Non-invasive Ventilation in Acute Cardiogenic Pulmonary Edema

Abstract & Commentary

By Dean Hess, PhD, RRT, Respiratory Care, Massachusetts General Hospital, Department of Anesthesiology, Harvard Medical School, Boston. Dr. Hess reports no financial relationship to this field of study. This article originally appeared in the November 2008 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD. Dr. Pierson is Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, and Dr. Thompson is Staff Pulmonologist, VA Medical Center; Associate Professor of Medicine, University of Washington. Drs. Pierson and Thompson report no financial relationships relevant to this field of study.

Synopsis: In patients with acute cardiogenic pulmonary edema, CPAP or NIV produces a more rapid improvement in respiratory distress and arterial blood gases than standard therapy.

Source: Gray A et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359:142-151.

Non-invasive ventilation (NIV) and continuous positive airway pressure (CPAP) have been shown to be of benefit in the treatment of patients with acute cardiogenic pulmonary edema (CPE). Gray et al conducted this study to determine whether NIV or CPAP reduces mortality in this patient population. This was a multicenter, open, prospective, randomized controlled trial. Patients were assigned to standard oxygen therapy, CPAP (5-15 cm H2O), or NIV (inspiratory pressure, 8-20 cm H2O; expiratory pressure, 4-10 cm H2O). The primary endpoint was death within seven days after the initiation of treatment.

Of 1,069 patients enrolled, 367 were assigned to standard oxygen therapy, 346 were assigned to CPAP, and 356 were assigned to NIV. There was no significant difference in seven-day mortality between patients receiving oxygen therapy (9.8%) and those receiving NIV (9.5%, p = 0.87). There was no significant difference in the combined endpoint of death or intubation within seven days between the patients who were assigned to NIV (11.1%) and those assigned to CPAP (11.7%, p = 0.81). Compared to oxygen therapy, NIV was associated with greater improvements at one hour after the beginning of treatment in patient-reported dyspnea (p = 0.008), heart rate (p = 0.004), pH (p < 0.001), and hypercapnia (p < 0.001). There were no treatment-related adverse events. Gray et al concluded that, in patients with acute CPE, NIV induces a more rapid improvement in respiratory distress and metabolic disturbance than standard oxygen therapy, but has no effect on short-term mortality.


Over the past 10 years, there has been increasing use of NIV in patients with acute respiratory failure. Many randomized, controlled trials have been published, and these have been combined into several meta-analyses. In fact, meta-analyses have reported benefit for NIV and CPAP for acute CPE, concluding that this therapy reduces the risk of intubation.

The first meta-analysis was by Pang et al in 1998.1 They found that CPAP (three studies) was associated with a decrease in the need for intubation (risk difference, -26%; 95% confidence intervals [CI], -13% to -38%) and a trend for a decrease in hospital mortality (risk difference, -6.6%; 95% CI, +3% to -16%) compared with standard therapy alone. In this meta-analysis, there was insufficient evidence to comment on the effectiveness of NIV compared with either standard therapy or CPAP and standard therapy.

The second meta-analysis was published in 2005 by Masip et al.2 In the combined analysis of CPAP and NIV, there was a significantly reduced mortality by nearly 45% compared with conventional therapy (RR, 0.55; 95% CI, 0.40-0.78; p < 0.001). Although mortality was reduced for CPAP (9 studies; RR, 0.53; 95% CI, 0.35-0.81; p = 0.003), this was not the case for NIV (6 studies; RR, 0.60; 95% CI, 0.34-1.05; p = 0.07). Both CPAP and NIV showed a significant decrease in intubation compared with conventional therapy; CPAP (RR, 0.40; 95% CI, 0.27-0.58; p < 0.001), NIV (RR, 0.48; 95% CI, 0.30-0.76; p < 0.001), and together (RR, 0.43; 95% CI, 0.32-0.57; p < 0.001).

A third meta-analysis by Gray et al reported that CPAP was associated with a significantly lower mortality rate than standard therapy (12 studies; RR, 0.59; 95% CI, 0.38-0.90; p = 0.015).3 There was a non-significant difference in mortality for the comparison between NIV and standard therapy (7 studies; RR, 0.63; 95% CI, 0.37-1.10; p = 0.11). The need for intubation was reduced with CPAP (RR, 0.44; 95% CI, 0.29-0.66; p = 0.0003) and with NIV (RR, 0.50; 95% CI, 0.27-0.90; p = 0.02), compared with standard therapy.

Finally, a meta-analysis by Winck et al showed a 22% absolute risk reduction (ARR) in intubation (95% CI, -34% to -10%; p < 0.001) and 13% in mortality (95% CI, -22% to -5%; p = 0.003) for CPAP compared to standard therapy (10 studies).4 For six studies of NIV compared to standard medical treatment, there was an 18% ARR in intubation (95% CI, -32% to -4%; p = 0.01) and 7% in mortality (95% CI, -14% to 0%; p = 0.06).

Meta-analyses have also compared CPAP with NIV. Masip et al reported no differences in intubation or mortality rates in the analysis of studies comparing the 2 techniques.2 Comparing NIV to CPAP, Peter et al found no difference in mortality risk (P = 0.38) or intubation rate (p = 0.86).3 Winck et al found a nonsignificant 3% ARR in intubation (95% CI -4% to 9%) and 2% in mortality (95% CI, -6% to 10%) with NIV compared to CPAP.4 Ho et al conducted a meta-analysis specifically comparing NIV and CPAP.5 From 7 studies, intubation (RR, 0.80; 95% CI, 0.33-1.94; p = 0.62) and hospital mortality (RR, 0.76; 95% CI, 0.32-1.78; p = 0.52) were similar between patients treated with CPAP and those treated with NIV.

Following the study by Mehta et al,6 there was concern about the safety of NIV, specifically for new myocardial infarction, in patients with acute cardiogenic pulmonary edema. However, this has not emerged as a significant concern in subsequent studies or meta-analyses.

How should this new study by Gray et al be viewed in the context of these meta-analyses? First, the intubation rate was extremely low in the Gray study: 0.8% in the standard therapy group; 0.3% in the CPAP group; and 1.1% in the NIV group. It's hard to imagine how any therapy can improve on the need for intubation when the overall intubation rate of the enrolled patients is so low. This suggests that the patients in this study were less acutely ill than those in previous studies included in the meta-analyses. The absence of a mortality benefit in this study is consistent with the meta-analyses described above, most of which failed to report a mortality benefit for NIV. This may be related to the relatively low mortality in this patient population. In the Masip meta-analysis,2 for example, the overall mortality was 15%. A quick-power analysis reveals that a sample size of more than 1,500 patients (about 700 in each group) is required to detect a reduction in mortality from 15% to 10% with a power of 0.8. So, it should be no surprise that a meta-analysis, let alone a single study, is unlikely to show a mortality benefit in this patient population.

Given the results of prior studies, many of us have adopted the use of NIV or CPAP as first-line therapy in patients presenting with acute CPE. This is supported not only by the results of randomized, controlled trials, but also by a sound underlying physiology. Increasing the intrathoracic pressure with NIV or CPAP reduces preload and afterload, which supports the failing heart while definitive therapies are administered. This should translate into improvements in heart rate, respiratory rate, dyspnea, and arterial blood gases. In fact, these benefits were reported in the study by Gray et al.

The study by Gray et al should not change the recommendation for CPAP of NIV as a first-line therapy in patients presenting with acute CPE. Similar outcomes are likely with CPAP or NIV; this is probably more of an academic than a practical point, given that the same equipment is used for either therapy in modern practice. CPAP or NIV produces a more rapid improvement in respiratory distress than standard therapy alone. CPAP and NIV reduce the need for intubation in patients sick enough to be at risk for intubation, which is supported by several meta-analyses.


1. Pang D, et al. The effect of positive pressure airway support on mortality and the need for intubation in cardiogenic pulmonary edema: a systematic review. Chest. 1998;114:1185-1192.

2. Masip J, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA. 2005;294:3124-3130.

3. Peter JV, et al. Effect of non-invasive positive pressure ventilation (NIPPV) on mortality in patients with acute cardiogenic pulmonary oedema: A meta-analysis. Lancet. 2006;367:1155-1163.

4. Winck JC, et al. Efficacy and safety of non-invasive ventilation in the treatment of acute cardiogenic pulmonary edema—a systematic review and meta-analysis. Crit Care. 2006;10:R69.

5. Ho KM, Wong K. A comparison of continuous and bi-level positive airway pressure non-invasive ventilation in patients with acute cardiogenic pulmonary oedema: A meta-analysis. Crit Care. 2006;10:R49.

6. Mehta S, et al. Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema. Crit Care Med. 1997;25:620-628.