggested that this last observation could be explained by decreased peripheral cardioaccelatory activity secondary to the reduced active muscle volume as well as decreased central drive due to less absolute muscular vasodilation. A recent study by Rutherford and coworkers (15) showed that significant decrements in both muscle size and strength remained up to 5 yr after full mobilization following nonmuscular lower limb trauma in seven patients. These decrements ranged from 6 to 27070 for muscle sizeand 17to 50070 for strength. They were not directly associated with the duration of immobilization, which varied from 1to 13months, and were not related to an inability to fully activate the muscles during testing. Although no measurements were made or estimated of leg volumes in these patients, the low maximum exercise capacities and heart rates, as well as the large ventilatory reserves particularly in the DLT, could suggest a deconditioning-related reduced muscle volume component. This is an area that warrants further investigation. Any initial improvement in exercisecapacity after transplantation was probably due to the continued effect of improved pulmonary physiology and physical training resulting from participation in the exercise rehabilitation program. Lack of further improvement in performance over time may be related to the absence of such a program for these patients after discharge from the structured posttransplant rehabilitation program, which usually occurs about 3 months postoperatively. One subject in the Rutherford (15) study with marked unilateral weakness participated in an intensive 3-month training program that restored the leg to nearly 100070 of its uninjured pair. The authors concluded that, unlike muscle injury, which generates new fibers, the slow recovery from immobilization-induced atrophy was probably due to the growth of mature fibers, which re-
quire a much greater stimulus than daily activity normally provides. Other studies have produced similar findings, as outlined in a recent review of this area (16). Several factors have been identified that will likely influence the degree of atrophy and the time necessary for recovery; these include age, sex, degree of disuse compared with normal usage, pretreatment, preexisting atrophy, fiber type, and muscle type (antigravity) (16). In our study, the similarity in exercise capacities of the SLT and DLT recipients is interesting in view of the considerable difference in postoperative pulmonary function. If atrophy is a significant contributor, then steps must be taken to lessen its impact. Preoperative rehabilitation is probably of limited utility because the ventilatory limitation of severe chronic obstructive pulmonary disease (and likely other end-stage lung diseases) prevents the imposition of sufficient stress to stimulate muscular development. Earlier transplantation or a much more aggressive postoperative training program may be necessary to allow these patients to achieve their full potential. If, on the other hand, exercise capacity is the same following SLT as DLT or HLT, this may have implications regarding the type of transplant chosen in a particular situation. SLT, since it has been performed successfully for several different types of end-stage disease (2, 17-19) and leads to optimal utilization of scarce donor lungs, could become the procedure of choice in most patients. Comparison of all aspects of outcome of SLT and DLT between well-matched recipient groups will help to better define the respective roles of these procedures. In conclusion, these results suggest that persistent exercise limitation after SLT and DLT is not respiratory in many instances. Prolonged illness may lead to a considerable decrement in skeletal muscle performance, which may not spontaneously recover with the return of normal activity. Continuation of a formal, more intensive rehabilitation program may result in significantly improved exercise performance. Although patients who survive SLT, DLT, and HLT are greatly improved, they still fall short of the ultimate aim of survival with normal functional capacity. References I. Reitz BA, Wallwork JL, Hunt SA, et al. Heartlung transplantation: successful therapy for patients
MAXIMAL EXERCISE TESTING IN LUNG TRANSPLANT RECIPIENTS
with pulmonary vascular disease. N Eng J Med 1982; 306:557-64. 2. Toronto lung transplant group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986; 314:1140-5. 3. Cooper JD, Patterson GA, Grossman R, Maurer J. Double lung transplantation for advanced chronic obstructive lung disease. Am Rev Respir Dis 1989; 139:303-7. 4. Dawkins KD, Jamieson SW, Hunt SA, et al. Long-term resuts and complications after combined heart and lung transplantation. Circulation 1985; 71:919-26. 5. Williams Tl, Grossman RF, Maurer JR. Longterm functional follow-up of lung transplant recipients. Clin Chest Med 1990; 11(2):347-58. 6. Burke CM, Baldwin JC, Morris AJ, et al. Twenty-eight cases of human heart-lung transplantations. Lancet 1986; 1:517-9.
7. Dawkins KD,Jamieson SW. Pulmonary function of the transplanted human lung. Annu Rev Med 1988; 37:263-9. 8. Maurer JR. Unilateral lung transplant. Pulm Perspect 1987; 4:1-3. 9. Jones NL, Campbell EJM. Clinical exercise testing, 3rd ed. Philadelphia: W. B. Saunders, 1988. 10. Cotes JE. Lung function: assessment and application in medicine, 4th ed. Oxford: Blackwell Scientific, 1979. II. Freedman S. Sustained maximum voluntary ventilation. Respir Physiol 1970; 8:230-44. 12. Williams Tf, Grossman RF, Maurer JR. Longterm functional follow-up of lung transplant recipients. Clin Chest Med 1990; 11(2):347-58. 13. Hainaut K, Duchateau J. Muscle fatigue, effects of training and disuse. Muscle Nerve 1989; 12:660-9. 14. Shephard RJ, Bouhlel E, Vanderwalle H,
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Monod H. Muscle mass as a factor limiting physical work. J Appl Physiol 1988; 64(4):1472-9. 15. Rutherford OM, Jones DA, Round JM. Longlasting unilateral muscle wasting and weakness following injury and immobilization. Scand J Rehab Med 1990; 22:33-7. 16. Appell HJ. Muscular atrophy following immobilization; a review. Sports Med 1990;10:42-58. 17. Trulock EP, Egan TM, Kouchoukos NT, et al. Singlelung transplant for severechronic obstructive pulmonary disease. Chest 1989; 96:738-42. 18. Starnes VA, Stinson EB, Oyer PE, et al. Single lung transplantation: a new therapeutic option for patients with pulmonary hypertension. Transplant Proc 1991; 23(1):1209-10. 19. Maurer JR, Winton TL, Patterson GA, et al. Single-lung transplantation for pulmonary vascular disease. Transplant Proc 1991; 23(1):1211-2.
