INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Normal left ventricular function is generally a mandatory selection criterion in patients considered for single- or double-lung transplantation. Among the different methods used to evaluate left ventricular function, radionuclide angiography is considered an effective means for assessing left heart systolic function. Although left heart systolic function is expected to be normal at rest in patients with severe chronic respiratory failure (1), we observed that in some patients who underwent lung transplantation in our center, preoperative left ventricular ejection fraction (LVEF) as measured with radionuclide angiocardiography was surprisingly below the normal range despite apparently preserved left ventricular contractile function as shown by echocardiography. By reevaluating left ventricular systolic function at some time after transplantation in patients with low LVEF, we attempted to determine whether reducing right ventricular afterload by successful lung transplantation would modify the value of isotopically measured LVEF.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Patients

From March 1988 to January 1995, 72 patients underwent lung transplantation (single- or double-lung procedure) in our center. During the preoperative patient-selection procedure, these patients had a thorough hemodynamic evaluation performed systematically in order to determine the level of their pulmonary hypertension and to exclude left ventricular systolic dysfunction. In each patient, the hemodynamic evaluation consisted of right heart catheterization, transthoracic two-dimensional echocardiography, and radionuclide angiographic assessment of LVEF. Left ventricular systolic dysfunction was excluded on the basis of a combination of: (1) the absence of wall-motion abnormalities, except for septal motion when pulmonary hypertension was present; and (2) apparently normal contractile function as shown by echocardiography, even if the value of isotopically measured LVEF was below the normal range. Coronary angiography was not routinely performed. Coronary artery disease was excluded on the basis of medical history, a standard electrocardiogram, and on absence of regional wall-motion abnormalities (hypokinesis, akinesis, or dyskinesis) on echocardiography or radionuclide angiography. Coronary angiography was performed only once, in a symptomless but quite aged (67 yr) patient. It did not disclose significant coronary lesions.

Postoperative Hemodynamic Assessment

A noninvasive evaluation of left ventricular systolic function was done prospectively between February and June 1995, at some time after the transplantation procedure. Patients with a low preoperative value ( 55%) for isotopic LVEF underwent two-dimensional transthoracic echocardiography and isotopic LVEF measurement postoperatively, and their results were compared with those of the preoperative evaluation. At the time of postoperative evaluation, all patients were clinically well and had no evidence of bronchiolitis obliterans syndrome or any other complication.

Radionuclide Ventriculography

Left ventricular ejection fraction was assessed by radionuclide angiocardiography, the patients being in all cases in sinus rhythm. Data acquisition was done with an SMV Gammatome II camera (Sopha Medical Vision, Buc, France) fitted with a high-resolution, parallel-hole collimator. Thirty minutes after intravenous administration of stannous pyrophosphate, red blood cells were labeled in vivo by injecting a bolus of 20 to 30 mCi of ^99mTc-pertechnetate into a brachial vein. During this first-pass study, the camera was in the 45-degree right anterior oblique position. Following this, a gated equilibrium study (16 frames/cycle, 64 × 64 pixels, with a 10 to 15% R-R interval acceptance window) was done with the patient in the left anterior oblique position, the angle of which was chosen to achieve a precise separation of the ventricular septum. A craniocaudal tilt was added in some cases. The study was stopped when an average of 300 kilocounts per frame were collected, resulting in an examination time of 10 to 20 min.

Data were processed by the standard SMV XT software. The first-pass study was used to assess the motion of the anterior and posterior walls and apex of the left ventricle. LVEF = end-diastolic volume (EDV)  end-systolic volume (ESV)/EDV = 1  ESV/EDV (EQUATION 1) was estimated from the equilibrium study with the formula:

(1)

where EDC = end-diastolic counts, EDBC = end-diastolic background counts, ESC = end-systolic counts, ESBC = end-systolic background counts. Background counts were obtained by multiplying the average background counts per pixel by the total number of ED or ES pixels. Boundaries of the left ventricle in the diastolic and in the systolic frames were automatically detected. The background correction region was automatically located adjacent to the apicolateral sector in the end-diastolic frame (6). Manual adjustments were possible but rarely needed. Automated techniques are now used for radionuclide angiographic measurement of LVEF. The normal values of LVEF depend on the program used (7, 8). Thus, the LVEF criteria for normality have to be determined on a local basis. The normal value of radionuclide angiographic LVEF used in our laboratory has been obtained in a population of 20 patients who had no history of cardiac disease, a normal cardiovascular examination, and a normal electrocardiogram. For each patient in our study, LVEF was determined with the same program pre- and postoperatively.

With the settings described previously, the normal values of LVEF in our laboratory are in the range of 68 ± 8%, and a variation of 5 EF units for a given patient is considered significant.

Echocardiography

Preoperative and postoperative echocardiographic examinations were performed with commercially available systems (Vingmed CFM 700, [Vingmed, Horten, Norway], Ultramark 4 ATL [Bellevue, WA], Sonos 1500 Hewlett-Packard [Andover, MA]), using a 2-MHz or a 2.5-MHz transducer. Examinations of left and right ventricles were made with parasternal long-axis, parasternal short-axis, apical four-chamber, apical two-chamber, and subcostal views. Measurements of left ventricular end-diastolic diameter and end-systolic diameter were obtained from parasternal long axis views as often as possible, or from subcostal views. Abnormalities of left ventricular wall motion were noted.

Statistical Analysis

The data presented are mean ± SD. A paired t test was used to compare the pre- and postoperative values of isotopic LVEF, left ventricular end-systolic diameter, and left ventricular end-diastolic diameter. An unpaired t test was used to compare preoperative values of LVEF, pulmonary artery pressure (Ppa), pulmonary artery occlusion pressure (Ppao), cardiac index (CI) in patients with and without a low preoperative LVEF. Statistical significance was taken as p < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Of the 72 patients in the study, a low value ( 55%) of isotopic LVEF was found in retrospect in 28 (39%). The distribution of isotopic LVEF in the 72 patients is shown in Figure 1. The underlying diseases in these 28 patients were pulmonary fibrosis (n = 8), obstructive lung disease (n = 17), and primary pulmonary hypertension (PPH) (n = 3). Of the 28 patients with a low LVEF, 15 had died following transplantation at the time of the study (January 1995) from noncardiac causes, and 13 were still alive. The causes of death in the 15 patients with low preoperative LVEF values were massive hemoptysis at 8 mo after transplantation, as a result of a transbronchial biopsy (n = 1); massive hemoptysis at 6 mo after transplantation as a result of lymphoma (n = 1); intracerebral hemorrhage at 12 mo after transplantation (n = 1); multiple organ failure due to acute pancreatitis at 18 d after transplantation (n = 1); intracerebral hemorrhage at 8 mo after transplantation (n = 1); peroperative alveolar hemorrhage due to vascular malformation in the donor (n = 1); septic shock (Staphylococcus aureus bacteremia) at 17 d after transplantation (n = 1); hemodynamic failure and severe reimplantation edema occurring within the first postoperative week and attributed to lung ischemia/reperfusion injury (n = 3); bacterial pneumonia and pulmonary embolism at 17 mo after transplantation (n = 1); septic shock (invasive aspergillosis) at 6 mo after transplantation (n = 1); hematophagic histiocytosis and subsequent intracerebral hemorrhage at 7 mo after transplantation (n = 1); septic shock (Pseudomonas aeruginosa pneumonia) at 2 mo after transplantation (n = 1); and status epilepticus at 2 mo after transplantation (n = 1). Among the 13 patients who were still alive at the time of the study, a postoperative hemodynamic evaluation could be performed in only 11, since two patients were living abroad. These 11 patients constituted the basis of the study. Their clinical characteristics are given in Table 1. Their mean age was 47 ± 7 yr (range: 30 to 67 yr) at the time of transplantation. The underlying diseases in these 11 patients were idiopathic pulmonary fibrosis (n = 4), panlobular emphysema (n = 6), and bilateral bronchiectasis (n = 1). Blood gas values and pulmonary function test results for the seven patients with obstructive disease and the four patients with restrictive disease are shown in Table 2. The transplantation procedure was a single-lung transplantation in 10 patients and a bilateral single-lung transplantation in one.

View larger version (10K): [in this window] [in a new window]   Figure 1.   Distribution of preoperative LVEF values in 72 patients who subsequently underwent transplantation. Among these patients, a low value (< 55%) of LVEF was found in 28 (39%).

Preoperatively, the average value of the mean aortic pressure () was 84 ± 12 mm Hg, the mean heart rate (HR) value was 82 ± 14 beats/min, and the mean value of isotopic LVEF was 51 ± 3% (range: 49% to 55%). On echocardiographic assessment, right ventricular dilation was noted in all but one patient (Patient 5). The overall mean left ventricular end-diastolic diameter for the group was 45 ± 4.5 mm (range: 38 to 51 mm), mean left ventricular end-systolic diameter was 31 ± 4 mm (range: 21 to 33 mm), and the mean echocardiographic LVEF was 57 ± 7.5%. No abnormality in segmental motion was observed except for the septum: a leftward displacement in septal motion was observed in seven patients. On right-sided catheterization, mean values of pulmonary artery pressure (), Ppao, and CI were 29 ± 6 mm Hg, 13 ± 4 mm Hg, and 3.3 ± 0.5 L/min/m², respectively. The individual preoperative data for the 11 patients are shown in Tables 3 and 4. By comparison, in the group of patients without low preoperative LVEF values, mean values of LVEF, , Ppao, and CI index were 66 ± 7% (p < 0.0001), 32 ± 13 mm Hg (p = NS), 12 ± 5 mm Hg (p = NS), and 3.2 ± 0.7 L/min/m² (p = NS), respectively.

The postoperative evaluation was performed 42 ± 13 mo (range: 24 to 64 mo) after the transplantation procedure. The average was 100 ± 10 mm Hg and the average mean heart rate was 88 ± 18 beats/min. As shown in Table 3, the mean value of isotopic LVEF increased significantly after transplantation, from 51 ± 3% to 65 ± 10% (p = 0.001), and individual values for LVEF fell within the normal range in eight patients. On echocardiography, a persistent right ventricular dilation (moderate) was observed only in two patients (Patients 5 and 11). As compared with preoperative values, mean left ventricular-end diastolic diameter increased significantly (p = 0.003) after surgery, to 51 ± 6 mm (range: 42 to 60 mm Hg). By contrast, mean left ventricular end-systolic diameter was 31 ± 4 mm (range: 26 to 37 mm) (i.e., not significantly different from preoperative values). Echocardiographic LVEF increased significantly, from 57 ± 7.5% to 67 ± 6%. No wall abnormality was observed except for a leftward displacement in septal motion, which continued to be noted in two patients.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The salient features of our study were: (1) the presence of a low preoperative LVEF in up to 40% of our patients who subsequently underwent transplantation; (2) a significant improvement in LVEF in most of the patients who were evaluated after transplantation.

Advanced chronic respiratory failure is characterized by a chronic right ventricular pressure overload that adversely affects right ventricular systolic function (9). Whether left ventricular function is normal or depressed in this condition is a controversial issue. Left ventricular hypertrophy is observed at autopsy in up to 30% of patients with chronic obstructive pulmonary disease (COPD) (10), and has also been described at echocardiography (2). Diastolic dysfunction of the left ventricular chamber has been well documented (1, 11), but the presence of systolic dysfunction is still debated. Several studies have shown that left ventricular systolic function at rest, as measured with radionuclide ventriculography, angiography, electron-beam computed tomography (CT), or echocardiography is within normal limits in most patients with stable COPD (1, 14, 15) and in patients with pulmonary artery hypertension (11, 13, 16). On the other hand, in COPD patients, the analysis of individual data in different studies indicates that a reduced radionuclide LVEF at rest is not unusual (14, 15, 17). Such a low LVEF was also noted in a case of chronic right ventricular pressure overload due to an isolated valvular pulmonic stenosis (18). In a recent study (19), Nordegraaf and colleagues measured LVEF by means of magnetic resonance imaging (MRI) in 10 emphysematous patients and in 10 age-matched control subjects, and found that the patients had significantly lower LVEF values (54 ± 7%) than did the control subjects (63 ± 7%). In their large series, Vizza and coworkers recently reported that a low LVEF was found in 3.8% of 158 COPD patients evaluated for lung transplantation. The threshold for considering LVEF abnormal was 45% (i.e., much lower than in our study) (20). During exercise, conflicting data have been reported, with some studies showing a normal increase in LVEF (21, 22) in patients with chronic pulmonary disease and others demonstrating an abnormal response (11, 15). Several factors have been proposed to account for the left ventricular systolic dysfunction observed in some patients, including intrinsic alteration in left ventricular muscle as a result of associated coronary artery disease, hypoxemia, a decrease in pleural pressure, and geometric distortion due to the bulging of the interventricular septum into the left ventricular cavity (10).

The preoperative data in the present study show that a moderately reduced LVEF is not unusual in patients with advanced chronic lung failure, thus confirming the results obtained by other authors using varying techniques to measure LVEF. The additional information provided by our study is that these low LVEF values are most often unrelated to a decreased intrinsic left ventricular contractility. The significant improvement in LVEF observed in most of our patients after transplantation does not support the hypothesis of an intrinsic alteration of the contractile properties of the left ventricle, but rather suggests that geometric distortion of the left ventricle played a major role in the low LVEF values that we observed. The same conclusion was drawn in the study by Vizza and coworkers (20), where LVEF increased postoperatively in the subset of patients with low LVEF who underwent lung transplantation. In patients with advanced chronic respiratory failure, chronic right ventricular pressure overload results in bulging of the interventricular septum into the left ventricle and in subsequent reduction in left ventricular end-diastolic and end-systolic volume (1, 2, 12, 13, 15, 23). In order to maintain LVEF, end-diastolic and end-systolic volume should decrease in the same proportion. If the end-diastolic volume of the left ventricle decreases in a greater proportion than its end-systolic volume, the result would be a reduced LVEF (EQUATION 1). This latter phenomenon is probably present in patients with end-stage lung diseases, since several authors have shown that such patients' left ventricular end-diastolic volume was proportionately more decreased than their left ventricular end-systolic volume (2, 23, 24, 25).

Successful lung transplantation leads to a reduction of pulmonary artery pressure, to a normalization of right ventricular volume and in turn to an expansion of left ventricular end-diastolic volume, and to an increase in LVEF. In a recent study, Rensing and associates (25) investigated 17 patients who underwent single lung transplantation for end-stage emphysema (preoperative : 31 ± 6.7 mm Hg). They evaluated right and left ventricular function both pre- and postoperatively with electron-beam CT. After surgery, right ventricular end-systolic volume decreased significantly (this change being paralleled by a decrease in pulmonary pressure), and left ventricular end-diastolic volume increased significantly (+25%) as did also left ventricular stroke volume (+29%). Left ventricular end-systolic volume also increased, but to a lesser extent (nonsignificantly). This was also the case in our study, in which postoperative echocardiographic measurements showed that, as compared with their values at preoperative examination, mean left ventricular end-diastolic diameter increased much more than did mean end-systolic diameter. Thus, in eight of our patients, interaction of the right and left ventricles may explain the low preoperative LVEF and its increase after transplantation. It is noteworthy that right-sided pressures obtained in patients who had a preoperative LVEF within normal range were similar to those of our 11 patients. One could hypothesize that the consequence of a similar degree of right ventricular afterload on the left ventricle may vary from one patient to another.

Our results illustrate a common misconception of the meaning of LVEF. The latter should not be considered a precise index of the contractile function of the left ventricular muscle, since it is highly dependent on loading conditions and on the process of left ventricular remodeling (26, 27). Whether a true intrinsic dysfunction existed in our three patients who did not show an improvement in LVEF after transplantation surgery is a matter of debate. In particular, the case of Patients 4 and 8 is disconcerting. These patients had a low preoperative LVEF, and this was still the case at follow-up, despite the absence of right ventricular dilation. The explanation for the failure of their LVEF to improve is not simple, and several hypotheses could be proposed for it, including that: (1) these two patients in fact had left ventricular dysfunction despite apparently normal left ventricular contraction at echocardiographic examination; (2) the extent of postoperative remodeling of the left ventricle may vary among patients after reduction of right ventricular afterload; and (3) other, unknown mechanisms than ventricular interdependence may explain preoperative remodeling of the left ventricle.

Because preoperative arterial blood gas values in our study demonstrated fairly severe hypoxemia in all patients and substantial hypercapnia in many, we must consider the possibility that this degree of derangement in gas exchange may produce a depression in left ventricular function that is reversible upon improvement in gas exchange after transplantation. For the purpose of describing the severity of the patients, preoperative blood gas values are presented in Table 2 for patients with obstructive disease during breathing of room air. When the preoperative hemodynamic evaluation was performed, the patients with hypoxemia were receiving oxygen in order to maintain their arterial oxygen saturation above 90%. Oxygen therapy could thus have attenuated the eventual effects of hypoxemia on left ventricular function. The latter effects have been studied in both experimental and clinical models. In anesthetized dogs, the left ventricular end-systolic pressure- volume relation (ESPVR) did not change when Sa_O2 was decreased from 95% to 64% (28). In healthy young men submitted to simulated altitude for 40 d, Suarez and colleagues (29) showed that left ventricular function was sustained at rest (Pa_O2 = 37 mm Hg) and increased during exercise (Pa_O2 = 32 mm Hg) despite hypoxic pulmonary hypertension. In COPD patients, McNee and coworkers found a significant correlation between LVEF and Pa_O2 (14), but their study also showed a correlation between right ventricular ejection fraction (RVEF) and Pa_O2, these correlations applied only to patients who were not receiving long-term oxygen treatment. The eventual effect of hypoxemia could thus be mediated by the interdependence of the right and left ventricles, since a diminished RVEF leads to right ventricular dilation.

Walley and associates (30) have demonstrated that induction of a profound respiratory acidosis (pH = 7.09, Pa_CO2 = 92 mm Hg) in anesthetized dogs resulted in a significant decrease in the slope of the left ventricular ESPVR. On the other hand, for lesser levels of hypercapnia (mean Pa_CO2 = 52 ± 9 mm Hg), MacNee and colleagues (14) found no correlation between Pa_CO2 and LVEF in the COPD patients they studied. Thus, it seems that isolated moderate hypoxemia and hypercapnia do not produce a significant depression of left ventricular function. Whether the latter is affected by the association of both of these gas-exchange disorders remains open to discussion.

Data concerning LVEF in patients with PPH who have more severe hemodynamic alterations than did our patients without severe gas-exchange derangements would indeed be useful for testing our hypothesis of ventricular interdependence. However, to our knowledge, few data are available about this in the literature. In the study of Krayenbuhl and coworkers (11), six patients had a biplanar angiographic determination of LVEF (mean LVEF was 59%). Among these six patients, LVEF was 55% or less (55%, 51%, 52%, 53% respectively) in four patients. The study by Yeoh and associates (31) included four patients who underwent single-lung transplantation for severe PPH or Eisenmenger's complex. Preoperative LVEF, which was available in three cases, was 39%, 36%, and 41%, respectively.

The issue of left ventricular systolic function in patients who undergo lung transplantation has been already addressed by several investigators (12, 23, 25, 32). Mean LVEF, as assessed preoperatively with echocardiography (33, 34), radionuclide angiography (12, 32), MRI (23), or electron-beam CT (25, 34) was found to be within the normal range. Despite a normal mean value of LVEF, a wide range of individual values was found in several of these studies (23, 25, 32, 34), indicating that a percentage of patients who subsequently underwent transplantation had a low LVEF prior to surgery. When assessed at some time after lung transplantation, mean LVEF remained unchanged (23, 25, 32, 33). We would probably have achieved similar results had we studied all patients who underwent lung transplantation, and not only those with a low preoperative LVEF.

Generally required among the numerous selection criteria for patients evaluated for single- or double-lung transplantation is the absence of moderate to severe left ventricular dysfunction (35). The normality of left ventricular systolic function is generally assessed by the combination of right heart catheterization, echocardiography, and isotopic measurement of LVEF, with the last procedure being considered an accurate method of assessing left ventricular systolic function (36- 38). Thus, a strict application of the results of isotopic measurement of LVEF might have led to the rejection of 40% of the patients in our study from the waiting list for transplantation. Our results indicate that most of these patients in fact had normal intrinsic left ventricular function. For this reason, it appears that relying upon a single value of LVEF (whatever the method of determination) for patients with chronic respiratory failure, may seriously underestimate the actual contractile function of the left ventricular muscle and unnecessarily exclude patients for transplantation. It is therefore necessary to cautiously interpret the results of isotopic measurement of LVEF and to compare the latter with results of echocardiographic analysis during both systole and diastole.

It could be argued that the high mortality rate in the group of our patients with low preoperative LVEF values raises a serious question about our conclusion that a preoperatively diminished LVEF should not be viewed as a contraindication to transplantation. The mortality rate in our patients was in accord with the mortality rate observed after lung transplantation. Postoperative assessment has been made on an average of 42 ± 13 mo after transplantation. According to the two international registries of lung transplantation, the expected survival at that time after transplantation has been about 50% in the St. Louis Registry (39) and less than 50% in the Registry of the International Society for Heart and Lung Transplantation (40).

Increased or borderline values of pulmonary artery wedge pressure (Ppaw) were found preoperatively in five patients in our study. This fact, already described in patients with advanced lung disease (9, 12, 25, 34), may be explained by the following factors: (1) the measured pressure may reflect the alveolar pressure according to the position of the tip of the Swan-Ganz catheter; (2) the increased Ppaw may truly reflect an increase in left ventricular end-diastolic pressure, which may be related to a decreased left ventricular compliance (due to ventricular interdependence), but also to an increased extramural pressure (i.e., an increased pleural pressure [which is common in COPD patients]).

In summary, a moderately reduced preoperative isotopic LVEF is not unusual in patients who undergo lung transplantation for severe chronic respiratory failure. This phenomenon is in general unrelated to an intrinsic alteration of left ventricular function, since a normalization of LVEF has most often been observed after transplant surgery. We hypothesize that such a reduced preoperative LVEF may instead be due to ventricular interdependence. A moderate decrease in radionuclide LVEF should not be a contraindication to lung transplantation, provided there are no qualitative abnormalities of left ventricular contraction on echocardiographic examination.

Limitations of the Study

The study was designed to retrospectively review patients with a low preoperative LVEF before lung transplantation, and to prospectively compare the preoperative and postoperative values of LVEF in patients who were still alive at the time of the study. A purely prospective study, with follow-up at predetermined time points of patients undergoing lung transplantation despite a low preoperative LVEF, would obviously have strengthened our conclusions.

Comparison of the preoperative size of the right ventricle with the initial LVEF would have been interesting. The precise quantification of right ventricular dilation by echocardiography is difficult in patients with end-stage lung disease, and is more readily done with other techniques such as electron beam CT or MRI.