Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure

Almost 2 decades after the introduction of noninvasive positive pressure ventilation (NPPV), researchers continue to try to catch up with the necessary evaluation to answer key clinical questions about this intervention. For instance, should NPPV be used in patients with acute respiratory failure? If so, do some patients benefit more than others? Can NPPV ever cause harm in this setting? While the puzzle is not complete, each study contributes a new piece that provides a glimpse of the big picture. Two studies, in this issue of the THE JOURNAL^{1 - 2} provide important data on the effectiveness of NPPV in acute respiratory failure.

The effect of NPPV in acute respiratory failure on outcomes, such as the need for endotracheal intubation, length of stay in the intensive care unit (ICU), duration of ventilation, and survival, varies among patients. The initial population primarily studied in randomized controlled trials was patients with acute exacerbations of chronic obstructive pulmonary disease (COPD).^{3 - 12} In a landmark randomized trial of 60 patients, Bott and colleagues³ suggested the benefit of NPPV. In the first multicenter trial, Brochard and coworkers⁴ found that NPPV not only decreased the need for intubation but also improved survival. At least 10 trials have been published focusing on patients with COPD alone or allowing subgroup analysis of these patients.^{3 - 12} The effectiveness of NPPV is reproducible across trials, although the magnitude of benefit varies. The largest benefit appears confined to patients with severe exacerbations of COPD who present with hypercarbia. When used safely in this setting, it appears that NPPV is not only more effective that standard medical therapy but also costs less.¹³

Patients with less serious exacerbations of COPD who are generally treated on the wards of North American hospitals have not been demonstrated to benefit from NPPV. A small trial (n = 24) evaluating treatment of patients with mild COPD exacerbations, none of whom required intubation, showed that NPPV afforded no benefit.¹² This lack of benefit may be because of the less seriously ill population enrolled or may reflect this study's insufficient power to detect differences in outcome, if benefit does exist. In patients with milder COPD exacerbations, the use of NPPV also is more costly.¹³ A central issue is how the use of NPPV decreases hospital mortality. Earlier trials suggested that the survival benefit for patients with severe exacerbations of COPD was due to avoiding endotracheal intubation and its associated complications. Brochard and coworkers⁴ found a trend toward a decrease in the rate of nosocomial pneumonia in patients treated with NPPV (relative risk, 0.28; 95% confidence interval, 0.06-1.27).

In this issue of THE JOURNAL, Girou and colleagues¹ report the results of a case-control study designed to estimate the association between invasive vs noninvasive ventilation and infectious complications. Cases (patients treated with NPPV) and controls (those receiving conventional mechanical ventilation) were matched for important characteristics, including admission diagnoses, age, Simplified Acute Physiology Score II, Logistic Organ Dysfunction score, and eligibility for NPPV. Of the total group of patients, 73% presented with acute exacerbations of COPD and the rest with cardiogenic pulmonary edema. The study results demonstrated fewer infectious complications, including nosocomial pneumonia, in patients treated with NPPV.

While inferences from a case-control study are weaker than those from other experimental designs, this method is useful to address the relation between NPPV and infections acquired in the ICU. Moreover, conducting further randomized controlled trials in which patients have a 50% chance of receiving NPPV could be viewed as scientifically and ethically questionable in light of the weight of evidence supporting the benefit of NPPV in patients with hypercarbic COPD exacerbations. Endotracheal intubation may promote, and certainly allows, easier recognition of purulent tracheobronchial secretions, thus creating a bias toward diagnosing a higher pneumonia rate in the intubated group. However, in the study by Girou et al, more strict diagnostic criteria, including the requirement for diagnostic bronchoscopy, were applied to patients who were intubated, an approach that would counter this bias. While some unmeasured confounding factors likely remain in this case-control analysis, the lower nosocomial infection rate in the NPPV group was substantial. The findings of this study, combined with those of others,^{4 ,14} support the suggestion that the increased survival of patients with COPD who receive NPPV may be due, in part, to the avoidance of pneumonia and other ICU-acquired infections.

Another important issue is whether patients presenting with acute respiratory failure that is not due to COPD benefit from NPPV. The findings in the literature are mixed and the answer is still unclear. One potential confounder across reported trials is the variable populations studied. Most trials have studied heterogeneous groups of patients without COPD who present with hypoxemic respiratory failure alone, primarily hypercarbic respiratory failure, or a combination of the 2. In a post hoc analysis, Wysocki et al¹⁵ suggested that patients with hypercarbic, rather than hypoxemic, respiratory failure are more likely to benefit from NPPV, but this has yet to be prospectively studied.

Despite enthusiasm arising from promising case series, initial trials including patients with hypoxemic respiratory failure found no difference in intubation or mortality rates between those treated with NPPV and those receiving standard care.^{15 - 16} The findings of more recent trials have been variable. In a study evaluating NPPV among patients with severe community-acquired pneumonia, Confalonieri et al¹¹ found that the benefit from NPPV was restricted to those patients with accompanying COPD. In contrast, 2 other trials studying selected groups of heterogeneous patients that included those presenting with hypoxemic respiratory failure reported lower intubation rates with NPPV.^{9 ,17} No survival benefit was found in either of these trials using conventional analysis (although one trial reported higher survival rates for NPPV patients using incidence rates⁹ ). In a recent study, Antonelli et al¹⁸ compared the use of NPPV in patients with hypoxemic respiratory failure who were seriously ill enough that they were all deemed to require mechanical ventilation; in this trial, the control group was intubated and conventionally ventilated. These authors reported lower rates of sinusitis and pneumonia, a shorter duration of ventilation and length of ICU stay, and a trend toward a lower mortality rate in the NPPV group. However, most clinicians who use NPPV do so earlier to avoid the need for intubation and conventional mechanical ventilation. As such, the population studied by this group may not represent the majority of patients whom clinicians would generally treat with NPPV.

While data regarding the effectiveness of NPPV are conflicting for patients with hypoxemic respiratory failure, the key clinical issue is whether it is worth trying to avoid endotracheal intubation and its attendant potential complications. The study by Declaux and colleagues² in this issue of THE JOURNAL now makes this approach questionable. This group conducted a multicenter, randomized controlled trial comparing the use of continuous positive airway pressure (CPAP) to standard medical treatment in patients presenting with acute pulmonary edema, the majority of whom had acute lung injury (the presence of bilateral pulmonary infiltrates on chest radiographs, PaO₂/FIO₂ ratio <300 mm Hg, and no evidence of heart failure). While both modes of support are applied similarly, CPAP and NPPV differ by the latter providing additional assistance during the inspiratory cycle of ventilation. Although the authors report better gas exchange in the CPAP group after the first hour, no other benefit was demonstrated thereafter. Of great concern, they found a higher rate of complications among the patients treated with CPAP. Most worrisome were the 4 cardiac arrests in the CPAP group that occurred at the time of intubation (3 patients) or at the time of removal of the CPAP mask for nursing care, resulting in worsening hypoxemia (1 patient). No cardiac arrests occurred in the standard therapy group.

How does this trial fit with recent NPPV trials suggesting benefit for hypoxemic respiratory failure? It may be that NPPV is truly superior to CPAP; perhaps this may explain the absence of benefit in this trial. Patient population is undoubtedly also a factor, as the patients in the study by Declaux et al mainly had acute lung injury. Patients with acute lung injury are more likely to require prolonged ventilatory support and develop pulmonary and nonpulmonary complications, but were enrolled in much smaller numbers in the NPPV trials. While the lack of effectiveness reported in this CPAP trial is important, the adverse event rates should be highlighted. While CPAP and NPPV do differ, there is no doubt that for some patients either intervention simply prolongs the time to inevitable intubation. For patients presenting with hypoxemic respiratory failure, delaying the time to intubation often results in the need to intubate patients who are more unstable than if NPPV had not been tried. The risk of cardiac arrest in this situation is higher and places some patients at unnecessary risk.

In summary, although NPPV has become a part of daily care for many patients with acute respiratory failure in many centers, the potential effectiveness of this intervention varies across patient populations. The benefit seems greatest for patients with almost pure hypercarbic respiratory failure, of which patients with COPD are the most common. As the degree of hypoxemia associated with respiratory failure becomes greater, evidence suggesting benefit is more meager. Another crucial determinant of success is the clinician who applies NPPV. Randomized controlled trials generally are conducted by experts in an acute care setting in which close attention to detail optimizes the effectiveness of NPPV. However, in actual practice, patient selection may not be so precise, clinical expertise may not be as great, and monitoring may not be as careful. As such, clinicians considering NPPV for patients with acute hypoxemic respiratory failure must remain mindful of the inconsistent benefit of NPPV reported in the literature and the potential for serious complications. Clearly, further study is required to identify those patients with hypoxemic respiratory failure who are most likely to benefit from NPPV and those who are at highest risk of adverse consequences. In the interim, institutions using this technology should apply principles of iterative continuous quality improvement by judicious application of NPPV, ongoing local evaluation, and careful attention to complication rates.