Study objectives: Pulmonary rehabilitation is an established treatment in patients with chronic lung disease but is not widely utilized. Most trials have been conducted in single centers. The National Emphysema Treatment Trial (NETT) provided an opportunity to evaluate pulmonary rehabilitation in a large cohort of patients who were treated in centers throughout the United States.
Design: Prospective observational study of cohort prior to randomization in a multicenter clinical trial.
Setting: University-based clinical centers and community-based satellite pulmonary rehabilitation programs.
Patients and intervention: A total of 1,218 patients with severe emphysema underwent pulmonary rehabilitation before and after randomization to lung volume reduction surgery (LVRS) or continued medical management. Rehabilitation was conducted at 17 NETT centers supplemented by 539 satellite centers.
Measurements and results: Lung function, exercise tolerance, dyspnea, and quality of life were evaluated at regular intervals. Significant (p < 0.001) improvements were observed consistently in exercise (cycle ergometry, 3.1 W; 6-min walk test distance, 76 feet), dyspnea (University of California, San Diego Shortness of Breath Questionnaire score, −3.2; Borg breathlessness score: breathing cycle, −0.8; 6-min walk, −0.5) and quality of life (St. George Respiratory Questionnaire score, −3.5; Quality of Well-Being Scale score, +0.035; Medical Outcomes Study 36-item short form score: physical health summary, +1.3; mental health summary, + 2.0). Patients who had not undergone prior rehabilitation improved more than those who had. In multivariate models, only prior rehabilitation status predicted changes after rehabilitation. In 20% of patients, exercise level changed sufficiently after rehabilitation to alter the NETT subgroup predictive of outcome. Overall, changes after rehabilitation did not predict differential mortality or improvement in exercise (primary outcomes) by treatment group.
Conclusions: The NETT experience demonstrates the effectiveness of pulmonary rehabilitation in patients with severe emphysema who were treated in a national cross-section of programs. Pulmonary rehabilitation plays an important role in preparing and selecting patients for surgical interventions such as LVRS.
Pulmonary rehabilitation enhances standard therapy for patients with emphysema by helping to control and alleviate symptoms, to optimize functional capacity, and to reduce the medical and economic burdens of disabling lung disease.1–9 Most clinical trials have been conducted in individual research-based centers, whereas the majority of pulmonary rehabilitation services are provided in clinical, community-based programs. The National Emphysema Treatment Trial (NETT), a multicenter trial evaluating lung volume reduction surgery (LVRS) in patients with advanced emphysema, provides a unique opportunity to examine the effectiveness of pulmonary rehabilitation administered in a variety of centers throughout the United States.10–11 In the NETT, all subjects who were eligible after the initial evaluation completed 6 to 10 weeks of standardized pulmonary rehabilitation prior to randomization. The rehabilitation program was directly supervised by the NETT center where the patient had enrolled, although portions of the program for some patients were carried out at a satellite facility certified by the supervising center.10 Although NETT was not specifically designed to evaluate pulmonary rehabilitation, it does allow a descriptive analysis of changes in health outcomes after pulmonary rehabilitation in a large cohort of patients who are widely distributed across the United States. The purpose of this report was to describe these analyses.
Study Design, Subjects, and Assessments
The overall design of the NETT and its preliminary results have been reported previously.10–13 The 17 participating NETT centers randomly assigned 1,218 patients with emphysema (mean FEV1, 26.9% predicted) to either undergo LVRS with medical therapy or to receive continued medical management alone.,11 All patients gave written informed consent on forms that had been approved by the human subjects committee at each center.
After an initial evaluation to establish preliminary eligibility and before randomization, all subjects were required to complete a comprehensive program of pulmonary rehabilitation regardless of whether they had undergone pulmonary rehabilitation at any time previously. Assessments were performed before and after this initial phase of rehabilitation. Only after successfully completing rehabilitation were subjects eligible to enter the randomized portion of the trial.
NETT Pulmonary Rehabilitation Program
The NETT rehabilitation program was designed to optimize physical and psychosocial function and to improve each patient’s understanding of lung disease and his/her ability to manage it. Secondary goals included the provision of detailed information to the patient about the complex NETT protocol to ensure, as follows: (1) truly informed consent; (2) bonding with the NETT center to optimize continued participation in this difficult, long-term trial; and (3) adherence to recommendations for optimal medical management. The basic principle of the rehabilitation program was a study-directed daily care program with specified center-based supervised sessions to ensure that all patients received standardized educational and psychosocial treatment and appropriate adjustment of exercise training. All patients were expected to continue their rehabilitation care plans daily at home throughout the study.
The NETT pulmonary rehabilitation program was divided into the following three phases: prerandomization; postrandomization; and long-term maintenance. The prerandomization phase included a total of 16 to 20 supervised sessions that were completed over a period of 6 to 10 weeks. The comprehensive program included components of exercise training (ie, lower extremity, upper extremity, flexibility, and strength), education, psychosocial assessment and treatment, and nutritional assessment and treatment. Individual goals were established during an initial rehabilitation evaluation during screening for the trial. The first four rehabilitation sessions were provided at a NETT center. The remaining 12 to 16 sessions were provided either at the same NETT center or at a satellite facility nearer to the patient’s home that had been certified by the NETT center that remained responsible for patient management. Individual satellite centers could be certified by more than one NETT center. The certifying NETT center was responsible for ensuring that satellite center staff members were trained in NETT procedures and for overseeing the patient’s rehabilitation program through regular communication including weekly progress reports and exercise session logs.
Each required session included supervised exercise training and either an education or psychosocial session. The exercise-training program incorporated lower extremity endurance exercise that was accomplished either by walking or by riding on a bicycle (five times per week), supported or unsupported upper extremity exercise (three times per week), flexibility exercises (five times per week), and strength training with latex resistive bands and tubing, free weights, or circuit training (three times per week). Each NETT center was responsible for developing a specific exercise-training program consistent with the NETT protocol and for ensuring compliance in its certified satellite centers. The education program was tailored to the individual patient, and covered both disease-specific and study-related topics. Psychosocial assessment was performed by rehabilitation staff during the initial evaluation, and was supplemented by the Beck Depression Inventory,14–15 the Self-Evaluation Questionnaire of state and trait anxiety,16and the Trail Making Test to assess divided attention and psychomotor functioning.17 Psychosocial counseling was provided by an appropriate mental health professional. Patients with serious psychological problems were referred to a psychologist or psychiatrist. After completing prerandomization pulmonary rehabilitation, each patient was reevaluated at the NETT center and was allowed to proceed to randomization only after completing this evaluation.
The postrandomization phase included an additional 8 to 9 weeks of supervised rehabilitation. LVRS patients began rehabilitation activities in the hospital as soon as was practical after surgery. At the time of hospital discharge, they received a minimum of two rehabilitation sessions at the NETT center followed by supervised sessions at least once weekly over 8 weeks at either the NETT center or a satellite center. Similar to the prerandomization phase, supervised sessions included reinforcement education, and exercise, psychosocial, and nutrition components. For medical patients, this phase began immediately after randomization. A minimum of two psychosocial sessions was required to assist the patient in overcoming any disappointment concerning the assigned treatment arm.
The long-term maintenance phase continued for the duration of follow-up in the NETT. Each NETT center maintained contact through scheduled in-person visits that were supplemented with regular telephone contact to assess adherence to the rehabilitation treatment plan. When necessary, additional supervised rehabilitation sessions could be prescribed.
Measures of physiologic and psychosocial function before and after rehabilitation were evaluated with descriptive statistics and paired t tests. In addition to the analysis for all patients, stratified analyses by prior rehabilitation experience and rehabilitation location were performed. All p values were based on two-sided tests and were not corrected for multiple comparisons. A p value of < 0.05 was considered to be significant. Multivariate analyses of determinants of change after rehabilitation were performed by forward stepwise linear regression. The dependent variables analyzed included maximum cycle ergometry workload, measured in watts (a primary outcome measure in the NETT),10–11 total St. George Respiratory Questionnaire score,18and the University of California, San Diego (UCSD) Shortness of Breath Questionnaire score.19 The following candidate-independent variables were selected for univariate analysis: FEV1; inspiratory capacity; residual volume (RV)/total lung capacity (TLC)ratio; diffusing capacity of the lung for carbon monoxide; cutaneous oxygen saturation on the oxygen titration walk; maximum workload and perceived symptoms of breathlessness and muscle fatigue on the cycle ergometry test; St. George Respiratory Questionnaire total and subscale scores; quality of well-being (QWB) score; Medical Outcomes Study 36-item short form (SF-36) subscale and physical and mental component scores; UCSD Shortness of Breath score; prior rehabilitation experience (yes/no); rehabilitation location (NETT center or satellite); and income level. For the multivariate models, candidate-independent variables for all analyses included age, gender, NETT center, and prerandomization value for the dependent variable in addition to any of the other independent variables for which the univariate model p value was < 0.15. Independent variables for the final multivariate model were then selected as predictive if the p value from stepwise forward selection was < 0.05.
In the primary report of the NETT results,11 key subgroups were identified because of important findings of differential outcome by treatment group. Maximum exercise capacity after rehabilitation and the distribution of emphysema proved to be important characteristics in defining these subgroups. Therefore, we examined the impact of pulmonary rehabilitation on subgroup assignment. Patients were categorized into high and low exercise capacity groups based on the 40th percentile gender-specific values that previously had been identified in the NETT (women, 25 W; men, 40 W) both before and after pulmonary rehabilitation.11 The McNemar test was used to test for the statistical significance of change in subgroup assignment from prerehabilitation to postrehabilitation. A separate analysis was performed for patients with and without prior pulmonary rehabilitation.
Additional multivariate analyses were performed to evaluate the potential effects of changes after pulmonary rehabilitation on predicting differential mortality and a 10-W change in maximum cycle work (primary outcome measures in NETT) by treatment. Mortality was analyzed using Cox regression. Improvement, as defined by a change in the maximum cycle work of ≥ 10 W, was analyzed using logistic regression. For these analyses, the independent variables selected for analysis included changes after prerandomization pulmonary rehabilitation in maximum workload, 6-min walk distance, St. George total score, QWB score, and UCSD Shortness of Breath Questionnaire score. The model for predicting differential outcome included the independent variable, the treatment group assignment, and the interaction between them. All analyses were performed using a statistical software package (SAS, version 8.0; SAS Institute; Cary, NC).
A total of 3,777 patients underwent comprehensive evaluation at 1 of the 17 participating centers. Of these patients, 1,796 met the preliminary eligibility criteria and began the prerandomization pulmonary rehabilitation program. Over the next 10 weeks, 578 of these patients did not proceed to randomization for a variety of reasons including the following: not completing the rehabilitation program or postprogram assessment; doing well in rehabilitation and becoming unwilling to risk surgery; decline in function during rehabilitation and being declared ineligible either by choice or by study investigators; making an informed choice not to continue after further discussions during rehabilitation; illness or other complication rendering patients ineligible for surgery; or exclusion by the surgeon. It should be noted that surgeons had the option to exclude any patient they were unwilling to operate on at the time of the preoperative evaluation that was required prior to randomization. Additional data were not available about these patients who were excluded from the study and further follow-up. The analyses presented in this article were based on complete prerandomization and postrandomization data that were collected on all patients in the final cohort who successfully completed pulmonary rehabilitation and proceeded to randomization.
Effects of Prerandomization Pulmonary Rehabilitation
The characteristics of the 1,218 patients at initial evaluation prior to rehabilitation are presented in Table 1
. Of note, 777 patients (64%) had received prior pulmonary rehabilitation, and 786 patients (65%) had utilized one of the satellite rehabilitation centers. As expected, on average, these patients had severe airflow obstruction and marked impairment in exercise capacity, symptoms of dyspnea, and reduction in health-related quality of life. On the oxygen titration test, 58% required supplemental oxygen to maintain saturation levels of > 90% by cutaneous oximetry.
Changes after pulmonary rehabilitation are presented in Table 2
for (1) all patients (n = 1218), (2) patients with prior pulmonary rehabilitation (n = 777) and without prior pulmonary rehabilitation (n = 441), and (3) patients who completed pulmonary rehabilitation using a satellite center (n = 786) or solely a NETT center (n = 432). Overall, there were highly statistically significant changes in all measures of exercise capacity, dyspnea, and quality of life except for the SF-36 pain score. With the exception of slightly less hyperinflation (ie, a decrease in the RV/TLC ratio of 0.6%), as expected, there were no significant changes in lung function. Improvements were significantly greater in patients without prior rehabilitation experience than for those with prior rehabilitation for measures of maximum work; 6-min walk distance; St. George total, activity, and impacts scores; UCSD Shortness of Breath score; and SF-36 scores of physical health summary, and components of physical functioning, emotional well-being, and general health perceptions. There were no significant differences in changes for patients who completed the prerandomization rehabilitation program at satellite centers vs NETT centers.
Box plots for changes in maximum cycle workload, St. George Respiratory Questionnaire total score, and UCSD Shortness of Breath Questionnaire score for all patients, as well as for those with and without prior pulmonary rehabilitation experience, are presented in Figure 1
. These demonstrate greater improvements in patients without prior rehabilitation. Approximately half of the NETT patients demonstrated clinically important improvements for each of these measures based on investigator estimates of minimal clinically important differences, as follows: cycle workload, 5 W; St. George Respiratory Questionnaire total score, 4 U20–; and UCSD Shortness of Breath Questionnaire score, 5 U.21
Changes in the eight subscales of the SF-36 health profile are presented in Figure 2
. After pulmonary rehabilitation, seven of the eight subscales showed significant improvement. Only the bodily pain score, which had been nearly normal at baseline, failed to improve.
Predictors of Improvement in Pulmonary Rehabilitation
The results of the multivariate analyses of determinants of changes after pulmonary rehabilitation are presented in Table 3
. In general, the amount of variability explained by the independent variables was very small, suggesting that the changes after pulmonary rehabilitation cannot be explained using prerehabilitation measures. Because of significant differences between NETT centers with respect to changes in maximum workload and St. George Respiratory Questionnaire total score, the estimates for these dependent variables were adjusted by NETT clinic. There were no significant differences between centers for the UCSD Shortness of Breath Questionnaire score.
Effect of Pulmonary Rehabilitation on NETT Subgroups
Prerandomization pulmonary rehabilitation had a significant effect on NETT subgroup assignment based on maximum exercise capacity for all non-high-risk patients11–12 as well as for subgroups with and without prior rehabilitation experience (Table 4
). Overall, 20% of patients changed subgroup after rehabilitation, 13.5% from the low exercise subgroup to the high exercise subgroup and 6.5% from the high exercise subgroup to the low exercise subgroups. The effect of rehabilitation on subgroup assignment was greater for patients without prior rehabilitation in whom 16.5% changed from the low exercise subgroup to the high exercise subgroup and 6.2% from the high exercise subgroup to the low exercise subgroup.
Effects of Pulmonary Rehabilitation on Primary NETT Outcome Measures
In multivariate analyses, changes in exercise, dyspnea, and quality of life after pulmonary rehabilitation were not significant predictors of differential mortality and change in maximum cycle work (the primary outcomes of NETT) by treatment group (data not shown).
The NETT study provides a remarkable demonstration of the effectiveness of pulmonary rehabilitation in a large cohort of patients with advanced emphysema who had been treated in a cross-section of programs in the United States. The study was not designed specifically to evaluate pulmonary rehabilitation, and there was no comparison group without rehabilitation. Nevertheless, significant improvements in exercise capacity, dyspnea, and health-related quality of life were observed consistently across many of the NETT centers (17) and satellite centers (539). The only variable that consistently demonstrated an effect on rehabilitation outcomes was whether the patient had rehabilitation experience prior to enrolling in the NETT. As expected, those patients without prior rehabilitation experience demonstrated the greatest gains.
These results confirm and extend those previously published from single, specialized centers as well as other multicenter outcome studies9,22 and provide strong evidence that the benefits from pulmonary rehabilitation as currently practiced are generalizable to community-based centers. In the overall analyses, the magnitude of improvement in most variables was less than that typically observed in single-center studies and less than the accepted thresholds for clinically important differences. However, patients in NETT were recruited regardless of prior pulmonary rehabilitation experience, although all were required to complete the NETT pulmonary rehabilitation program before randomization. Because prior rehabilitation experience appears to have blunted the response to pulmonary rehabilitation, the results in patients without prior rehabilitation (Table 2) may be a truer indication of the expected response in this patient group. In these patients, the average changes after rehabilitation did reach the levels generally considered to represent clinically important differences for the measures of exercise capacity, dyspnea, and health-related quality of life.
It should also be noted that patients enrolled in the NETT had more severe obstructive lung disease than that typically found in pulmonary rehabilitation programs. The mean FEV1 in the NETT (26.9% predicted) was lower than that reported in any study in one evidence-based review (range, 35 to 80% predicted; median, 43% predicted).1
We attempted to standardize the NETT rehabilitation protocol by training all rehabilitation staff and certifying satellite centers. Even among the 17 NETT centers, there were some significant center-specific differences in the magnitude of change in maximum exercise capacity and the St. George Respiratory Questionnaire score. There were no significant center differences noted in the UCSD Shortness of Breath Questionnaire score, indicating that improvements in dyspnea were quite consistent.
Although measured changes in the rehabilitation program were not predictors of a differential effect on the primary outcome measures in NETT by treatment (survival or maximum exercise capacity), our experience suggests that pulmonary rehabilitation did play an important role in evaluating and preparing patients for surgery and in maintaining patients in the study. In designing the NETT protocol, we were quite concerned about the difficulties in maintaining subject compliance with the challenging study requirements. It was thought that close contact with the pulmonary rehabilitation staff during the prerandomization and immediate postrandomization phases would be important in ensuring that patients fully understood the study requirements and were committed to returning for follow-up, regardless of their treatment assignment. Although there are no data that are specific to the effect of rehabilitation, the impression of many centers was that this was a critical element in the extraordinary adherence to treatment achieved in the NETT.
Besides optimizing preoperative physical and emotional function, an important function of pulmonary rehabilitation was to help select appropriate patients for surgery and to ensure that patients made a truly informed choice about treatment options. Although we cannot quantify it precisely, the experience in the NETT was that many patients (perhaps 10%) who came to the study eager for surgery experienced such positive effects from pulmonary rehabilitation that they were subsequently unwilling to proceed to randomization and accept the surgical risks. Other patients, who might have initially seemed appropriate for surgery, were subsequently found during pulmonary rehabilitation to be too ill or fragile for surgery.
In extrapolating NETT results to clinical practice, the subgroups identified on the basis of postrehabilitation exercise capacity proved to be important. These results demonstrated that 20% of patients changed their subgroup designation after rehabilitation. Although most of these changes (67%) were from the low exercise subgroup to the high exercise subgroup, some patients (33%) changed from the high (33%) to the low exercise subgroup. This occurred slightly more commonly in patients with prior rehabilitation experience (37% vs 27% of subgroup changes, respectively) who may have already achieved maximum benefit from rehabilitation. However, this was also due to patients experiencing exacerbations during rehabilitation that impeded their progress but were not severe enough to prevent them from completing the program and qualifying for randomization.
Despite the extensive requirements of NETT and the out-of-pocket expenses, many patients traveled long distances and made a considerable effort to participate. In designing the pulmonary rehabilitation program for the NETT, we were concerned about the variability in services that might be provided in so many satellite centers, but wanted to make the protocol as available as possible to patients throughout the country. The fact that 65% of randomized patients utilized satellite centers indicates the strong motivation of many patients and justifies the inclusion of geographically dispersed centers. In retrospect, the relative consistency of improvements from pulmonary rehabilitation observed across centers in the NETT relieves these concerns.
Although these analyses focus on the prerandomization phase of pulmonary rehabilitation, it should be remembered that the NETT rehabilitation program was designed to be a daily home-care program that was continued throughout the study. Patients were required to return for additional supervised visits after randomization and were monitored for adherence through regular telephone and in-person contacts. Also, NETT centers had the option of prescribing additional supervised rehabilitation sessions if they were deemed necessary. This is distinctly different from the usual practice of pulmonary rehabilitation that is often restricted to one treatment period of a few months duration and without allowance for continued follow-up, reassessment, or retreatment.
Overall, pulmonary rehabilitation in the NETT produced significant benefits for these patients with advanced emphysema and played an important role in the selection of appropriate patients for possible LVRS. The consistency of the results, both in the NETT centers and at the satellite centers, demonstrates the effectiveness of pulmonary rehabilitation in the management of patients with chronic lung diseases.
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; and Ameena Al-Amin.
Baylor College of Medicine, Houston, TX:
Marcia Katz, MD (Principal Investigator); Carolyn Wheeler, RN, BSN (Principal Clinic Coordinator); Elaine Baker, RRT, RPFT; Peter Barnard, PhD, RPFT; Phil Cagle, MD; James Carter, MD; Sophia Chatziioannou, MD; Karla Conejo-Gonzales; Kimberly Dubose, RRT; 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; Owen Wilson, PhD; Christine Young PT; Rafael Espada, MD (Principal Investigator from 1996 to 2002); Rose Butanda (from 1999 to 2001); Minnie Ellisor (2002); Pamela Fox, MD (from 1999 to 2001); Katherine Hale, MD (from 1998 to 2000); Everett Hood, RPFT (from 1998 to 2000); Amy Jahn (from 1998 to 2000); Satish Jhingran, MD (from 1998 to 2001); Karen King, RPFT (from 1998 to 1999); Charles Miller III, PhD (from 1996 to 1999); Imran Nizami, MD (Co-Principal Investigator, from 2000 to 2001); Todd Officer (from 1998 to 2000); Jeannie Ricketts (1998 −2000); Joe Rodarte, MD (Co-Principal Investigator from 1996 to 2000); Robert Teague, MD (Co-Principal Investigator from 1999 to 2000); and Kedren Williams (from 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; and Scott Swanson, MD (Co-Principal Investigator, from 1996 to 2001).
Cedars-Sinai Medical Center, Los Angeles, CA:
Rob McKenna, MD (Principal Investigator); Zab Mohsenifar, MD (Co-Principal Investigator); Carol Geaga, RN (Principal Clinic Coordinator); Manmohan Biring, MD; Susan Clark, RN, MN; Jennifer Cutler, MD; Robert Frantz, MD; Peter Julien, MD; Michael Lewis, MD; Jennifer Minkoff-Rau, MSW; Valentina Yegyan, BS, CPFT; and Milton Joyner, BA (from 1996 to 2002).
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 Kurokawa, RRT, CPFT; Scott Marlow, RRT; Kevin McCarthy, RCPT; Pricilla McCreight, RRT, CPFT; Atul Mehta, MD; Moulay Meziane, MD; Omar Minai, MD; Mindi Steiger, RRT; Kenneth White, RPFT; Janet Maurer, MD (Principal Investigator, from 1996 to 2001); Terri Durr, RN (from 2000 to 2001); Charles Hearn, DO (from 1998 to 2001); Susan Lubell, PA-C (from 1999 to 2000); Peter O’Donovan, MD (from 1998 to 2003); and Robert Schilz, DO (from 1998 to 2002).
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 Berkmen, MD; Patricia Berkoski, MS, RRT (Site coordinator, LIJ); Frances Brogan, MSN, RN; Amy Chong, BS, CRT; Glenda DeMercado, BSN; Angela DiMango, MD; Sandy Do, MS, PT; Bessie Kachulis, MD; Arfa Khan, MD; Berend Mets, MD; Mitchell O’ Shea, BS, RT, CPFT; Gregory Pearson, MD; Leonard Rossoff, MD; Steven Scharf, MD, PhD (Co-Principal Investigator, from 1998 to 2002); Maria Shiau, MD; Paul Simonelli, MD; Kim Stavrolakes, MS, PT; Donna Tsang, BS; Denise Vilotijevic, MS, PT; Chun Yip, MD; Mike Mantinaos, MD (from 1998 to 2001); Kerri McKeon, BS, RRT, RN (from 1998 to 1999); and Jacqueline Pfeffer, MPH, PT (from 1997 to 2002).
Duke University Medical Center, Durham, NC:
Neil MacIntyre, MD (Principal Investigator); R. Duane Davis, MD (Co-Principal Investigator); John Howe, RN (Principal Clinic Coordinator); R. Edward Coleman, MD; Rebecca Crouch, RPT; Dora Greene; Katherine Grichnik, MD; David Harpole, Jr., MD; Abby Krichman, RRT; Brian Lawlor, RRT; Holman McAdams, MD; John Plankeel, MD; Susan Rinaldo-Gallo, MED; Sheila Shearer, RRT; Jeanne Smith, ACSW; Mark Stafford-Smith, MD; Victor Tapson, MD; Mark Steele, MD (from 1998 to 1999); and Jennifer Norten, MD (from 1998 to 1999).
Mayo Foundation, Rochester, MN:
James Utz, MD (Principal Investigator); Claude Deschamps, MD (Co-Principal Investigator); Kathy Mieras, CCRP (Principal Clinic Coordinator); Martin Abel, MD; 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; Jennifer Lamb; David Midthun, MD; Carl Mottram, RRT; Stephen Swensen, MD; Anne-Marie Sykes, MD; Karen Taylor; Norman Torres, MD; Rolf Hubmayr, MD (from 1998 to 2000); Daniel Miller, MD (from 1999 to 2002); Sara Bartling, RN (from 1998 to 2000); and Kris Bradt (from 1998 to 2002).
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; and Reuben Cherniack, MD (Principal Investigator, from 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; Charles Emery, PhD; Mark Gerhardt, MD, PhD; Mark King, MD; David Rittinger; and Mahasti Rittinger.
Saint Louis University, Saint Louis, MO:
Keith Naunheim, MD (Principal Investigator); Robert Gerber, MD (Co-Principal Investigator); Joan Osterloh, RN, MSN (Principal Clinic Coordinator); Susan Borosh; Willard Chamberlain, DO; Sally Frese; Alan Hibbit; Mary Ellen Kleinhenz, MD; Gregg Ruppel; Cary Stolar, MD; Janice Willey; Francisco Alvarez, MD (Co-Principal Investigator, from 1999 to 2002); and Cesar Keller, MD (Co-Principal Investigator, from 1996 to 2000).
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, CCTC; Wissam Chatila, MD; Francis Cordova, MD; Gilbert D’Alonzo, DO; Michael Keresztury, MD; Karen Kirsch; Chul Kwak, MD; Kathy Lautensack, RN, BSN; Madelina Lorenzon, CPFT; Ubaldo Martin, MD; Peter Rising, MS; Scott Schartel, MD; John Travaline, MD; Gwendolyn Vance, RN, CCTC; Phillip Boiselle, MD (from 1997 to 2000); and Gerald O’ Brien, MD (from 1997 to 2000).
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, MPH; Catherine Larsen, MPH; Trina Limberg, RRT; Michael Magliocca, RN, CNP; Frank J. Papatheofanis, MD, PhD; Dawn Sassi-Dambron, RN; and 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; Steven Scharf, MD, PhD; David Shade; Stanley Siegelman, MD; Kenneth Silver, MD; Clarence Weir; and 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; Mercedes True; Brian Woodcock, MD; and Lori Zaremba, RN.
University of Pennsylvania, Philadelphia, PA:
Larry Kaiser, MD (Principal Investigator); John Hansen-Flaschen, MD (Co-Principal Investigator); Mary Louise Dempsey, BSN, RN (Principal Clinic Coordinator); Abass Alavi, MD; Theresa Alcorn, Selim Arcasoy, MD; 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; Harold Palevsky, MD; 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 (from 1997 to 2001); and Angela Wurster, MSN, CRNP (from 1997 to 1999).
University of Pittsburgh, Pittsburgh, PA:
Frank Sciurba, MD (Principal Investigator); James Luketich, MD (Co-Principal Investigator); Colleen Witt, MS (Principal Clinic Coordinator); Gerald Ayres; 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; Gerene Bauldoff, RN, MSN (from 1997 to 2000); Manuel Brown, MD (from 1997 to 2002); Elisabeth George, RN, MSN (Principal Clinic Coordinator from 1997 to 2001); Robert Keenan, MD (Co-Principal Investigator from 1997 to 2000); Theodore Kopp, MS (from 1997 to 1999); and Laurie Silfies (from 1997 to 2001).
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; Jeanne Hoffman; Andra Ibrahim, MD; Diane Lockhart; Stephen Marglin, MD; Kenneth Martay, MD; Patricia McDowell; Donald Oxorn, MD; Liz Roessler; Michelle Toshima; and Susan Golden (from 1998 to 2000).
Agency for Healthcare Research and Quality, Rockville, MD:
Lynn Bosco, MD, MPH; Yen-Pin Chiang, PhD; Carolyn Clancy, MD; and Harry Handelsman, DO.
Centers for Medicare and Medicaid Services, Baltimore, MD:
Steven M Berkowitz, PhD; Tanisha Carino, PhD; Joe Chin, MD; JoAnna Baldwin; Karen McVearry; Anthony Norris; Sarah Shirey; Claudette Sikora; and Steven Sheingold, PhD (from 1997 to 2004).
Coordinating Center, The Johns Hopkins University, Baltimore, MD:
Steven Piantadosi, MD, PhD (Principal Investigator); James Tonascia, PhD (Co-Principal Investigator); Patricia Belt; Amanda Blackford, ScM; Karen Collins; Betty Collison; Ryan Colvin, MPH; John Dodge; Michele Donithan, MHS; Vera Edmonds; Gregory L. Foster, MA; Julie Fuller; Judith Harle; Rosetta Jackson; 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, ScM; and Robert Wise, MD.
Cost Effectiveness Subcommittee:
Robert M. Kaplan, PhD (Chair); J. Sanford Schwartz, MD (Co-Chair); Yen-Pin Chiang, PhD; Marianne C. Fahs, PhD; A. Mark Fendrick, MD; Alan J. Moskowitz, MD; Dev Pathak, PhD; Scott Ramsey, MD, PhD; Steven Sheingold, PhD; A. Laurie Shroyer, PhD; Judith Wagner, PhD; and Roger Yusen, 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; Thomas Schroeder, MA; Karma Kreizenbeck; Kristin Berry, MS; and Nadia Howlader, MS.
CT Scan Image Storage and Analysis Center, University of Iowa, Iowa City, IA:
Eric Hoffman, PhD (Principal Investigator); Janice Cook-Granroth, BS; Angela Delsing, RT; Junfeng Guo, PhD; Geoffrey McLennan, MD; Brian Mullan, MD; Chris Piker, BS; Joseph Reinhardt, PhD; Blake Robinswood; Jered Sieren, RTR; and William Stanford, MD.
Data and Safety Monitoring Board:
John A. 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; and Magdy Younes, MD.
Marketing Center, Temple University, Philadelphia, PA:
Gerard Criner, MD (Principal Investigator); and 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; and Margaret Wu, PhD (from 1996 to 2001).
Arthur Gelb, MD, Lakewood Regional Medical Center, Lakewood, CA.
Table 1. Characteristics of the Patients Prior to Pulmonary Rehabilitation (n = 1,218)*
| Save Table
|Age at randomization, yr||67.1 ± 6.1|
|Race or ethnic group|
| Non-Hispanic white||1156 (95)|
| Non-Hispanic black||42 (3)|
| Other||20 (2)|
| Female||472 (39)|
| Male||746 (61)|
| Less than high-school||247 (20)|
| High school||385 (32)|
| More than high-school||403 (33)|
| College||183 (15)|
|Prior rehabilitation||777 (64)|
|Satellite or other NETT clinic used for rehabilitation||786 (65)|
|FEV1 after BD||26.9 ± 7.1|
| % predicted|
| L||0.77 ± 0.24|
|RV/TLC ratio after BD, %||65.2 ± 8.1|
|IC after BD, L||1.71 ± 0.6|
|Dlco,% predicted||28.5 ± 9.8|
|Maximum work, W||35.9 ± 21.1|
| Borg scale†|
| Muscle fatigue (at maximum workload)||5.2 ± 2.5|
| Breathlessness (at maximum workload)||5.8 ± 2.3|
|Distance walked in 6 min, feet||1,142.0 ± 312.4|
| Borg scale|
| Muscle fatigue||3.4 ± 2.3|
| Breathlessness||5.0 ± 2.1|
|Oxygen flow rate (during 6-min walk, based on O2 titration walk), L/min|
| 0||512 (42)|
| 1–2||366 (30)|
| ≥ 3||338 (28)|
|Quality of life|
| St. George Respiratory Questionnaire†|
| Total score||56.5 ± 13.0|
| Activity score||81.9 ± 12.7|
| Impacts score||41.4 ± 16.7|
| Symptoms score||58.3 ± 19.3|
| UCSD Shortness-of-Breath Questionnaire score‡||65.7 ± 19.0|
| QWB average daily score§||0.537 ± 0.122|
| SF 36∥|
| Physical health summary score||28.3 ± 7.4|
| Mental health summary score||53.2 ± 10.9|
| Physical functioning score||22.1 ± 16.8|
| Role limit (physical health problems) score||20.9 ± 30.8|
| Role limit (personal/emotional problems) score||68.5 ± 41.0|
| Energy/fatigue score||43.8 ± 19.6|
| Emotional well-being score||74.6 ± 17.5|
| Social functioning score||61.8 ± 27.7|
| Bodily pain score||75.8 ± 23.7|
| General health perceptions||37.6 ± 20.2|
Table 2. Response to Rehabilitation: Changes from Prerehabilitation to Postrehabilitation for All Patients and by Prior Rehabilitation Experience*
| Save Table
|Prior Rehabilitation||Rehabilitation Performed at|
|All Patients (n = 1,218)||Yes (n = 777)||No (n = 441)||Satellite (n = 786)||NETT Center (n = 432)|
|FEV1 after BD|
| % predicted||− 0.13 ± 3.67||− 0.13 ± 3.57||− 0.12 ± 3.85||− 0.18 ± 3.64||− 0.02 ± 3.73|
| L||− 0.01 ± 0.11||− 0.01 ± 0.11||0.00 ± 0.11||− 0.01 ± 0.12||0.00 ± 0.10|
|RV/TLC ratio after BD, %||− 0.6 ± 5.1†||− 0.5 ± 5.1||− 0.7 ± 5.1||− 0.5 ± 5.1||− 0.8 ± 4.9|
|IC after BD use, L||− 0.00 ± 0.36||− 0.02 ± 0.34||0.03 ± 0.39||− 0.02 ± 0.36||0.03 ± 0.35|
|Maximum work, W||3.1 ± 11.1†||2.4 ± 10.4||4.3 ± 12.0‡||2.7 ± 11.1||3.9 ± 11.0|
| Borg scale|
| Muscle fatigue||− 0.9 ± 2.3†||− 0.8 ± 2.3||− 1.0 ± 2.3||− 0.8 ± 2.3||− 1.0 ± 2.4|
| Breathlessness||− 0.8 ± 2.2†||− 0.7 ± 2.1||− 1.0 ± 2.4||− 0.8 ± 2.3||− 0.8 ± 2.2|
|Distance walked in 6 min, feet||75.5 ± 176.3†||60.7 ± 184.6||101.7 ± 157.3‡||70.7 ± 180.4||84.2 ± 168.4|
| Borg scale|
| Muscle fatigue||− 0.3 ± 2.1†||− 0.2 ± 2.0||− 0.5 ± 2.2||− 0.3 ± 2.0||− 0.5 ± 2.2|
| Breathlessness||− 0.5 ± 1.9†||− 0.4 ± 1.9||− 0.6 ± 2.0||− 0.5 ± 1.9||− 0.5 ± 2.0|
|Quality of life|
| St. George Respiratory Questionnaire|
| Total score||− 3.5 ± 9.8†||− 2.6 ± 9.6||− 5.1 ± 10.1‡||− 3.6 ± 9.7||− 3.2 ± 10.0|
| Activity score||− 2.4 ± 10.7†||− 1.3 ± 10.2||− 4.4 ± 11.4‡||− 2.3 ± 10.6||− 2.8 ± 11.0|
| Impacts score||− 4.4 ± 13.3†||− 3.5 ± 13.2||− 6.1 ± 13.5‡||− 4.7 ± 13.2||− 3.8 ± 13.6|
| Symptoms score||− 2.4 ± 16.1†||− 2.0 ± 16.1||− 3.0 ± 16.3||− 2.6 ± 16.2||− 1.9 ± 16.1|
| UCSD Shortness-of-Breath Questionnaire||− 3.2 ± 13.4†||− 2.3 ± 13.5||− 4.8 ± 13.0‡||− 3.1 ± 13.5||− 3.4 ± 13.1|
| QWB average daily score||0.035 ± 0.117†||0.034 ± 0.113||0.036 ± 0.125||0.032 ± 0.114||0.040 ± 0.122|
| SF 36|
| Physical health summary score||1.3 ± 7.1†||0.9 ± 7.2||2.2 ± 6.8‡||1.4 ± 6.9||1.3 ± 7.4|
| Mental health summary score||2.0 ± 9.6†||1.8 ± 9.8||2.3 ± 9.2||1.9 ± 9.5||2.2 ± 9.9|
| Physical functioning score||3.6 ± 14.9†||2.6 ± 14.9||5.5 ± 14.8‡||3.4 ± 14.3||4.1 ± 16.0|
| Role limit score|
| Physical health problems||7.9 ± 37.9†||6.7 ± 38.2||10.1 ± 37.5||8.7 ± 37.6||6.4 ± 38.5|
| Personal/emotional problems||6.1 ± 46.0†||6.0 ± 47.2||6.2 ± 44.0||4.6 ± 45.0||8.8 ± 47.7|
| Energy/fatigue score||4.9 ± 17.4†||4.3 ± 17.3||6.0 ± 17.5||5.1 ± 17.1||4.6 ± 18.0|
| Emotional well-being score||3.2 ± 14.3†||2.3 ± 14.1||4.7 ± 14.7‡||3.0 ± 14.1||3.6 ± 14.8|
| Social functioning score||4.9 ± 25.3†||4.2 ± 25.0||6.0 ± 26.0||5.9 ± 25.2||3.1 ± 25.4|
| Bodily pain score||1.2 ± 22.9||0.3 ± 22.9||2.7 ± 22.9||0.4 ± 22.3||2.6 ± 24.0|
| General health perceptions||2.9 ± 16.6†||1.8 ± 16.4||4.7 ± 17.0‡||2.6 ± 16.1||3.4 ± 17.6|
Figure Jump LinkFigure 1. Box plots of changes from prerandomization pulmonary rehabilitation program in exercise capacity (maximum workload), health-related quality of life (St. George Respiratory Questionnaire total score), and dyspnea (UCSD Shortness of Breath [SOB] Questionnaire score) for all 1,218 patients, as well as for subgroups with and without prior pulmonary rehabilitation experience. Dashed lines represent the following estimated minimal clinically important differences: 5-W increase for maximum workload; 4-U decrease for the St. George Respiratory Questionnaire total score; and 5-U decrease for the UCSD Shortness of Breath Questionnaire score.Grahic Jump Location
Figure Jump LinkFigure 2. Changes in the subscales of the SF-36. PF = physical functioning; RP = role limit (physical health problems); Pain = bodily pain; GH = general health perceptions; EF = energy/fatigue; SF = social functioning; RE = role limit (personal/emotional problems); EW = emotional well-being (higher values indicate better quality of life); Pre Rehab = prerehabilitation; Post Rehab =postrehabilitation.Grahic Jump Location
Table 3. Multivariate Regression Model Estimates and 95% Confidence Limits for Change in Function or Quality of Life Before and After Rehabilitation*
| Save Table
|Outcome Covariate||Coefficients||p Value|
|Change in maximum exercise capacity (R2 = 0.11)|
| Age, yr||− 0.17||− 0.27, − 0.07||0.001|
| Gender (female vs male)||− 4.09||− 5.44, − 2.74||< 0.001|
| Prior participation in rehabilitation (no vs yes)||1.59||0.30, 2.89||0.02|
|Change in St. George Respiratory Questionnaire score (R2 = 0.25)|
| Prior participation in rehabilitation (no vs yes)||− 1.68||− 2.74, − 0.62||0.002|
| IC in 0.1 L||− 0.10||− 0.19, − 0.01||0.03|
| SF-36 physical summary score||− 0.16||− 0.25, − 0.08||< 0.001|
| SF-36 mental summary score||− 0.08||− 0.14, − 0.03||0.004|
| UCSD SOB score||0.09||0.05, 0.13||< 0.001|
|Change in UCSD SOB score (R2 = 0.23)|
| Prior participation in rehabilitation (no vs yes)||− 2.70||− 4.10, − 1.31||< 0.001|
| IC in 0.1 L||− 0.30||− 0.42, − 0.18||< 0.001|
| FEV1 % predicted||− 0.18||− 0.27, − 0.08||< 0.001|
| SF-36 physical summary score||− 0.22||− 0.33, − 0.11||< 0.001|
| St. George Respiratory Questionnaire score||0.16||0.09, 0.23||< 0.001|
Table 4. Classification of Patients Into High and Low Exercise NETT Subgroups Before and After Pulmonary Rehabilitation for All Non-High-Risk Patients as well as Those Patients With and Without Prior Experience of Pulmonary Rehabilitation
| Save Table
|All non-high-risk patients (n = 1,078)|
| After||≤ 0.001|
|All non-high risk patients with prior rehabilitation (n = 672)|
|All non-high risk patients with no prior rehabilitation (n = 406)|
| After||≤ 0.001|
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