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(Chest. 2003;123:1394-1400.)
© 2003 American College of Chest Physicians

Single-Breath Diffusing Capacity of the Lung for Carbon Monoxide*

A Predictor of PaO2, Maximum Work Rate, and Walking Distance in Patients With Emphysema

Zab Mohsenifar, MD, FCCP; Shing M. Lee, ScM; Philip Diaz, MD; Gerard Criner, MD, FCCP; Frank Sciurba, MD, FCCP; Mark Ginsburg, MD, FCCP and Robert A. Wise, MD, FCCP

* From the Cedars-Sinai Medical Center (Dr. Mohsenifar), Los Angeles, CA; the Bloomberg School of Public Health (Mr. Lee) and the School of Medicine (Dr. Wise), the Johns Hopkins University, Baltimore, MD; the Temple University School of Medicine (Dr. Criner), Philadelphia, PA; Columbia University (Dr. Ginsburg), New York, NY; the University of Pittsburgh School of Medicine (Dr. Sciurba), Pittsburgh, PA; and the Ohio State University (Dr. Diaz), Columbus, OH.

Correspondence to: Zab Mohsenifar, MD, FCCP, Cedars-Sinai Medical Center, Division of Pulmonary/Critical Care Medicine, 8700 Beverly Blvd, Room 6732, Los Angeles, CA 90049; e-mail: mohsenifarz{at}cshs.org


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Objective: The National Emphysema Treatment Trial (NETT) is a randomized, multicenter, clinical trial comparing two different methods of lung volume reduction surgery plus medical therapy to medical treatment alone in patients with advanced emphysema. The purpose of this article was to use the data obtained from the NETT to assess the ability of the single-breath diffusing capacity of the lung for carbon monoxide (DLCO) to predict the need for supplemental oxygen during rest and exercise, as well as overall exercise capacity.

Methods: One thousand seventy-one patients with a mean (± SD) FEV1 of 0.76 ± 0.24 L were studied.

Results: The mean DLCO was 8.0 ± 3.1 mL/min/mm Hg (28 ± 10% of predicted). The mean resting PaO2 was 64 ± 10 mm Hg. There was a positive association between DLCO and both resting PaO2 and the requirement for oxygen during a walk at 1 mile per hour (mph). The odds of requiring supplemental oxygen while walking at 1 mph was nine times greater in patients with a DLCO of <= 20% of predicted than for patients with a DLCO of > 35% of predicted, after adjusting for age and gender. Eighty four percent of individuals with a DLCO of <= 20% required supplemental oxygen with low levels of exercise compared to 38% of those with a DLCO of > 35%.

Conclusion: Our results demonstrated that patients with reduced DLCO, particularly when <= 20% of predicted, are more likely to have reduced PaO2 at rest and are more likely to require supplemental oxygen with low levels of activity. Thus, DLCO is useful in evaluating whether supplemental oxygen is required for exercise.

Key Words: diffusing capacity • emphysema • exercise tests • gas exchange • lung disease • PaO2


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Single-breath diffusing capacity of the lung for carbon monoxide (DLCO) has been used to assess gas transfer across the lung.1 A reduced DLCO may be a physiologic manifestation of a number of diseases, including pulmonary emphysema.2 In a variety of studies, DLCO has been used to investigate the causes of dyspnea, to detect disease, and/or to assess the progression of disease.3 4 5 6 7 These studies also have demonstrated that normal or modestly reduced DLCO was very specific in excluding arterial desaturation during exercise. Conversely, an abnormal DLCO was not very sensitive in predicting abnormal gas exchange during exercise. However, due to the small number of patients with very low FEV1 and DLCO values in these studies, the generalizability of these findings has been limited. The purpose of this article was to test the hypothesis of whether DLCO would be predictive of resting hypoxemia, the need for supplemental O2 during exercise, and the maximum work capacity in well-characterized patients with advanced emphysema that had been confirmed by high-resolution CT scans.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
The National Emphysema Treatment Trial (NETT) is a randomized, multicenter, clinical trial comparing lung volume reduction surgery plus medical therapy to medical therapy alone in patients with advanced pulmonary emphysema.8 Prior to enrollment in the study, patients underwent a comprehensive baseline evaluation, which included a 6-min walk test (6MWT) and complete cardiopulmonary exercise (CPX) testing, along with measures of quality of life and lung function testing.

The NETT was conducted at 17 clinical centers throughout the United States. Detailed inclusion/exclusion criteria have been published previously.8 In brief, patients must have bilateral emphysema with an FEV1 of <= 45% of predicted, an elevated total lung capacity and residual volume, and a PaCO2 < 60 mm Hg. Patients must require <= 6 L/min oxygen during exercise, must have been nonsmokers for at least 4 months prior to enrollment, and must abstain from smoking during screening. Additionally, enrollees have to be free of significant comorbid disease, which would preclude surgery or limit survival. Of note is that DLCO was not an inclusion/exclusion criterion in this study. The trial has been sanctioned by the institutional review boards of all of the participating centers.

Participants underwent an extensive evaluation prior to enrollment in the trial. This included history and physical examination, lung function testing, chest CT scans, cardiac stress testing, and echocardiography. Pulmonary function studies, including single-breath DLCO, were performed in the clinical laboratories at each center, in accordance with American Thoracic Society standards.9 10 11 12 Normal reference values were derived from those of Crapo and colleagues.10 13 14 CPX testing was performed on electromagnetically braked cycle ergometers at a rate that increased by 5 or 10 W/min. The exercise studies were conducted using a fraction of inspired oxygen of 0.3 to prevent oxygen desaturation.

A 6MWT was performed the day after maximum CPX testing.15 Prior to the 6MWT, patients had undergone an oxygen titration exercise test on a treadmill (no incline) to determine whether they required oxygen during the 6MWT. First, supplemental oxygen was titrated to keep the oxygen saturation at >= 90% with the patient sitting quietly. Next, supplemental oxygen was titrated to keep the oxygen saturation at >= 90% for at least 3 min while the patient walked on a treadmill at 1 mile per hour (mph). If participants required > 6 L/min oxygen, they were excluded from the trial.

If the participant was judged to be capable of walking at a higher speed, the treadmill speed was increased to either 2 or 3 mph, and oxygen again was titrated to keep the oxygen saturation at >= 90%. The amount of oxygen used for the subsequent 6MWT was the highest amount needed during the oxygen titration protocol. For the purposes of this study, however, we limited our analysis to the oxygen requirement during the 1 mph 6MWT. Eligible patients were enrolled in a comprehensive pulmonary rehabilitation program prior to randomization.

Statistical Analysis
The baseline characteristics are presented as percentages or mean ± SD. Linear and logistic regression models were used to assess the ability of DLCO, FEV1, and FVC to predict resting PaO2, oxygen requirement during 1 mph walking, maximum work capacity, and 6MWT distance. DLCO was corrected for the altitude and hemoglobin levels during the analysis,9 and results were divided into the following five categories: <= 20% of predicted; 21 to 25% of predicted; 26 to 30% of predicted; 31 to 35% of predicted; and > 35% of predicted. All analyses were adjusted by age and gender. Additional analyses were performed with FEV1 and FVC as individual predictors to assess their association with the outcomes after adjusting by DLCO, age, and gender. All analyses were performed using computer software (SAS, version 8.0; SAS Institute; Cary, NC). Statistical significance was inferred if the p value was < 0.01. The p values were adjusted for multiple-variable testing.16


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
The data presented in this report represent the results from prerehabilitation testing of subjects randomized between January 1998 and September 2001. Baseline demographics of the study group of 1,071 patients are presented in Table 1 . Baseline postbronchodilator spirometric function and DLCO (before rehabilitation) are presented in Table 2 . The mean FEV1 was 0.76 ± 0.24 L, and the mean DLCO was 8.0 ± 3.1 mL/min/mm Hg, which was 28 ± 10% of predicted. The mean resting PaO2 was 64 ± 10 mm Hg. The amount of supplemental oxygen required to complete the 1 mph walk and the amount of oxygen used during the 6MWT also are presented in Table 2 .


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  		Table 1.. Baseline Demographic Characteristics*

 

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  		Table 2.. Functional Measures, Prerehabilitation*

 
Table 3 demonstrates the significant positive relationship between quintiles of DLCO and resting PaO2 after adjusting for age and gender. FEV1 was also a significant predictor of PaO2 after adjusting for DLCO, age, and gender. For every percent increase in FEV1, there was an estimated increase of 0.19 mm Hg in PaO2 (p < 0.001). FVC, however, was not a significant correlate of PaO2.


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  		Table 3.. Resting PaO2 by DLCO Levels, Prerehabilitation

 
Table 4 demonstrates that DLCO was a significant predictor of whether oxygen was required to complete a 1 mph walk during the oxygen titration test. Odds ratios for requiring supplemental oxygen during 1 mph walking comparing different levels of DLCO are also shown in Table 4 . The lower the level of DLCO, the greater the odds of requiring oxygen. For patients with a DLCO of <= 20%, the odds of requiring oxygen for walking at 1 mph was nine times that for patients with a DLCO of > 35% of predicted. Unlike the case with resting PaO2, both FEV1 and FVC, after adjusting for DLCO, age, and gender were significant predictors of oxygen requirement during a 1 mph walk (p < 0.001 and p = 0.003, respectively).


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  		Table 4.. Patients Requiring Oxygen to Complete 1 mph Treadmill Walk, by DLCO Levels, Before Rehabilitation*

 
Table 5 demonstrates the positive correlation between quintiles of DLCO and maximum exercise capacity. Finally, Table 6 shows a significant positive correlation between quintiles of DLCO and 6 MWT results. Of note is that there was a twofold increase in maximum work comparing the lowest to highest DLCO windows, while there was only a 30% increase in 6MWT distance between the lowest and highest DLCO categories. FEV1 and FVC were also significant predictors of both 6MWT distance and maximum work output after adjusting for DLCO, age, and gender (p < 0.001). For every percent increase in FEV1 percent predicted, there was an estimated increase of 1.22 W in maximum exercise capacity and for every percent increase in FVC percent predicted, there was an estimated increase of 0.42 W in maximum exercise. Similarly, for every percent increase in FEV1 percent predicted, there was an increase of 12.71 feet in 6MWT distance, and for every percent increase in FVC percent predicted, there was an increase of 4.18 feet in 6MWT results.


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  		Table 5.. Maximum Work by DLCO Levels, Before Rehabilitation

 

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  		Table 6.. 6MWT Distance by DLCO Levels, Before Rehabilitation

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
The major findings of this study were as follows: (1) single-breath DLCO was found to have an inverse relationship with resting PaO2, oxygen requirement during 1 mph walk, maximum exercise capacity, and 6MWT; and (2) FEV1 and FVC correlated with oxygen requirement during a 1 mph walk, maximum exercise capacity, and 6MWT distance after adjusting for DLCO, age, and gender. However, only FEV1 was found to correlate with resting PaO2 after adjusting for DLCO, age, and gender.

DLCO is reduced in patients with many conditions, including emphysema, interstitial lung disease, and pulmonary vascular disease. Previous investigations3 4 5 6 7 have addressed the role of pulmonary function measurements, including DLCO, in predicting oxygen desaturation with exercise. Owens et al4 studied 48 patients with COPD and concluded that DLCO and FEV1 of > 55% of predicted were very specific in excluding arterial oxygen desaturation. However, the sensitivity of low DLCO or FEV1 was not as good. Due to the small number of patients with a very low DLCO, the authors were not able to divide their patients into various gradations of severity (as we did in our study). Similarly, Ries et al6 demonstrated that pulmonary function testing might be useful in identifying patients who are unlikely to develop hypoxemia during exercise. Hadeli et al7 reviewed a large number of patients retrospectively and found that a low DLCO, along with obstruction, had a sensitivity of 75% in predicting oxygen desaturation during exercise. However, the mean FEV1 was 1.5 ± 0.55 L, which is nearly twice the mean of the present study patients.

Diffusing capacity is not considered to be a major determinant of resting PaO2 and/or exercise capacity in patients with severe emphysema. Complex interactions between ventilation/perfusion mismatch, total ventilation, cardiac output, and metabolic rate (together affecting mixed venous oxygen tension) are the key determinants of arterial oxygenation at rest and during exercise in patients with severe emphysema.17 The correlation of resting PaO2 with DLCO found in our patients suggests that patients with lower DLCO have more ventilation/perfusion mismatch and/or hypoventilation.

It is of interest that DLCO correlated with maximum exercise capacity and 6MWT distance in our study. The reason why single-breath DLCO would limit exercise even when hypoxemia is corrected by supplemental oxygen is not clear from this study. Possible mechanisms might include cardiovascular limitation and/or myopathic changes with a markedly reduced DLCO serving as a marker for such abnormalities. Abnormalities in magnetic resonance spectroscopy of the limb muscles of patients with emphysema at rest and during exercise along with reduced oxidative enzyme activities in the vastus lateralis muscles of patients with obstructive pulmonary disease suggest reduced aerobic capacity of the working muscles in these patients.18 19 Thus, factors impairing limb muscle strength and endurance could limit exercise capacity. We postulate that a severely reduced DLCO may be a general marker of more severe disease. As noted previously, there was a twofold increase in maximum power between the lowest and highest DLCO categories vs a 30% increase in 6MWT distance. The reason for this discordance is not clear, but it might be related to the fact that maximum exercise study was performed on a 30% fraction of inspired oxygen, while during the 6MWT supplemental oxygen was given at a level sufficient to keep the oxygen saturation at >= 90%.

One of the unique features of this study is the large group of patients with advanced emphysema as confirmed by CT scanning. There are no published studies addressing large groups of emphysema patients with respect to the prediction of resting PaO2, the need for supplemental oxygen during low levels of exercise, maximum exercise capacity, or 6MWT distance based on varying levels of DLCO. DLCO is a simple and noninvasive test that may be useful in predicting oxygen desaturation and exercise tolerance in patients with advanced emphysema.

While previous studies have demonstrated a threshold value of DLCO that predicts desaturation, this is the first large study that clearly defines a "graded dose-response" relationship between quintiles of percent predicted values of DLCO and PaO2. Furthermore, we measured oxygen desaturation with mild exercise as opposed to maximum exercise, as had been done in previous studies.4 5 Thus, our study provides better predictability of oxygen saturation with the low levels of exercise that would be sustained for longer periods during the normal activities of daily living. Finally, the fact that this large study was performed in 17 centers makes the conclusions more generalizable.

In summary, we found the DLCO to be inversely correlated with resting PaO2, 6MWT distance, maximum exercise, and the need for supplemental oxygen during exercise. Therefore, during the assessment of patients with severe emphysema, those with reduced DLCO, and particularly a DLCO of < 20% of predicted, are more likely to have reduced resting PaO2, 6MWT distance, and maximum exercise capacity, and to require increased levels of supplemental oxygen with low levels of activity.


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
Appendix: Members of the NETT Research Group
Office of the Chair of the Steering Committee, University of Pennsylvania, Philadelphia, PA: Alfred P. Fishman, MD (Chair); Betsy Ann Bozzarello; Ameena Al-Amin.

Clinical Centers Baylor College of Medicine, Houston, TX: Rafael Espada, MD (Principal Investigator); Marcia Katz, MD (Co-Principal Investigator); Carolyn Wheeler, RN, BSN (Principal Clinic Coordinator); Elaine Baker, RRT, RPFT; Peter Barnard, PhD, RPFT; James Carter, MD; Sophia Chatziioannou, MD; Karla Conejo Gonzales; Minnie Ellisor; John Haddad, MD; David Hicks, RRT, RPFT; Neal Kleiman, MD; Mary Milburn-Barnes, CRTT; Chinh Nguyen, RPFT; Michael Reardon, MD; Joseph Reeves-Viets, MD; Steven Sax, MD; Amir Sharafkhaneh, MD; Christine Young; Rose Butanda (1999 to 2001); Kimberly DuBose, RRT (1998 to 2001); Pamela Fox, MD (1999 to 2001); Katherine Hale, MD (1998 to 2000); Everett Hood, RPFT (1998 to 2000); Amy Jahn (1998 to 2000); Satish Jhingran, MD (1998 to 2001); Karen King, RPFT (1998 to 1999); Charles Miller III, PhD (1998 to 1999); Imran Nizami, MD (Co-Principal Investigator, 1999 to 2001); Todd Officer (1998 to 2000); Jeannie Ricketts (1998 to 2000); Joe Rodarte, MD (Co-Principal Investigator, 1996 to 2000); Robert Teague, MD (Co-Principal Investigator, 2000); Kedren Williams (1998 to 1999).

Brigham and Women’s Hospital, Boston, MA: John Reilly, MD (Principal Investigator); David Sugarbaker, MD (Co-Principal Investigator); Carol Fanning, RRT (Principal Clinic Coordinator); Simon Body, MD; Sabine Duffy, MD; Vladmir Formanek, MD; Anne Fuhlbrigge, MD; Philip Hartigan, MD; Sarah Hooper, EP; Andetta Hunsaker, MD; Francine Jacobson, MD; Marilyn Moy, MD; Susan Peterson, RRT; Roger Russell, MD; Diane Saunders; Scott Swanson, MD (Co-Principal Investigator, 1996 to 2002).

Cedars-Sinai Medical Center, Los Angeles, CA: Rob McKenna, MD (Principal Investigator); Zab Mohsenifar, MD (Principal Investigator); Carol Geaga, RN (Principal Clinic Coordinator); Manmohan Biring, MD; Susan Clark, RN, MN; Robert Frantz, MD; Milton Joyner, BA; Peter Julien, MD; Michael Lewis, MD; Jennifer Minkoff-Rau, MSW; Valentina Yegyan, BS, CPFT.

Cleveland Clinic Foundation, Cleveland, OH: Malcolm DeCamp, MD (Principal Investigator); James Stoller, MD (Co-Principal Investigator); Yvonne Meli, RN,C (Principal Clinic Coordinator); John Apostolakis, MD; Darryl Atwell, MD; Jeffrey Chapman, MD; Pierre DeVilliers, MD; Raed Dweik, MD; Erik Kraenzler, MD; Rosemary Lann, LISW; Nancy Mangalindan, RRT, CPFT; Scott Marlow, RRT; Kevin McCarthy, RCPT; Pricilla McCreight, RRT, CPFT; Atul Mehta, MD; Moulay Meziane, MD; Omar Minai, MD; Peter O’Donovan, MD; Mindi Steiger, RRT; Kenneth White, RPFT; Janet Maurer, MD (Principal Investigator, 1966 to 2001); Robert Schilz, DO (1998 to 2002); Terri Durr, RN (2000 to 2001).

Columbia University, New York, NY in consortium with Long Island Jewish Medical Center, New Hyde Park, NY: Mark Ginsburg, MD (Principal Investigator); Byron Thomashow, MD (Co-Principal Investigator); Patricia Jellen, MSN, RN (Principal Clinic Coordinator); John Austin, MD; Matthew Bartels, MD; Yahya Berkman, MD; Patricia Berkoski, MS, RRT (Site Coordinator, Long Island Jewish Medical Center); Frances Brogan, MSN, RN; Amy Chong, BS, CRT; Glenda DeMercado, BSN; Angela DiMango, MD; Bessie Kachulis, MD; Arfa Khan, MD; Mike Mantinaos, MD; Berend Mets, MD; Mitchell O’Shea, BS, RT, CPFT; Gregory Pearson, MD; Jacqueline Pfeffer, MPH, PT; Leonard Rossoff, MD; Steven Scharf, MD, PhD (Co-Principal Investigator, 1998 to 2002); Maria Shiau, MD; Paul Simonelli, MD; Kim Stavrolakes, MS, PT; Donna Tsang, BS; Denise Vilotijevic, MS, PT; Chun Yip, MD; Kerri McKeon, BS, RRT, RN (Site Coordinator, Long Island Jewish Medical Center, 1998 to 2000).

Duke University Medical Center, Durham, NC: Neil MacIntyre, MD (Principal Investigator); R. Duane Davis, MD (Co-Principal Investigator); John Howe, RN (Principal Clinic Coordinator); Rebecca Crouch, RPT; Katherine Grichnik, MD; David Harpole, Jr, MD; Abby Krichman, RRT; Brian Lawlor, RRT; Holman McAdams, MD; Susan Rinaldo-Gallo, MED; Jeanne Smith, ACSW; Mark Stafford-Smith, MD; Victor Tapson, MD.

Mayo Foundation, Rochester, MN: James Utz, MD (Principal Investigator); Claude Deschamps, MD (Co-Principal Investigator); Kathy Mieras (Principal Clinic Coordinator); Mark Allen, MD; Deb Andrist, RN; Gregory Aughenbaugh, MD; Sharon Bendel, RN; Eric Edell, MD; Marlene Edgar; Bonnie Edwards; Beth Elliot, MD; James Garrett, RRT; Delmar Gillespie, MD; Judd Gurney, MD; Boleyn Hammel; Karen Hanson, RRT; Lori Hanson, RRT; Gordon Harms, MD; June Hart; Thomas Hartman, MD; Robert Hyatt, MD; Eric Jensen, MD; Nicole Jenson, RRT; Sanjay Kalra, MD; Philip Karsell, MD; David Midthun, MD; Carl Mottram, RRT; Stephen Swensen, MD; Anne-Marie Sykes, MD; Karen Taylor; Norman Torres, MD.

National Jewish Medical and Research Center, Denver, CO: Barry Make, MD (Principal Investigator); Marvin Pomerantz, MD (Co-Principal Investigator); Mary Gilmartin, RN, RRT (Principal Clinic Coordinator); Joyce Canterbury; Martin Carlos; Phyllis Dibbern, PT; Enrique Fernandez, MD; Lisa Geyman, MSPT; Connie Hudson; David Lynch, MD; John Newell, MD; Robert Quaife, MD; Jennifer Propst, RN; Cynthia Raymond, MS; Jane Whalen-Price, PT; Kathy Winner, OTR; Martin Zamora, MD; Reuben Cherniack, MD (Principal Investigator, 1997 to 2000).

Ohio State University, Columbus, OH: Philip Diaz, MD (Principal Investigator); Patrick Ross, MD (Co-Principal Investigator); Tina Bees (Principal Clinic Coordinator); Jan Drake; Ronald Harter, MD; Mark King, MD; David Rittinger; Mahasti Rittinger.

Saint Louis University, St. Louis, MO: Keith Naunheim, MD (Principal Investigator); Francisco Alvarez, MD (Co-Principal Investigator); Joan Osterloh, RN, BSN (Principal Clinic Coordinator); Susan Borosh; Willard Chamberlain, DO; Sally Frese; Alan Hibbit; Mary Ellen Kleinhenz, MD; Gregg Ruppel; Cary Stolar, MD; Janice Willey.

Temple University, Philadelphia, PA: Gerard Criner, MD (Principal Investigator); Satoshi Furukawa, MD (Co-Principal Investigator); Anne Marie Kuzma, RN, MSN (Principal Clinic Coordinator); Roger Barnette, MD; Neil Brister, MD; Kevin Carney, RN, BS; Wissam Chatila, MD; Francis Cordova, MD; Gilbert D’Alonzo, DO; Michael Keresztury, MD; Karen Kirsch; Kathy Lautensack, RN, BSN; Madelina Lorenzon, CPFT; Ubaldo Martin, MD; Peter Rising, MS; Scott Schartel, MD; John Travaline, MD; Gwendolyn Vance, RN.

University of California, San Diego, San Diego, CA: Andrew Ries, MD, MPH (Principal Investigator); Robert Kaplan, PhD (Co-Principal Investigator); Catherine Ramirez, BS, RCP (Principal Clinic Coordinator); David Frankville, MD; Paul Friedman, MD; James Harrell, MD; Jeffery Johnson; David Kapelanski, MD; David Kupferberg, MD; Catherine Larsen, MPH; Trina Limberg, RRT; Michael Magliocca, RN, CNP; Frank J. Papatheofanis, MD, PhD; Dawn Sassi-Dambron, RN; Melissa Weeks.

University of Maryland at Baltimore, Baltimore, MD, in consortium with Johns Hopkins Hospital, Baltimore, MD: Mark Krasna, MD (Principal Investigator); Henry Fessler, MD (Co-Principal Investigator); Iris Moskowitz (Principal Clinic Coordinator); Timothy Gilbert, MD; Jonathan Orens, MD; David Shade; Kenneth Silver, MD; Clarence Weir; Charles White, MD.

University of Michigan, Ann Arbor, MI: Fernando Martinez, MD (Principal Investigator); Mark Iannettoni, MD (Co-Principal Investigator); Catherine Meldrum, BSN, RN, CCRN (Principal Clinic Coordinator); William Bria, MD; Kelly Campbell; Paul Christensen, MD; Kevin Flaherty, MD; Steven Gay, MD; Paramjit Gill, RN; Paul Kazanjian, MD; Ella Kazerooni, MD; Vivian Knieper; Tammy Ojo, MD; Lewis Poole; Leslie Quint, MD; Paul Rysso; Thomas Sisson, MD; Michael Spear; Mercedes True; Wendy Woniewski; Brian Woodcock, MD; Lori Zaremba, RN.

University of Pennsylvania, Philadelphia, PA: Larry Kaiser, MD (Principal Investigator); John Hansen-Flaschen, MD (Co-Principal Investigator); Mary Louise Geraghty, BSN, RN (Principal Clinic Coordinator); Abass Alavi, MD; Theresa Alcorn, Judith Aronchick, MD; Stanley Aukberg, MD; Bryan Benedict, RRT; Susan Craemer, BS, RRT, CPFT; Ron Daniele, MD; Jeffrey Edelman, MD; Warren Gefter, MD; Laura Kotler-Klein, MSS; Robert Kotloff, MD; David Lipson, MD; Wallace Miller, Jr., MD; Richard O’Connell, RPFT; Staci Opelman, MSW; William Russell, RPFT; Heather Sheaffer, MSW; Rodney Simcox, BSRT, RRT; Susanne Snedeker, RRT, CPFT; Jennifer Stone-Wynne, MSW; Gregory Tino, MD; Peter Wahl; James Walter, RPFT; Patricia Ward; David Zisman, MD; James Mendez, MSN, CRNP (1997 to 2001, Principal Clinic Coordinator 1999 to 2001); Angela Wurster, MSN, CRNP (Principal Clinic Coordinator, 1997 to 1999).

University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, MD (Principal Investigator); James Luketich, MD (Co-Principal Investigator); Colleen Synan, MS (Principal Clinic Coordinator); Gerald Ayres; Manuel Brown, MD; Michael Donahoe, MD; Carl Fuhrman, MD; Robert Hoffman, MD; Joan Lacomis, MD; Joan Sexton; William Slivka; Diane Strollo, MD; Erin Sullivan, MD; Tomeka Simon; Catherine Wrona, RN, BSN.

University of Washington, Seattle, WA: Joshua Benditt, MD (Principal Investigator), Douglas Wood, MD (Co-Principal Investigator); Margaret Snyder, MN (Principal Clinic Coordinator); Kymberley Anable; Nancy Battaglia; Louie Boitano; Andrew Bowdle, MD; Leighton Chan, MD; Cindy Chwalik; Bruce Culver, MD; Thurman Gillespy, MD; David Godwin, MD; Andra Ibrahim, MD; Diane Lockhart; Stephen Marglin, MD; Kenneth Martay, MD; Patricia McDowell; Alicia Morgan; Donald Oxorn, MD; Susan Golden (1998 to 2000).

Other Participants Agency for Healthcare Research and Quality, Rockville, MD: Lynn Bosco, MD, MPH; Yen-Pin Chiang, PhD; Carolyn Clancy, MD; Harry Handelsman, DO.

Centers for Medicare and Medicaid Services, Baltimore, MD: Steven Sheingold, PhD; Tanisha Carino; JoAnna Farrell; Karen McVearry; Anthony Norris; Sarah Shirey; Claudette Sikora; Kenneth Simon, MD, MBA.

Coordinating Center, The Johns Hopkins University, Baltimore, MD: Steven Piantadosi, MD, PhD (Principal Investigator); James Tonascia, PhD (Co-Principal Investigator); Patricia Belt; Karen Collins; Betty Collison; John Dodge; Michele Donithan, MHS; Vera Edmonds; Judith Harle; Rosetta Jackson; Heather Koppelman; Shing Lee, ScM; Charlene Levine; Hope Livingston; Jill Meinert; Jennifer Meyers; Deborah Nowakowski; Kapreena Owens; Shangqian Qi, MD; Michael Smith; Brett Simon, MD; Paul Smith; Alice Sternberg, ScM; Mark Van Natta, MHS; Laura Wilson; Robert Wise, MD.

Cost Effectiveness Data Center, Fred Hutchinson Cancer Research Center, Seattle, WA: Scott Ramsey, MD, PhD (Principal Investigator); Ruth Etzioni, PhD; Sean Sullivan, PhD; Douglas Wood, MD; Larry Kessler, ScD; Thomas Schroeder, MA; Robert Smith, MS; Kristin Berry, MS; Nancy Myers.

CT Scan Image Storage and Analysis Center, University of Iowa, Iowa City, IA: Eric Hoffman, PhD (Principal Investigator); Janice Cook-Granroth; Angela Delsing, RT; Junfeng Guo, PhD; Geoffrey McLennan, MD; Brian Mullan, MD; Chris Piker; Joseph Reinhardt, PhD; Blake Robinswood; Jered Sieren; William Stanford, MD.

Data and Safety Monitoring Board: John Waldhausen, MD (Chair); Gordon Bernard, MD; David DeMets, PhD; Mark Ferguson, MD; Eddie Hoover, MD; Robert Levine, MD; Donald Mahler, MD; A. John McSweeny, PhD; Jeanine Wiener-Kronish, MD; O. Dale Williams, PhD; Magdy Younes, MD.

Marketing Center, Temple University, Philadelphia, PA: Gerard Criner, MD (Principal Investigator); Charles Soltoff, MBA.

Project Office, National Heart, Lung, and Blood Institute, Bethesda, MD: Gail Weinmann, MD (Project Officer); Joanne Deshler (Contracting Officer); Dean Follmann, PhD; James Kiley, PhD; Margaret Wu, PhD (1996 to 2001).


   Footnotes
 
Abbreviations: CPX = cardiopulmonary exercise; DLCO = diffusing capacity of the lung for carbon monoxide; mph = mile per hour; NETT = National Emphysema Treatment Trial; 6MWT = 6-min walk test

A list of the members of the National Emphysema Treatment Trial Research Group is located in the Appendix.

This research was supported by contracts with the National Heart, Lung, and Blood Institute (grants N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR761010, N01HR761011, N01HR761012, N01HR761013, N01HR761014, N01HR761015, N01HR761016, N01HR76118, and N01HR761019), the Centers for Medicare and Medicaid Services (formerly the Health Care Financing Administration), and the Agency for Healthcare Research and Quality.

Received for publication August 20, 2002. Accepted for publication November 14, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

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E. M. Snyder, B. D. Johnson, and K. C. Beck
An open-circuit method for determining lung diffusing capacity during exercise: comparison to rebreathe
J Appl Physiol, November 1, 2005; 99(5): 1985 - 1991.
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