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J Thorac Cardiovasc Surg 1994;107:1337-1345
© 1994 Mosby, Inc.
CARDIAC AND PULMONARY REPLACEMENT |
Ann Arbor, Mich.
From the Section of Thoracic Surgery,a Department of Surgery, the Department of Radiology,b and the Division of Pulmonary Medicine,c Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Mich.
Address for reprints: Louis A. Brunsting, MD, The University of Michigan Hospitals, Section of Thoracic Surgery, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0344.
Abstract
The primary determinants of pulmonary function after heart-lung or double lung transplantation are the volume and compliance of the recipient's thoracic cage. This study evaluated the influence of recipient chest wall factors on static and dynamic lung volumes after single lung transplantation for chronic obstructive pulmonary disease. Fourteen patients with chronic obstructive pulmonary disease received 15 single lung transplants (one retransplant). Posttransplantation follow-up data at 3 and 6 months, in the absence of infection or rejection, were available in nine patients. Overall pulmonary function at 6 months improved from preoperative levels to 55% to 65% of predicted values (forced vital capacity 38% to 55%, forced expiratory volume at 1 second 18% to 55%, maximum voluntary ventilation 21% to 65%), and allograft-specific pulmonary function improved to nearly normal predicted single-lung values (forced vital capacity 89%, forced expiratory volume at 1 second 90%, maximum voluntary ventilation 105%). Postoperative pulmonary function in these patients correlated significantly with preoperative thoracic volume measured by planimetry of chest radiographs. No correlation between postoperative pulmonary function was demonstrated with either the estimated volume of donated lung tissue or relative donor-to-recipient size matching. These findings support the concept that recipient chest wall factors determine postoperative pulmonary function in patients undergoing single lung transplantation for chronic obstructive pulmonary disease. Furthermore, the allograft lung functions at a normal level for the recipient and does not appear to be constrained by hyperinflation of the contralateral lung. (J THORACCARDIOVASCSURG1994;107:1337-45)
In the absence of rejection or infection, the primary determinants of pulmonary function after either heart-lung 
1-3 or double lung 4 transplantation are the volume and compliance of the recipient's thoracic cage. This relationship forms the basis for a mild, persistent restrictive pulmonary defect that is observed in these patients, independent of the size of the donor lungs 2 and not related to any abnormality of the elastic properties of the allograft parenchyma. 5
Although single lung transplantation (SLT) has become standard therapy for patients with end-stage pulmonary fibrosis, 6-8 controversy exists regarding the application of this procedure versus double lung transplantation for patients with chronic obstructive pulmonary disease (COPD). 9-14 In SLT, the pulmonary allograft shares the thorax with the hyperinflated native lung, engendering concern that the native lung will "crowd out" the allograft. 9,10 Though the current literature supports SLTas a feasible therapeutic option for end-stage COPD, 11-14 little data exist examining the role of chest wall factors in determining posttransplantation function in this population. Furthermore, the effect of interaction between native lung and pulmonary allograft on the pulmonary function of the allograft in patients with COPD is poorly understood. Therefore, the purpose of this study was to evaluate posttransplantation pulmonary function in patients receiving SLT for COPD, with emphasis on static and dynamic lung volumes and allograft-specific pulmonary function.
PATIENTS AND METHODS
From November 1990 to June 1993, 42 patients have undergone 44 pulmonary transplant procedures at the University of Michigan. Isolated SLT for COPD was done 15 times in 14 patients (one retransplant for primary graft dysfunction). Modified Euro-Collins solution with prostaglandin E1 was used for organ preservation. Ischemic time averaged 191 minutes (range 160 to 234 minutes). Immunosuppression consisted of steroids (500 mg intravenous methylprednisolone intraoperatively, followed by a taper and long-term maintenance at 5 to 20 mg daily; cyclosporine (2.5 to 5 mg preoperatively, 3 mg/hr intravenously after operation, then orally to maintain serum levels of 200 to 300 ng/ml); and azathioprine (2 mg/kg daily starting the night after transplantation). No cytolytic induction therapy was used. At regular intervals after transplantation, patients underwent complete pulmonary function testing and quantitative ventilation-perfusion scanning. Nine patients had complete data from these studies at 3 and 6 months after transplantation and form the basis of this report. Reasons for exclusion were as follows: one patient underwent transplantation recently with insufficient follow-up for inclusion, one patient died at 3 months of Pneumocystis carinii infection, and three patients (including the one who underwent retransplantation) had persistent infections (two of these died and one survived after prolonged independent ventilation of the native and allograft lungs).
Pulmonary function testing was done in the clinical laboratory at the University of Michigan. Spirometry was done with the use of a calibrated pneumotachograph (Medical Graphics Co., St. Paul, Minn.). Lung volumes were measured in a whole-body plethysmograph by the technique of Dubois and associates. 15 Total lung capacity (TLC; in liters), forced vital capacity (FVC; in liters), forced expiratory volume at 1 second (FEV1; in liters), and maximum voluntary ventilation (MVV; in liters per minute) were examined for this report. Quantitative ventilation-perfusion scans were done with a gamma scintillation camera with a low-energy, all-purpose collimator using a 20% window centered on the 140 keV photo peak after inhalation of a small amount of aerosolized technetium 99m–diethylenetriaminepentaacetic acid from a reservoir containing 50 mCi and subsequent intravenous injection of 5 mCi 99mTc-macroaggregated albumin. Multiple views were obtained for each tracer and quantitated after correction for the contribution of 99mTc-diethylenetriaminepentaacetic acid to theperfusion images. 16
Measured pulmonary function values were corrected to reflect the contribution of the transplanted lung by multiplying the total values by the fractional ventilation of the transplanted lung as derived by the quantitative ventilation-perfusion scans. Standard equations were used to calculate predicted values for TLC, 17,18 FVC, 17 FEV1, 17 and MVV 19 for both the donor and recipient. These were reduced by 15% for nonwhite patients and corrected to single-lung values using a factor of 0.45 for left lungs and 0.55 for right lungs. Preoperative pulmonary function results for the recipient were corrected with the same factor. Recipient TLC was estimated from preoperative upright radiographs using planimetry. 20
Significant differences between measurements were identified by paired t test or one-way analysis of variance for repeated measures, as appropriate, with localization of analysis of variance differences by Scheffe's method. Correlation between posttransplantation dynamic lung volumes and preoperative measurements of donor or recipient static lung volumes or donor-to-recipient size matching was identified by linear regression analysis. Statistical significance was defined as a p value of 0.05 or less.
RESULTS
Donor and recipient physical characteristics are shown in Table I. Donors were significantly younger and heavier than recipients. Table II contains TLC data for comparison of donor-to-recipient lung size matching. There was no statistical difference between donor predicted and either recipient predicted or actual preoperative values.
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Table III. FEV1 and MVV demonstrated significant improvement at 3 and 6 months. Overall FVC went from 38% of predicted before operation to 58% and 55% at 3 and 6 months, respectively, whereas overall TLC decreased slightly from 139% of predicted before operation to 117% and 110% at 3 and 6 months, respectively. These changes were not statistically significant. The mean values for FVC, FEV1, and MVV at 6 months ranged from 55% to 65% of predicted values for the recipient, representing significant limitation of overall pulmonary function. In contrast, the function of the transplanted lung (Table IV) demonstrated significant improvement in FVC, FEV1, and MVV from preoperative values. Allograft-specific pulmonary function at 6 months closely approximated that predicted for the recipient on the basis of age, sex, and height. Fig. 2 summarizes both overall and allograft-specific pulmonary function results as a percent of predicted normal for the recipient.
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Studies of heart-lung transplant recipients demonstrate an early decrease in lung volumes after transplantation, with increase to and stabilization at volumes approximating pretransplantation values at 6 to 12 months, regardless of the size of the donor lungs. 1-4 The early decrease in lung volumes is attributable to the effects of the surgical incision on chest wall mechanics, with a time course of resolution between 3 and 6 months. 21-23 The persistent restrictive pattern has been shown by Glanville and associates 5 to be due to recipient chest wall volume constraints and impaired chest wall mechanics, rather than a loss of intrinsic elastic properties of the allograft parenchyma.
Patients undergoing SLT for COPD have a severe obstructive pattern and elevated static lung volumes on preoperative pulmonary function testing. This is in distinct contrast to findings in patients with a pulmonary vascular disease, who have a mild restrictive defect and constitute the majority of heart-lung transplant recipients, and in patients with pulmonary fibrosis, who also undergo SLT but have severe restriction and reduced static lung volumes on preoperative pulmonary function testing. Though posttransplantation pulmonary function is largely determined by recipient chest wall characteristics in these two other lung transplant populations, 1-4 this relationship has not been previously examined in patients receiving SLT for COPD.
Posttransplantation pulmonary function, in the absence of infection or rejection, is the result of interaction between recipient chest wall factors (volume, compliance, and muscle conditioning) and the combination of allograft and native lung parenchymal factors (volume, compliance, and airway mechanics). In this study, posttransplantation dynamic lung volumes correlated significantly with preoperative recipient thoracic volume (TLC by planimetry), supporting the concept that recipient chest wall factors play a defining role in posttransplantation pulmonary function in this population of patients, as well. Though chest wall mechanics clearly play a role in determining overall postoperative lung volumes, the degree of influence of parenchymal factors remains uncertain. If overall thoracic volume remains constant, the influence of parenchymal factors should be reflected by a positive correlation between postoperative allograft-specific dynamic pulmonary function and either the volume of lung tissue donated or the relative size matching between donor and recipient. In the current study, no such correlations were observed, and overall postoperative thoracic volume was not statistically different from preoperative volume. Thus, similar to the result in patients undergoing heart-lung transplantation or SLT for pulmonary fibrosis, recipient chest wall factors appear to outweigh parenchymal factors in determining posttransplantation pulmonary function in patients undergoing SLT for COPD.
The interaction between native and allograft lungs represents a confounding factor in determining postoperative function of the allograft in SLT. In patients with COPD, the difference in compliance between the hyperinflated native lung and the pulmonary allograft favors expansion of the native lung, raising concern that the native lung will "crowd out" the allograft. 9,10 In this study, allograft lungs received approximately 80% of overall ventilation and perfusion at 3 and 6 months, with excellent ventilation-perfusion matching. These findings are consistent with published data 13 and provide the first line of evidence that hyperinflation of the native lung does not hinder allograft function in these patients. Preferential ventilation of the allograft in patients with COPD reflects persistent obstruction to air flow and loss of functional parenchyma in the native lung, despite the compliance mismatch favoring expansion of the native lung. Preferential perfusion of the allograft results from loss of parenchyma and gas exchange surface in the native lung and elevated pulmonary vascular resistance in the native lung. Whether this increased native pulmonary vascular resistance is a static factor or whether autoregulation occurs to optimize ventilation-perfusion matching between the innervated native lung and the denervated allograft is unknown.
Examination of allograft-specific pulmonary function after SLT for COPD demonstrates significant improvement with respect to preoperative function. Allograft-specific dynamic lung volumes (FVC, FEV1, and MVV) at 3 and 6 months approximate normal predicted single-lung values for the recipient, providing the second line of evidence that allograft function is not hampered by overinflation of the native lung in these patients. It is interesting that patients receiving SLT for both COPD and pulmonary fibrosis* achieve nearly identical levels of allograft-specific pulmonary function at 6 months, despite diametrically opposed chest wall and contralateral lung physiologic conditions.
The technique of using differential ventilation scanning during tidal breathing to correct overall spirometric values obtained during a forced expiratory maneuver may introduce error in the calculation of allograft-specific pulmonary function. Greater dynamic bronchial compression in the native, diseased lung during the first second of a forced maneuver probably results in a disproportionately high flow from the allograft and a falsely low value of allograft-specific FEV1. MVV is heavily dependent on early-phase expiratory flow, 24 so allograft-specific values of MVV may also be falsely low. Although the native lung contributes disproportionately during the terminal phase of such a maneuver, allograft-specific vital capacity represents the sum of both early and late phases and is therefore less likely to be affected by such factors. However, we do not believe potential error introduced by this technique affects our conclusions. First, the native lung contributes only 20% of overall ventilation. Therefore the magnitude of potential error in FEV1 and MVV is upwardly bounded by this figure and is more likely 10% or less. Second, our measurements of allograft-specific FEV1 and MVV approximate 100% of predicted normal values for the recipient. If these values are an underestimation, the true values would be even higher. Finally, the relative uniformity in the severity of disease in the native lung of all recipients would tend to minimize the effect of any introduced error on regression analyses.
It is also important to emphasize that the data presented in this study were obtained in the absence of detectable infection or rejection, in an attempt to address the relative contribution of chest wall versus parenchymal factors. Though these data help elucidate the physiologic basis for the observed clinical benefit of SLT for COPD in many patients, 14 caution should be used in interpreting these results when the relative benefits of SLT versus double lung transplantation is considered for patients with COPD. Both infection and rejection cause decreased allograft compliance, which results in decreased allograft ventilation and significant ventilation-perfusion mismatch in patients with SLT. 25 This may be clinically more significant for patients receiving SLT for COPD rather than for pulmonary fibrosis, because of the discrepancy between the compliance of the native lung in the two disease processes. Patients undergoing double lung transplantation for COPD may have reduced pulmonary compliance with infection or rejection, but do not undergo similar changes in ventilation-perfusion matching and have more ventilatory reserve than patients with SLT. 12
Long-term pulmonary function in SLT for COPD remains to be defined. Little data beyond 6 months after transplantation exist in the literature, and allograft-specific function has not been reported beyond that time period.
In summary, chest wall volume and mechanics are important determinants of posttransplantation pulmonary function in patients undergoing SLT for COPD, outweighing pulmonary parenchymal factors. Furthermore, the balance of mechanical effects from the pulmonary allograft, the native lung, and the recipient chest wall results in allograft-specific function that approximates normal predicted single-lung values for the recipient.
Appendix: DISCUSSION
Dr. Frederick L. Grover (Denver, Colo.).
Dr. Brunsting and his associates are to be congratulated for a careful study evaluating the influence of recipient chest wall factors on static and dynamic lung volumes after SLT for patients with end-stage emphysema. As noted, the authors found that approximately 80% of both the perfusion and ventilation went to the transplanted lung with excellent ventilation-perfusion matching. The functional vital capacity increased from 38% of predicted to 58%. TLC decreased from 139% to 117% and the mean values for FVC, FEV1, and MVV at 6 months increased to the 55% to 65% range.
When the function of the transplanted lung was determined, that is, the transplanted lung itself, there was a significant improvement in the FVC, FEV1, and MVV values from preoperative values to about 100% of predicted. Indeed the specific pulmonary function of the allograft at 6 months closely approximately that predicted for the recipient on the basis of the recipient's age, sex, and height.
In addition, the authors have demonstrated by regression analysis a significant correlation between the recipient's preoperative thoracic volume measured by the planimetry method and postoperative dynamic lung volumes. They did not find a significant correlation, and this is an important point, between postoperative pulmonary function and the predicted volume of the donated lung tissue or the relative size matching between donor and recipient.
Before 1989, there was a great deal of concern about doing SLT for obstructive pulmonary disease because of the fear of compression of the transplanted lung by the hyperinflated native lung and the belief that this would cause ventilation-perfusion mismatch and a poor clinical result. Dr. Brunsting's study has definitely demonstrated that this is not the case and this supports numerous other studies including those of the St. Louis group, which noted an increased value of FEV1 from approximately 18% to 45% postoperatively, and my former group in San Antonio, which reported very similar ventilation-perfusion data to that in the present paper, as well as similar FEV1 and FVC data.
Our results in Denver for our first six patients who underwent SLT for COPD, four on the right side and two on the left side, reveal an increase in the FEV1 from 0.52 to 1.53 L and the FVC from 1.72 to 2.55 L in a reduction of the TLC from 8.27 L to 6.47 L, again very similar to these current data. We have not calculated, however, the relative contribution of the transplanted lung itself.
The Toronto and St. Louis groups investigated the relationships of lung transplant recipients' posttransplantation vital capacity to recipients' predicted normal vital capacity and the donors' predicted normal vital capacity much as Dr. Brunsting's group has done. I think the importance of the data today is that most of the other data were related to patients with pulmonary fibrosis, a restrictive group, whereas Dr. Brunsting's group is addressing in particular the group of patients with COPD.
One question that frequently arises in patients undergoing SLT for COPD is whether there is any difference in the postoperative function in patients who have undergone right versus left SLT, and indeed my colleague Dr. Trinkle in San Antonio has thought that the right side is preferable to the left. Although their data show an increase in pulmonary function in that area, right versus left, when the absolute values are evaluated, they are not statistically significant.
I reviewed the data for right versus left SLT in the current paper and noted, however, that the overall FEV1 at 6 months was 66% of predicted for right lungs versus 47% for left lungs and the functional vital capacity was 70% for the right versus 44% for the left. The allograft 6-month postoperative FEV1 was 96% of predicted on the right side versus 84% on the left, and the FVC was 101% on the right side versus 80% on the left, which suggests some advantage of right over left. I also looked again at the data as the investigators did in detail to see if the large-size donor lung correlated at all with this, and it did not.
I therefore have a few questions for you. First, have you analyzed your data for right versus left lung? If so, does the right offer better long-term function or are these numbers too small to make such a conclusion at this time?
Dr. Brunsting.
Dr. Grover, it is a pleasure to have you comment on this paper at this meeting. We all recognize your pioneering work at San Antonio with Dr. Trinkle in using SLT for this disease.
With regard to your first question, we have not specifically analyzed right versus left lung, that is, four versus five cases, and I appreciate your doing that for me. Certainly from the numbers you presented, it looks like there may be a trend and perhaps if we are able to increase the number of patients to analyze, we may be able to make a statement about that. I think the numbers are probably too small at this point.
Dr. Grover.
The second question is that your conclusion that the recipient chest wall factors determine postoperative pulmonary function is based on a group of nine patients in whom the height and the weight of the donor exceeded that of the recipient. Would these findings hold true if there was a significant undersizing of the donor lung? Or could one then expect lung parenchymal factors to play a greater role than that of the recipient chest wall factors?
Dr. Brunsting.
That is possible. The number of patients is small. However, two out of the nine patients included in the regression received significantly undersized grafts with the ratio of donor-to-recipient estimated values of 87%.
Dr. Grover.
As a technical consideration, because the hyperexpanded lung frequently extends at least somewhat across the midline in the native lung, how did you correct for this in your ventilation-perfusion scanning to be sure that you were looking at right lung versus left?
Dr. Brunsting.
It was done by analysis of the images. There is no specific set technique for doing that other than to look at the images and to manually quantify where the right lung is and where the left lung is on the images.
Dr. Grover.
My last question is this: On the basis of this study and your clinical experience, what criteria are used at the University of Michigan for selecting donors for SLT for emphysema?
Dr. Brunsting.
The question of using SLT versus double lung transplantation for COPD is quite interesting. As we have discussed previously, I do not think anyone has a final answer at this time. Caution should be exercised in viewing these data as wholehearted support for SLT in this disease. These data were collected in the absence of rejection and infection, and therefore represent the physiologic situation at the "best of times." Our clinical observation has been that patients who receive SLT versus double lung transplantation for COPD have less physiologic reserve when they become ill. When either infection or rejection develops, the relative compliance of the transplant versus native lung decreases further, and you can see hyperinflation of the native lung during that time.
Our current practice is to use SLT for older patients with less physiologic anticipated recovery. In younger patients who have been more active up until the time of their disease, we have been using double lung transplantation. The St. Louis group has presented higher 1-year actuarial survival in their SLT group than in their double lung transplant group. That has not been our impression. So far, in our SLT group we have had three deaths in 14 patients, and in our double lung transplant group for COPD we have had no mortality in 10 patients.
Footnotes
Read at the Nineteenth Annual Meeting of The Western Thoracic Surgical Association, Carlsbad, Calif., June 23-26, 1993. 
*Brunsting LA, Lupinetti FM, Cascade PN, et al. Pulmonary function in single lung transplantationfor pulmonary fibrosis (unpublished data).
*Brunsting LA, Lupinetti FM, Cascade PN, et al. Pulmonary function in single lung transplantationfor pulmonary fibrosis (unpublished data).
References
This article has been cited by other articles:
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 S. H. Loring, S. J. Mentzer, and J. J. Reilly Sources of graft restriction after single lung transplantation for emphysema J. Thorac. Cardiovasc. Surg., July 1, 2007; 134(1): 204 - 209. [Abstract] [Full Text] [PDF]
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Contralateral Pneumonectomy After Single-Lung Transplantation for Emphysema Ann. Thorac. Surg., April 1, 1996; 61(4): 1286 - 1287. [Full Text]
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– 0.712; r = 0.777; p = 0.0001. B, FEV1 (y = 0.531