Noninvasive Ventilation Has Not Been Shown To Be Ineffective in Stable COPD

Andrea Rossi

Respiratory Division,Bergamo General Hospital,Bergamo, Italy

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After several uncontrolled studies and some randomized clinical trials (RCT), a general consensus has been reached that noninvasive positive pressure ventilation (NPPV) can play an important role in the treatment of selected patients with acute respiratory failure due to exacerbation of chronic obstructive pulmonary disease (COPD) (1). This consensus remains in place despite the following problems: an RCT with negative results (2); considerable prescreening in the recruitment of NPPV candidates (3); and the small patient populations in some studies (4).

A similar optimistic attitude exists favoring the institution of long-term noninvasive ventilation (NIV) in patients with chronic respiratory failure due to neuromuscular or chest wall (restrictive) disorders (5); yet there have been no prospective studies with control groups published for restrictive patients, and most of the trials were uncontrolled and often retrospective in nature. It has been reported that the cumulative positive results have created an agreement in favor of NIV in this group of patients (6) and that undertaking a RCT would be unethical (7). By contrast, the perception for NIV in stable COPD is less positive. Many authors claim that stable COPD remains a questionable and controversial indication for NIV (7). Long-term mechanical ventilation is an expensive treatment necessitating a high level of motivation and compliance from patients. However, why should "questionable, controversial, and not definitely proved" be considered synonymous with "ineffective"? As Shakespeare would have phrased it:

Friends, Romans, Countrymen, lend me your ears; I come not to praise NIV. . . . (10)

It is stated that long-term oxygen therapy is the only treatment that has been demonstrated to prolong survival of COPD patients in controlled trials (8). Currently, there are no data that support the use of long-term mechanical ventilation as a means to reduce mortality of COPD (9). Is mortality the only end-point in medicine? Did any RCT show that inhaled steroids improve survival in asthma? Nevertheless, international guidelines state that inhaled steroids are the first-line therapy for bronchial asthma (11).

There are several reasons why NIV should not be excluded from potential treatments that might benefit patients with end-stage COPD. First, several physiologic studies have shown that patients with advanced COPD and chronic CO₂ retention want to breathe but that they have great difficulties in sustaining spontaneous ventilation because of the severe imbalance between the mechanical load and respiratory muscle capacity. Severe ventilation-perfusion mismatching worsens gas exchange. Furthermore, nocturnal hypoventilation associated with episodic oxygen desaturation and worsening of hypercapnia is a common finding in patients with stable COPD (9). Although oxygen therapy may correct the hypoxemia, this treatment is associated with aggravation of hypercapnia (12). Worsening of hypercapnia during sleep upwardly resets the set-point for CO₂, increasing Pa_CO2 during the day with detrimental consequences for heart, respiratory muscles, and cognitive function (9). Nocturnal hypoventilation may create a vicious cycle, which could potentially be reversed by nocturnal NIV (9). Chronic hypercapnia does not kill (13), but it aggravates sleep fragmentation and respiratory muscle dysfunction, worsening a patient's quality of life. Some short-term studies have demonstrated that nocturnal NIV could improve respiratory function in patients with advanced COPD by providing a period of rest for the respiratory muscles, and by reversing nocturnal hypoventilation (9).

The physiologic benefits of NIV are expected to translate into an overall improved respiratory function and sense of well-being.

In an uncontrolled study of nocturnal NIV in COPD patients with CO₂ retention, a sustained improvement in daytime Pa_CO2 was documented after 6 mo of treatment (14). In a prospective RCT (15), nocturnal NIV, compared to oxygen therapy alone, caused a significant improvement in daytime blood gases, sleep quality, and quality of life. Although this study was carefully planned with a crossover design, the period of observation was short (3 mo) and the study population was small (14 patients). The so-called negative studies neither enrolled larger groups nor were longer. One study (16) was initiated in 23 patients but only 7 patients completed 3 mo. Similarly, Lin (17) completed the study in 10 patients for a total period of observation of 4 wk. Why should the "negative" results by Stumpf (16) and Lin (17) carry more weight than the "positive" data by Meecham-Jones (15)?

Most of the pessimistic attitude toward long-term NIV in severe, stable COPD is due to the negative results of a large RCT by Shapiro and colleagues (18). They failed to show additional benefits from negative pressure ventilation (NPV) over oxygen therapy and comprehensive rehabilitation programs. However, that study was addressing the hypothesis of chronic respiratory muscle fatigue and was performed mostly in nonhypercapnic COPD. By contrast, short-term physiologic, although uncontrolled, studies consistently showed improvements in daytime Pa_CO2 as well as inspiratory muscle strength (9). Another RCT did not exclude the possibility that NPV might provide benefits to COPD patients with chronic hypercapnia and even suggested that it might be helpful in those patients (19).

In general, the "positive" studies recruited patients with higher stable Pa_CO2 than the "negative" studies (9). In all the studies a variable proportion of patients refused the treatment administered by means of either negative or positive pressure. However, a long-term follow-up on NPPV in severe COPD reported that the average duration of continuation was 2 to 3 yr (8). The problem of compliance to long-term inhaled therapy exists in asthma (11)does this suggest that inhaled steroids are ineffective in asthma?

Finally, it should be recalled that preliminary data from a multicenter French study showed a modest improvement in survival among patients treated with NIV compared with patients receiving conventional oxygen therapy, although the difference did not reach statistical significance (20).

Therefore, the statement that NIV is ineffective in stable COPD just because there is no prospective RCT providing evidence of a significant improvement in survival sounds unduly inflexible and as dangerous as the haste of the honorable men to bury Caesar. Looking forward to seeing you in Filippi.

	References

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