Correspondence
Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema
N Engl J Med 2008; 359:2068-2069November 6, 2008
- Article
To the Editor:
Gray et al. (July 10 issue)1 report that the Three Interventions in Cardiogenic Pulmonary Oedema (3CPO) trial showed no benefit from noninvasive ventilation for reducing the intubation rate or short-term mortality. These findings are of concern and appear to conflict with previous trial data.2,3
This trial may be biased and lack generalizability for several reasons. First, sick patients, who required “lifesaving or emergency intervention” and might have benefited most, were excluded. Second, 19.4% of patients did not complete their assigned treatment. Third, there was considerable cross-contamination among the treatment groups.
Furthermore, there were no objective criteria for intubation. We are alarmed by the noticeably low intubation rate (3%) in the 3CPO trial, as compared with pooled data from both the noninvasive-ventilation groups (32%) and the control groups (12%) in previous studies.2 Moreover, the observed mortality at 7 days (9.6%) greatly exceeded the intubation rate.
Why were these patients with cardiogenic pulmonary edema who did not undergo ventilation dying? It is uncertain whether decisions regarding end-of-life care or the use of life support in this elderly cohort may have confounded the observed outcome.
3 ReferencesRobert C. McDermid, M.D.
Sean M. Bagshaw, M.D.
University of Alberta, Edmonton, AB T6G 2B7, Canada
robmcdermid@telus.net 1
Gray A ,Goodacre S ,Newby DE ,Masson M ,Sampson F ,Nicholl J . Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med 2008;359:142-151
Full Text | Web of Science | Medline2
Masip J ,Roque M ,Sanchez B ,Fernandez R ,Subirana M ,Exosito JA . Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA 2005;294:3124-3130
CrossRef | Web of Science | Medline3
Peter JV ,Moran JL ,Phillips-Hughes J ,Graham P ,Bersten AD . 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
CrossRef | Web of Science | Medline
To the Editor:
The lack of a beneficial effect of noninvasive ventilation in the 3CPO trial contrasts with previous guidelines and meta-analyses.1-4 First, both the mortality and intubation rates were much lower in the 3CPO trial than in the meta-analysis (Table 1Table 1
Comparison of Overall Mortality and Intubation Rates in the 3CPO Trial and a Previous Meta-Analysis.), indicating that the populations were different. Second, patients in the 3CPO trial did not have hypoxemia (average baseline partial pressure of arterial oxygen, 98 to 101 mm Hg), and this fact might explain the low intubation rate in the study. Although it was not described, there was probably some delay in initiating the protocol. A delay of only 15 minutes markedly attenuates the beneficial effect of noninvasive ventilation.5 Third, progressive respiratory failure, treated by means of intubation in patients who received standard oxygen therapy in previous studies, was managed mainly with rescue noninvasive ventilation in the 3CPO study. This crossover did not alter the intubation rate, suggesting that noninvasive ventilation was effective in these patients but might be responsible for a significant bias against noninvasive ventilation. Accordingly, further trials involving critically ill patients at an earlier phase, including patients in the prehospital setting, should definitely disclose whether noninvasive ventilation may improve outcomes.5 ReferencesJosep Masip, M.D.
Consorci Sanitari Integral, 08025 Barcelona, SpainAlexandre Mebazaa, M.D.
University Paris 7, 75010 Paris, FranceGerasimos S. Filippatos, M.D.
University of Athens, 12461 Athens, Greece1
The Task Force on Acute Heart Failure of the European Society of Cardiology
CrossRef | Web of Science | Medline2
Masip J ,Roque M ,Sanchez B ,Fernandez R ,Subirana M ,Exosito JA . Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA 2005;294:3124-3130
CrossRef | Web of Science | Medline3
Peter JV ,Moran JL ,Phillips-Hughes J ,Graham P ,Bersten AD . 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
CrossRef | Web of Science | Medline4
Winck JC ,Azevedo LF ,Costa-Pereira A ,Antonelli M ,Wyatt JC . 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-R69
CrossRef | Web of Science | Medline5
Plaisance P ,Pirracchio R ,Berton C ,Vicaut E ,Payen D . A randomized study of out-of-hospital continuous positive airway pressure for acute cardiogenic pulmonary oedema: physiological and clinical effects. Eur Heart J 2007;28:2895-2901
CrossRef | Web of Science | Medline
Author/Editor Response
We disagree with McDermid and Bagshaw that our trial was not generalizable. The 3CPO trial was specifically designed to be pragmatic and inclusive. We included all patients presenting to the emergency department with acute cardiogenic pulmonary edema and recruited 71% of eligible patients. In contrast, previous meta-analyses1,2 lack generalizability, since they included only small, selective, and heterogeneous studies. Only 10 to 30% of eligible patients were recruited into these studies, with widely varying group sizes (range, 9 to 65 patients), intubation rates (0 to 65%), and in-hospital mortality (0 to 30%). In the meta-analysis by Masip et al.,1 one third of the studies were conducted in the intensive care setting rather than in the emergency department, and this is likely to further explain some of the differences, including the degree of hypoxemia and intubation rates.
Some patients requiring intervention for life-threatening conditions (125 of 1511 patients screened) were excluded from the 3CPO trial, but mortality among nonrecruited patients was identical. A secondary analysis involving trial patients showed no interaction between disease severity and treatment effect. The 30-day mortality in the 3CPO trial was 15.6%, which is similar to the 15.3% in-hospital mortality reported in published meta-analyses in which the length of the hospital stay was not reported.1,2
In our trial, randomization was performed rapidly with the use of a 24-hour automated telephone system, eliminating any delays. The trial intervention achieved clear differences in physiological variables that are directly comparable to those in previously reported trials.1,2 One fifth of the patients crossed over to the alternative treatment in each of the groups, but they did so for different reasons. Many patients were unable to tolerate noninvasive ventilation — especially bilevel ventilation — and this limits its widespread applicability. By design, we allowed noninvasive ventilation to be used if standard treatment failed. Clinical equipoise dictated that noninvasive ventilation was an acceptable alternative to intubation in this circumstance. Intubation is invasive, potentially hazardous, and of no clear, proven benefit.
Finally, with regard to the comments by Masip and colleagues, we do not conclude that noninvasive ventilation is ineffective, only that it does not reduce early mortality. Noninvasive ventilation should be considered as adjunctive treatment in patients who have severe respiratory distress or who do not have a response to standard therapy.
2 ReferencesAlasdair Gray, M.D.
Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
alasdair.gray@luht. scot. nhs. uk Steve Goodacre, Ph.D.
University of Sheffield, Sheffield S1 4DA, United KingdomDavid Newby, M.D.
University of Edinburgh, Edinburgh EH16 4SB, United Kingdom1
Masip J ,Roque M ,Sanchez B ,Fernandez R ,Subirana M ,Exosito JA . Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA 2005;294:3124-3130
CrossRef | Web of Science | Medline2
Peter JV ,Moran JL ,Phillips-Hughes J ,Graham P ,Bersten AD . 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
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
, Laurent Ducros, Damien Logeart, Eric Vicaut, Patrick Henry, Patrick Plaisance, Jean-Philippe Collet, Claire Broche, Papa Gueye, Muriel Vergne, David Goetgheber, Pierre-Yves Pennec, Vanessa Belpomme, Jean-Michel Tartière, Sophie Lagarde, Marius Placente, Marie-Laurence Fievet, Gilles Montalescot, Didier Payen. (2011) CPAP for acute cardiogenic pulmonary oedema from out-of-hospital to cardiac intensive care unit: a randomised multicentre study. Intensive Care Medicine 37:9, 1501-1509
CrossRef2
Josiah C. Daily, Henry E. Wang. (2011) Noninvasive Positive Pressure Ventilation: Resource Document for the National Association of EMS Physicians Position Statement. Prehospital Emergency Care 15:3, 432-438
CrossRef3
J. T. Parissis, M. Nikolaou, A. Mebazaa, I. Ikonomidis, J. Delgado, F. Vilas-Boas, I. Paraskevaidis, A. Mc Lean, D. Kremastinos, F. Follath. (2010) Acute pulmonary oedema: clinical characteristics, prognostic factors, and in-hospital management. European Journal of Heart Failure 12:11, 1193-1202
CrossRef
