The Use of Noninvasive Ventilation in Emergency Department Patients With Acute Cardiogenic Pulmonary Edema: A Systematic Review

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1 CARDIOLOGY/ORIGINAL RESEARCH The Use of Noninvasive Ventilation in Emergency Department Patients With Acute Cardiogenic Pulmonary Edema: A Systematic Review Sean P. Collins, MD, MSC Lisa M. Mielniczuk, MD Heather A. Whittingham, MD Mark E. Boseley, MD David R. Schramm, MD Alan B. Storrow, MD From the Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH (Collins); the Division of Cardiology, Brigham and Women s Hospital, Boston, MA (Mielniczuk); the Division of Pulmonary Critical Care, University Health Network, University of Toronto, Toronto, Ontario, Canada (Whittingham); the Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Boston, MA (Boseley); the Department of Otolaryngology, University of Ottawa, Ottawa, Ontario, Canada (Schramm); and the Department of Emergency Medicine, Vanderbilt University, Nashville, TN (Storrow). Study objective: Acute cardiogenic edema is a common cause of respiratory distress in emergency department (ED) patients. Noninvasive ventilation by noninvasive positive pressure ventilation or continuous positive airway pressure has been studied as a treatment strategy. We critically evaluate the evidence for the use of noninvasive ventilation on rates of hospital mortality and endotracheal intubation. Methods: We searched the databases of MEDLINE, EMBASE, and the Cochrane Library from 1980 to Additional sources included key journals, bibliographies of selected articles, and expert contact. We included studies that incorporated a randomized design; patients older than 18 years and with acute cardiogenic edema; diagnosis and treatment initiated in the ED; noninvasive ventilation in addition to standard medical therapy compared to standard medical therapy alone, or noninvasive positive pressure ventilation compared to continuous positive airway pressure (both in addition to standard medical therapy); and data on hospital mortality or intubation. A random-effects model was used to obtain the summary risk ratios (RRs) and 95% confidence intervals (CIs) for hospital mortality and intubation. Results: A pooled analysis of 494 patients suggested that noninvasive ventilation in addition to standard medical therapy significantly reduced hospital mortality compared to standard medical therapy alone (RR 0.61; [95% CI 0.41, 0.91]). Similarly, a meta-analysis of 436 patients suggested that noninvasive ventilation was associated with a significant decrease in intubation rates (RR 0.43; [95% CI 0.21, 0.87]). Conclusion: Our results suggest that noninvasive ventilation with standard medical therapy is advantageous over standard medical therapy alone in ED patients with acute cardiogenic edema. Future studies, powered appropriately for mortality and intubation rates, are necessary to confirm these findings. [Ann Emerg Med. 2006;48: ] /$-see front matter Copyright 2006 by the American College of Emergency Physicians. doi: /j.annemergmed INTRODUCTION Background Acute cardiogenic edema is a common cause of respiratory distress in patients presenting to the emergency department (ED). Patients with less severe symptoms of acute heart failure may respond to conventional treatment with oxygen, diuretics, and vasodilators. However, a subset of patients with respiratory compromise will require endotracheal intubation and mechanical ventilation. Unfortunately, this therapy has been associated with significant morbidity, such as nosocomial infection, increased need for sedation (and thus longer duration of ventilation), and upper airway complications of endotracheal tube placement. 1 As a result, there has been considerable interest in developing less invasive alternatives that can decrease the need for intubation. 260 Annals of Emergency Medicine Volume 48, NO. 3 : September 2006

2 Collins et al Editor s Capsule Summary What is already known on this topic Noninvasive ventilation is effective in patients with noncardiac causes of respiratory failure. The evidence for noninvasive ventilation use in patients with respiratory failure caused by heart failure is conflicting. What question this study addressed This systematic review examined outcomes in randomized controlled trials that compared noninvasive ventilation plus standard care to standard care alone in patients with respiratory failure caused by severe heart failure. What this study adds to our knowledge The meta-analyses included roughly 450 patients and showed that noninvasive ventilation reduced mortality and intubation rates compared with standard therapy. The literature was insufficient to establish whether continuous positive airway pressure is better or worse than noninvasive positive pressure ventilation methods in these patients. How this might change clinical practice Noninvasive ventilation should be considered in patients with respiratory failure caused by congestive heart failure because it has been shown to improve outcomes. Two noninvasive ventilation strategies have been studied in the treatment of acute cardiogenic edema. Continuous positive airway pressure is a modality that maintains a constant positive pressure during inspiration and expiration and has been shown to have several benefits. Continuous positive airway pressure decreases the work of breathing 2 and left ventricular afterload while maintaining cardiac index. 3 Noninvasive positive pressure ventilation (or bilevel positive airway pressure [BiPAP]), which provides inspiratory pressure support coupled with positive endexpiratory pressure, theoretically provides the same benefits of continuous positive airway pressure, as well as inspiratory 4 assistance to further decrease the work of breathing. Both treatment modalities are delivered through a tight-fitting facial or nasal mask. Several small randomized clinical trials in patients with acute cardiogenic edema have demonstrated a reduced need for intubation and mechanical ventilation with continuous positive airway pressure. These studies lacked sufficient power to 5-7 detect a decrease in mortality. A systematic review and metaanalysis performed in 1998 suggested an absolute risk difference of 26% in the need for intubation with continuous positive airway pressure compared to standard care alone and a trend 8 toward decreased hospital mortality. Of the 3 trials included, one included patients that were not clearly identified and treated 7 in the ED. Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema Importance 8 At the time of the Pang et review, al only 1 trial of noninvasive positive pressure ventilation in acute cardiogenic edema had been published. That study demonstrated greater respiratory and hemodynamic improvement in the noninvasive positive pressure ventilation group compared with continuous positive airway pressure, but both continuous positive airway pressure and noninvasive positive pressure ventilation had similar rates of intubation and hospital mortality. 4 However, there was an increased incidence of myocardial infarction reported in the noninvasive positive pressure ventilation group. Since 1998, there have been a number of additional small randomized trials comparing noninvasive ventilation in addition to standard medical therapy versus standard medical therapy alone, or noninvasive positive pressure ventilation was compared to continuous positive airway pressure (both in addition to standard medical therapy) in an attempt to clarify the role of 9-18 noninvasive ventilation in cardiogenic edema. Two of these trials suggested a decreased rate of intubation with noninvasive ventilation compared with standard medical therapy, 9,11 and one suggested a decreased rate of hospital mortality in the noninvasive ventilation group when compared 11 with standard medical therapy. The remainder of the studies suggests that noninvasive ventilation had no effect on rates of hospital mortality or intubation. To date, there have been no systematic reviews that have focused solely on the use of noninvasive ventilation in ED patients with acute cardiogenic edema. Goals of This Investigation The purpose of this systematic review was to critically evaluate the body of evidence on noninvasive ventilation in patients who had acute cardiogenic edema and presented to the ED. Four interventions were assessed: (1) noninvasive ventilation (continuous positive airway pressure or noninvasive positive pressure ventilation) compared with standard medical therapy alone; (2) a comparison of continuous positive airway pressure and noninvasive positive pressure ventilation; (3) continuous positive airway pressure compared with standard medical therapy alone; and (4) noninvasive positive pressure ventilation compared with standard medical therapy alone. The primary and secondary outcome measurements (metameters) were hospital mortality and the rate of intubation, respectively. MATERIALS AND METHODS Study Design In reporting the results of this systematic review, the authors have followed the recommended guidelines from the Quality of 19 Reporting of Meta-Analysis (QUORUM) Statement. A comprehensive literature search of MEDLINE, EMBASE, and the Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Clinical Trials Register) from January 1980 to July 2005 was performed. The Volume 48, NO. 3 : September 2006 Annals of Emergency Medicine 261

3 Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema key words used were congestive heart failure, heart failure, edema, cardiogenic edema, lung edema, positive pressure ventilation, noninvasive ventilation, noninvasive positive pressure ventilation, NPPV, intermittent positive-pressure ventilation, positivepressure respiration, intermittent positive-pressure breathing, BiPAP, and CPAP. The searches were limited to human studies, English language publications, and randomized controlled trials or controlled clinical trials. Two authors (LM, HW) performed independent searches to identify potentially appropriate abstracts. Search results were presented in a meeting of the 5 investigators, and each abstract was reviewed for the prespecified selection criteria listed below. Articles were included in the final analysis according to consensus opinion. In addition to an electronic database search, a hand search was performed of the following key cardiac and journals from January 2000 to August 2005: Critical Care Medicine, Intensive Care Medicine, Chest, American Journal of Cardiology, Circulation, and the Journal of the American College of Cardiology. We reviewed the references of the selected studies, 1,8,20,21 recent reviews, and previous meta-analyses. We also searched the Harvard Hollis library, the Harvard electronic research database, the central database of registered clinical trials (available online at and the abstracts database from the Society of Critical Care Medicine 34 th Critical Care Congress (January 2005). Two subject experts and an authority in meta-analysis were also consulted. The following inclusion criteria were used to select articles for this review: (1) studies were randomized trials; (2) patients were older than 18 years and had acute cardiogenic edema; (3) patients were identified and treatment was started in the ED; (4) noninvasive ventilation in addition to standard medical therapy was compared to standard medical therapy alone, or noninvasive positive pressure ventilation was compared to continuous positive airway pressure; and (5) studies included the primary and secondary measurements identified for this analysis. Studies that a priori identified and solely enrolled patients with acute myocardial infarction as the cause of edema were excluded from this meta-analysis. Data abstraction of intubation rates and hospital mortality was performed by one of the authors (LM), and results were confirmed by a second author (DS). Discrepancies were discussed and adjudicated by the remaining authors. Two of the authors (MB, SC) independently and in duplicate reviewed the selected studies to determine validity scores. Disagreements were discussed between the 2 reviewers and, if necessary, adjudicated by a third investigator (DS). We used a previously validated scale 22 and prespecified criteria that were similar to those used 1 in previous meta-analyses specific to noninvasive ventilation. The Jadad scores range from 1-5, with a higher score indicative of a study that had adequate randomization, blinding, and follow-up. The modified Keenan score compared studies with respect to randomization, comparability of groups at baseline, standardized treatment and cointervention, outcomes Collins et al definitions, intention-to-treat analyses, and detailed follow-up information. The selected articles were reviewed for the following study characteristics: (1) centralized randomization and adequate concealment, (2) appropriate blinding to the intervention studied (noninvasive positive pressure ventilation or continuous positive airway pressure), (3) documented inclusion and exclusion criteria and comparability of groups at baseline, (4) a well-described protocol for duration and titration of continuous positive airway pressure/noninvasive positive pressure ventilation and oxygen, (5) a defined protocol for standard medical care, (6) intention-to-treat analysis, (7) a follow-up period lasting at least the duration of hospitalization, and (8) a priori specification of intubation criteria. Meta-analyses were performed to determine the risk ratios (RR) and 95% confidence intervals (CI) for hospital mortality and intubation. For each analysis, data were assessed for interstudy heterogeneity visually, by use of the 2 test for heterogeneity, and a measure of between-study variance ( 2 ). We summarized all studies in which the RRs and 95% CIs were available for hospital mortality or need for intubation. One of the studies was excluded from analysis for intubation because of the inability to discriminate subsequent intubations outside of the ED according to information provided in the article. Using a random-effects model, we calculated the summary RRs and 95% CIs for hospital mortality and need for intubation. Publication bias was explored with the use of funnel plots and Egger s test. An a priori hypothesis about heterogeneity relating to the quality of the study (study validity score 7) was explored with a sensitivity analysis. All analyses were done using Stata version 9.0 (Stata Corporation, College Station, TX). RESULTS Characteristics of Study Subjects The initial search strategy identified 22,658 possible publications relevant to this meta-analysis (Figure 1). After applying the initial exclusion criteria to this search, a total of 442 trials were reviewed in more detail for inclusion. The majority of these studies (n 415) were excluded because they did not involve the management of acute cardiogenic edema (n 112), involved patients with respiratory failure caused by multiple conditions (n 111), did not involve a randomization process (n 67), or, on abstract review, had little or no relevance to the topic of interest (n 125). The remaining 28 publications were reviewed in their entirety and eventual inclusion based on the authors consensus opinion. At this level of review, reasons for exclusion included inappropriate outcomes (n 7); all-cause respiratory failure (n 4); ICU study (n 3); noninvasive ventilation arm also involved another experimental treatment (high-dose isosorbide dinitrate), not considered standard therapy for both groups (n 1); and a priori acute myocardial infarction patients enrolled (n 1). As a result of the search strategy outlined, 11 articles were eventually chosen for this meta-analysis Annals of Emergency Medicine Volume 48, NO. 3 : September 2006

4 Collins et al Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema 22,658 potentially relevant trials Limit to English (n=12,184) Limit >1980 (n=9,828) Limit to RCT (n=591) Limit to Adults (n= 442) Potentially appropriate trials for meta-analysis (n=28) Trials included in meta-analysis (n=11) CPAP vs. NPPV: (n=4) CPAP vs. standard medical therapy (n=3) NPPV vs. standard medical therapy (n=2) CPAP vs. NPPV vs. standard medical therapy (n=2) Trials Excluded: Not CHF (n= 112) Nonspecific respiratory failure: (n=111) Not randomized: (n=67) Other: (n=125) Trials Excluded: Outcomes not meeting criteria (n=7) Nonspecific respiratory failure: (n=4) Not emergency department patients: (n=3) Comparison to other active arm: (n=1) Not randomized: (n=1) Trial involving acute MI patients (n=1) Figure 1. Flow diagram of selection process to obtain articles chosen for meta-analysis. RCT, Randomized clinical trial; CHF, congestive heart failure; CPAP, continuous positive airway pressure; NPPV, noninvasive positive pressure ventilation; MI, myocardial infarction. Six trials compared noninvasive positive pressure ventilation to continuous positive airway pressure in addition to standard care (Figure 1, Table E1, available online at Five trials compared continuous positive airway pressure to standard care alone. Four trials compared noninvasive positive pressure ventilation to standard care alone. Ten of 11 studies included a mortality endpoint. In all of the selected studies, patient medical histories, examinations, chest radiograms, and additional tests such as ECG were used to identify cardiogenic edema. All studies selected specifically excluded patients presenting with myocardial infarction. The results of our validity assessment are displayed in Table E2 (available online at The scores ranged from 4 to 9 of a possible 10 points using the 1 modified Keenan criteria. The Jadad scores ranged from 1 to 3 21 of a possible 5 points. All studies had points deducted for blinding because of the inherent difficulty of blinding the treating physicians to whether the patient is receiving noninvasive ventilation or oxygen therapy. As a result, the maximum modified Keenan score was 9 of 10 (1 point deducted for the inability to blind), and the maximum Jadad score was 3 of 5 (2 points deducted for the inability to blind). Seven studies compared the risk of hospital mortality between patients treated with noninvasive ventilation compared to standard medical therapy alone (Figure 2). One of the studies demonstrated that noninvasive ventilation was associated with a 11 significant reduction in hospital mortality. The remainder of the studies showed a trend toward improved hospital mortality that did not reach statistical significance. However, when the results of the 7 trials were pooled (n 494), noninvasive ventilation was associated with a significant improvement in hospital mortality (RR 0.61; [0.41, 0.91]). The 2 test for heterogeneity ( ) was not significant (P.56), and the between-study variance suggested that there was minimal heterogeneity. The associated Egger s test (P.13) did not suggest any significant publication bias affecting this analysis (Figure E1, available online at Six studies assessed the risk of intubation between patients treated with noninvasive ventilation compared to standard 1,9 medical therapy (Figure 3). Two studiesdemonstrated a significant reduction in intubation individually, whereas the Volume 48, NO. 3 : September 2006 Annals of Emergency Medicine 263

5 Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema Collins et al Figure 2. Pooled RR for mortality: noninvasive ventilation versus standard care. NIV, Noninvasive ventilation. Figure 3. Pooled RR for eventual intubation: noninvasive ventilation versus standard care. remaining studies did not reach significance. When the 6 studies (n 436) were pooled, there was a significant decrease in intubation rates in the noninvasive ventilation group compared to the standard therapy group (RR 0.43; [0.21, 0.87]). The 2 test for heterogeneity ( ) was not significant (P.06), but the between-study variance suggested that there was a moderate amount of heterogeneity. The associated Egger s test (P.35) did not suggest any significant publication bias affecting this analysis (Figure E2, available online at Six studies directly compared continuous positive airway pressure to noninvasive positive pressure ventilation in the management of acute cardiogenic edema (Figure 4). There were no significant differences in hospital mortality identified between the groups. A pooled analysis of 274 patients confirmed no significant differences between groups (RR 1.23; [0.46, 3.29]). The 2 test of heterogeneity ( ) was not significant (P.34) and the between-study variance suggested that there was a minimal amount of heterogeneity. The associated Egger s test (P.81) did not suggest any significant publication bias affecting this analysis (Figure E3, available online at Five studies (n 203) assessed the risk of intubation in patients treated with either continuous positive airway pressure 264 Annals of Emergency Medicine Volume 48, NO. 3 : September 2006

6 Collins et al Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema Figure 4. Pooled RR for mortality: continuous positive airway pressure versus noninvasive positive pressure ventilation. Figure 5. Pooled RR for eventual intubation: continuous positive airway pressure versus noninvasive positive pressure ventilation. or noninvasive positive pressure ventilation in addition to standard medical therapy (Figure 5). There was no statistical difference between groups in either the individual studies or the pooled analysis (RR 0.78; [0.28, 2.20]). The 2 test for heterogeneity ( ) was not significant (P.98) and there was no between-study variance, suggesting that there was a minimal amount of heterogeneity among the studies. The associated Egger s test (P.71) did not suggest any significant publication bias affecting this analysis (Figure E4, available online at Five studies compared continuous positive airway pressure versus standard medical therapy on hospital mortality (Table 1). All 5 trials showed no significant improvement in hospital mortality when compared with standard medical therapy alone. When the results of the 5 trials were pooled (n 279), the use of continuous positive airway pressure was associated with a trend in improvement in hospital mortality (RR 0.44; [0.19, 1.03]). Five trials assessed the effect of continuous positive airway pressure on the need for intubation. Two of the 5 trials showed a significant decrease in intubation rates in the continuous positive airway pressure group when compared with standard care. The other 3 trials suggested that continuous positive airway pressure had no effect on intubation. Pooling of the 5 trials (n 279) suggested that the use of continuous positive airway pressure significantly reduced the risk of subsequent intubation in ED patients with acute cardiogenic edema (RR 0.34; [0.14, 0.84]). Volume 48, NO. 3 : September 2006 Annals of Emergency Medicine 265

7 Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema Collins et al Table 1. Pooled RRs of continuous positive airway pressure or noninvasive positive pressure ventilation versus standard therapy. Analysis Outcome Studies N Continuous positive airway pressure vs standard care Noninvasive positive pressure ventilation vs standard care Pooled RR 95% CI Heterogeneity, P Publication Bias, P* Mortality Intubation Mortality Intubation *Publication bias refers to the tendency of investigators to submit positive studies and the tendency of editors to accept them. The likelihood of unpublished negative data s affecting the meta-analysis is expressed statistically using Egger s test. A significant P value is indicative of results that may be affected by future trials that may contradict the current findings. The associated Egger s tests did not suggest any significant publication biases affecting these analyses (Figures E5-E8, available online at Table 2. Results of sensitivity analyses on the pooled RRs. Analysis Noninvasive ventilation vs standard care Continuous positive airway pressure vs NPPV Adjusted Outcome Unadjusted Pooled RR Unadjusted 95% CI Pooled RR Adjusted 95% CI Mortality Intubation Mortality Intubation NPPV vs standard care Mortality Intubation Four studies compared noninvasive positive pressure ventilation with standard medical therapy (Table 1). None of the individual trials suggested that noninvasive positive pressure ventilation had an effect on hospital mortality when compared with standard therapy. The pooled effect of 261 patients suggested that noninvasive positive pressure ventilation decreases the risk of hospital mortality when compared with standard therapy alone (RR 0.66; [0.37, 1.19]). Only 1 of these studies demonstrated a reduction in the risk of intubation with 11 noninvasive positive pressure ventilation. The pooled analysis of the 4 trials (N 261), however, showed that noninvasive positive pressure ventilation had no effect on the risk of subsequent intubation (RR 0.58; [0.28, 1.20]). Sensitivity Analysis Our a priori sensitivity analysis focused on the impact of low-quality studies (validity score 7) on the pooled RRs (Table 2). The sensitivity analyses of noninvasive ventilation compared with standard care suggested that a single poorquality study 13 had only a small impact on the pooled RR, and the overall association of decreased hospital mortality and endotracheal intubation rates in the noninvasive ventilation groups remained significant. The sensitivity analysis of continuous positive airway pressure compared with noninvasive positive pressure ventilation suggested that a single poor-quality study 14 had minimal effect on the overall RR for hospital mortality or intubation rates. There was still no significant difference between continuous positive airway pressure and noninvasive positive pressure ventilation. There were no lowquality studies in the continuous positive airway pressure compared with standard care group of analyses. The sensitivity analyses of noninvasive positive pressure ventilation versus standard care also suggested that eliminating a single poorquality study 13 did not affect the overall RR for hospital mortality or intubation rates. LIMITATIONS This analysis was based on aggregate data from all the individual studies. In this meta-analysis, the similarity of inclusion criteria and intervention protocols between studies suggests comparable patient populations and was supported by the lack of significant heterogeneity. Although baseline characteristics were similar between treatment groups, the inability to adjust statistically for differences in other factors beyond treatment group assignment could have influenced the hospital mortality or intubation rates. A potential solution to account for these potential confounders is to access raw data and perform a meta-analysis based on individual patients. The majority of these studies were powered for intubation and not for mortality, though all prospectively monitored patients for mortality. An advantage of meta-analyses is to combine underpowered studies to increase the sample size and confidence in the results. However, our findings suggest 266 Annals of Emergency Medicine Volume 48, NO. 3 : September 2006

8 Collins et al that a prospective trial, powered primarily for mortality, is necessary. We attempted to minimize bias by using an extensive search strategy, including computerized databases, reviewing the bibliographies of selected articles, hand searching several journals, and contacting noninvasive ventilation and metaanalysis experts. In an attempt to avoid inclusion bias, we focused our literature search on only those trials that were prospective and randomized. Two independent reviewers performed independent literature searches to ensure consistent search results and minimize exclusion of key articles. Finally, results from meta-analyses do not always reflect results from subsequent prospective, randomized clinical trials. A previous review of this topic has suggested the outcomes of randomized, controlled trials were not predicted accurately 35% of the time by the meta-analyses published previously on the same topic. It has been suggested that readers of meta-analyses should go beyond the point estimates and CIs of a meta-analysis and evaluate the consistency of the results of the individual studies included. When the results of the individual studies are mostly on the same side of the no-difference line, the metaanalysis is more 23 noteworthy. DISCUSSION To our knowledge, this is the first meta-analysis of noninvasive ventilation in ED patients with acute cardiogenic edema. The results of this meta-analysis suggest that a strategy of noninvasive ventilation plus standard medical therapy significantly reduces hospital mortality and need for endotracheal intubation when compared with standard medical therapy alone. From this analysis, it can be estimated that early application of noninvasive ventilation in the ED can decrease the relative risk of mortality by 39% and the necessity of endotracheal intubation by 57%. The use of noninvasive ventilation as a temporizing measure in patients with cardiogenic edema makes sense from a clinical standpoint. Definitive therapy, such as vasodilators and diuretics, requires time for administration (preparing intravenous solutions), as well as time for therapeutic effect to occur. Although noninvasive ventilation appears to have positive effects on the work of breathing and left ventricular afterload, 2,3 it does not correct the underlying problem (increased systemic vascular resistance, decreased cardiac output, and volume overload), and it should not be viewed as definitive therapy. Aggressive treatment of the underlying hemodynamic abnormalities is the mainstay of therapy in acute decompensated heart failure. It would be advantageous to identify which noninvasive ventilation strategy (either continuous positive airway pressure or noninvasive positive pressure ventilation) offers the most optimal therapeutic advantage. According to all available data, there is no evidence to suggest superiority of either continuous positive airway pressure or noninvasive positive pressure ventilation. When continuous positive airway pressure and noninvasive positive pressure ventilation were compared with Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema each other, there was no difference between the 2 groups. In fact, the trend toward decreased mortality with noninvasive positive pressure ventilation, yet decreased intubation rates with continuous positive airway pressure, suggests either different underlying effects of each modality or instability in the estimates. This lack of statistical significance between continuous positive airway pressure and noninvasive positive pressure ventilation may reflect the small sample sizes in the original studies (and thus wide CIs), rather than true heterogeneity of results. The measures of heterogeneity were actually modest in this analysis. Event rates were low; therefore, individual studies were inadequately powered to detect differences. Future studies must be designed to have the power necessary to be able to detect a difference. Previous research has suggested that continuous positive airway pressure and noninvasive positive pressure ventilation impart hemodynamic changes in heart failure patients by 3,24,25 increasing intrathoracic pressure. Increased intrathoracic pressure reduces cardiac preload by impeding cardiac filling and reduces cardiac afterload by reducing left ventricular transmural pressure. Although these effects may be detrimental in patients with normal cardiac function, leading to a decrease in cardiac 26 output and blood pressure, patients with cardiac dysfunction and elevated capillary wedge pressure may benefit 27 from the decrease in preload and afterload. Our study is consistent with the most recent meta-analysis of 8 acute cardiogenic edema. The pooled analysis (n 179 patients) in that study suggested that, compared with standard medical therapy, continuous positive airway pressure had significantly decreased rates of intubation compared with standard medical therapy alone (risk reduction 26%, CI 13% to 38%) and an insignificant trend toward decreased mortality (risk reduction 7%; 16% risk reduction to 3% risk increase). This same group has recently published a meta-analysis about acute hypoxemic respiratory failure (excluding acute cardiogenic edema) and found a similar risk reduction with noninvasive positive pressure ventilation compared with standard medical therapy alone (risk reduction 23%; CI 10% to 35%). 1 A recent review updating the previous continuous 4 positive airway pressure meta-analysis with 1 additional study 21 found similar results. Though there is no mention about the statistical analysis that was performed (fixed versus random effects, study heterogeneity, analysis program), they found a significant reduction in the need for intubation and no difference in mortality rates when continuous positive airway pressure was compared with standard medical therapy. Furthermore, the additional study used in the updated metaanalysis did not have a control arm, and therefore, the results of this meta-analysis must be interpreted with caution. Although there was a trend toward decreased rates of hospital mortality and intubation, some concerns have been raised about the safety of noninvasive positive pressure ventilation in the setting of acute cardiogenic edema. One study suggested an increase in the myocardial infarction rate with the Volume 48, NO. 3 : September 2006 Annals of Emergency Medicine 267

9 Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema Collins et al use of noninvasive positive pressure ventilation compared with 4 continuous positive airway pressure. However, the 2 groups differed significantly with respect to the proportion of patients presenting with chest pain. Thus, the differences observed may reflect underlying differences in baseline patient characteristics, rather than an outcome attributable to the therapy. One difficulty in making this distinction is that patients who present to the ED with flash edema often have normal initial cardiac enzyme levels. Identification of an acute coronary syndrome that had precipitated edema may not occur until long after ED presentation, perhaps suggesting a misleading association between noninvasive positive pressure ventilation use and myocardial ischemia. Unfortunately, the more recent studies comparing continuous positive airway pressure to noninvasive positive pressure ventilation that reported myocardial infarction rates were similarly unable to make this distinction and do not provide sufficient data on 10,13 patient presentation to draw any definitive conclusions. The one study specifically examining myocardial infarction rates with noninvasive positive pressure ventilation compared to continuous positive airway pressure showed no difference between groups (continuous positive airway pressure 3/22; noninvasive positive pressure ventilation 2/24; P nonsignificant). 17 Clearly, further study is required to clarify this concern because this outcome does not lend itself to metaanalysis, given the available data. In conclusion, the results from our meta-analyses suggest that noninvasive ventilation, when compared with standard care, has a significantly favorable impact on mortality and endotracheal intubation rates in patients presenting to the ED with acute cardiogenic edema. Future studies are needed to specifically address the noninvasive ventilation modality of choice and to clarify the issue of myocardial infarction. To be adequately powered to discriminate outcomes such as hospital mortality, intubation, and myocardial infarction between continuous positive airway pressure and noninvasive positive pressure ventilation groups, a large-scale study will be required. Supervising editor: Brian H. Rowe, MD, MSc Author contributions: SC, LM, HW, MB, DS conceived the study and performed the overall literature search and data abstraction. SC and LM performed data analysis. SC, LM, HW, MB, DS, AS contributed to the writing of the manuscript. SC takes responsibility for the paper as a whole. Funding and support: The authors report this study did not receive any outside funding or support. Publication dates: Received for publication September 21, Revision received November 17, Accepted for publication January 25, Reprints not available from the authors. Address for correspondence: Sean P. Collins, MD, University of Cincinnati, Department of Emergency Medicine, 231 Albert Sabin Way, Cincinnati, OH, ; , fax ; sean.collins@uc.edu REFERENCES 1. Keenan SP, Sinuff T, Cook DJ, et al. Does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? a systematic review. Crit Care Med. 2004;32: Katz JA, Marks JD. Inspiratory work with and without continuous positive airway pressure in patients with acute respiratory failure. Anesthesiology. 1985;63: Naughton MT, Rahman MA, Hara K, et al. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. 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10 Collins et al Noninvasive Ventilation for Acute Cardiogenic Pulmonary Edema natriuretic peptide concentrations. Eur Heart J. 2002;23: Bellone A, Monari A, Cortellaro F, et al. Myocardial infarction rate in acute edema: noninvasive pressure support ventilation versus continuous positive airway pressure. Crit Care Med. 2004;32: Bellone A, Vettorello M, Monari A, et al. Noninvasive pressure support ventilation vs. continuous positive airway pressure in acute hypercapnic edema. Intensive Care Med. 2005; 31: Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement: quality of reporting of meta-analyses. Lancet. 1999;354: Vital F, Atallah H, Ladeira MT, et al. Non-invasive positive pressure ventilation in cardiogenic edema [protocol]. Cochrane Database Syst Rev 2005; Nadar S, Prasad N, Taylor RS, et al. Positive pressure ventilation in the management of acute and chronic cardiac failure: a systematic review and meta-analysis. Int J Cardiol. 2005;99: Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17: LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337: Baratz DM, Westbrook PR, Shah PK, et al. Effect of nasal continuous positive airway pressure on cardiac output and oxygen delivery in patients with congestive heart failure. Chest. 1992; 102: Philip-Joet FF, Paganelli FF, Dutau HL, et al. Hemodynamic effects of bilevel nasal positive airway pressure ventilation in patients with heart failure. Respiration. 1999;66: Jardin F, Farcot JC, Boisante L, et al. Influence of positive endexpiratory pressure on left ventricular performance. N Engl J Med. 1981;304: Grace MP, Greenbaum DM. Cardiac performance in response to PEEP in patients with cardiac dysfunction. Crit Care Med. 1982; 10: Volume 48, NO. 3 : September 2006 Annals of Emergency Medicine 269

11 Table E1. Evidence table summarizing each of included studies. Sample Size Source Site Year Country Inclusion Criteria Exclusion Criteria Interventions Outcomes L Her, 2004 Kelly, CPAP (7.5 cm H2O) vs. GCS <= 7 Standard Overall hosp. mortality 4 sites edema, in ER SpO2 <= 85% on O2 48hr need for intubation France Age 75, RR 25 PaO2 300 on O2 SBP <= 90mmHg Chronic respiratory insufficiency Improvement in PaO2 Complications 58 CPAP (7.5 cm H2O) vs Pneumonia or pneumothorax Standard Overall hosp. mortality 1 site edema, in ER Intervention with other than MI rate, Hospital Scotland RR > 20 standard therapy (O2, diuretics, Length of stay, plasma Bersten, 1991 Bellone, 2005 Dyspnea < 6hrs opiates) brain natriuretic peptide 39 MI with shock CPAP (10 cm H2O) vs Standard Overall hosp. mortality 1 site edema, in ER SBP < 90 mmhg Need for intubation Australia Respiratory distress Severe stenotic valvular disease Length of stay PaO2 < 70 mmhg on O2 COPD with CO2 retention Complications PaCO2 >45 mmhg on O2 36 Unresponsive, agitated patients CPAP (10 cm H2O) vs Overall hosp. mortality edema, in ER Cardiogenic shock 1 site (SBP < 90 mmhg) NPPV (initially 5/15 cm H2O) Need for intubation Italy SpO2 < 90% on O2 Respiratory or cardiac arrest Bellone, 2004 Cross, 2003 Mehta, 1997 Nava, 2003 RR > 30 COPD, chronic renal failure PaCO2 >45 mmhg on O2 46 Unresponsive, agitated patients CPAP (10 cm H2O) vs Overall hosp. mortality Acute coronary syndrome 1 site edema, in ER NPPV (initially 5/15 cm H2O) Need for intubation Respiratory or cardiac arrest Italy SpO2 < 90% on O2 Cardiogenic shock (SBP < 90 RR > 30 mmhg) 101 patients Respiratory failure, Unresponsive, agitated patients CPAP (5-20 cm H2O) vs Overall hosp. mortality ER 3 sites RR > 25, Traumatic or congenital causes NPPV (5/10 to 5/25 cm H2O) Need for intubation SpO2 < 90% on RA Length of stay, Australia SpO2 < 93% on O2 Pneumonia, already intubated complications 27 Unresponsive, agitated patients CPAP (10 cm H2O) vs Overall hosp. mortality SBP < 90 mmhg, already 1 site edema, in ER intubated NPPV (5/15 cm H2O) Need for intubation United States RR > 30 Respiratory or cardiac arrest Length of stay, MI rate 130 Unresponsive, agitated patients NPPV (5/10 cm H2O) vs Overall hosp. mortality 5 sites edema, in ER Shock, ventricular arrythmia Standard Need for intubation Severe hypoxia, immediate need Italy PaO2 < 250 on O2 for Length of stay RR > 30 intubation, acute MI, chronic renal MI rate failure, pneumothorax Levitt, Immediate need for intubation NPPV (3/8 to 5/8 cm H2O) vs Overall hosp. mortality 1 site edema, in ER Standard therapy Need for intubation United States RR > 30 MI rate Park, patients Unresponsive, agitated patients CPAP (10-16 cm H2O) vs Overall hosp. mortality 1 site Cardiogenic Intractable vomiting, acute M.I, NPPV (10/15 to 16/21 cm H2O) 60 day mortality Brazil edema, in ER RR > 25, age > 16 another decompensated disorder vs standard Need for intubation disease (COPD, pneumonia, etc) Length of stay, complications Crane, patients Cardiogenic Unresponsive, agitated patients SBP < 90 mmhg, temp > 38C CPAP (10 cm H2O) vs Overall hosp. mortality 2 sites England edema, in ER RR > 23 Acute MI, need for dialysis NPPV (15/5 cm H2O) vs standard 7 day mortality COPD, Chronic obstructive disease; GCS, Glasgow Coma Scales. 269.e1 Annals of Emergency Medicine Volume 48, NO. 3 : September 2006

12 Table E2. Validity scores judged by two independent raters. *Randomized *Concealment *Blinding *Patient Selection *Comparability of Groups *Treatment Protocol *Cointerventions *Outcome Definitions *Extent of Followup *Intention-totreat Analysis Total Score Jadad score L Her et al. (2004) Kelly et al. (2002) Bersten et al. (1991) Bellone et al. (2005) Bellone et al. (2004) Cross et al. (2005) Mehta et al. (1997) Nava et al. (2003) Levitt et al. (2001) Park et al. (2004) Crane et al. (2004) *For the modified Keenan criteria (columns 2-11) a score of 0 was given if the characteristic was absent and a score of 1 if the characteristic was present. Figure E1. Funnel plot of noninvasive ventilation versus standard care: mortality. Figure E2. Funnel plot of noninvasive ventilation versus standard care: intubation. Volume 48, NO. 3 : September 2006 Annals of Emergency Medicine 269.e2

13 Figure E3. Funnel plot of continuous positive airway pressure versus noninvasive positive pressure ventilation: mortality. Figure E4. Funnel plot of continuous positive airway pressure versus noninvasive positive pressure ventilation: intubation. Figure E5. Funnel plot of continuous positive airway pressure versus standard care: intubation. 269.e3 Annals of Emergency Medicine Volume 48, NO. 3 : September 2006

14 Figure E6. Funnel plot of continuous positive airway pressure versus standard care: mortality. Figure E7. Funnel plot of noninvasive positive pressure ventilation versus standard care: mortality. Figure E8. Funnel plot of noninvasive positive pressure ventilation versus standard care: intubation. Volume 48, NO. 3 : September 2006 Annals of Emergency Medicine 269.e4