© 2007 American Thoracic Society doi: 10.1164/rccm.200705-682ED
Oxygen Therapy in COPD: What Do We Know?Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
There are known knowns; there are things we know we know. We also know there are known unknowns, that is to say we know there are some things we do not know. But there are also unknown unknowns—the ones we don't know we don't know.—Donald Rumsfeld Facts are stupid things.—Ronald Reagan It's what a fellow thinks he knows that hurts him.—Kin HubbardWhile the death rates for other chronic diseases decline in the United States, the death rate for chronic obstructive pulmonary disease (COPD) continues to increase (1, 2). It is time to reassess what is and is not known about oxygen therapy for COPD. Long-term oxygen therapy improves survival in some populations with COPD (3, 4). The Nocturnal Oxygen Treatment Trial (NOTT) and Report of the Medical Research Council (MRC) evaluated long-term oxygen therapy in patients with COPD with severe hypoxemia. Both studies demonstrated a survival benefit with supplemental oxygen, but only in those who were instructed to use it 15–24 h per day. Current guidelines and Medicare reimbursement policies are derived from these two relatively small studies (290 patients) (5, 6). Guidelines and reimbursement policies for patients with exercise desaturation were promulgated with even less evidence. Medicare charges for oxygen were $2.2 billion in 2002, with annual inflation of 12–13% per year (7, and unpublished CMS data). The economic impact of oxygen use in populations with COPD necessitates further studies. In this issue of the Journal (pp. 343–349), Nonoyama and colleagues evaluate the effect of oxygen therapy in patients with COPD experiencing desaturation with exertion, but not at rest (8). Data are lacking regarding benefit of oxygen therapy in this setting (9). A novel design was used to approach this clinical question. N-of-1 randomized controlled trials were implemented to study the effects of oxygen on individual participants. In this design, participants serve as their own controls, crossing over between two masked treatments several times. The strength of the design is its ability to observe individual responses to an intervention and thus account for variable responses of individuals, mitigating the need for larger trials that aim to define responses on a population basis (10). Such trials can be used to personalize treatments for patients while we are awaiting the fulfillment of promises of pharmacogenetics to predict individual responses to treatment. However, this trial design does have limitations. It assumes that the treatment effect is of rapid onset and offset, without carry-over effects between treatment periods. These assumptions are likely true for some oxygen effects, but not others. For example, the effect of oxygen on increasing peak exercise capacity in patients with COPD is of rapid onset and offset. However, if oxygen treatment in such patients is accompanied by increased aerobic exercise, there may be training effects that take weeks or months to occur and weeks or months to dissipate (11). Moreover, several issues prevent the broad clinical implementation of this design: the need for consent and institutional oversight, a research infrastructure to conduct such trials for clinical purposes, and potentially negative attitudes by patients and physicians in a therapeutic relationship. This study presents several key findings regarding the short- and long-term effects of oxygen therapy. It confirms the previously described increase in exercise capacity seen acutely with oxygen therapy in patients with COPD with mild hypoxemia (12, 13). It has been unclear if this observation translates into a more persistent increase in clinical endurance outside of the laboratory. To address this, the authors measured home five-minute walk testing and dyspnea scores. Throughout the intervention periods, which included two-week periods of either oxygen or placebo in a random sequence repeated three times, a minimal improvement was seen in distance walked with oxygen (427 versus 412 steps, P = 0.04). While the modified Borg dyspnea scale did decrease (less dyspnea) with oxygen from 3.2 to 2.8 (P = 0.04), the difference was small. Other dyspnea indices did not improve with oxygen therapy. The authors conclude that only a small proportion of patients with mild resting hypoxemia and exercise desaturation receive an important benefit from home oxygen. Implicit in this conclusion is the assumption that patients were in fact mobile and active during the study period. After all, an intervention designed to improve dyspnea will have no effect if the patient is not involved in activities that induce dyspnea. The authors acknowledge the impact of activity level on benefit of oxygen therapy. In this study, the total time per day participants used the portable cylinder was 0.7 ± 0.6 hours in the oxygen group and 0.6 ± 0.6 hours with placebo cylinders. Essentially, patients used portable oxygen approximately 40 minutes per day, raising question as to their level of dyspnea-inducing activities and confirming the findings of Pitta and colleagues that patients with COPD acclimate to an inactive lifestyle (14). This observation highlights a key distinction in clinical descriptors of COPD: functional capacity (what a patient is able to do) versus functional status (what a patient actually does). This study shows that oxygen therapy with exertion in those with exercise desaturation increases functional capacity but not functional status. The findings by Nonoyama and colleagues challenge those of us who prescribe oxygen to explore the intricacies of real-world activity levels of our patients and how oxygen may benefit those individuals. It also challenges us to learn what supplemental oxygen therapy can accomplish when coupled with an exercise training program designed to potentiate oxygen's effects. Continued efforts with innovative approaches, such as those used by Nonoyama, will allow the treatment of COPD to move away from the limited data of the past into a future where COPD no longer damages and shortens the lives of so many. FOOTNOTES Conflict of Interest Statement: M.B.D. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.A.W. has been a paid consultant to Praxair in 2006. REFERENCES
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