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Right and left ventricular performance after single and double lung transplantation
J
THORAC CARDIOVASC SURG
1991;102:115-23
Right and left ventricular performance after single and double lung transplantation Twelve single lung and nine double lung transplant recipients were studied before transplantation and at 3 months and 1 year after transplantation with serial right and left ventricular radionuc6de angiograms. The resting right ventricular ejection fraction increased in the double lung recipients from 31 % ± 5% before transplantation to 43% ± 11 % at 3 months after transplantation (p < 0.05) and then remained stable to 1 year. The single lung recipients also demonstrated a significant rise in ejection fraction from 25 % ± 11 % before transplantation to 36 % ± 12 % at 3 months after transplantation. Again, this remained stable to 1 year. The exercise right ventricular ejection fraction also showed a significant posttransplantation rise in the double lung recipients (p < 0.005) that remained stable to 1 year. In the single lung recipients a trend was seen for a rise in the exercise right ventricular ejection fraction that did not reach statistical significance by 1 year after transplantation. Neither group had a significant change in rest or exercise left ventricular ejection fraction. The systemic blood pressure increased significantly by 1 year after transplantation in both groups. The heart rate increase with exercise at 3 months after transplantation was significantly greater in the single lung group (42 ± 13 beats/min) than in the double lung group (14 ± 13 beats/min) (p < 0.005). These data indicate that a significant improvement in right ventricular function occurs after single and double lung transplantation.
R.Carere, MD, FRCP(C) (by invitationj.t" G. A. Patterson, MD, FRCS(C),b P. Liu, MD, FRCP(C) (by invitationj.v'" T. Williams, MD, FRACP (by invitation)," J. Maurer, MD, FRCP(C) (by invitation)," R. Grossman, MD, FRCP(C) (by invitation)," and The Toronto Lung Transplant Group, Toronto, Ontario, Canada
In the past decade lung transplantation has evolved to become a viable therapeutic option for previously fatal lung diseases.' In 1986 the Toronto Lung Transplant Group described the first long-term success of a single
From the Division of Thoracic Surgery," the Division of Cardiology," and the Division of Pulmonary Medicine," University of Toronto, Toronto, Ontario, Canada. Partially sponsored by the Cystic Fibrosis Foundation, The Metro Toronto and York Region Lung Association, and the Heart and Stroke Foundation of Ontario, Grants T-239, 1494, and A-1304. Read at the Seventieth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, May 7-9,1990. Address for reprints: G. A. Patterson, MD, 12-230 Eaton Wing North, Toronto General Hospital, Toronto, Canada M5G 2C4. "Pettit research fellow at the University of Toronto, Toronto, Ontario, Canada. ""Research Scholar with the Heart and Stroke Foundation of Ontario.
12/6/28124
lung transplantationfor pulmonaryfibrosis.? Our group subsequently described the experimental development and use of clinical doublelung transplantation.'- 4 Longterm follow-up data have recently been described by Grossmanand colleagues' in the singlelunggroupand by Cooper and colleagues? in the double lung group. Lung disease impacts on cardiac function, primarily affecting the rightventricle. As the lungdisease progresses to involve the pulmonary vascular bed, the normally volume-dependent right ventricle must undergoan adaptiveresponse to an increased afterload.?- 8 After a period of time progressive impairmentof right ventricularfunction is a potential sequela of many lung diseases. Lung transplantation allows a unique opportunity to observe howa change in pulmonaryfunction affectscardiovascular function. After a singlelung transplantation a patient is left with one diseased native lung in situ and one allograft. A doublelung recipient, however, benefits from receiving twodonorlungswith a normal pulmonary 115
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SINGLE LUNG 10
10
50
50
40
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Fig. 1. Resting right ventricular ejection fraction (EF) before transplantation and at 3 months and I year after transplantation for single and double lung transplant recipients. S.D., Standard deviation.
Table I. Characteristics of study population
vascular bed. In either case pulmonary vascular resistance in the transplanted lung(s) would be expected to decrease, which would result in a lowered impedance to right ventricular outflow compared with the preoperative state. The purpose of this study was to assess the rest and exercise changes in right and left ventricular function, systemic blood pressure, and heart rate after single and double lung transplantation.
donor airway necrosis, and late development of bronchiolitis obliterans. One other double lung recipient was excluded because of primary myocardial dysfunction before transplantation further complicated by a postoperative cardiac arrest. A patient who received a double lung transplant followed 19 days later by a single lung transplant because of complications with the right bronchial anastomosis was also excluded. The two study groups had a similar mean age (Table I). There was a greater number of men than women in the single lung group and a more equal sex distribution in the double lung group. The two groups were distinguished by different pathologic diagnoses. The single lung recipients predominantly had pulmonary fibrosis whereas the double lung recipients were pathologically more heterogeneous. Their diseases were mainly of obstructive and septic pulmonary types. The 'pathophysiology in pulmonary mechanics for each group is reflected in the pulmonary function test results forced expiratory volume in one second/forced vital capacity (Table I), with the single lung group demonstrating restrictive physiology and the double lung group demonstrating obstructive physiology. Patients in both groups.were otherwise free of diseases that might influence their exercise capacity. Preoperatively there was no need for antihypertensives, inotropes, antiarrhythmics, or medications likely to affect cardiac performance in either group. After transplantation one of 12 single lung recipients was placed on a regimen of {1-blocker therapy; no double lung recipients were on this type of therapy. All patients were placed on a regimen of azathioprine, prednisone, cyclosporine, and co-trimoxazole after transplantation.
Study population
Method
Between November 1983 and February 1989,20 patients underwent single lung transplantation at The Toronto General Hospital. From November 1986 to February 1989,15 patients underwent double lung transplantation. Our study group (Table I) consisted of those 12 single lung recipients and nine double lung recipients who had reached l-year follow-up. Fifteen patients were not included in this study because of death within 1 year in eight single lung and in four double lung recipients. Right ventricular dysfunction was not a factor in the death of these patients. The most common causes of death were sepsis,
Radionuclide angiogram acquisition. Supine rest and symptom-limited exercise technetium 99m gated radionuclide angiography studies were conducted with an Elcint 409 AG camera (Elcint, Haifa, Israel). For determination of right ventricular ejection fraction, gated first-pass and equilibrium studies were performed at rest, whereas equilibrium studies alone were used during exercise. The resting first-pass study was acquired after a 500 MBq bolus of 99mTc pertechnetate was injected through a large-bore free-flowing intravenous tube inserted into the brachial vein. Images were acquired in the 30-
Single lung recipients No.
Age (yr) Female/male Diagnosis
Doublelung recipients
12 49 ± 8
9 43 ± 6
4/8 Pulmonary fibrosis (10) Eisenmenger's syndrome (1) a)-Antitrypsin deficiency (I)
5/4 aI-Antitrypsin deficiency (3); emphysema (2) Bronchiolitis obliterans (1) Bronchiectasis (2) Eosinophilic granuloma (1)
FEVt/FVC 118 ± 10 (% predicted)
50 ± 20
FEV1/FVC, Forced expiratory volume in I second/forced vital capacity.
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Ventricular performance after lung transplantation
Number 1 July 1991
1 17
Table II. Response to exercise of singleand double lung transplant recipients Before transplantation
3 mo after transplantation
Single lung Double lung
2.73 ± 1.54 3.0 ± 1.6
*
Single lung Double lung
286.2 ± 96.9 359.5 ± 128.9
t t
1 yr after transplantation
Duration of exercise (min) 3.77 ± 2.0 3.67 ± 2.4
4.1 ± 2.6 3.33 ± 1.7
Six-minute walk distance (m) 555.1 ± 133.5 607.7 ± 74.8
607.8 ± 143.1 629.7 ± 88.1
Values are mean ± standard deviation. for single lung before transplantation t03 months after transplantation. tp < 0.001 for single and double lung groups before transplantation versus 3 months after transplantation.
"n < 0.05
Table III. Summary of intragroup pretransplantation to posttransplantation ejection fraction and blood pressure
responses
Single lung RVEF Rest Exercise LVEF Rest Exercise Blood pressure Rest Systolic Diastolic Exercise Systolic Diastolic
Double lung
Pre
3mo
1 yr
Pre
3mo
1 yr
25 ± 8%* 25 ± 9%
36 ± 12%* 31 ± 14%
33 ± 12% 36 ± 9%
31 ± 5%* 24 ± 3%t
43 ± 11%* 45 ± 12%t
41 ± 10% 45 ± 6%
58 ± 10% 60 ± 5%
56 ± 8% 62 ± 12%
57 ± 5% 63 ± 8%
58 ± 13% 55 ± 9%
65 ± 10% 64 ± 10%
57 ± 12% 63 ± 10%
118 ± 13t 76 ± 11*
135 ± 19t 87 ± 9*
133 ± 15 85 ± 7
122 ± 10 79 ± 8
133 ± 14 82 ± 7
135 ± 7+ 91 ± 11+
144 ± 22* 89 ± 10
162 ± 18* 92 ± 9
161 ± 12 91 ± II
163 ± 14 88 ± 7
146 ± 29 84 ± II
168 ± 21 93 ± 14
*p < 0.05. tp < 0.005. :j:p< 0.05 for pretransplantation versus I-year results.
degree right anterior oblique projection onto a 64 X 64 matrix with an APC 1 high-sensitivity collimator (Elcint). The right and left ventricular equilibrium studies were conducted from the left anterior oblique best septal projection with an APC 3 lowenergy general-purpose collimator at 16 frames per RR interval; 750 MBq of 99mTc pertechnetate was used to label the blood pool after the patient had received pyrophosphate as a reducing agent. Right and left ventricular ejection fractions were measured at rest and during exercise by commercially available semiautomated edge detection software. Phase images were used to isolate the right ventricle from the surrounding atrial structures. Bicycle exercise. The supine bicycle exercise protocol began at a 200 km/rnin workload on an electronically braked exercise table (846T Quinton Instruments, Seattle, Wash.). The workload was increased in increments of 200 km/rnin every 3 minutes as tolerated by the patients. Only data from completed workload stages were used. Patients were encouraged to exercise to their maximum. The heart rate was recorded continuously via electrocardiographic monitoring, whereas the blood pressure was measured at I-minute intervals by an automatic cuff inflator (lnfrasonde D4000, Puritan Bennett, Los Angeles,
Calif.). Studies were acquired 1 to 4 months before lung transplantation and again at 3 months and 12 months after transplantation with the same protocol. Six-minute walk test. Six-minute walk tests were performed on all patlents.? Patients walked a levelmeasured course, and the total distance walked (meters) in 6 minutes was recorded. Patients were allowed to stop as often as required during the test. Statistical analysis. All values are expressed as mean ± standard deviation. Intragroup comparisons were made with the paired Student's t test; intergroup comparisons were made with the unpaired Student's t test. A p value of less than 0.05 was considered significant.
Results Exercise capacity. Most patients required oxygen supplementation for preoperative exercise testing. All postoperativestudieswere conducted without supplemental oxygen. Supine bicycle exercise. Both groups demonstrated an overall increase in exercise duration and workload
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SINGLE LUNG
DOUBLE LUNG
50
10
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20
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Fig. 2. Exercise right ventricular ejection fraction (EF) before transplantation and at 3 months and I year after transplantation for single and double lung transplant recipients.
SINGLE LUNG
g I:J
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10
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70
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r
r
1 1
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12m..
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3m..
12 m-.
Fig. 3. Resting left ventricular ejection fraction (EF) before transplantation and at 3 months and I year after transplantation for single and double lung transplant recipients.
achieved after transplantation (Table II). This was statistically significant only in the single lung group, however. The majority of patients in both groups were able to complete only one stage of exercise (3 minutes at 200 kmJmin) both before and after transplantation. Six-minute walk. Both single and double lung recipients demonstrated a significant improvement in distance walked during the 6-minute exercise test at 3 months after transplantation. This improvement was maintained at 12 months after transplantation (Table 11). First-pass right ventricular ejection fraction. Significant technical limitations were encountered with the first-pass technique used to measure the right ventricular ejection fraction. The technetium trace bolus was of poor quality in more than 50% of the studies, so that data for analysis of the ejection fraction were unreliable. This was probably a result of elevated pulmonary artery pressures and increased resistance to pulmonary blood flow,venous
congestion, right atrial dilatation, and, occasionally, concomitant tricuspid valve regurgitation. Because of these difficulties the results of the first-pass ejection fraction studies are unreliable and are not included in this report. Equilibrium right ventricular ejection fraction Rest study. When the resting right ventricular ejection fraction was determined by the equilibrium method (Fig. 1 and Table III), a significant posttransplantation increase was observed in both the single and double lung groups. No further change was seen in the ejection fraction up to 1 year after transplantation in either group. Exercise study. A similar result was seen with the exercise right ventricular ejection fraction (Fig. 2 and Table III). An increase was seen at 3 months after transplantation in both groups. However, this was of greater magnitude and statistically significant only in the double lung group. Again, the improved ejection fractions are maintained to 1 year, and, in fact, in the single lung group
Volume 102 Number 1 July 1991
Ventricular performance after lung transplantation
DOUBLE LUNG
SINGLE LUNG 110
110
70 110
E ... 50
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Fig. 4. Exercise left ventricular ejection fraction (EF) before transplantation and at 3 months and I year after transplantation for single anddouble lung transplant recipients. SINGLE LUNG 110
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E
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Fig. 5. Resting systolic blood pressure before transplantation andat 3 months and 1 year after transplantation in single and double lung transplant recipients. NS, Not significant. the trend is for a continued risedespitethe lack of statistical significance (p = 0.06). Left ventricular ejection fraction. The left ventricular ejection fraction at rest and during exercise remained stable throughout the study period in both groups of patients (Figs. 3 and 4 and Table III). Blood pressure Rest. Both groups had an increase in systemic blood pressure after transplantation (Figs. 5 and 6 and Table III). The single lung group demonstratedthis rise early, withsignificantly highersystolic and diastolic pressures at 3 months after transplantation. The higher pressures are sustained to 1 year with no further tendency to increase. The double lung recipients also had a rise in their blood pressure after transplantation that was statistically significant at 1 year after transplantation. Exercise. The exercise blood pressuredata are gener-
ally stable throughout the study (Table III). The only statistically significant difference occursbetween the pretransplantation and 3-month posttransplantation value for the singlelungrecipients. This in fact is not sustained, and the I-year value is not different from the pretransplantation value. Heart rate. The restingand exercise heart rates do not change significantly during the study period in either group (Table IV). If the difference between the peak exercise and restingheart rates (heart rate increasewith exercise) is considered, an interesting difference is observed between the groups. The singlelung recipients have a stable increase in heart rate with exercise at all three study periods. The doublelung recipients, however, havelessof an increasein heart rate with exercise at the 3-monthposttransplantation study (p = 0.06) compared with the single lung recipients. This changes by I year
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DOUBLE LUNG
SINGLE LUNG 110
120
100
110
10 go
:z: E E
80
70 10 50 40
•r 1
1
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Fig. 6. Resting diastolic blood pressure before transplantation and at 3 months and I year after transplantation in single and double lung recipients.
Table IV. Resting, exercise, and average delta (change from rest to exercise) heart rates (beats/min) data for the pretransplantation and posttransplantation periods* Single lung Pre Heart rate (beats/min) 75 ± 26 Rest Exercise 102 ± 36 Delta 33 ± 14
3 mo 80 ± 28 ± 39 42 ± 13
J 15
I
Double lung J yr 72 ± 25 100 ± 36 35 ± 13 P < 0.005
Pre
3 mo
J yr
89 ± 16 116 ± 10 35 ± 18
94 ± 13 108 ± 18 14 ± 13
85 ± 11 120 ± 10 34 ± 16
I
'Only the }-month posttransplantation change was found to be significantly different between the groups; note that the delta is the average of individual patient deltas and not the difference of exercise minus rest shown on chart.
when the heart rate increase is back to a pretransplantation value. If the amount of change in the heart rate from rest to peak exercise is compared between the two groups (Table IV), there is no difference between the groups except at 3 months after transplantation, when the single lung recipients have a significantly greater increase in heart rate with exercise. Discussion Right ventricular performance has been used as a selection criterion for isolated lung transplantation because of uncertainty regarding the potential for recovery of right heart function despite the anticipated posttransplantation decrease in right heart afterload. In our early experience patients with right ventricular ejection fractions less than 25% were not considered to be candidates for single or double lung transplantation and were usually referred for combined heart-lung transplantation. Because lung transplantation was applied to patients with more impaired right ventricular function, particularly those with pulmonary fibrosis and associated severe pulmonary hypertension, a prompt improvement in the right
ventricular ejection fraction was observed after transplantation. The data presented here demonstrate a sustained improvement in the right ventricular ejection fraction during at least 1 year after lung transplantation. Improvement was seen in both the single and double lung recipient groups, although the exercise data reached statistical significanceonly in the double lung recipients. These data suggest that the magnitude of the cardiovascular hemodynamic response to single versus double lung transplantation may be somewhat different. Within the single lung recipients a variable response was observed, with some patients receiving greater benefit than others in terms of right ventricular functional recovery. The double lung recipients, however, consistently demonstrated a significant improvement in right ventricular function as measured by this technique. Although the right ventricular ejection fraction can be artificially high in the presence of significant tricuspid regurgitation, this did not appear to be a major factor in these patients. The study was not designed to assess formally the degree of tricuspid regurgitation. However,
Volume 102 Number 1 July 1991
only one single lung recipient had clinically apparent tricuspid regurgitation that was confirmed at echocardiographic study. No other patient had tricuspid regurgitation by clinical or echocardiographic assessment. Measuring the right ventricular ejection fraction by the first-pass technique was found to be unreliable in this group of patients because of technical factors. The major problem encountered was breakup of the technetium bolus before it reached the right ventricle. This was due to a combination of pulmonary hypertension, venous congestion, and right atrial enlargement. In some cases tricuspid regurgitation may have been another confounding problem. Obtaining reliable first-pass data for ejection fraction analysis continues to be a challenge in this group of patients. The equilibrium method of assessing right ventricular function appears to be most reliable and useful for serial follow-up. This study was not intended to further investigate the mechanisms that might explain the relative difference observed between the two groups; however, several mechanisms could be operative. A significant correlation between the radionuclide angiographic ejection fraction and mean pulmonary artery pressure and pulmonary vascular resistance has previously been demonstrated. 10-1 2 It is likely that the two groups studied here differ, with a lower pulmonary vascular resistance in the double lung recipients in the postoperative period. Double lung recipients have an essentially normal pulmonary vascular bed as opposed to one diseased (native) and one normal (allograft) vascular bed in the single lung recipients. We 5 have previously reported preferential perfusion of the transplanted lung after a single lung transplantation. This implies that the upper limits of vascular compliance are approached when a single lung must accept the greater portion of the cardiac output. The result is a relative increase in vascular resistance and pulmonary arterial pressure that would be particularly aggravated when cardiac output increases during exercise. This is supported by experimental work in a canine pneumonectomy model that demonstrated significant increases in pulmonary pressure and resistance in the remaining lung.l ' The clinical implication of this relative difference in the recovery of right ventricular performance is that it could impact on decision making in patient selection for either single or double lung transplantation. If severe right ventricular dysfunction exists, a double lung transplant might optimize the likelihood of adequate postoperative right ventricular function. If right ventricular function is better preserved preoperatively, a single lung transplant would be adequate for good postoperative function. Traditional recipient criteria have considered patients with pulmonary fibrosis as candidates for single lung
Ventricular performance after lung transplantation
12 1
transplantation, those with obstructive or septic lung disease candidates for double lung transplantation, and those with pulmonary hypertension for combined heart-lung transplantation. I More recently the Toronto Lung Transplant Group has challenged this and successfully performed single lung transplantation in patients with obstructive lung disease I4 and in patients with severe pulmonary vascular disease.P Unfortunately determination of the lower limit of recoverable right ventricular function by current assessment criteria is impossible. We and others have observed immediate recovery of right ventricular function in patients undergoing single lung transplantation whose preoperative right ventricular ejection fraction was less than 10%. We have also seen severe tricuspid regurgitation disappear immediately after implantation of a single lung graft in a patient with primary pulmonary hypertension. Currently if a patient has severe, unmanageable clinical right ventricular failure, we would not anticipate prompt right ventricular recovery and would recommend combined heart-lung transplantation. We would make the same recommendation for a patient with Eisenmenger's syndrome who has an irreparable cardiac defect. However, it is difficult to be dogmatic about these judgments, made already by ourselves and others, because the total clinical experience and follow-up to date are limited. The impact of severe pulmonary disease on left ventricular function is indirect through ventricular interaction and possibly chronic hypoxia. Because there is no direct hemodynamic burden on the left ventricle, the single and double lung recipients studied had well-preserved left ventricular function before and after transplantation. Systemic systolic and diastolic blood pressures were increased after transplantation in both groups of patients, a result that may be related to the use of cyclosporine. The difference in the heart rate response to exercise can be explained more readily by cardiac denervation as a consequence of removal of both native lungs and sectioning of the trachea in the double lung recipients." Our group has shown that the heart rate response of double lung transplant recipients to autonomic stimuli such as atropine and carotid sinus massage is often that of a denervated heart." Cardiac denervation does not occur in a single lung transplantation procedure because a more limited dissection is possible.!? The response of the double lung recipient is similar to that of the cardiac transplant recipient who also has cardiac denervation.l'' There was no difference in exercise duration or peak workload that would account for the different heart rate responses. It is intriguing that the heart rate response to exercise is
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restored in the double lung recipients by 1 year after transplantation. This suggests the possibility of reinnervation or perhaps adaptation of cardiac receptors. We have recently performed double lung transplantation by using bilateral bronchial anastomoses and bilateral sequential single lung transplantation, rather than the double lung transplantation procedure that we originally described in which we employed a tracheal anastomosis. This may result in less disruption of cardiac innervation and therefore may avoid the effects of cardiac denervation. Definite improvements in exercise tolerance were observed after transplantation in both groups of patients on the 6-minute walk test. Although not a sophisticated test, the 6-minute walk does provide meaningful and reproducible data on the exercise capacity of patients with pulmonary and cardiac diseases.?: 19 The extent to which cardiac performance may continue to limit the exercise capacity of these patients is unknown. In summary, a sustained improvement in right ventricular function occurs after lung transplantation, probably because of an improvement of right ventricular loading conditions. There are alterations in autonomic tone suggesting cardiac denervation in double lung recipients who become attenuated during the first postoperative year. These effects should be considered in assessment and follow-up of transplant candidates. REFERENCES 1. Patterson GA, Cooper JD. Status of lung transplantation. Surg Clin North Am 1988;68:545-58. 2. Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986; 314:1140-5. 3. Patterson GA, Cooper JD, Dark JH, et al. Experimental and clinical double lung transplantation. J THORAC CARD10VASC SURG 1988;95:70-4. 4. Patterson GA, Cooper JD, Goldman B, et al. Technique of successful clinical double-lung transplantation. Ann Thorae Surg 1988;45:626-33. 5. Grossman RF, Frost A, Zamel N, et al. Results of single lung transplantation for bilateral pulmonary fibrosis. N Engl J Med 1990;322:727-33. 6. Cooper JD, Patterson GA, Grossman R, Maurer JR, and The Toronto Lung Transplant Group. Double lung transplant for advanced chronic obstructive lung disease. Am Rev Respir Dis 1989;139:303-7. 7. Barnard D, Albert JS. Right ventricular function in health and disease. Curr Probl CardioI1987;12:417-49. 8. Weber KT, Janicki JS, ShroffSG, LikoffMJ, Sutton MG. The right ventricle: physiologic and pathophysiologic considerations. Crit Care Med 1983;11:323-8.
9. Buttand RJA, Pang J, Gross ER, Woodcock AA, Geddes DM. Two, six and 12 minute walking tests in respiratory disease. Br Med J 1982;284:1607-8. 10. Korr KS, Gandsman EJ, Winkler ML, Shulman RS, Bough EW. Hemodynamic correlates of right ventricular ejection fraction measured with gated radionuclide angiography. Am J CardioI1982;49:71-7. 11. Brent BN, Berger HJ, Matthay RA, Mahler D, Pytlik L, Zaret BL. Physiologic correlates of right ventricular ejection fraction in chronic obstructive pulmonary disease: a combined radionuclide and hemodynamic study. Am J Cardiol 1982;50:255-62. 12. Brent BN, Mahler D, Matthay RA, Berger HJ, Zaret BL. Noninvasive diagnosis of pulmonary arterial hypertension in chronic obstructive pulmonary disease: right ventricular ejection fraction at rest. Am J Cardiol 1984;53:1349-53. 13. Crouch JD, Lucas CL, Keagy BA, Wilcox BR, Ha B. The acute effects of pneumonectomy on pulmonary vascular impedance in the dog. Ann Thorac Surg 1987;43:613-6. 14. Patterson GA, Maurer JR, Williams Tf, Cardoso P, Scavuzzo M, Todd TRJ, and The Toronto Lung Transplant Group. Comparison of outcomes of double and single lung transplantation for obstructive lung disease. J THORAC CARDIOVASC SURG 1991;101:623-32. 15. Fremes SE, Patterson GA, Williams WG, Goldman BS, Todd TR, Maurer J. Single lung transplantation and closure of patent ductus arteriosus for Eisenmenger's syndrome. J THoRAc CARDIOVASC SURG 1990;100:1-5. 16. Schaefers MD, Waxman MB, Patterson GA, Frost AE, Maurer J, Cooper JD. Cardiac innervation after double lung transplantation. J THORAC CARDIOVASC SURG 1990; 99:22-9. 17. Cooper JD, Pearson FG, Patterson GA, et al. Technique of successful lung transplantation in humans. J THORAC CARDIOVASC SURG 1987;93:173-81. 18. Savin WM, Haskell WL, Schroeder JS, et al. Cardiorespiratory responses of cardiac transplant patients to graded, symptom limited exercise. Circulation 1980;62:55-9. 19. Lipkin DP, Scriver AJ, Crake T, Poole-Wilson PA. Six minute walking test for assessing exercise capacity in chronic heart failure. Br Med J 1986;292:653-5.
The Toronto Lung Transplant Group
Surgery: G. A. Patterson, F. G. Pearson, T. L. Winton, M. Goldberg. Pulmonary medicine: J. Maurer, R. Grossman. Cardiology: R. G. Carere, P. P. Liu. Anesthesiology: W. De Majo. Pathology: D. Chamberlain, Psychiatry: J Craven (coordinator), M. Scavuzzo. Discussion Dr. Christian E. A. Cabrol (Paris, France). 1 would like to confirm the observation of Dr. Patterson and his group on the improvement in cardiac performance after isolated lung transplantation in patients with borderline cardiac performance.
Volume 102 Number 1 July 1991
In II double lung transplantations done in the last 3 years, we had four such patients in whom we observed an improvement not only in the right ventricular function because of the decrease of the pretransplantation elevated pulmonary vascular resistance, but also in the left ventricular performance. We observed on the echocardiogram that the change was due to a change in the geometry of the interventricular septum and better filling of the left ventricle because of the increased transverse diameter of the left ventricle. Did you observe such echocardiographic changes, and what was the result of your investigation? Dr. Patterson. We have had some difficulty interpreting our left ventricular echocardiographic data. We have not noticed any difference in postoperative left ventricular volume but have wondered whether there might well be some alteration in that function because of a change in septal geometry that might occur postoperatively. However, we have not made that same observation. Dr. J. Kent Trinkle (San Antonio. Tex.). We have also evaluated right ventricular function after single lung transplantation. We have not performed the double lung operation. The improvement in right ventricular performance seems to be in direct proportion to the decline in pulmonary artery pressure, and, therefore, afterload reduction. We have operated on 6 patients who had systemic level pulmonary artery pressures preoperatively, 3 with primary pulmonary hypertension, and 3 with pulmonary hypertension secondary to pulmonary fibroSIS.
Our first patient, who had primary pulmonary hypertension, was operated on in September of 1989. We did a left single lung transplant. Her x-ray film taken 10days postoperatively showed increased vascular markings to the left lung. The ventilation/ perfusion scan 10 days postoperatively showed that 93% of the
Ventricular performance after lung transplantation
12 3
perfusion was to the transplanted lung. The pulmonary artery pressure had dropped from over 100 to 35 mm Hg systolic at this point, and her right ventricular ejection fraction had doubled. We now do the transplants on the right because it is easier to use the pump-oxygenator with cannulas in the aorta and the right atrial appendage. In a woman who received a right lung transplant 6 weeks ago for primary pulmonary hypertension, there were, again, increased vascular markings. The ventilation/perfusion scan showed 93% perfusion to the transplanted lung 6 weeks postoperatively. The pulmonary artery pressure dropped from systemic levels to 28 mm Hg systolic with a mean of 18. The right ventricular ejection fraction had increased from 27% to 58%. What we are seeing is dramatic afterload reduction of the right ventricle, and probably the improvement in right ventricular ejection fraction is proportional to the drop in pulmonary artery pressure. We have been disappointed that we have not seen much improvement in the left ventricle. I thought that in patients with pulmonary hypertension there would be some improvement just from decreasing the paradoxical septal motion alone, but we have not been able to document that. Dr. Patterson. I am certain that that's correct, that it definitely has to do with immediate and persistent reduction in right ventricular afterload. We have made the same observations in the intensive care unit during the early days postoperatively. We wanted to compare that improvement in right ventricular function over time. We did not do right heart catheterizations in these patients at 3 and 12 months. The studies reported here are noninvasive studies only, but I think these results confirm our long-held suspicion that patients with marked impairment of right ventricular function can successfully undergo isolated lung transplantation.
THORAC CARDIOVASC SURG
1991;102:115-23
Right and left ventricular performance after single and double lung transplantation Twelve single lung and nine double lung transplant recipients were studied before transplantation and at 3 months and 1 year after transplantation with serial right and left ventricular radionuc6de angiograms. The resting right ventricular ejection fraction increased in the double lung recipients from 31 % ± 5% before transplantation to 43% ± 11 % at 3 months after transplantation (p < 0.05) and then remained stable to 1 year. The single lung recipients also demonstrated a significant rise in ejection fraction from 25 % ± 11 % before transplantation to 36 % ± 12 % at 3 months after transplantation. Again, this remained stable to 1 year. The exercise right ventricular ejection fraction also showed a significant posttransplantation rise in the double lung recipients (p < 0.005) that remained stable to 1 year. In the single lung recipients a trend was seen for a rise in the exercise right ventricular ejection fraction that did not reach statistical significance by 1 year after transplantation. Neither group had a significant change in rest or exercise left ventricular ejection fraction. The systemic blood pressure increased significantly by 1 year after transplantation in both groups. The heart rate increase with exercise at 3 months after transplantation was significantly greater in the single lung group (42 ± 13 beats/min) than in the double lung group (14 ± 13 beats/min) (p < 0.005). These data indicate that a significant improvement in right ventricular function occurs after single and double lung transplantation.
R.Carere, MD, FRCP(C) (by invitationj.t" G. A. Patterson, MD, FRCS(C),b P. Liu, MD, FRCP(C) (by invitationj.v'" T. Williams, MD, FRACP (by invitation)," J. Maurer, MD, FRCP(C) (by invitation)," R. Grossman, MD, FRCP(C) (by invitation)," and The Toronto Lung Transplant Group, Toronto, Ontario, Canada
In the past decade lung transplantation has evolved to become a viable therapeutic option for previously fatal lung diseases.' In 1986 the Toronto Lung Transplant Group described the first long-term success of a single
From the Division of Thoracic Surgery," the Division of Cardiology," and the Division of Pulmonary Medicine," University of Toronto, Toronto, Ontario, Canada. Partially sponsored by the Cystic Fibrosis Foundation, The Metro Toronto and York Region Lung Association, and the Heart and Stroke Foundation of Ontario, Grants T-239, 1494, and A-1304. Read at the Seventieth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, May 7-9,1990. Address for reprints: G. A. Patterson, MD, 12-230 Eaton Wing North, Toronto General Hospital, Toronto, Canada M5G 2C4. "Pettit research fellow at the University of Toronto, Toronto, Ontario, Canada. ""Research Scholar with the Heart and Stroke Foundation of Ontario.
12/6/28124
lung transplantationfor pulmonaryfibrosis.? Our group subsequently described the experimental development and use of clinical doublelung transplantation.'- 4 Longterm follow-up data have recently been described by Grossmanand colleagues' in the singlelunggroupand by Cooper and colleagues? in the double lung group. Lung disease impacts on cardiac function, primarily affecting the rightventricle. As the lungdisease progresses to involve the pulmonary vascular bed, the normally volume-dependent right ventricle must undergoan adaptiveresponse to an increased afterload.?- 8 After a period of time progressive impairmentof right ventricularfunction is a potential sequela of many lung diseases. Lung transplantation allows a unique opportunity to observe howa change in pulmonaryfunction affectscardiovascular function. After a singlelung transplantation a patient is left with one diseased native lung in situ and one allograft. A doublelung recipient, however, benefits from receiving twodonorlungswith a normal pulmonary 115
II6
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SINGLE LUNG 10
10
50
50
40
g l:i
DOUBLE LUNG
•I
30
1
20
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.........,
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10
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i
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10
_!IJL
0 Pre
3 mOIl
Pre
12 mOIl
3 mOIl
12 moe
Fig. 1. Resting right ventricular ejection fraction (EF) before transplantation and at 3 months and I year after transplantation for single and double lung transplant recipients. S.D., Standard deviation.
Table I. Characteristics of study population
vascular bed. In either case pulmonary vascular resistance in the transplanted lung(s) would be expected to decrease, which would result in a lowered impedance to right ventricular outflow compared with the preoperative state. The purpose of this study was to assess the rest and exercise changes in right and left ventricular function, systemic blood pressure, and heart rate after single and double lung transplantation.
donor airway necrosis, and late development of bronchiolitis obliterans. One other double lung recipient was excluded because of primary myocardial dysfunction before transplantation further complicated by a postoperative cardiac arrest. A patient who received a double lung transplant followed 19 days later by a single lung transplant because of complications with the right bronchial anastomosis was also excluded. The two study groups had a similar mean age (Table I). There was a greater number of men than women in the single lung group and a more equal sex distribution in the double lung group. The two groups were distinguished by different pathologic diagnoses. The single lung recipients predominantly had pulmonary fibrosis whereas the double lung recipients were pathologically more heterogeneous. Their diseases were mainly of obstructive and septic pulmonary types. The 'pathophysiology in pulmonary mechanics for each group is reflected in the pulmonary function test results forced expiratory volume in one second/forced vital capacity (Table I), with the single lung group demonstrating restrictive physiology and the double lung group demonstrating obstructive physiology. Patients in both groups.were otherwise free of diseases that might influence their exercise capacity. Preoperatively there was no need for antihypertensives, inotropes, antiarrhythmics, or medications likely to affect cardiac performance in either group. After transplantation one of 12 single lung recipients was placed on a regimen of {1-blocker therapy; no double lung recipients were on this type of therapy. All patients were placed on a regimen of azathioprine, prednisone, cyclosporine, and co-trimoxazole after transplantation.
Study population
Method
Between November 1983 and February 1989,20 patients underwent single lung transplantation at The Toronto General Hospital. From November 1986 to February 1989,15 patients underwent double lung transplantation. Our study group (Table I) consisted of those 12 single lung recipients and nine double lung recipients who had reached l-year follow-up. Fifteen patients were not included in this study because of death within 1 year in eight single lung and in four double lung recipients. Right ventricular dysfunction was not a factor in the death of these patients. The most common causes of death were sepsis,
Radionuclide angiogram acquisition. Supine rest and symptom-limited exercise technetium 99m gated radionuclide angiography studies were conducted with an Elcint 409 AG camera (Elcint, Haifa, Israel). For determination of right ventricular ejection fraction, gated first-pass and equilibrium studies were performed at rest, whereas equilibrium studies alone were used during exercise. The resting first-pass study was acquired after a 500 MBq bolus of 99mTc pertechnetate was injected through a large-bore free-flowing intravenous tube inserted into the brachial vein. Images were acquired in the 30-
Single lung recipients No.
Age (yr) Female/male Diagnosis
Doublelung recipients
12 49 ± 8
9 43 ± 6
4/8 Pulmonary fibrosis (10) Eisenmenger's syndrome (1) a)-Antitrypsin deficiency (I)
5/4 aI-Antitrypsin deficiency (3); emphysema (2) Bronchiolitis obliterans (1) Bronchiectasis (2) Eosinophilic granuloma (1)
FEVt/FVC 118 ± 10 (% predicted)
50 ± 20
FEV1/FVC, Forced expiratory volume in I second/forced vital capacity.
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Ventricular performance after lung transplantation
Number 1 July 1991
1 17
Table II. Response to exercise of singleand double lung transplant recipients Before transplantation
3 mo after transplantation
Single lung Double lung
2.73 ± 1.54 3.0 ± 1.6
*
Single lung Double lung
286.2 ± 96.9 359.5 ± 128.9
t t
1 yr after transplantation
Duration of exercise (min) 3.77 ± 2.0 3.67 ± 2.4
4.1 ± 2.6 3.33 ± 1.7
Six-minute walk distance (m) 555.1 ± 133.5 607.7 ± 74.8
607.8 ± 143.1 629.7 ± 88.1
Values are mean ± standard deviation. for single lung before transplantation t03 months after transplantation. tp < 0.001 for single and double lung groups before transplantation versus 3 months after transplantation.
"n < 0.05
Table III. Summary of intragroup pretransplantation to posttransplantation ejection fraction and blood pressure
responses
Single lung RVEF Rest Exercise LVEF Rest Exercise Blood pressure Rest Systolic Diastolic Exercise Systolic Diastolic
Double lung
Pre
3mo
1 yr
Pre
3mo
1 yr
25 ± 8%* 25 ± 9%
36 ± 12%* 31 ± 14%
33 ± 12% 36 ± 9%
31 ± 5%* 24 ± 3%t
43 ± 11%* 45 ± 12%t
41 ± 10% 45 ± 6%
58 ± 10% 60 ± 5%
56 ± 8% 62 ± 12%
57 ± 5% 63 ± 8%
58 ± 13% 55 ± 9%
65 ± 10% 64 ± 10%
57 ± 12% 63 ± 10%
118 ± 13t 76 ± 11*
135 ± 19t 87 ± 9*
133 ± 15 85 ± 7
122 ± 10 79 ± 8
133 ± 14 82 ± 7
135 ± 7+ 91 ± 11+
144 ± 22* 89 ± 10
162 ± 18* 92 ± 9
161 ± 12 91 ± II
163 ± 14 88 ± 7
146 ± 29 84 ± II
168 ± 21 93 ± 14
*p < 0.05. tp < 0.005. :j:p< 0.05 for pretransplantation versus I-year results.
degree right anterior oblique projection onto a 64 X 64 matrix with an APC 1 high-sensitivity collimator (Elcint). The right and left ventricular equilibrium studies were conducted from the left anterior oblique best septal projection with an APC 3 lowenergy general-purpose collimator at 16 frames per RR interval; 750 MBq of 99mTc pertechnetate was used to label the blood pool after the patient had received pyrophosphate as a reducing agent. Right and left ventricular ejection fractions were measured at rest and during exercise by commercially available semiautomated edge detection software. Phase images were used to isolate the right ventricle from the surrounding atrial structures. Bicycle exercise. The supine bicycle exercise protocol began at a 200 km/rnin workload on an electronically braked exercise table (846T Quinton Instruments, Seattle, Wash.). The workload was increased in increments of 200 km/rnin every 3 minutes as tolerated by the patients. Only data from completed workload stages were used. Patients were encouraged to exercise to their maximum. The heart rate was recorded continuously via electrocardiographic monitoring, whereas the blood pressure was measured at I-minute intervals by an automatic cuff inflator (lnfrasonde D4000, Puritan Bennett, Los Angeles,
Calif.). Studies were acquired 1 to 4 months before lung transplantation and again at 3 months and 12 months after transplantation with the same protocol. Six-minute walk test. Six-minute walk tests were performed on all patlents.? Patients walked a levelmeasured course, and the total distance walked (meters) in 6 minutes was recorded. Patients were allowed to stop as often as required during the test. Statistical analysis. All values are expressed as mean ± standard deviation. Intragroup comparisons were made with the paired Student's t test; intergroup comparisons were made with the unpaired Student's t test. A p value of less than 0.05 was considered significant.
Results Exercise capacity. Most patients required oxygen supplementation for preoperative exercise testing. All postoperativestudieswere conducted without supplemental oxygen. Supine bicycle exercise. Both groups demonstrated an overall increase in exercise duration and workload
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SINGLE LUNG
DOUBLE LUNG
50
10
.to
g I:J
!O
20
10
•r
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j
1
I
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!!.
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J
50
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•
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!
1
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0
_ ! SoD.
0 Pre
:Smw
12mn
12mw
Fig. 2. Exercise right ventricular ejection fraction (EF) before transplantation and at 3 months and I year after transplantation for single and double lung transplant recipients.
SINGLE LUNG
g I:J
DOUBLE WNG
10
10
70
70
10
50
r
r
1 1
1
g
1
I:J
40
10 50
40
!O
_II! S.D.
20 Pre
3m..
12m..
J
I
I
I
I
1
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_ ! SoD.
20 Pre
3m..
12 m-.
Fig. 3. Resting left ventricular ejection fraction (EF) before transplantation and at 3 months and I year after transplantation for single and double lung transplant recipients.
achieved after transplantation (Table II). This was statistically significant only in the single lung group, however. The majority of patients in both groups were able to complete only one stage of exercise (3 minutes at 200 kmJmin) both before and after transplantation. Six-minute walk. Both single and double lung recipients demonstrated a significant improvement in distance walked during the 6-minute exercise test at 3 months after transplantation. This improvement was maintained at 12 months after transplantation (Table 11). First-pass right ventricular ejection fraction. Significant technical limitations were encountered with the first-pass technique used to measure the right ventricular ejection fraction. The technetium trace bolus was of poor quality in more than 50% of the studies, so that data for analysis of the ejection fraction were unreliable. This was probably a result of elevated pulmonary artery pressures and increased resistance to pulmonary blood flow,venous
congestion, right atrial dilatation, and, occasionally, concomitant tricuspid valve regurgitation. Because of these difficulties the results of the first-pass ejection fraction studies are unreliable and are not included in this report. Equilibrium right ventricular ejection fraction Rest study. When the resting right ventricular ejection fraction was determined by the equilibrium method (Fig. 1 and Table III), a significant posttransplantation increase was observed in both the single and double lung groups. No further change was seen in the ejection fraction up to 1 year after transplantation in either group. Exercise study. A similar result was seen with the exercise right ventricular ejection fraction (Fig. 2 and Table III). An increase was seen at 3 months after transplantation in both groups. However, this was of greater magnitude and statistically significant only in the double lung group. Again, the improved ejection fractions are maintained to 1 year, and, in fact, in the single lung group
Volume 102 Number 1 July 1991
Ventricular performance after lung transplantation
DOUBLE LUNG
SINGLE LUNG 110
110
70 110
E ... 50
•1I
...
•I
1
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•1
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1
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......
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30 20
I I9
30
mean! S.D.
20
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_ ! SoD.
p,..
3m_
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Fig. 4. Exercise left ventricular ejection fraction (EF) before transplantation and at 3 months and I year after transplantation for single anddouble lung transplant recipients. SINGLE LUNG 110
110
1110
1110
f
1.co
l
E
E
DOUBLE LUNG
120 100
10
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E
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3ma
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I T
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moll
Fig. 5. Resting systolic blood pressure before transplantation andat 3 months and 1 year after transplantation in single and double lung transplant recipients. NS, Not significant. the trend is for a continued risedespitethe lack of statistical significance (p = 0.06). Left ventricular ejection fraction. The left ventricular ejection fraction at rest and during exercise remained stable throughout the study period in both groups of patients (Figs. 3 and 4 and Table III). Blood pressure Rest. Both groups had an increase in systemic blood pressure after transplantation (Figs. 5 and 6 and Table III). The single lung group demonstratedthis rise early, withsignificantly highersystolic and diastolic pressures at 3 months after transplantation. The higher pressures are sustained to 1 year with no further tendency to increase. The double lung recipients also had a rise in their blood pressure after transplantation that was statistically significant at 1 year after transplantation. Exercise. The exercise blood pressuredata are gener-
ally stable throughout the study (Table III). The only statistically significant difference occursbetween the pretransplantation and 3-month posttransplantation value for the singlelungrecipients. This in fact is not sustained, and the I-year value is not different from the pretransplantation value. Heart rate. The restingand exercise heart rates do not change significantly during the study period in either group (Table IV). If the difference between the peak exercise and restingheart rates (heart rate increasewith exercise) is considered, an interesting difference is observed between the groups. The singlelung recipients have a stable increase in heart rate with exercise at all three study periods. The doublelung recipients, however, havelessof an increasein heart rate with exercise at the 3-monthposttransplantation study (p = 0.06) compared with the single lung recipients. This changes by I year
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DOUBLE LUNG
SINGLE LUNG 110
120
100
110
10 go
:z: E E
80
70 10 50 40
•r 1
1
r
• 1
go
:z: E E
I--p(0.05~ _~S.D.
p,..
10
I
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I--p=NS~
p
50
12 mo.
• 1
•1T
•1
lID
40
3 mo.
I
100
•1
p,..
3m"
_~
12
SJl.
motI
Fig. 6. Resting diastolic blood pressure before transplantation and at 3 months and I year after transplantation in single and double lung recipients.
Table IV. Resting, exercise, and average delta (change from rest to exercise) heart rates (beats/min) data for the pretransplantation and posttransplantation periods* Single lung Pre Heart rate (beats/min) 75 ± 26 Rest Exercise 102 ± 36 Delta 33 ± 14
3 mo 80 ± 28 ± 39 42 ± 13
J 15
I
Double lung J yr 72 ± 25 100 ± 36 35 ± 13 P < 0.005
Pre
3 mo
J yr
89 ± 16 116 ± 10 35 ± 18
94 ± 13 108 ± 18 14 ± 13
85 ± 11 120 ± 10 34 ± 16
I
'Only the }-month posttransplantation change was found to be significantly different between the groups; note that the delta is the average of individual patient deltas and not the difference of exercise minus rest shown on chart.
when the heart rate increase is back to a pretransplantation value. If the amount of change in the heart rate from rest to peak exercise is compared between the two groups (Table IV), there is no difference between the groups except at 3 months after transplantation, when the single lung recipients have a significantly greater increase in heart rate with exercise. Discussion Right ventricular performance has been used as a selection criterion for isolated lung transplantation because of uncertainty regarding the potential for recovery of right heart function despite the anticipated posttransplantation decrease in right heart afterload. In our early experience patients with right ventricular ejection fractions less than 25% were not considered to be candidates for single or double lung transplantation and were usually referred for combined heart-lung transplantation. Because lung transplantation was applied to patients with more impaired right ventricular function, particularly those with pulmonary fibrosis and associated severe pulmonary hypertension, a prompt improvement in the right
ventricular ejection fraction was observed after transplantation. The data presented here demonstrate a sustained improvement in the right ventricular ejection fraction during at least 1 year after lung transplantation. Improvement was seen in both the single and double lung recipient groups, although the exercise data reached statistical significanceonly in the double lung recipients. These data suggest that the magnitude of the cardiovascular hemodynamic response to single versus double lung transplantation may be somewhat different. Within the single lung recipients a variable response was observed, with some patients receiving greater benefit than others in terms of right ventricular functional recovery. The double lung recipients, however, consistently demonstrated a significant improvement in right ventricular function as measured by this technique. Although the right ventricular ejection fraction can be artificially high in the presence of significant tricuspid regurgitation, this did not appear to be a major factor in these patients. The study was not designed to assess formally the degree of tricuspid regurgitation. However,
Volume 102 Number 1 July 1991
only one single lung recipient had clinically apparent tricuspid regurgitation that was confirmed at echocardiographic study. No other patient had tricuspid regurgitation by clinical or echocardiographic assessment. Measuring the right ventricular ejection fraction by the first-pass technique was found to be unreliable in this group of patients because of technical factors. The major problem encountered was breakup of the technetium bolus before it reached the right ventricle. This was due to a combination of pulmonary hypertension, venous congestion, and right atrial enlargement. In some cases tricuspid regurgitation may have been another confounding problem. Obtaining reliable first-pass data for ejection fraction analysis continues to be a challenge in this group of patients. The equilibrium method of assessing right ventricular function appears to be most reliable and useful for serial follow-up. This study was not intended to further investigate the mechanisms that might explain the relative difference observed between the two groups; however, several mechanisms could be operative. A significant correlation between the radionuclide angiographic ejection fraction and mean pulmonary artery pressure and pulmonary vascular resistance has previously been demonstrated. 10-1 2 It is likely that the two groups studied here differ, with a lower pulmonary vascular resistance in the double lung recipients in the postoperative period. Double lung recipients have an essentially normal pulmonary vascular bed as opposed to one diseased (native) and one normal (allograft) vascular bed in the single lung recipients. We 5 have previously reported preferential perfusion of the transplanted lung after a single lung transplantation. This implies that the upper limits of vascular compliance are approached when a single lung must accept the greater portion of the cardiac output. The result is a relative increase in vascular resistance and pulmonary arterial pressure that would be particularly aggravated when cardiac output increases during exercise. This is supported by experimental work in a canine pneumonectomy model that demonstrated significant increases in pulmonary pressure and resistance in the remaining lung.l ' The clinical implication of this relative difference in the recovery of right ventricular performance is that it could impact on decision making in patient selection for either single or double lung transplantation. If severe right ventricular dysfunction exists, a double lung transplant might optimize the likelihood of adequate postoperative right ventricular function. If right ventricular function is better preserved preoperatively, a single lung transplant would be adequate for good postoperative function. Traditional recipient criteria have considered patients with pulmonary fibrosis as candidates for single lung
Ventricular performance after lung transplantation
12 1
transplantation, those with obstructive or septic lung disease candidates for double lung transplantation, and those with pulmonary hypertension for combined heart-lung transplantation. I More recently the Toronto Lung Transplant Group has challenged this and successfully performed single lung transplantation in patients with obstructive lung disease I4 and in patients with severe pulmonary vascular disease.P Unfortunately determination of the lower limit of recoverable right ventricular function by current assessment criteria is impossible. We and others have observed immediate recovery of right ventricular function in patients undergoing single lung transplantation whose preoperative right ventricular ejection fraction was less than 10%. We have also seen severe tricuspid regurgitation disappear immediately after implantation of a single lung graft in a patient with primary pulmonary hypertension. Currently if a patient has severe, unmanageable clinical right ventricular failure, we would not anticipate prompt right ventricular recovery and would recommend combined heart-lung transplantation. We would make the same recommendation for a patient with Eisenmenger's syndrome who has an irreparable cardiac defect. However, it is difficult to be dogmatic about these judgments, made already by ourselves and others, because the total clinical experience and follow-up to date are limited. The impact of severe pulmonary disease on left ventricular function is indirect through ventricular interaction and possibly chronic hypoxia. Because there is no direct hemodynamic burden on the left ventricle, the single and double lung recipients studied had well-preserved left ventricular function before and after transplantation. Systemic systolic and diastolic blood pressures were increased after transplantation in both groups of patients, a result that may be related to the use of cyclosporine. The difference in the heart rate response to exercise can be explained more readily by cardiac denervation as a consequence of removal of both native lungs and sectioning of the trachea in the double lung recipients." Our group has shown that the heart rate response of double lung transplant recipients to autonomic stimuli such as atropine and carotid sinus massage is often that of a denervated heart." Cardiac denervation does not occur in a single lung transplantation procedure because a more limited dissection is possible.!? The response of the double lung recipient is similar to that of the cardiac transplant recipient who also has cardiac denervation.l'' There was no difference in exercise duration or peak workload that would account for the different heart rate responses. It is intriguing that the heart rate response to exercise is
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restored in the double lung recipients by 1 year after transplantation. This suggests the possibility of reinnervation or perhaps adaptation of cardiac receptors. We have recently performed double lung transplantation by using bilateral bronchial anastomoses and bilateral sequential single lung transplantation, rather than the double lung transplantation procedure that we originally described in which we employed a tracheal anastomosis. This may result in less disruption of cardiac innervation and therefore may avoid the effects of cardiac denervation. Definite improvements in exercise tolerance were observed after transplantation in both groups of patients on the 6-minute walk test. Although not a sophisticated test, the 6-minute walk does provide meaningful and reproducible data on the exercise capacity of patients with pulmonary and cardiac diseases.?: 19 The extent to which cardiac performance may continue to limit the exercise capacity of these patients is unknown. In summary, a sustained improvement in right ventricular function occurs after lung transplantation, probably because of an improvement of right ventricular loading conditions. There are alterations in autonomic tone suggesting cardiac denervation in double lung recipients who become attenuated during the first postoperative year. These effects should be considered in assessment and follow-up of transplant candidates. REFERENCES 1. Patterson GA, Cooper JD. Status of lung transplantation. Surg Clin North Am 1988;68:545-58. 2. Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986; 314:1140-5. 3. Patterson GA, Cooper JD, Dark JH, et al. Experimental and clinical double lung transplantation. J THORAC CARD10VASC SURG 1988;95:70-4. 4. Patterson GA, Cooper JD, Goldman B, et al. Technique of successful clinical double-lung transplantation. Ann Thorae Surg 1988;45:626-33. 5. Grossman RF, Frost A, Zamel N, et al. Results of single lung transplantation for bilateral pulmonary fibrosis. N Engl J Med 1990;322:727-33. 6. Cooper JD, Patterson GA, Grossman R, Maurer JR, and The Toronto Lung Transplant Group. Double lung transplant for advanced chronic obstructive lung disease. Am Rev Respir Dis 1989;139:303-7. 7. Barnard D, Albert JS. Right ventricular function in health and disease. Curr Probl CardioI1987;12:417-49. 8. Weber KT, Janicki JS, ShroffSG, LikoffMJ, Sutton MG. The right ventricle: physiologic and pathophysiologic considerations. Crit Care Med 1983;11:323-8.
9. Buttand RJA, Pang J, Gross ER, Woodcock AA, Geddes DM. Two, six and 12 minute walking tests in respiratory disease. Br Med J 1982;284:1607-8. 10. Korr KS, Gandsman EJ, Winkler ML, Shulman RS, Bough EW. Hemodynamic correlates of right ventricular ejection fraction measured with gated radionuclide angiography. Am J CardioI1982;49:71-7. 11. Brent BN, Berger HJ, Matthay RA, Mahler D, Pytlik L, Zaret BL. Physiologic correlates of right ventricular ejection fraction in chronic obstructive pulmonary disease: a combined radionuclide and hemodynamic study. Am J Cardiol 1982;50:255-62. 12. Brent BN, Mahler D, Matthay RA, Berger HJ, Zaret BL. Noninvasive diagnosis of pulmonary arterial hypertension in chronic obstructive pulmonary disease: right ventricular ejection fraction at rest. Am J Cardiol 1984;53:1349-53. 13. Crouch JD, Lucas CL, Keagy BA, Wilcox BR, Ha B. The acute effects of pneumonectomy on pulmonary vascular impedance in the dog. Ann Thorac Surg 1987;43:613-6. 14. Patterson GA, Maurer JR, Williams Tf, Cardoso P, Scavuzzo M, Todd TRJ, and The Toronto Lung Transplant Group. Comparison of outcomes of double and single lung transplantation for obstructive lung disease. J THORAC CARDIOVASC SURG 1991;101:623-32. 15. Fremes SE, Patterson GA, Williams WG, Goldman BS, Todd TR, Maurer J. Single lung transplantation and closure of patent ductus arteriosus for Eisenmenger's syndrome. J THoRAc CARDIOVASC SURG 1990;100:1-5. 16. Schaefers MD, Waxman MB, Patterson GA, Frost AE, Maurer J, Cooper JD. Cardiac innervation after double lung transplantation. J THORAC CARDIOVASC SURG 1990; 99:22-9. 17. Cooper JD, Pearson FG, Patterson GA, et al. Technique of successful lung transplantation in humans. J THORAC CARDIOVASC SURG 1987;93:173-81. 18. Savin WM, Haskell WL, Schroeder JS, et al. Cardiorespiratory responses of cardiac transplant patients to graded, symptom limited exercise. Circulation 1980;62:55-9. 19. Lipkin DP, Scriver AJ, Crake T, Poole-Wilson PA. Six minute walking test for assessing exercise capacity in chronic heart failure. Br Med J 1986;292:653-5.
The Toronto Lung Transplant Group
Surgery: G. A. Patterson, F. G. Pearson, T. L. Winton, M. Goldberg. Pulmonary medicine: J. Maurer, R. Grossman. Cardiology: R. G. Carere, P. P. Liu. Anesthesiology: W. De Majo. Pathology: D. Chamberlain, Psychiatry: J Craven (coordinator), M. Scavuzzo. Discussion Dr. Christian E. A. Cabrol (Paris, France). 1 would like to confirm the observation of Dr. Patterson and his group on the improvement in cardiac performance after isolated lung transplantation in patients with borderline cardiac performance.
Volume 102 Number 1 July 1991
In II double lung transplantations done in the last 3 years, we had four such patients in whom we observed an improvement not only in the right ventricular function because of the decrease of the pretransplantation elevated pulmonary vascular resistance, but also in the left ventricular performance. We observed on the echocardiogram that the change was due to a change in the geometry of the interventricular septum and better filling of the left ventricle because of the increased transverse diameter of the left ventricle. Did you observe such echocardiographic changes, and what was the result of your investigation? Dr. Patterson. We have had some difficulty interpreting our left ventricular echocardiographic data. We have not noticed any difference in postoperative left ventricular volume but have wondered whether there might well be some alteration in that function because of a change in septal geometry that might occur postoperatively. However, we have not made that same observation. Dr. J. Kent Trinkle (San Antonio. Tex.). We have also evaluated right ventricular function after single lung transplantation. We have not performed the double lung operation. The improvement in right ventricular performance seems to be in direct proportion to the decline in pulmonary artery pressure, and, therefore, afterload reduction. We have operated on 6 patients who had systemic level pulmonary artery pressures preoperatively, 3 with primary pulmonary hypertension, and 3 with pulmonary hypertension secondary to pulmonary fibroSIS.
Our first patient, who had primary pulmonary hypertension, was operated on in September of 1989. We did a left single lung transplant. Her x-ray film taken 10days postoperatively showed increased vascular markings to the left lung. The ventilation/ perfusion scan 10 days postoperatively showed that 93% of the
Ventricular performance after lung transplantation
12 3
perfusion was to the transplanted lung. The pulmonary artery pressure had dropped from over 100 to 35 mm Hg systolic at this point, and her right ventricular ejection fraction had doubled. We now do the transplants on the right because it is easier to use the pump-oxygenator with cannulas in the aorta and the right atrial appendage. In a woman who received a right lung transplant 6 weeks ago for primary pulmonary hypertension, there were, again, increased vascular markings. The ventilation/perfusion scan showed 93% perfusion to the transplanted lung 6 weeks postoperatively. The pulmonary artery pressure dropped from systemic levels to 28 mm Hg systolic with a mean of 18. The right ventricular ejection fraction had increased from 27% to 58%. What we are seeing is dramatic afterload reduction of the right ventricle, and probably the improvement in right ventricular ejection fraction is proportional to the drop in pulmonary artery pressure. We have been disappointed that we have not seen much improvement in the left ventricle. I thought that in patients with pulmonary hypertension there would be some improvement just from decreasing the paradoxical septal motion alone, but we have not been able to document that. Dr. Patterson. I am certain that that's correct, that it definitely has to do with immediate and persistent reduction in right ventricular afterload. We have made the same observations in the intensive care unit during the early days postoperatively. We wanted to compare that improvement in right ventricular function over time. We did not do right heart catheterizations in these patients at 3 and 12 months. The studies reported here are noninvasive studies only, but I think these results confirm our long-held suspicion that patients with marked impairment of right ventricular function can successfully undergo isolated lung transplantation.