SAN FRANCISCO—The National Emphysema Treatment Trial (NETT) was designed to compare emphysema outcomes after maximal medical therapy—alone or in combination with lung volume reduction surgery (LVRS).[1] However, this large, ongoing clinical study has already provided valuable knowledge about other aspects of emphysema, researchers acknowledged at the recent annual meeting of the American Thoracic Society.

The five-year study focuses on patients with severe airflow obstruction and hyperinflation, as well as computed tomographic (CT) evidence of emphysema. By the end of the study, NETT researchers intend to have enrolled 2,500 such patients for treatment at 17 primary clinical research centers and more than 300 satellite facilities; of the roughly 3,000 patients who have been screened to date, about 1,000 patients have been randomized. Enrollees must be nonsmokers or be willing to quit smoking.

During an initial pre-randomization phase, all patients undergo extensive medical screening. Patients then receive six to 10 weeks of treatment, which includes maximizing medical therapy and participating in pulmonary rehabilitation. At randomization, half the patients are assigned to continue on this regimen; the other half undergo LVRS, either by median sternotomy or by video-assisted thoracic surgery. Patients in each arm then receive an additional eight weeks of pulmonary rehabilitation; in addition, they are asked to return for follow-up at 6, 12, 24, and 36 months.

PROVOCATIVE FINDINGS FROM EARLY SUB-STUDIES

One of the most interesting findings from the NETT to date was demonstrated in a small sub-study: Resting hemodynamics in emphysema patients are not as bad as they may seem during initial cardiac catheterization, which often shows moderate to severe pulmonary hypertension. That finding is based on a sub-study of 107 severe emphysema patients, 67 of whom were eventually enrolled in the NETT. Results were presented by Steven M. Scharf, MD, PhD, one of NETT’s principal investigators and section head of pulmonary research at the Long Island Jewish Medical Center in New Hyde Park, New York.[2]

The patients in the sub-study, who ranged in age from 51 to 78 years, underwent standard right heart catheterization for measurement of cardiac output and pulmonary artery (PA), right atrial, right ventricular, systolic, and diastolic pressures. A rapid thermistor catheter was used so that the forward right ventricular ejection fraction could also be measured. The left ventricular ejection fraction was determined with gated blood pool studies and multiple gated acquisition scans.

Twenty-five patients also underwent supine esophageal pressure measurement within a week or so of cardiac catheterization, and the investigators assumed that the results were representative of the overall sub-study population. “This … allowed us to calculate transmural pressures,” Dr. Scharf said.

The patients had a mean arterial oxygen tension (PO2) of 67 mm Hg, a mean forced expiratory volume in one second (FEV1) of 27% predicted, and a mean emphysema score of 17 (out of a maximum of 24) on CT scan. They were neither hypercapnic nor hypoxic, commented Dr. Scharf. Nevertheless, their emphysema was fairly severe, at least in a number of lung segments, he noted.

The mean PA systolic pressure was nearly 38 mm Hg, clearly high, and the mean PA diastolic pressure was about 21 mm Hg. The PA mean pressure averaged 26 mm Hg. “So these patients appeared to be in a pulmonary hypertensive group,” said Dr. Scharf.

In fact, pulmonary hypertension was graded moderate in 75% and severe in nearly 16% of patients. Once the PA systolic transmural pressure was subtracted, however, only 28% of the patients fell into the moderate group and none were judged to have severe pulmonary hypertension.

A similar pattern emerged when the investigators assessed pulmonary hypertension severity with the PA mean pressure and then subtracted the end-expiratory esophageal pressure.

This phenomenon also occurred with the pulmonary capillary wedge pressure (PCWP), which initially appeared to be mildly to moderately elevated in 53% of the patients and greatly elevated in about 8%. “When [we subtracted] out the pleural pressure, none of the patients had a wedge pressure above 20 and only 12% had a mildly to moderately elevated wedge pressure,” Dr. Scharf said.

THE CORRELATIONS WERE INTRIGUING

The sub-study also found some interesting correlations. The PA mean pressure rose as daytime resting PO2 fell, for example, although Dr. Scharf described this correlation as “not very tight.” A much tighter correlation emerged between the PA mean pressure and the PCW pressure. This was characterized by a 7-mm Hg increase in the former for every 10-mm Hg rise in the latter.

Further, there was a strong correlation between the CT score—an emphysema-severity estimate based on serial lung scans—and diffusion capacity. But neither of these variables predicted PA pressure, noted Dr. Scharf. From the data demonstrated in this sub-study, Dr. Scharf has formed the following conclusions:

• While pulmonary hypertension appears to be prevalent in emphysema patients, it actually is not when transmural pressure is considered.
• Right and left ventricular systolic dysfunction are not common in emphysema.
• Transmural pressure and PCWP are important determinants of PA pressure, whereas hypoxemia is only a mild predictor. Estimates of parenchymal destruction have no predictive value.

PREDICTING LVRS OUTCOMES WITH CT

Another sub-study of the NETT is investigating whether baseline chest CT findings may predict patient outcomes after LVRS.[3] This sub-study was described by Fernando J. Martinez, MD, also a principal investigator and an Associate Professor of Internal Medicine at the University of Michigan in Ann Arbor.

Two thirds of emphysema patients who undergo LVRS have significantly better lung function in the immediate postoperative period, Dr. Martinez noted, although only 10% still show improvement four years later. The rate of decline during that time is quite heterogeneous, however; some patients maintain improvements in lung function for several years or more, whereas in others, lung function declines much sooner. A reliable predictor of the response to LVRS would therefore be helpful in deciding if the procedure is worth the risk, Dr. Martinez said.

With assistance from other investigators he has begun to develop such a predictor using data from earlier, small CT studies of emphysema patients. For example, one study revealed decreased emphysema volume after LVRS and showed that the extent of the change in emphysema volume could help predict outcome.

Other studies have found that the greatest short-term FEV1 improvements after LVRS occur in patients with the most heterogeneous CT patterns of disease.

Combining this data, Ella Kazerooni, MD, a colleague of Dr. Martinez, created a practical measure of the heterogeneity of emphysema based on quantitative CT scanning—the CT ratio (CTR). This ratio compares upper and lower lobe emphysema volumes as they appear on baseline (preoperative) CT scans. A CTR of 1 indicates homogenous disease; high CTRs (from 2 to 4) denote heterogeneous emphysema.

Drs. Martinez, Kazerooni, and collaborators applied the CTR prospectively to emphysema patients seen at their medical center prior to the NETT. They found that high CTRs have a high positive predictive value for short- and long-term FEV1 improvement after LVRS, but a CTR of 1 is not very predictive of postoperative FEV1 improvement.

Nevertheless, some patients with homogeneous emphysema may benefit from LVRS, Dr. Martinez added. The baseline inspiratory conductance may be a better predictor of surgical outcomes in this group, who may have more of an airway component to their disease and thus would not be expected to show much FEV1 improvement postoperatively, he noted, citing the work of other investigators.

Because Dr. Martinez’s method of predicting LVRS outcomes is based on small numbers of patients, most of whom had predominantly upper-lobe involvement, the NETT will explore these issues through a collaboration between its clinical investigators and the Image Analysis Center at the University of Iowa, under the direction of Eric Hoffman, PhD. These investigators will examine qualitative and quantitative emphysema measurement in a large number of patients characterized with strict, well defined methods.

—Timothy Begany

References
1. The National Emphysema Treatment Trial Research Group. Rationale and design of the National Emphysema Treatment Trial (NETT): a prospective randomized trial of lung volume reduction surgery. J Thorac Cardiovasc Surg. 1999;118:518-528.
2. Scharf SM. Hemodynamics in COPD. Paper presented at: American Thoracic Society 97th International Conference; May 22, 2001; San Francisco.
3. Martinez FJ. COPD: Is it emphysema or airway disease? Paper presented at: American Thoracic Society 97th International Conference; May 22, 2001; San Francisco.

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