Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

This is an update of a systematic review previously published in 2008 about non-invasive positive pressure ventilation (NPPV). NPPV has been widely used to alleviate signs and symptoms of respiratory distress due to cardiogenic pulmonary oedema. NPPV prevents alveolar collapse and helps redistribute intra-alveolar fluid, improving pulmonary compliance and reducing the pressure of breathing.

Objectives

To determine the effectiveness and safety of NPPV in the treatment of adult patients with cardiogenic pulmonary oedema in its acute stage.

Search methods

We searched the following databases on 20 April 2011: CENTRAL and DARE, (The Cochrane Library, Issue 2 of 4, 2011); MEDLINE (Ovid, 1950 to April 2011); EMBASE (Ovid, 1980 to April 2011); CINAHL (1982 to April 2011); and LILACS (1982 to April 2011). We also reviewed reference lists of included studies and contacted experts and equipment manufacturers. We did not apply language restrictions.

Selection criteria

We selected blinded or unblinded randomised or quasi-randomised clinical trials, reporting on adult patients with acute or acute-on-chronic cardiogenic pulmonary oedema and where NPPV (continuous positive airway pressure (CPAP) or bilevel NPPV) plus standard medical care was compared with standard medical care alone.

Data collection and analysis

Two authors independently selected articles and abstracted data using a standardised data collection form. We evaluated study quality with emphasis on allocation concealment, sequence generation allocation, losses to follow-up, outcome assessors, selective outcome reporting and adherence to the intention-to-treat principle.

Main results

We included 32 studies (2916 participants), of generally low or uncertain risk of bias. Compared with standard medical care, NPPV significantly reduced hospital mortality (RR 0.66, 95% CI 0.48 to 0.89) and endotracheal intubation (RR 0.52, 95% CI 0.36 to 0.75). We found no difference in hospital length of stay with NPPV; however, intensive care unit stay was reduced by 1 day (WMD -0.89 days, 95% CI -1.33 to -0.45). Compared with standard medical care, we did not observe significant increases in the incidence of acute myocardial infarction with NPPV during its application (RR 1.24, 95% CI 0.79 to 1.95) or after (RR 0.70, 95% CI 0.11 to 4.26). We identified fewer adverse events with NPPV use (in particular progressive respiratory distress and neurological failure (coma)) when compared with standard medical care.

Authors' conclusions

NPPV in addition to standard medical care is an effective and safe intervention for the treatment of adult patients with acute cardiogenic pulmonary oedema. The evidence to date on the potential benefit of NPPV in reducing mortality is entirely derived from small-trials and further large-scale trials are needed.

Résumé scientifique

Ventilation non invasive en pression positive (PAPC ou VNIPP à double niveau) pour œdème pulmonaire cardiogénique

Contexte

Ceci est une mise à jour d'une revue systématique précédemment publiée en 2008 sur la ventilation non invasive à pression positive (VNIPP). La VNIPP est couramment utilisée pour soulager les signes et symptômes de détresse respiratoire due à un œdème pulmonaire cardiogénique. La VNIPP prévient le collapsus alvéolaire et contribue à redistribuer le fluide intra-alvéolaire, améliorant ainsi la compliance pulmonaire et réduisant la pression de respiration.

Objectifs

Déterminer l'efficacité et l'innocuité de la VNIPP dans le traitement des patients adultes atteints d'œdème pulmonaire cardiogénique en phase aiguë.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans les bases de données suivantes le 20 avril 2011 : CENTRAL et DARE, (The Cochrane Library, numéro 2 de 4, 2011), MEDLINE (Ovid, de 1950 à avril 2011), EMBASE (Ovid, de 1980 à avril 2011), CINAHL (de 1982 à avril 2011) et LILACS (de 1982 à avril 2011). Nous avons également examiné les références bibliographiques des études incluses et contacté des experts et des fabricants d'équipement. Nous n’avons imposé aucune restriction concernant la langue.

Critères de sélection

Nous avons choisi des essais cliniques randomisés ou quasi-randomisés, en aveugle ou non, ayant rendu compte de patients adultes présentant un œdème pulmonaire cardiogénique aigu ou chronique et dans lesquels la VNIPP (pression aérienne positive continue (PAPC) ou VNIPP à deux niveaux) en supplément aux soins médicaux standard était comparée aux seuls soins médicaux standard.

Recueil et analyse des données

Deux auteurs ont, de manière indépendante, sélectionné des articles et extrait les données à l'aide d'un formulaire standardisé de collecte de données. Nous avons évalué la qualité des études en mettant l'accent sur ​​l'assignation secrète, la génération de séquence, les pertes de suivi, les évaluateurs de résultats, le compte-rendu sélectif de résultats et le respect du principe d'intention de traiter.

Résultats principaux

Nous avons inclus 32 études (soit 2916 participants) présentant généralement un risque de biais faible ou incertain. En comparaison avec les soins médicaux standard, la VNIPP avait réduit de manière significative la mortalité hospitalière (RR 0,66 ; IC 95% 0,48 à 0,89) et l'intubation endotrachéale (RR 0,52 ; IC 95% 0,36 à 0,75). Nous n'avons pas trouvé de différence dans la longueur du séjour hospitalier avec la VNIPP, mais le séjour en unité de soins intensifs avait été réduit de 1 jour (DMP -0,89 jours ; IC 95% -1,33 à -0,45). En comparaison avec les soins médicaux standard, nous n'avons pas observé d'augmentation significative de l'incidence de l'infarctus aigu du myocarde durant l'application de la VNIPP (RR 1,24 ; IC à 95% 0,79 à 1,95) ou postérieurement (RR 0,70 ; IC 95% 0,11 à 4,26). Nous avons recensé moins d'effets indésirables avec la VNIPP (en particulier de détresse respiratoire progressive et de défaillance neurologique (coma)) qu'avec les soins médicaux standard.

Conclusions des auteurs

La VNIPP en supplément des soins médicaux standard est une intervention efficace et sûre pour le traitement des patients adultes atteints d'œdème aigu pulmonaire cardiogénique. À ce jour, les données sur un bénéfice potentiel de la VNIPP pour la réduction de la mortalité proviennent exclusivement de petits essais ; des essais supplémentaires à grande échelle sont nécessaires.

Resumo

Ventilação não invasiva com pressão positiva (CPAP ou VNIPP binível) no edema pulmonar cardiogênico

Introdução

Esta é uma atualização da revisão sistemática publicada em 2008 sobre ventilação não invasiva com pressão positiva (VNIPP). A VNIPP tem sido muito utilizada para aliviar sinais e sintomas de insuficiência respiratória devido a edema pulmonar cardiogênico. A VNIPP previne o fechamento alveolar e ajuda a redistribuir o líquido intra-alveolar, melhorando a complacência pulmonar e reduzindo o trabalho respiratório do paciente.

Objetivos

Avaliar a efetividade e a segurança da VNIPP no tratamento de pacientes adultos com edema agudo pulmonar cardiogênico.

Métodos de busca

Nós realizamos as buscas nas seguintes bases de dados, em 20 de abril de 2011: CENTRAL e DARE, (The Cochrane Library, Edição 2 de abril, 2011); MEDLINE (via Ovid, de 1950 a abril de 2011); EMBASE (via Ovid, de 1980 a abril 2011); CINAHL (de 1982 a abril 2011); e LILACS (de 1982 a abril 2011). Também revisamos a lista de referências dos estudos incluídos e contatamos especialistas e fabricantes de equipamentos. Não houve restrição quanto ao idioma das publicações.

Critério de seleção

Nós selecionamos estudos clínicos randomizados e quasi-randomizados com ou sem mascaramento, que incluíram adultos com edema pulmonar agudo cardiogênico ou crônico agudizado, tratados com VNIPP (com pressão contínua, CPAP, ou com VNIPP binível) mais tratamento médico habitual em comparação com o tratamento médico habitual.

Coleta dos dados e análises

Dois autores selecionaram de forma independente os artigos e resumiram os dados utilizando um formulário padronizado de coleta de dados. Avaliamos a qualidade dos estudos com ênfase na ocultação da alocação, na geração da sequência da alocação, nas perdas de acompanhamento, nos avaliadores dos desfechos, no relato seletivo dos desfechos e na aderência ao princípio da intenção de tratar.

Principais resultados

Incluímos 32 estudos (2916 participantes), sendo que a maioria tinha um risco de viés baixo ou incerto. Comparada com o tratamento médico padrão, a VNIPP reduz significativamente a mortalidade hospitalar (RR 0.66, intervalo de confiança de 95%, 95% CI, de 0.48 a 0.89) e a intubação endotraqueal (RR 0.52, 95% CI 0.36 a 0.75). Nós não encontramos diferença na duração da internação hospitalar com a VNIPP, mas a permanência na unidade de terapia intensiva foi reduzida por um dia (WMD -0.89 dias, 95% CI -1.33 a -0.45). Em comparação com o tratamento médico padrão, não observamos aumento significativo na incidência de infarto agudo do miocárdio com a VNIPP durante (RR 1.24, 95% CI 0.79 a 1.95) ou após (RR 0.70, 95% CI 0.11 a 4.26) sua aplicação. Identificamos menos eventos adversos com a VNIPP (em especial progressão da insuficiência respiratória e insuficiência neurológica/coma) quando comparado ao tratamento médico padrão.

Conclusão dos autores

A VNIPP, em combinação o tratamento médico padrão, é uma intervenção efetiva e segura para tratar adultos com edema agudo pulmonar cardiogênico. As evidências até o presente sobre o potencial benefício da VNIPP em reduzir a mortalidade hospitalar são totalmente baseadas em estudos pequenos, e portanto são necessários outros estudos com tamanho amostral maior.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Flávia Maria Ribeiro Vital)

摘要

非侵襲性正壓呼吸器(Non-invasive positive pressure ventilation, CPAP or bilevel NPPV)用在心因性肺水腫(cardiogenic pulmonary oedema)的病人

背景

這是一篇刊登於2008年有關非侵襲性正壓呼吸器的系統性回顧(NPPV)。NPPV被廣泛使用於緩解心因性肺水腫造成的呼吸窘迫症狀。NPPV能夠防止肺泡塌陷,也能幫助肺泡內液體的重新分布,進而改善肺臟順應性,降低呼吸的壓力。

目的

探討NPPV用於治療成人急性期心因性肺水腫的效果和安全性。

搜尋策略

我們於2011年4月20日搜尋了以下的資料庫:CENTRAL and DARE, (The Cochrane Library, Issue 2 of 4, 2011); MEDLINE (Ovid, 1950 to April 2011); EMBASE (Ovid, 1980 to April 2011); CINAHL (1982 to April 2011); and LILACS (1982 to April 2011)。我們也回顧了參考文獻中有涵蓋的研究,還連絡了專家以及儀器製造商。我們並沒有設定語言的限制條件。

選擇標準

我們選取了盲的或非盲的隨機或改良式的隨機臨床試驗,這些試驗探討急性或慢性心因性肺水腫急性發作的成人病人,以及NPPV加標準醫療處置和僅使用標準醫療處置的比較。

資料收集與分析

兩位作者獨立地選取文章並用標準的資料收集格式將資料寫成要點。我們評估研究品質主要將重點放在分派隱匿(allocation concealment)、分派序號產生(sequence generation allocation)、失去追蹤(losses to follow-up)、臨床結果評估者(outcome assessors)、選擇性報告結果(selective outcome reporting)以及遵循意圖治療原則(intention-to-treat principle)。

主要結果

我們收錄了32個低或不確定偏誤風險的研究(2916個受試者)。跟標準醫療處置比起來,NPPV顯著地降低了院內死亡率(RR 0.66, 95% CI 0.48 to 0.89)以及氣管內插管(endotracheal intubation)的使用(RR 0.52, 95% CI 0.36 to 0.75)。我們沒有在住院天數發現差異,但NPPV使待在加護病房的天數減少一天(WMD -0.89 days, 95% CI -1.33 to -0.45)。跟標準醫療處置比起來,我們沒有觀察到使用NPPV的期間(RR 1.24, 95% CI 0.79 to 1.95)或之後(RR 0.70, 95% CI 0.11 to 4.26)使急性心肌梗塞的發生率明顯的上升。我們觀察到NPPV的使用比標準醫療處置產生的不良事件少(特別是漸進性呼吸窘迫progressive respiratory distress和神經衰竭neurological failure(昏迷))。

作者結論

NPPV加上標準醫療處置在治療急性心因性肺水腫的成人病患上是個有效又安全的做法。到目前為止支持NPPV對減少死亡率有潛在益處的證據都是從小型試驗得來的,未來需要更多大型試驗來佐證。

譯註

翻譯者:羅峻涵
服務單位:中山醫學大學
職稱:醫學系六年級學生、實習醫師

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

摘要

非侵入正压通气(持续正压通气或双水平正压通气)治疗心源性肺水肿

研究背景

本系统综述是对发表于2008年的无创正压通气系统综述的更新。无创正压通气已被广泛用于缓解心源性肺水肿造成的呼吸窘迫症状和体征,可防止肺泡萎险,促进肺泡内液再分配,改善肺顺应性,减轻呼吸压力。

研究目的

评价无创正压通气治疗急性心源性肺水肿患者的有效性和安全性。

检索策略

我们于2011年4月检索了以下数据库: Cochrane 临床对照试验数据库和疗效评价文摘库(Cochrane图书馆,2/4期,2011年);美国联机医学文献分析和检索系统(Ovid,1950年到2011年4月);医学文献资料库(Ovid,1980年到2011年4月);护理学数据库(1982年到2011年4月)和丁香园(1982年到2011年4月)。我们还核对了所纳文献并联系相关专家与药厂获取可能存在的其他温馨啊。检索无语言限制。

标准/纳入排除标准

我们纳入实施盲法或非盲法的随机或半随机临床试验,受试者为急性或慢加急性心源性肺水肿成人患者,对比了无创正压通气(持续气道正压通气或双水平无创正压通气)结合常规治疗与单独采用常规治疗的效果。

数据收集与分析

两位作者独立运用标准数据收集模式选取文章并提取数据。我们评价了研究质量的方案隐藏、随机序列生成、失访、结局评估、选择性报告和对意向性分析原则的依从。

主要结果

我们纳入了32项研究(2916位受试者),偏倚风险一般较低或不确定。与常规治疗相比,无创正压通气疗法很明显的减少了住院死亡率(相对危险率为0.66%,95%;可信区间0.48-0.89)和气管插管术的使用(相对危险率为0.52%,95%;可信区间0.36-0.75)。采用无创正压通气和常规治疗结合组在住院期方面与常规治疗组无差异,但加护病房天数减少一天(加权平均差为-0.89天,可信区间-1.33到-0.45)。

作者结论

除了常规疗法,无创正压通气也是一种治疗成年人急性心源性肺水肿的安全有效的方法。到目前为止能说明无创正压通气疗法可降低死亡率的证据均来自于小样本量试验,因此有待于进行进一步的大样本量临床试验。

翻译注解

译者:北京中医药大学英语专业本科生赵雅平、郭倩。审校:郭倩、赵雅平、李迅(北京中医药大学循证医学中心)

Plain language summary

Non-invasive positive pressure ventilation for cardiogenic pulmonary oedema

Acute heart failure has a high incidence in the general population and may lead to  the accumulation of fluid in the lungs, which is called acute cardiogenic pulmonary oedema (ACPE). This review aimed to determine the effectiveness and safety of non-invasive positive pressure ventilation (NPPV) (continuous positive airway pressure (CPAP) or bilevel NPPV) plus standard medical care, compared with standard medical care alone in adults with ACPE. We included 32 studies (2916 participants) of generally low or uncertain risk of bias. Results from randomised controlled trials indicate that NPPV can significantly reduce mortality as well as the need for endotracheal intubation rate, the number of days spent in the intensive care unit without increasing the risk of having a heart attack during or after treatment. We identified fewer adverse events with NPPV use (in particular progressive respiratory distress and neurological failure [coma]) when compared with standard medical care. In our comparison of CPAP and bilevel NPPV, CPAP may be considered the first option in selection of NPPV due to more robust evidence for its effectiveness and safety and lower cost compared with bilevel NPPV. The evidence to date on the potential benefit of NPPV in reducing mortality is entirely derived from small-trials and further large-scale trials are needed.

Résumé simplifié

Ventilation non invasive en pression positive pour œdème pulmonaire d'origine cardiaque

L'incidence de l'insuffisance cardiaque aiguë dans la population générale est importante ; cette insuffisance peut conduire à l'accumulation de liquides dans les poumons, que l'on appelle œdème aigu pulmonaire cardiogénique (OAPC). Cette revue visait à déterminer l'efficacité et l'innocuité de la ventilation non invasive à pression positive (VNIPP) (pression aérienne positive continue (PAPC) ou VNIPP à deux niveaux) en supplément aux soins médicaux standard, par rapport aux seuls soins médicaux standard chez les adultes souffrant d'OAPC. Nous avons inclus 32 études (soit 2916 participants) présentant généralement un risque de biais faible ou incertain. Les résultats d'essais contrôlés randomisés montrent que la VNIPP peut réduire considérablement la mortalité ainsi que le taux de besoin d'intubation endotrachéale et le nombre de jours passés en unité de soins intensifs, sans augmentation du risque de crise cardiaque pendant ou après le traitement. Nous avons recensé moins d'effets indésirables avec la VNIPP (en particulier de détresse respiratoire progressive et de défaillance neurologique [coma]) qu'avec les soins médicaux standard. Notre comparaison de la PAPC et de la VNIPP à deux niveaux indique que la PAPC peut être considérée comme la première option pour le choix d'une VNIPP en raison de preuves plus solides de son efficacité et de son innocuité, et de son moindre coût. À ce jour, les données sur un bénéfice potentiel de la VNIPP pour la réduction de la mortalité proviennent exclusivement de petits essais ; des essais supplémentaires à grande échelle sont nécessaires.

Notes de traduction

Traduit par: French Cochrane Centre 3rd June, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Resumo para leigos

Ventilação não invasiva com pressão positiva para pacientes com edema pulmonar cardiogênico

A insuficiência cardíaca aguda tem alta incidência na população geral e pode levar ao acúmulo de líquido nos pulmões, o que é chamado de edema agudo pulmonar cardiogênico (EAPC). Esta revisão teve o objetivo de avaliar a efetividade e a segurança da ventilação não invasiva com pressão positiva (VNIPP), seja de forma contínua (CPAP) ou em dois níveis (VNIPP binível), associada com o tratamento médico padrão, comparada com apenas o tratamento médico padrão em adultos com EAPC. Nós incluímos 32 estudos (2.916 participantes), a maioria com risco de viés baixo ou incerto. Os resultados dos ensaios clínicos randomizados indicam que a VNIPP pode reduzir significativamente a mortalidade, assim como a frequência de intubação endotraqueal e o número de dias na unidade de terapia intensiva, sem aumentar o risco de ocorrer um ataque cardíaco durante ou após o tratamento. Nós identificamos menos eventos adversos com o uso de VNIPP (em especial, progressão da insuficiência respiratória e coma) quando comparado com o tratamento médico padrão. Baseado na comparação do CPAP com a VNIPP binível, a CPAP deve ser considerada a primeira opção na escolha da VNIPP, uma vez que existem evidências mais fortes para efetividade e segurança dessa intervenção e seu custo é mais baixo do que a VNIPP binível. As evidências disponíveis até o presente sobre o potencial benefício da VNIPP em reduzir a mortalidade hospitalar são baseadas em estudos pequenos e, por isso, são necessários novos estudos envolvendo mais participantes.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Flávia Maria Ribeiro Vital)

淺顯易懂的口語結論

非侵襲性正壓呼吸器用在心因性肺水腫的病人

急性心衰竭(acute heart failure)在一般民眾的發生率高,有可能導致一體積在肺部,稱為急性心因性肺水腫。這個回顧目的在比較非侵襲性正壓呼吸器(NPPV) (continuous positive airway pressure (CPAP) or bilevel NPPV)加上標準醫療處置和僅使用標準醫療處置用於治療成人急性心因性肺水腫的效果和安全性。我們收錄了32個低或不確定偏誤風險的研究(2916個受試者)。隨機分派試驗的結果顯示NPPV顯著的降低死亡率、氣管內插管的需求以及在加護病房待的天數,且不會提高治療期間或之後心臟病的風險。我們觀察到NPPV的使用比標準醫療處置產生的不良事件少(特別是漸進性呼吸窘迫progressive respiratory distress和神經衰竭neurological failure(昏迷))。我們比較CPAP和bilevel NPPV後認為CPAP是選擇NPPV時的首選,因為關於它的效果和安全性的證據較多且價格比起bilevel NPPV來的低。到目前為止支持NPPV對減少死亡率有潛在益處的證據都是從小型試驗得來的,未來需要更多大型試驗來佐證。

譯註

翻譯者:羅峻涵
服務單位:中山醫學大學
職稱:醫學系六年級學生、實習醫師

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

概要

非侵入正压通气(持续正压通气或双水平正压通气)治疗心源性肺水肿

急性心力衰竭在普通人群中发生率较高,可能会引起肺部积水,即心源性肺水肿。本综述旨在探究与单独使用常规疗法相比,无创正压通气(持续气道正压通气或双水平无创正压通气)结合常规疗法治疗急性心源性肺水肿成人患者的安全性和有效性。我们纳入了偏倚风险一般较低或不确定的32项研究(2916位受试者)。随机对照试验的结果显示无创正压通气疗法能明显降低死亡率和气管插管术的使用,同时也减少了加护病房天数,且治疗后不会增加心脏病发作的风险。与常规治疗相比,无创正压通气不良反应更少(尤其是渐进性呼吸窘迫和神经功能障碍[昏迷])。在选择无创正压通气时,与双水平正压通气相比,持续正压通气可能是首要选择,因为有充分理由相信其有较高的安全性和有效性,且比双水平正压通气费用更低。到目前为止能说明无创正压通气疗法可降低死亡率的证据均来自于小样本量试验,因此有待于进行进一步的大样本量临床试验。

翻译注解

译者:北京中医药大学英语专业本科生赵雅平、郭倩。审校:郭倩、赵雅平、李迅(北京中医药大学循证医学中心)

Summary of findings(Explanation)

Summary of findings for the main comparison. Non-invasive positive pressure ventilation (CPAP and bilevel NPPV) for cardiogenic pulmonary edema
  1. 1 The most studies have mixed populations (with different levels of severity and co-morbidities).
    2 Was included only two quasi-randomised trials, but sensitivity analysis with quasi-randomised studies exclusion (Bersten 1991; Weitz 2007), showed the results to remain statistically significant. L'Her 2004 was interrupted early due to a greater number in deaths and complications in the control group.
    3 Although there is less 300 events in meta-analysis, when add Gray's study that analysed the mortality in 30 days, our meta-analysis of hospital mortality show that these study reinforce the favourable use of NPPV in ACPE with more 300 events.
    4 Was included only two quasi-randomised trials, but sensitivity analysis with quasi-randomised studies exclusion (Bersten 1991; Weitz 2007), showed the results to remain statistically significant. Park 2004 was interrupted early due to a difference in the frequency of intubations. Lin 1991 lost 35 of the 80 (44%) randomised patients for having fulfilled the criteria of exclusion or having presented failures on the received intervention.
    5 There is less 300 events in meta-analysis.
    6 Although two studies (Sharon 2000; Thys 2002) were interrupted early due to the incidence of acute myocardial infarction and the second due to a batch of failures of treatment and clinical decline.
    7 Was included one quasi-randomised trial (Weitz 2007). Lin 1991 lost 35 of the 80 (44%) randomised patients for having fulfilled the criteria of exclusion or having presented failures on the received intervention.
    8 Was included two quasi-randomised trials (Bersten 1991; Weitz 2007). L'Her 2004 was interrupted early due to a greater number in deaths and complications in the control group and not present the results in relation to autonomy for the activities of daily living, patient comfort and some planned adverse effects to be observed. Lin 1991 lost 35 of the 80 (44%) randomised patients for having fulfilled the criteria of exclusion or having presented failures on the received intervention. Thys 2002 was interrupted early due to a batch of failures of treatment and clinical decline.
    9 The grouping of the studies demonstrated relevant heterogeneity which was eliminated with the exclusion of Gray 2008 study, but we have not found plausible justification for this result
    10 RR < 0.5
    11 Was included two quasi-randomised trials (Bersten 1991; Weitz 2007). L'Her 2004 and Thys 2002 were interrupted early, the first due to a greater number in deaths and in the control group and the second due to a batch of failures of treatment and clinical decline. L'Her 2004 did not present the results in relation to autonomy for the activities of daily living, patient comfort and some planned adverse effects to be observed. Lin 1991 lost 35 of the 80 (44%) randomised patients for having fulfilled the criteria of exclusion or having presented failures on the received intervention.
    12 The grouping of the studies demonstrated relevant heterogeneity.
    13 Was included two quasi-randomised trials (Bersten 1991; Weitz 2007). Thys 2002 was interrupted early due to a batch of failures of treatment and clinical decline.

Non-invasive positive pressure ventilation (CPAP and bilevel NPPV) for cardiogenic pulmonary oedema
Patient or population: patients with cardiogenic pulmonary oedema
Settings: Emergency Department or Intensive Care Unit
Intervention: Non-invasive positive pressure ventilation (CPAP and bilevel NPPV)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlNon-invasive positive pressure ventilation (CPAP and bilevel NPPV)
Hospital mortalityYStudy population1RR 0.66
(0.48 to 0.89)
1107
(20 studies)
⊕⊕⊕⊕
high 2,3
 
204 per 1000135 per 1000
(98 to 182)
Moderate1
200 per 1000132 per 1000
(96 to 178)
Endotracheal intubation rateStudy populationRR 0.52
(0.36 to 0.75)
1261
(22 studies)
⊕⊕⊝⊝
low 4,5
 
249 per 1000130 per 1000
(90 to 187)
Moderate
300 per 1000156 per 1000
(108 to 225)
Incidence of acute myocardial infarction (During intervention)Study populationRR 1.24
(0.79 to 1.95)
461
(8 studies)
⊕⊕⊕⊝
moderate 5,6
 
153 per 1000190 per 1000
(121 to 299)
Moderate
169 per 1000210 per 1000
(134 to 330)
Incidence of acute myocardial infarction (After intervention)Study populationRR 0.7
(0.11 to 4.26)
154
(4 studies)
⊕⊝⊝⊝
very low 5,7
 
26 per 100018 per 1000
(3 to 111)
Moderate
13 per 10009 per 1000
(1 to 55)
Intolerance to allocated treatmentStudy populationRR 0.47
(0.29 to 0.77)
1848
(13 studies)
⊕⊕⊕⊝
moderate 8,9,10
 
234 per 1000110 per 1000
(68 to 180)
Moderate
350 per 1000165 per 1000
(101 to 269)
Hospital length of stay The mean hospital length of stay in the intervention groups was
0.8 lower
(2.1 lower to 0.51 higher)
 542
(10 studies)
⊕⊝⊝⊝
very low 11,12
 
Intensive care unit length of stay (Copy) The mean intensive care unit length of stay (copy) in the intervention groups was
0.89 lower
(1.33 to 0.45 lower)
 222
(6 studies)
⊕⊕⊝⊝
low 5,13
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

This is an update of a systematic review previously published in 2008 about non-invasive positive pressure ventilation (NPPV) in acute cardiogenic pulmonary oedema (ACPE) (Vital 2008).

Recent publications showed that about 5.7 million Americans and 15 million Europeans have heart failure (HF) (AHA 2012; Dickstein 2008). In the United States, the estimate annual rates per 1000 population of new HF events for white men are 15.2 for those 65 to 74 years of age, 31.7 for those 75 to 84 years of age, and 65.2 for those 85 years of age. For white women in the same age groups, the rates are 8.2, 19.8, and 45.6, respectively. For black men, the rates are 16.9, 25.5, and 50.6, and for black women, the estimated rates are 14.2, 25.5, and 44.0, respectively (AHA 2012). Acute HF is defined as the rapid onset of signs and symptoms secondary to abnormal cardiac function. HF may occur in the presence or absence cardiac disease and may culminate in acute cardiogenic pulmonary oedema (ACPE) manifested by severe respiratory distress. The most common causes of ACPE are ischaemia, acute coronary syndromes, hypertensive crisis, valvular dysfunction, acute arrhythmias, pericardial disease, increased filling pressures or elevated systemic resistance and dilated cardiomyopathy (Dickstein 2008; Gibelin 2002; Guimarães 2004; Nieminen 2005; Williams 1995). ACPE typically presents with severe respiratory distress, tachypnoea,orthopnoea, crackles on auscultation, and oxygen desaturation (Dickstein 2008; Nieminen 2005). Patients with acute HF have a poor prognosis. The one-year mortality rate associated with acute myocardial infarction complicated by acute HF is nearly 30% (Nieminen 2005). Furthermore, the in-hospital and one-year mortality rates associated with ACPE are 12% and 40%, respectively (Nieminen 2005). The incidence and burden of illness imposed by acute HF and ACPE are substantial, underscoring the need for effective preventative and treatment strategies.

In ACPE, cardiac failure results in increased back pressure on the pulmonary circulation which in turn, precipitates extravasation of fluid into the alveoli. In addition to overwhelming the capacity of the lymphatics for fluid removal (Allison 1991), the oedema fluid dilutes surfactant and neutralises its lubricating properties. Consequently, the lungs become less compliant and the effort of breathing increases (Chadda 2002; Martínez 1995; Meyer 1998; Park 2001). In the upright patient, most oedema fluid collects at the lung bases. The oedema fluid causes intrapulmonary shunting and, consequently, ventilation-perfusion (V-Q) mismatch and redistribution of blood flow to the upper lobes. ACPE presents clinically with difficulty breathing, hypoxaemia and anxiety. The resulting sympathetic nervous system activation manifests clinically with tachycardia, hypertension, peripheral vasoconstriction and diaphoresis (Allison 1991).

Clinicians treat patients with ACPE with supplemental oxygen, diuretics, nitrates, nitroglycerin and morphine sulfate. Additional treatments may be required to address the etiology of ACPE and may include antihypertensive therapy, inotropic agents, thrombolysis or urgent surgery (Dickstein 2008; Guimarães 2004; Nieminen 2005; Remme 1997; Williams 1995). A subset of patients with ACPE may require endotracheal intubation and mechanical ventilation (Meyer 1998). Mechanical ventilation supports oxygenation by recruiting previously collapsed alveoli (Levitt 2001; Williams 1995) and thereby improves lung compliance. However, invasive ventilation increases the risk for complications including nosocomial infections (pneumonia, sinusitis) and tracheal injury (Gay 2009; Keenan 1997). Consequently, may prolong intensive care unit (ICU) and hospital stay (Pang 1998). Patients with ACPE can be supported with NPPV, which has been shown to improve mortality and endotracheal intubation rate (ETI) as an initial treatment for patients with acute exacerbations of chronic obstructive pulmonary disease (Ram 2004).

NPPV includes forms of ventilatory support applied without the use of an endotracheal tube, and is considered to include continuous positive airway pressure (CPAP), without or with inspiratory pressure support (bilevel NPPV or BiPAP® - Respironics, Inc, Murrysville, PA). The goals of NPPV use in the treatment of ACPE are to improve oxygenation, reduce the effort of breathing and increase cardiac output (Evans 2001). CPAP achieves these goals by maintaining positive airway pressure throughout the respiratory cycle thereby preventing alveolar collapse at end-expiration. CPAP increases lung compliance and decreases the effort of breathing, while decreasing cardiac preload and afterload (Allison 1991; Bersten 1991; Räsänen 1985). CPAP improves arterial oxygenation (PaO2) by increasing the functional residual capacity of the lungs and reducing intrapulmonary shunt (Räsänen 1985). With CPAP high mean airway pressures are avoided and lower mean intra-thoracic pressures develop during inspiration with favourable effects on venous return and a lower risk of barotrauma (Covelli 1982; Kelly 1997). Treatment with CPAP has beneficial effects on haemodynamics by ameliorating hypertension and tachycardia (Väisänen 1987). Unlike CPAP, bilevel NPPV combines inspiratory positive airway pressure with positive end-expiratory pressure. Consequently, bilevel NPPV differs from CPAP in providing inspiratory assistance to rest the muscles of respiration (Mehta 1997). CPAP and bilevel NPPV are applied with either a nasal or oronasal mask at the patient-ventilator interface (Chadda 2002; Keenan 1997). Complications associated with NPPV use include air leaks, mask discomfort, skin breakdown, eye irritation, sinus congestion, oronasal drying and patient-ventilator dyssynchrony. Pneumothoraces and pneumonias can occur with NPPV administration but are less frequent compared to invasive ventilation (Bach 1997; Gay 2009). NPPV may also delay endotracheal intubation with patient deterioration in the intervening time period (Wood 1998).

Over the past 30 years, numerous reports have appeared in the literature regarding the potential effectiveness of NPPV for patients with ACPE (Masip 2000; Park 2001; Räsänen 1985). The delay in uptake of the evidence may be due to the need for increased patient supervision, the experience of staff with NPPV, NPPV availability and concerns regarding potential adverse effects (Bersten 1991; Pang 1998). Evidence from at least one randomised trial supports that NPPV accelerates recovery of vital signs and blood gases while avoiding intubation (Park 2001). The role of bilevel NPPV in patients with ACPE remains controversial. In a comparison of CPAP with bilevel NPPV, the latter demonstrated more rapid recovery of respiratory and haemodynamic parameters (Lin 1991), but bilevel NPPV was also associated with an increased incidence of acute myocardial infarction (Mehta 1997).

In spite of the potential advantages of NPPV for the management of ACPE, there appears to be a lack of high quality clinical evidence to support use of these interventions. The purpose of this systematic review was to identify, critically appraise and summarise the evidence for NPPV use for ACPE.

Objectives

The primary objective of this review was to determine the effectiveness and safety of NPPV (CPAP and/or bilevel NPPV) plus standard medical care compared to standard medical care in adults with ACPE on hospital mortality and other clinically important outcomes. The second objective of this review was to directly compare the effects of CPAP and bilevel NPPV on clinically important outcomes.

Methods

Criteria for considering studies for this review

Types of studies

We included blinded or unblinded randomised controlled trials (RCTs) or quasi-randomised controlled trials (QRCTs) in our review. We defined QRCTs as those in which the allocation procedure was unlikely to be adequately concealed (i.e. randomisation according to odd or even numbers, day of the week, social security number, or medical record number).

Types of participants

We included trials reporting on adult patients (>18 years) with acute or acute-on-chronic cardiogenic pulmonary oedema. We used the criteria of the American Heart Association (AHA) and/or the European Society of Cardiology (ESC) to define ACPE (Nieminen 2005; Williams 1995). Alternatively, a diagnosis of acute HF was based upon symptoms and clinical signs including dyspnoea, shortness of breath, nonproductive or cough productive of sputum), pallor, cyanosis, normal or elevated blood pressure, rales on auscultation and the presence of cold clammy skin. The diagnosis had to be supported by a chest radiograph, electrocardiograms, serum biomarkers of acute myocardial infarction or acute HF or echocardiography.

We excluded trials investigating NPPV for patients with a primary diagnosis of pneumonia, alternative etiologies of respiratory failure and its use as a weaning strategy.

Types of interventions

The control group included any form of standard medical care (SMC) provided for the management of cardiogenic pulmonary oedema (Nieminen 2005), excluding NPPV or alternative methods of ventilatory support.

The intervention group was standard medical care for the management of cardiogenic pulmonary oedema plus NPPV (CPAP and/or bilevel NPPV) applied through a nasal or facemask.

Types of outcome measures

Primary outcomes
  • Hospital mortality

Secondary outcomes
  • ETI

  • Incidence of acute myocardial infarction during and after intervention (during the hospital stay)

  • Intolerance to the allocated treatment (patients with criteria for intubation, but this situation did not happen, because they could get another type of ventilatory support)

  • Hospital length of stay (between admission to hospital up to death event or hospital leaving)

  • Intensive care unit (ICU) length of stay (time length in between admission to ICU up to death event or ICU leaving)

  • Arterial blood gases (PaCO2, PaO2) and pH one-hour post intervention

  • Vital signs: respiratory rate, heart rate, blood pressure 1-hour post intervention

  • Treatment failure (the combination of mortality and intubation and intolerance to the allocated treatment)

  • Adverse events

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews Effectiveness (DARE) on The Cochrane Library (Issue 2, 2011), MEDLINE (Ovid, 1950 to 20 April 2011), EMBASE (Ovid, 1980 to 20 April 2011), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO, 1982 to 20 April 2011) and LILACS (1982 to 20 April 2011) . When the searches were run in 2009 we combined the search strategies with the highly sensitive search strategies to identify RCTs in MEDLINE (Dickersin 1994), EMBASE (Lefebvre 1996), and LILACS (Castro 1999). When the searches were re-run in 2011 the MEDLINE and EMBASE searches used the most current highly sensitive search filters for RCTs (Lefebvre 2011).

The search strategies for each database are presented in Appendix 1 (and Appendix 2 (2009 and 2011 searches, respectively).

Searching other resources

We reviewed the bibliographies of retrieved articles to identify related published and unpublished studies.
We contacted authors of included RCTs, experts in NPPV and ventilator manufacturers to obtain information on other published and unpublished studies. No language restrictions were applied.

Data collection and analysis

We followed the recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions in preparing this review (Higgins 2011).

Selection of studies

Two authors (FV and ML) independently screened citations and selected trials meeting the inclusion criteria. Disagreements were resolved by a third author (AA).

Data extraction and management

Two authors (FV and ML) abstracted data using a standardised data collection form which highlighted characteristics of the study (design, methods of randomisation, withdrawals and dropouts, intention-to-treat analysis (ITT), informed consent, place and multicenter study), participants (age, gender, number, diagnostic criteria, inclusion and exclusion criteria) and interventions (type of NPPV, timing and duration of therapy, co-interventions, SMC (intervention and dose)) and the outcomes reported. We requested unpublished data from primary authors to supplement outcomes where needed. A third author (ANA) resolved disagreements. If consensus could not be reached, we contacted the author of the trial for additional information.

Assessment of risk of bias in included studies

We assessed the methodological quality of the included trials with emphasis on allocation concealment, generation of allocation sequence, detection bias, attrition bias, selective outcome reporting and adherence to ITT as follows (Higgins 2011; Schulz 1995):

Allocation concealment
  • Low risk of bias: randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study

  • Moderate risk of bias: randomisation stated but no information on method used is available

  • High risk of bias: method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group (quasi-randomised studies)

Generation of allocation sequence
  • Low risk of bias: adequate sequence generation

  • Moderate risk of bias: not reported in the paper or by contacting authors

  • High risk of bias: not adequate (quasi-randomised studies)

Detection bias
  • Low risk of bias: outcome assessors were independent from the individuals administering/supervising the assigned treatments

  • Moderate risk of bias: not reported in the paper or by contacting authors

  • High risk of bias: outcome assessors aware about the assigned treatments

Attrition bias
  • Low risk of bias: drop-outs without substantial (statistically significant) difference between the two comparison groups and/or a substantial drop-out rate within the sample as a whole

  • Moderate risk of bias: not reported in the paper or by contacting authors

  • High risk of bias: drop outs with substantial (statistically difference) between the two treatment groups and/or a substantial drop-out rate within the sample as a whole

Selective outcome reporting
  • Low risk of bias: reports of the study free of suggestion of selective outcome reporting

  • Moderate risk of bias: not reported in the paper or by contacting authors

  • High risk of bias: reports of the study with suggestion of selective outcome reporting

Adherence to the intention-to-treat principle
  • Yes: specifically reported by authors that intention-to-treat analysis was undertaken and this was confirmed on study assessment

  • No: not reported and lack of intention-to-treat analysis confirmed on study assessment (patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation)

We also noted whether informed consent was obtained and whether the study was blinded.

Assessment of heterogeneity

We assessed the impact of heterogeneity using the I2 test (Higgins 2011). This test illustrates the percentage of variability in effect estimates resulting from heterogeneity, as opposed to sampling error. In the presence of the significant heterogeneity (>50%) and a sufficient number of studies reporting the outcome of interest, we conducted exploratory analyses to investigate potential sources of heterogeneity (e.g. participants, treatments and study quality). We hypothesised that age, gender and comorbidities may represent potential sources of heterogeneity among participants. Heterogeneity may be related to the initial treatment(s) used, the levels of pressure applied with NPPV or treatment duration. We considered P values < 0.10 to be statistically significant.

Data synthesis

We pooled dichotomous and continuous variables using relative risk (RR) and weighted mean difference (WMD), respectively, using random-effects models. We presented the number needed to treat (NNT) and risk difference (RD) for statistically significant results and assessed their robustness using a fixed-effect model. We report summary estimates of treatment effect with their associated 95% confidence intervals (CIs). All analyses were performed using the Cochrane Collaboration's statistical software, (Review Manager 2013). We considered P values < 0.05 to be statistically significant.

Sensitivity analysis

We decided a priori to conduct sensitivity analysis to assess the impact of excluding QRCTs on the outcomes of mortality and endotracheal intubation. Finally, we constructed funnel plots to assess for publication bias (Egger 1997).

Quality of the evidence

We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the overall quality of evidence (Guyatt 2008; Higgins 2011).

Results

Description of studies

Study search

We identified 1248 citations from our electronic searches (250 in MEDLINE, 427 in EMBASE, 378 in CENTRAL, 137 in CINAHL, 37 in LILACS, and 19 in DARE). We identified two additional studies through searches in bibliographic references and through correspondence with authors. Two authors (FV, ML) pre-selected 35 references for more detailed review through abstract and title screening (see Figure 1 and Figure 2). All disagreements were resolved by a third reviewer (ANA). We have included 11 new studies with 21 previously included studies, totaling 32 studies involving 2,916 participants (Agmy 2008; Bautin 2005; Bellone 2004; Bellone 2005; Bersten 1991; Crane 2004; Delclaux 2000; Ferrari 2007; Ferrari 2010; Ferrer 2003; Fontanella 2010; Frontin 2010; Gray 2008; Kelly 2002; Levitt 2001; L'Her 2004; Liesching 2003; Lin 1991; Lin 1995; Martin-Bermudez 2002; Masip 2000; Mehta 1997; Moritz 2007; Nava 2003; Park 2001; Park 2004; Räsänen 1985; Sharon 2000; Takeda 1997; Takeda 1998; Thys 2002; Weitz 2007). This included 23 RCTs comparing NPPV plus standard medical care (CPAP and/or bilevel NPPV) to standard medical care and 14 RCTs comparing CPAP plus standard medical care and bilevel NPPV plus standard medical care directly. One of the studies was a mega trial (Gray 2008). Further details of the included studies are available in the section Characteristics of included studies and justifications for studies excluded are described in Characteristics of excluded studies.

Figure 1.

QUOROM statement flow diagram of 2005

Figure 2.

Figure 4. PRISMA statement flow diagram of 2011

Study design

Of the 32 parallel design studies, 30 were RCTs and 2 were QRCTs (Bersten 1991; Weitz 2007). Twenty seven studies were reported in full and five studies were reported in abstract form (Agmy 2008; Bautin 2005; Fontanella 2010; Liesching 2003; Martin-Bermudez 2002).

Population

The 32 studies were based in several countries including Finland, Australia, Taiwan, Japan, Spain, Israel, USA, Brazil, UK, Belgium, Egypt, Russian, Germany, France and Italy. Eight studies were multicentre studies (Crane 2004; Delclaux 2000; Ferrari 2010; Ferrer 2003; Gray 2008; L'Her 2004; Moritz 2007; Nava 2003). All studies reported on adult patients with acute or acute-on-chronic cardiogenic pulmonary oedema. The number of patients recruited in each study ranged from 8 to 1069 with similar numbers of patients in the intervention and control groups. We have included in the systematic review one mega trial (Gray 2008); however, only their adverse events and the outcome intolerance to the allocated treatment were recorded. The average age of participants was 74 years. The prevalence of cardiogenic pulmonary oedema for men and women was 47% and 53%, respectively.

While nine studies were conducted in the ICU (Agmy 2008; Bautin 2005; Delclaux 2000; Ferrer 2003; Fontanella 2010; Lin 1991; Räsänen 1985; Takeda 1997; Takeda 1998), four studies were undertaken in the emergency department and included patients referred to the ICU after being on a ward (Bersten 1991; Masip 2000; Mehta 1997; Thys 2002). Additionally, Park 2001 reported that it was conducted in the hospital without reference to a specific location, two studies did not report the venue (Liesching 2003; Martin-Bermudez 2002), and two other studies reported that the interventions were initiated in a mobile ICU and continued in the emergency department (Sharon 2000; Weitz 2007). Frontin 2010 reported that the interventions were initiated in a mobile ICU and continued in ICU. The remaining studies were solely undertaken in the emergency department.

Intervention

Of the studies identified, ten compared CPAP to SMC (Bersten 1991; Delclaux 2000; Frontin 2010; Kelly 2002; L'Her 2004; Lin 1991; Lin 1995; Räsänen 1985; Takeda 1997; Takeda 1998), and eight compared bilevel NPPV to SMC (Bautin 2005; Ferrer 2003; Levitt 2001; Masip 2000; Nava 2003; Sharon 2000; Thys 2002; Weitz 2007 ). Additionally, there were five three-arm studies comparing CPAP to bilevel NPPV and to SMC (Agmy 2008; Crane 2004; Gray 2008; Park 2001; Park 2004). Finally, nine studies directly compared CPAP with bilevel NPPV (Bellone 2004; Bellone 2005; Ferrari 2007; Ferrari 2010; Fontanella 2010; Liesching 2003; Martin-Bermudez 2002; Mehta 1997; Moritz 2007).

In Table 1, we present, where reported, the different IPAP and EPAP levels used and the duration of NPPV administration. The choice of patient-ventilator interface for NPPV administration varied among the included studies with three studies using nasal masks exclusively (Mehta 1997; Takeda 1997; Takeda 1998). Two studies offered a choice between nasal and face masks based on patient effort (Ferrer 2003; Levitt 2001). One study used nasal masks for bilevel NPPV administration and face masks for CPAP administration (Park 2001). Four studies did not report the patient-ventilator interface used (Agmy 2008; Gray 2008; Liesching 2003; Sharon 2000). The remaining studies reported using face masks for NPPV administration.

Table 1. IPAP Level and EPAP Level and time of intervention
  1. CPAP - continuous positive airway pressure; EPAP - expiratory positive airway pressure; IPAP - inspiratory positive airway pressure; PEEP - positive expiratory end pressure; SD - standard deviation; * statistically significant.

Study

IPAP level

(cmH2O)

EPAP in bievel NPPV

(cmH2O)

PEEP in CPAP (cmH2O)

Time of bilevel NPPV

(hours)

Time of CPAP

(hours)

Bautin 20055.1 (SD 0.3)9.8 (SD 1.1)   
Bellone 2004 5101.6 (SD 0.6)1.7 (SD 0.7)
Bellone 2005 5103.41 (SD 1.1)3.6 (SD 1.3)
Bersten 1991  10 9.3 (SD 4.9)
Crane 200415510  
Ferrari 200715 (SD 3.1)7 (SD 1.2)8.8 (SD 1.9)6.0 (SD 4.7)8.1 (SD 8.3)
Ferrari 200914 (SD 3.1)6.7 (SD 1.4)8.8 (SD 1.7)5.9 (SD 4.0)8.4 (SD 7.1)
Fontanella 201018 (SD 3)10 (SD 2)8 (SD 2)  
Frontin 2010  10  
Gray 200914 (SD 5)7 (SD 3)10 (SD 4)2.0 (SD 1.3)2.2 (SD 1.5)
Kelly 2002  7.5  
L'Her 2004  7.5 8 (SD 6)
Liesching 200312410  
Martin-Bermudez 2002   1.3 (SD 0.8)1.8 (SD 1)
Masip 200015.2 (SD 2.4)5 4.2 (SD 1.5) 
Mehta 199714.35 (SD 1.73)510.08 (SD 1.24)7.1 (SD 4.7)6.4 (SD 5.8)
Moritz 200712 (SD 3.2)4.9 (SD 0.9)7.7 (SD 2.1)2.82.3
Nava 200314.5 (SD 21.1)6.1 (SD 3.2) 11.4 (SD 3.6) 
Park 20011247.52.5 (SD 0.6)2.8 (SD 1.5)
Park 200417 (SD 2)11 (SD 2)11 (SD 2)2.0 (SD 1.0)1.7 (SD 0.6)
Rasanen 1985  10  
Sharon 20009.3 (SD 2.3)4.2 (SD 3.1)   
Takeda 1997    11.9 (SD 8.4)
Thys 200216.5 (SD 3.3)6.1 (SD 1.5) 1.2 (SD 0.2) 
Weitz 200712.5 (SD 1.2)5   

In addition to supplemental oxygen, studies reported the use of pharmacologic treatments including furosemide, morphine, diamorphine, sodium nitroprusside, glyceryl trinitrate, nitrate, isosorbide dinitrate, nitroglycerin, digoxin, digitalis, dopamine, dobutamine, epinephrine, norepinephrine, diazepam, chlorpromazine and antibiotics. Generally the medical team was free to choose the type of medication and its dose for the management of pulmonary oedema. However, one study used high doses of isosorbide dinitrate in the control group (Sharon 2000).

Outcomes

Almost all studies reported hospital mortality, except for Frontin 2010, Gray 2008 and Liesching 2003. Frontin 2010 reported mortality after 30 days. Gray 2008 reported mortality after 7 and 30 days from the beginning of the intervention. In order to perform a meta-analysis taking into considering the weight of the mega-trial (which presented opposite results to the first version of this review), we included data on mortality in a separate meta-analysis. However, we were unable to consider the total number after randomisation by group in this meta-analysis since Gray 2008 did not provide this information, which precluded intention-to-treat analysis according to dichotomous outcomes expected. The remaining outcomes were variably reported by the included studies. All dichotomous outcomes were described in adherence with the intention-to-treat principle. All authors reported their studies using mean and standard deviations for continuous outcomes. We transformed units from kilo pascals to millimetres of mercury in pooling results reported for arterial blood gases in two studies (Crane 2004; Kelly 2002).

Risk of bias in included studies

The summary of risk of bias can be viewed illustratively in Figure 3 and Figure 4.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 4.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

All studies included stated that treatment allocation was made randomly. The following studies, which adequately reported the method of allocation concealment, were classified as "low risk of bias": Bellone 2004; Bellone 2005; Crane 2004; Delclaux 2000; Ferrari 2007; Ferrari 2010; Frontin 2010; Gray 2008; Kelly 2002; L'Her 2004; Martin-Bermudez 2002; Masip 2000; Moritz 2007; Nava 2003; Park 2001; Park 2004; Räsänen 1985; Takeda 1998; Thys 2002. The following studies did not describe the method of allocation concealment and were classified as "moderate risk of bias": Agmy 2008; Bautin 2005; Ferrer 2003; Fontanella 2010; Levitt 2001; Liesching 2003; Lin 1991; Lin 1995; Mehta 1997; Sharon 2000; Takeda 1997. The following two studies had an inadequate (quasi-randomised) method and were classified as "high risk of bias": Bersten 1991; Weitz 2007.

In 19 studies sequence generation was described in an appropriate way (Bellone 2004; Bellone 2005; Crane 2004; Delclaux 2000; Ferrari 2007; Ferrari 2010; Ferrer 2003; Frontin 2010; Gray 2008; Levitt 2001; L'Her 2004; Martin-Bermudez 2002; Masip 2000; Mehta 1997; Moritz 2007; Nava 2003; Park 2001; Park 2004; Sharon 2000). Bersten 1991 and Weitz 2007 did not describe sequence generation.

Incomplete outcome data

Just two studies have presented significant losses during follow up: Mehta 1997 had lost 9 of the 36 (25%) randomised patients due to infections, exacerbation of COPD and delay in obtaining the informed permission or to initiate intervention; and Lin 1991 lost 35 of the 80 (44%) randomised patients for having fulfilled the exclusion criteria or having failed to receive the intervention.

Selective reporting

The majority of the studies planned and reported the outcomes analysed. Two studies omitted some information (Ferrari 2010; L'Her 2004 ). Ferrari 2010 planned to analyse the effect of NPPV on systemic blood pressure but did not report this outcome. L'Her 2004 did not present the results in relation to autonomy for activities of daily living, patient comfort and adverse effects.

Other potential sources of bias

Detection bias was the domain that generated more uncertainty in risk analysis of bias. The majority of studies did not report on blinding. Given the nature of the intervention, blinding of participants and personnel to the intervention was not feasible. Studies by Mehta and Thys were reported as being single-blinded, but in these instances the patient was reportedly blinded to his/her intervention (Mehta 1997; Thys 2002), which appears inconsistent with blinding. Only Delclaux 2000, Gray 2008, Martin-Bermudez 2002 and Moritz 2007 reported that the evaluators were independent.

Twenty-one studies performed analysis by ITT. For our analysis, we performed the analysis of all dichotomous variables by intention-to-treat.

Five studies were stopped early due to preliminary analysis which demonstrated significant differences between groups (L'Her 2004; Mehta 1997; Park 2004; Sharon 2000; Thys 2002). For examples, differences were seen in Mehta 1997 and Sharon 2000 due to the incidence of acute myocardial infarction, in Thys 2002 due to a batch of failures of treatment and clinical decline, in L'Her 2004 due to a greater number in deaths and complications in the control group and in Park 2004 due to a difference in the frequency of intubations. Seven studies did not explicitly report that informed consent was obtained (Agmy 2008; Bautin 2005; Fontanella 2010; Liesching 2003; Lin 1995; Martin-Bermudez 2002; Räsänen 1985).

Sharon's study used different doses of isosorbide dinitrate as standard treatment in the different randomised groups, which may have influenced its results.

The analysis of funnel plot for the outcome hospital mortality demonstrates the indicates asymmetry and the potential risk of publication bias (Figure 5).

Figure 5.

Funnel plot of comparison: 1 Hospital Mortality, outcome: 1.1 NPPV (CPAP and BILEVEL) x SMC.

Quality of the evidence  

About 50% of the studies were considered as low risk of bias (Figure 3). The sole domain of quality that most studies did not report on was whether the analysis of outcomes was undertaken by the same person who applied the interventions (detection bias) (Figure 4). As such, we believe that the quality of the evidence included in this review is at moderate risk of bias.

More specifically, we defined seven relevant outcomes in order to assess the quality of evidence by GRADE (Guyatt 2008; Higgins 2011). The primary outcome (mortality) was supported by high quality evidence, two outcomes (incidence of acute myocardial infarction during intervention and intolerance to the allocated treatment) were considered to be supported by moderate quality evidence. Two outcomes (endotracheal intubation rate and ICU length of stay) were considered to be supported by low quality of evidence and for incidence of acute myocardial infarction after intervention and hospital length of stay were considered to be supported by very low quality evidence (Summary of findings for the main comparison).

Effects of interventions

See: Summary of findings for the main comparison Non-invasive positive pressure ventilation (CPAP and bilevel NPPV) for cardiogenic pulmonary edema

For studies comparing NPPV to SMC, we report our results as NPPV (CPAP and bilevel NPPV) versus SMC, CPAP alone versus SMC and bilevel NPPV alone versus SMC. In addition, we report results for studies directly comparing CPAP to bilevel NPPV. We report the pooled results for all primary and secondary analyses and sensitivity analyses conducted to explore potential sources of heterogeneity on the outcomes of hospital mortality and endotracheal intubation. The summary of our findings can be seen in Summary of findings for the main comparison.

Hospital mortality

In 20 trials involving 1107 patients, we found a reduction in hospital mortality for patients treated with NPPV plus SMC compared with SMC care alone (RR 0.66, 95% CI 0.48 to 0.89). This translates into a RD of - 0.07 or 7% (95% CI -0.12 to -0.02) and NNT of 14 (Analysis 1.1). Sensitivity analysis with the exclusion of quasi-randomised studies (Bersten 1991; Weitz 2007), did not change the results (RR 0.65, 95% CI 0.46 to 0.91; Analysis 1.2). However if we consider Gray 2008 and Frontin 2010 that analysed the mortality in 7 and/or 30 days, our meta-analysis of hospital mortality indicates that these studies reinforce the favourable use of NPPV in ACPE (RR 0.72, 95% CI 0.55 to 0.94 and RR 0.75, 95% CI 0.60 to 0.95, respectively Analysis 15.1 and Analysis 16.1).This result could have been anticipated using cumulative meta-analysis techniques (Figure 6; MIX 2006).

Figure 6.

Cumulative meta-analysis

Comparing CPAP plus SMC with SMC alone (13 trials, 699 patients) there was a lower hospital mortality rate in CPAP-treated patients (RR 0.60, 95% CI 0.39 to 0.94; Analysis 1.6). The beneficial effect of CPAP translates into a RD of -11% (95% CI -0.18 to -0.04) and a NNT of 9. The effect of CPAP on hospital mortality remained significant after exclusion of a single QRCT (Bersten 1991) (RR 0.57, 95% CI 0.35 to 0.94; Analysis 1.7).

However, we found no benefit of bilevel NPPV plus SMC compared with SMC care alone on hospital mortality (11 trials, 506 patients, RR 0.65, 95% CI 0.39 to 1.09; Analysis 1.8), and after exclusion of quasi-randomised studies (Bersten 1991; Weitz 2007) (Analysis 1.9). However, the similar effect size and wider confidence intervals for bilevel NPPV compared to the overall NPPV and CPAP-specific results is noted.

We found no differences in hospital mortality comparing CPAP plus SMC and bilevel NPPV plus SMC directly (12 trials, 694 patients, RR 1.10, 95% CI 0.61 to 1.97; Analysis 1.12).

ETI rate

In 22 trials (1261 patients) we found a lower ETI rate for patients treated with NPPV plus SMC compared with SMC (RR 0.52, 95% CI 0.36 to 0.75; Analysis 2.1). This translates into a RD of - 0.12 or 12% (95% CI -0.19 to -0.04) and a NNT of 8. Exclusion of two QRCTs (Bersten 1991; Weitz 2007) also revealed beneficial effect of NPPV compared to SMC (RR 0.53, 95% CI 0.37 to 0.78; Analysis 2.2). This remained in Gray 2008 and Frontin 2010 that analysed the frequency intubation in seven days (RR 0.55, 95% CI 0.38 to 0.78; Analysis 17.1).

When we compared CPAP plus SMC with SMC (14 trials, 825 patients) we found a significantly lower endotracheal intubation favouring CPAP-treated patients (RR 0.47, 95% CI 0.33 to 0.67, RD -15%, 95% CI -0.24 to -0.06, NNT 7; Analysis 2.4). This result remained robust after exclusion of a single quasi-randomised trial (Bersten 1991) (RR 0.48, 95% CI 0.34 to 0.67; Analysis 2.5).

We found no benefit of bilevel NPPV plus SMC compared with SMC alone on ETI rate (12 trials, 536 patients, RR 0.55, 95% CI 0.26 to 1.17; Analysis 2.6). However with significant heterogeneity and after exclusion of the QRCT (Weitz 2007) and Sharon 2000 (whose patients received different doses of drugs) this altered the results: lower ETI favouring bilevel NPPV-treated patients (RR 0.45, 95% CI 0.26 to 0.80; Analysis 2.7).

In 13 trials (721 patients) comparing CPAP plus SMC to bilevel NPPV plus SMC care, there did not appear to be any difference between the two techniques in reducing ETI (RR 1.04, 95% CI 0.55 to 1.97; Analysis 2.10).

Incidence of acute myocardial infarction

In eight trials (461 patients) we found non-significant differences in the occurrence of acute myocardial infarction during treatment with NPPV plus SMC compared to SMC (Analysis 3.1). A similar non-significant differences were found in comparisons of CPAP plus SMC compared to bilevel NPPV plus SMC (Analysis 3.4), CPAP plus SMC care compared to SMC or bilevel NPPV plus SMC compared to SMC (Analysis 3.2; Analysis 3.3).

Only four studies (154 patients) comparing NPPV plus SMC to SMC alone reported no difference in the incidence of acute myocardial infarction after intervention (Analysis 4.1); two studies reported no difference after CPAP plus SMC care compared to SMC (RR 1.08, 95% CI 0.11 to 10.23; Analysis 4.2); three studies with bilevel NPPV plus SMC to SMC reported no difference in the incidence of acute myocardial infarction after intervention (RR 0.52, 95% CI 0.02 to 11.54; Analysis 4.3); two studies compared CPAP plus SMC to bilevel NPPV plus SMC and demonstrated no difference (RR 1.57, 95% CI 0.57 to 4.32; Analysis 4.4).

Intolerance to the allocated treatment

Thirteen studies (1848 patients) found a lower incidence of intolerance in the NPPV plus SMC (16%) compared to SMC (23%) (RR 0.47, 95% CI 0.29 to 0.77; Analysis 5.1), The grouping of the studies demonstrated relevant heterogeneity, which was eliminated with the exclusion of Gray 2008 (Analysis 5.2). We have not found plausible justification for this result. Nine studies (1304 patients) noted significantly lower intolerance with CPAP plus SMC compared to SMC (RR 0.55, 95% CI 0.36 to 0.85; Analysis 5.3); seven studies (995 patients) found no difference related with intolerance to bilevel NPPV plus SMC care compared to SMC (RR 0.58, 95% CI 0.24 to 1.42; Analysis 5.4). Three studies (894 patients) found no difference between CPAP plus SMC and bilevel NPPV plus SMC with respect to intolerance (RR 0.94, 95% CI 0.35 to 2.53; Analysis 5.5).

Length of hospital and ICU stay

Ten trials (542 patients) demonstrated no significant difference in hospital length of stay between NPPV plus SMC compared to SMC (WMD -0.80 days, 95% CI -2.10 to 0.51; Analysis 6.1). Though heterogeneity diminished after exclusion of one QRCT (Weitz 2007), it did not change the significance of our results (Analysis 6.2). Five studies (337 patients) demonstrated no differences CPAP plus SMC compared to SMC (WMD -0.51 days, 95% CI -1.69 to 0.67; Analysis 6.3). Seven studies (311 patients) showed no difference between bilevel plus SMC and SMC alone (WMD -1.38 days, 95% CI -3.38 to 0.62; Analysis 6.4), and similar results were obtained between CPAP plus SMC and bilevel NPPV plus SMC (WMD -0.46 days, 95% CI -1.99 to 1.07; Analysis 6.5).

Six studies (222 patients) comparing NPPV plus SMC to SMC alone demonstrated significantly shorter ICU stay favouring the NPPV group (WMD -0.89 days, 95% CI -1.33 to -0.45; Analysis 7.1). Three studies (169 patients) indicated a significantly shorter ICU stay for patients treated with CPAP plus SMC (WMD -1.09 days, 95% CI -1.63 to -0.56; Analysis 7.2). A further three studies (53 patients) showed no difference between bilevel NPPV plus SMC and SMC (WMD -0.65 days, 95% CI -1.37 to 0.06; Analysis 7.3) while no difference was seen between CPAP plus SMC and bilevel NPPV plus SMC (WMD 0.31 days, 95% CI -0.78 to 1.40; Analysis 7.4).

Vital signs one hour after intervention

Respiratory rate

Nine studies (438 patients) revealed significantly lower respiratory rates in patients on NPPV plus SMC in comparison with SMC (WMD -2.86 bpm, 95% CI -3.85 to -1.87; Analysis 8.1). Seven studies (300 patients) had lower respiratory rate on CPAP plus SMC compared to SMC (WMD -2.39 bpm, 95% CI -3.70 to -1.07; Analysis 8.2), while six studies (254 patients) showed lower respiratory rate in patients on bilevel NPPV plus SMC in comparison with those receiving SMC (WMD -3.52 bpm, 95% CI -4.80 to -2.23; Analysis 8.3). Five studies (218 patients) did not show a significant difference between CPAP plus SMC and bilevel NPPV plus SMC (WMD 0.57 bpm, 95% CI -1.00 to 2.13; Analysis 8.4).

Heart rate (HR)

Nine studies (438 patients) showed no significant difference between NPPV plus SMC and SMC in terms of heart rate (WMD -4.01 bpm, 95% CI -8.16 to 0.15; Analysis 9.1). Seven studies (300 patients) found no difference between CPAP plus SMC and SMC (WMD -4.45 bpm, 95% CI -10.81 to 1.92; Analysis 9.3). The grouping of the studies in these two analyses demonstrated heterogeneity, which was eliminated with the exclusion of Rasanen's and L'Her's studies and we have not found plausible justification for this result (Analysis 9.2 and Analysis 9.4). Six studies (254 patients) revealed lower heart rate in patients on bilevel NPPV plus SMC in comparison with SMC (WMD -4.21bpm, 95% CI -7.77 to -0.65; Analysis 9.5) and no significant results were seen in four studies (182 patients) comparing CPAP plus SMC and bilevel NPPV plus SMC (WMD 0.56 bpm, 95 %CI -5.22 to 4.11; Analysis 9.6).

Systolic blood pressure (SBP)

Six studies (182 patients) found no statistically significant difference between NPPV plus SMC and SMC groups in SBP (WMD -1.64 mmHg, 95% CI -7.83 to 4.56; Analysis 10.1). Six studies (211 patients) found no statistically significant difference between CPAP plus SMC and SMC groups in SBP (WMD -0.12 mmHg, 95% CI -6.56 to 6.81; Analysis 10.2). Similar non-significant differences were seen in comparison of bilevel NPPV plus and SMC (WMD 1.93 mmHg, 95% CI -7.94 to 11.80; Analysis 10.3), and CPAP plus SMC versus bilevel NPPV plus SMC (WMD -1.17 mmHg, 95% CI -10.79 to 8.44; Analysis 10.4). However, the last analysis showed significant heterogeneity, which was resolved after removing Bellone 2004, which showed higher baseline SBP value than other studies (Analysis 10.5).

Diastolic blood pressure (DBP)

Five studies (138 patients) compared NPPV plus SMC and SMC care on DBP but found no difference (WMD -1.49 mmHg, 95% CI -6.43 to 3.45; Analysis 11.1). Five studies (167 patients) compared CPAP plus SMC and SMC on DBP but found no difference (WMD -0.92 mmHg, 95% CI -9.10 to 7.27; Analysis 11.2). However, heterogeneity was observed, which diminished after excluding studies Räsänen 1985 and Crane 2004 (there was a lower value for baseline DBP (mean and SD) in the latter studies in comparison with the others). After excluding those studies, the remaining three studies (107 patients) showed statistically significant lower DBP in patients on CPAP in comparison with those receiving SMC (WMD -7.32 mmHg, 95% CI -12.79 to -1.86; Analysis 11.3). No difference was seen when bilevel NPPV plus SMC care was compared to SMC (four studies; 87 patients) (WMD -0.96 mmHg, 95% CI -6.09 to 4.16; Analysis 11.4) or CPAP plus SMC vs bilevel NPPV plus SMC (WMD -2.60 mmHg, 95% CI -9.58 to 4.37; Analysis 11.5). A change was observed when Crane 2004 and Martin-Bermudez 2002 were excluded, showing statistically significant better DBP in patients (n=62) on CPAP plus SMC in comparison with those receiving bilevel NPPV plus SMC, but we have not found plausible justification for this result (WMD -7.86 mmHg, 95% CI -13.03 to -2.70; Analysis 11.6).

Mean blood pressure (MBP)

Three studies (256 patients) found no statistically significant difference between NPPV plus SMC compared to SMC (WMD -2.41 mmHg, 95% CI -8.27 to 3.45; Analysis 12.1); similar non-significance was seen in comparison of CPAP plus SMC and SMC (one study, 89 patients) (WMD 3.00 mmHg, 95% CI -5.31 to 11.31; Analysis 12.2), in bilevel NPPV plus SMC compared to SMC (two studies, 167 patients) (WMD -5.42 mmHg, 95%CI -11.60 to 0.76; Analysis 12.3), and in comparison of CPAP plus SMC and Bilevel NPPV plus standard medical care (one study, 80 patients) (WMD -4.40 mmHg, 95% CI -13.25 to 4.45; Analysis 12.4) .

Arterial blood gases and pH one hour after intervention

Four studies (140 patients) showed significantly higher PaO2 levels being found in NPPV plus SMC patients in comparison with those receiving SMC (WMD 10.04 mmHg, 95% CI 1.09 to 19.00; Analysis 13.1 ). Five studies (177 patients) found no difference in arterial oxygen levels (PaO2) between CPAP plus SMC and SMC alone (WMD -2.64 mmHg, 95% CI -25.87 to 20.59; Analysis 13.2). Pooling of these five studies showed significant heterogeneity. Exclusion of the Lin 1991 and Räsänen 1985 studies, which were conducted in ICU settings, showed significantly better PaO2 after one hour of intervention in SMC care patients in comparison with those receiving NPPV (WMD -22.09 mmHg, 95% CI -34.35 to -9.83; Analysis 13.3). Three studies (79 patients) comparing bilevel NPPV plus SMC versus SMCe did not show any significant difference between the groups (WMD 4.79 mmHg, 95% CI -11.11 to 20.69; Analysis 13.4). Three studies showed significantly higher PaO2 levels being found in bilevel NPPV plus SMC patients in comparison with those receiving CPAP plus SMCe (WMD -27.00 mmHg, 95% CI -44.75 to -9.25; Analysis 13.5).

We did not pool PaCO2 and pH one hour after intervention as these outcomes require assessment with respect to baseline values (normal for each patient). Pooling of these parameters may not be meaningful.

Treatment failure

We defined treatment failure as a composite of mortality, endotracheal intubation and intolerance to the allocated treatment. No study in this review reported this outcome.

Adverse events

Table 2 summarises the types and number of reported adverse events for both CPAP and bilevel NPPV, where they were reported, regardless of comparative intervention.

Table 2. Summary of adverse events
  1. CI - confidence interval; CPAP - continuous positive airway pressure; RR - relative risk; SD - standard deviation; * statistically significant..

Adverse eventsNumber of events (CPAP)Total number CPAPNumber of event (bilevel NPPV)Total number (bilevel NPPV)RR (95% CI)
Skin damage2472174580.06 (0.01, 0.43)*
Pneumonia0401760.63 (0.03, 15.03)
Pulmonary aspiration047613830.27 (0.01, 6.57)
Gastric distention51788510.18 (0.06, 0.52)*
GI bleeding0113851.02 (0.06, 18.63)
Vomitting738194190.86 (0.32, 2.27)
Pneumothorax044014300.33 (0.01, 7.97)
Asphyxia/claustrophobia0201651.05 (0.04, 24.76)
Mask discomfort15364224400.82 (0.43, 1.57)
Sinusitis0431650.50 (0.02, 12.00)
Conjunctivitis070   
Eye irritation  020 
Cardiac arrest6333134100.57 (0.22, 1.48)
Stroke  065 
Seizure  065 
Hypotension36332373461.01 (0.66, 1.56)
Arrhythmia requiring treatment12332253450.50 (0.25, 0.98)*
Progressive respiratory distress17333213460.84 (0.45, 1.57)
Increase breathing discomfort16287192910.85 (0.45, 1.63)

Fifteen studies reported adverse events with 232 events occurring in 1109 NPPV plus SMC treated patients and 154 events occurring in 751 SMC care treated patients. The adverse events reported were: skin damage, pneumothorax, pulmonary aspiration, gastric distension, vomiting, mask discomfort, hypotension, arrhythmia, progressive respiratory distress, gastrointestinal bleeding, asphyxia, conjunctivitis, sinusitis, eyes irritation, stroke, seizure, neurological failure (coma) and cardiorespiratory arrest. Participants receiving SMC had less skin damage and those treated with  NPPV had less progressive respiratory distress and neurological failure (coma). Confining the analysis to trials published after 2000 did not alter these results. A detailed description of these complications can be found in Table 3, Analysis 14.1 and Analysis 14.2.

Table 3. Adverse events by NPPV versus SMC
  1. CI - confidence interval; NPPV - noninvasive positive pressure ventilation; RR - relative risk; SMC - standard medical care; * statistically significant.

Adverse eventsStudiesNPPV groupSMC groupRR (95% CI)
Skin damage11 studies (Rasanen 1985, Bersten 1991, Takeda 1998, Masip 2000, Kelly 2002, Thys 2002, Nava 2003, Crane 2004, L'Her 2004, Park 2004, Bautin 2005)17/3180/2766.62 (1.20, 36.55)*
Pneumonia3 study (Lin 1991, Nava 2003, Bautin 2005)1/1164/1160.35 (0.05, 2.20)
Pulmonary aspiration5 studies (Rasanen 1985, Bersten 1991, Lin 1991, Kelly 2002, Gray 2008)1/7870/4681.58 (0.06, 38,61)
Gastrointestinal
bleeding
3 study (Takeda 1998, Masip 2000, Nava 2003)3/962/961,37 (0.27, 6.89)
Gastric distension8 studies (Rasanen 1985, Bersten 1991, Lin 1991, Takeda 1998, Thys 2002, Park 2004, L'Her 2004, Frotin 2010)13/2530/23113.26 ( 0.82, 215.12)
Vomiting5 studies (Masip 2000, Thys 2002, Crane 2004, Park 2004, Gray 2008)16/8008/4291.06 (0.46, 2.47)
Asphyxia2 study (Bersten 1991, Nava 2003)1/850/853.00 (0.12, 72.31)
Pneumothorax6 studies (Bersten 1991, Kelly 2002, Nava 2003, L'Her 2004, Gray 2008, Frotin 2010)1/8941/5800.72 (0.08, 6.89)
Conjunctivitis2 studies (Kelly 2002, L'Her 2004)0/700/77inestimable
Sinusitis2 study (Nava 2003, L'Her 2004)1/1080/1113.00 (0.12, 72.31)
Mask discomfort7 study (Masip 2000, Nava 2003, L'Her 2004, Park 2004, Bautin 2005, Weitz 2007, Frotin 2010)7/2650/2475.39 (0.97, 30.09)
Hypotension1 study (Gray 2008)73/67846/3520.82 (0.58, 1.16)
Arrhythmia1 study (Gray 2008)37/67723/3500.83 (0.50, 1.38)
Progressive respiratory distress2 studies (L'Her 2004, Gray 2008)39/72236/4000.58 (0.37, 0.89)*
Neurological failure (coma)1 study (L'Her 2004)1/4411/460,10 (0.01, 0,71)*
Cardiorespiratory arrest3 studies (Nava 2003, L'Her 2004, Gray 2008)21/78622/4660.60 (0.29, 1.26)
Eye irritation1 study (Masip 2000)0/200/20inestimable
Stroke1 study (Nava 2003)0/650/65inestimable
Seizure1 study (Nava 2003)0/651/650.33 (0.01, 8.03)

Ten studies reported adverse events with 88 events complications in the 544 CPAP plus SMC treated patients and 146 events in the 572 SMC treated patients. The adverse events reported were: skin damage, pneumonia, pulmonary aspiration, gastrointestinal bleeding, gastric distension, vomiting, asphyxia, pneumothorax, conjunctivitis, sinusitis, mask discomfort, hypotension, arrhythmia, progressive respiratory distress, cardiorespiratory arrest and neurological failure (coma). The CPAP group had fewer  progressive respiratory distress, cardiorespiratory arrest and neurological failure (coma). Details of adverse events in patients receiving CPAP and standard medical care are provided in Table 4 and Analysis 14.3.

Table 4. Adverse events by CPAP versus SMC
  1. CI - confidence interval; CPAP - continuous positive airway pressure; RR - relative risk; SMC - standard medical care; * statistically significant.

Adverse EventsStudiesCPAP groupSMC groupRR (95% CI)
Skin damage

7 studies (Rasanen 1985, Bersten 1991, Takeda 1998,

Kelly 2002, Crane 2004, L'Her 2004, and Park 2004)

1/1680/1753.00 (0.13, 69.52)
Pneumonia1 study (Lin 1991)0/400/40inestimable
Pulmonary aspiration

5 studies (Rasanen 1985, Bersten 1991, Lin 1991,

Kelly 2002, Gray 2008)

0/4400/468inestimable
Gastrointestinal
bleeding
1 study (Takeda 1998)0/111/110.33 (0.02,7.39)
Gastric distension

7 studies (Rasanen 1985, Bersten 1991, Lin 1991,

Takeda 1998, Park 2004, L'Her 2004, Frotin 2010)

5/2210/22611.00 ( 0.64, 189.65)
Vomiting3 studies (Crane 2004, Park 2004, Gray 2008)7/3818/4040.93 (0.34, 2.54)
Asphyxia1 study (Bersten 1991)0/200/20inestimable
Pneumothorax

5 studies (Bersten 1991, Kelly 2002, L'Her 2004,

Gray 2008, Frotin 2010)

0/4830/515inestimable
Conjunctivitis2 studies (Kelly 2002, L'Her 2004)0/700/77inestimable
Sinusitis1 study (L'Her 2004)0/430/46inestimable
Mask discomfort3 studies (L'Her 2004, Park 2004, Frotin 2010)0/1300/135inestimable
Hypotension1 study (Gray 2008)36/33246/3520.83 (0.55, 1.25)
Arrhythmia1 study (Gray 2008)12/33223/3500.55 (0.28, 1.09)
Progressive respiratory distress2 studies (L'Her 2004, Gray 2008)18/37636/4000.53 (0.31, 0.92)*
Neurological failure (coma)1 study (L'Her 2004)1/4411/460,10 (0.01, 0,71)*
Cardiorespiratory arrest2 studies (L'Her 2004, Gray 2008)8/37621/4010.41 (0.18, 0.91)*

Eight studies reported adverse events with 144 events occurring in 368 bilevel NPPV plus SMC care patients and 136 events occurring in 384 SMC. The adverse events reported were: skin damage, pneumonia, gastrointestinal bleeding, gastric distension, vomiting, pneumothorax, eyes irritation, sinusitis, mask discomfort, claustrophobia, cardiac arrest, stroke, seizure, gastric aspiration, hypotension, arrhythmia and progressive respiratory distress. Participants in the SMC group had a lower rate of skin damage  Details of the adverse events in people receiving bilevel NPPV plus SMC are provided in Table 5 and Analysis 14.4.

Table 5. Adverse events by bilevel NPPV versus SMC
  1. CI - confidence interval; NPPV - noninvasive positive pressure ventilation; RR - relative risk; SMC - standard medical care; * statistically significant.

Adverse EventsStudiesBilevel NPPV GroupSMC GroupRR (95% CI)
Skin damage6 studies (Masip 2000, Thys 2002, Nava 2003, Crane 2004, Park 2004, Bautin 2005)16/1480/1487.16 (1.27, 40.50)*
Pneumonia2 study (Nava 2003, Bautin 2005)1/764/760.35 (0.05, 2.20)
Gastrointestinal
bleeding
2 studies (Nava 2003, Masip 2000)3/851/852.32 (0.35, 15.42)
Gastric distension2 studies (Thys 2002, Park 2004)8/320/3215.87 (0.96, 262.30)
Vomiting5 studies (Masip 2000, Thys 2002, Crane 2004, Park 2004, Gray 2008)9/4198/4291.21 (0.47, 3.11)
Pneumothorax2 study (Nava 2003, Gray 2008)1/4111/4211.01 (0.11, 9.63)
Eye irritation1 study (Masip 2000)0/200/20inestimable
Sinusitis1 study (Nava 2003)1/650/653.00 (0.12, 72.31)
Mask discomfort5 studies (Masip 2000, Nava 2003, Park 2004, Bautin 2005, Weitz 2007)7/1350/1395.39 (0.97, 30.09)
Claustrophobia1 study (Nava 2003)1/650/653.00 (0.12, 72.31)
Cardiac arrest2 study (Nava 2003, Gray 2008)13/41017/4200.96 (0.25, 3.61)
Stroke1 study (Nava 2003)0/650/65inestimable
Seizure1 study (Nava 2003)0/651/650.33 (0.01, 8.03)
Pulmonary aspiration1 studies (Gray 2008)1/3470/3573.09 (0.13, 75.50)
Hypotension1 study (Gray 2008)37/34646/3520.82 (0.54, 1.23)
Arrhythmia1 study (Gray 2008)25/34523/3501.10 (0.64, 1.90)
Progressive respiratory distress1 study (Gray 2008)21/34635/3540.61 (0.36, 1.03)

Five studies reported adverse events with 156 events occurring in 389 bilevel NPPV plus SMC treated patients and 126 events occurring in 376 CPAP plus SMC treated patients. The adverse events reported were: skin damage, pneumothorax, pulmonary aspiration, gastric distension, vomiting, mask discomfort, increased breathing discomfort, hypotension, arrhythmia, progressive respiratory distress, cardiorespiratory arrest, pharyngeal damage and cough. Patients treated with CPAP had fewer arrhythmias. A detailed description of the complications can be found in Table 6 and Analysis 14.5.

Table 6. Adverse events by bilevel NPPV versus CPAP
  1. CI - confidence interval; CPAP - continuous positive airway pressure; NPPV - noninvasive positive pressure ventilation; RR - relative risk; SMC - standard medical care; * statistically significant.

Adverse eventsSstudiesBilevel NPPV groupCPAP groupRR (95% CI)
Skin damage5 studies (Mehta 1997, Martin-Bermudez 2002, Crane 2004, Park 2004, Gray 2008)4/4006/3900.64 (0.19, 2.16)
Pulmonary aspiration3 studies (Mehta 1997, Martin-Bermudez 2002, Gray 2008)1/4070/3892.88 (0.12, 70.43)
Gastric distension3 studies (Mehta 1997, Martin-Bermudez 2002, Park 2004)8/895/831.49 (0.56, 4.00)
Vomiting4 studies (Martin-Bermudez 2002, Crane 2004, Park 2004, Gray 2008)11/43711/4200.97 (0.43, 2.19)
Pneumothorax2 studies (Mehta 1997, Gray 2008)1/3650/3502.89 (0.12, 70.63)
Mask discomfort4 studies (Mehta 1997, Martin-Bermudez 2002, Park 2004, Gray 2008)17/37516/3601.03 (0.53, 2.00)
Increased breathing discomfort1 study (Gray 2008)16/29111/2851.42 (0.67, 3.02)
Hypotension2 studies (Martin-Bermudez 2002, Gray 2008)41/38740/3710.98 (0.65, 1.48)
Arrhythmia1 study (Gray 2008)25/34512/3322.00 (1.02, 3.92)*
Progressive respiratory distress1 study (Gray 2008)21/34617/3331.19 (0.64, 2.21)
Cardiorespiratory arrest1 study (Gray 2008)10/3456/3331.61 (0.59, 4.38)
Pharyngeal damage1 study (Martin-Bermudez 2002)1/411/390.95 (0.06, 14.69)
Cough1 study (Martin-Bermudez 2002)1/411/390.32 (0.01, 7.57)

Discussion

The inclusion of eleven new studies in this review did not change significantly the results for the effectiveness of the use of NPPV compared with SMC, but it was possible to identify modest differences between CPAP and bilevel NPPV.

Summary of main results

Our meta-analysis demonstrates the effectiveness of NPPV and CPAP compared to SMC in reducing hospital mortality. Our results support that one death can be avoided for every 14 ACPE patients treated with NPPV. Similarly, one death can be prevented for every nine ACPE patients treated with CPAP. This means that 69 lives out of 1000 could be saved with the addition of NPPV to SMC. The reduction in mortality was supported by studies comparing CPAP to SMC but not by studies comparing bilevel NPPV to SMC or CPAP to bilevel NPPV. The effect size of bilevel NPPV was notably similar to CPAP compared to SMC, but these results were more imprecise. Potential reasons for these discordant findings may include the relatively small number of patients experiencing events in these studies leading to low power; incorporating more recent studies that may have led to reduced mortality from SMC; or a true difference between CPAP and bilevel NPPV, which is corroborated by the findings from studies that directly compare CPAP and bilevel NPPV in patients with ACPE. However, the mega trial published by Gray 2008 analysed mortality 7 and 30 days after the NPPV initiation in patients with ACPE and did not identify any important differences between the NPPV groups compared to the SMC. Nonetheless, when we include these data in a meta-analysis of our primary outcome (in-hospital mortality), we find a persistent benefit of NPPV in reducing mortality in patients with ACPE. We do identify limitations in Gray 2008 that may contribute with findings divergences. First, Gray 2008 reported that it used ITT analyses but its analysis did not include all randomised patients (follow-up bias). Second, the study did not report the total distribution of randomisation by group, which impeded the meta-analysis of various outcomes and could be considered as a potential source of heterogeneity (Higgins 2011). Third, the reporting of continuous variables included only mean value of the difference between zero and one hour after the intervention and not as mean and standard deviation. However, it has not been possible to obtain these data for our meta-analysis.

We also found that NPPV significantly reduced endotracheal intubation compared to SMC. Only eight patients need to be treated with NPPV to avoid 1 intubation. We noted similar results in studies comparing CPAP to SMC where the NNT was 7. Although NPPV has demonstrated to effectively reduce the intubation rate, it was not possible to assess if NPPV could postpone this outcome, as suggested in the study of Wood 1998. This randomised study reported significant delay in intubation and mechanical ventilation of acute respiratory distress syndrome (ARDS) patients treated with bilevel NPPV compared with SMC. The difference however was not found to be statistically significant (P=0.06), perhaps due to a low event rate (seven in the bilevel NPPV group and five in the SMC group). Likewise, the outcomes of mortality and intubation rate did not show statistically significant difference between the groups. In contrast to Confaloniere`s study of patients with pneumonia, although bilevel NPPV reduced the intubation rate, no difference in the time to intubate and initiate mechanical ventilation was observed (Confalonieri 1999).

An additional important finding of our review was that the incidence of acute myocardial infarction was not increased either during or after NPPV use. This is an important finding, as some studies (Mehta 1997; Rusterholtz 1999; Sharon 2000) had noted an increased incidence of acute myocardial infarction in patients treated with bilevel NPPV. To this end, few studies clearly distinguished between acute myocardial infarction at randomisation or evolving during or after NPPV initiation. Consistent with our results, Bellone and colleagues applied stringent criteria to detect acute myocardial infarction (Bellone 2004) and noted non-significant differences in acute myocardial infarction among CPAP and bilevel NPPV treated patients. Recent RCTs (Ferrari 2007; Moritz 2007; Gray 2008) have also shown no significant differences on the incidence of acute myocardial infarction and other relevant outcomes when compared CPAP to bilevel NPPV.

NPPV also appears to reduce the risk of progression of respiratory failure and neurological failure (coma) compared to SMC. These results were mainly influenced by studies conducted with CPAP, which additionally demonstrated a reduction in cardiovascular arrest and adverse events risk in general when compared to SMC. NPPV is associated with increased risk for skin damage, but this adverse event is not generally considered major. This adverse event outcome was primarily influenced by Nava's studies, which may be related to the particular time and use of NPPV mask in that study. CPAP demonstrated a lower risk of developing arrhythmias when compared to using bilevel NPPV. It is possible that this reduced risk of adverse events with the use of CPAP could be related to lower positive pressure levels than those used in the bilevel NPPV, which may influence haemodynamics and/or O2 consumption. Despite similar effect sizes between CPAP and bilevel NPPV in terms of our primary outcome, these safety data are notable.

Our review did not reveal a significant difference between NPPV and SMC in terms of hospital length of stay. However, our review supports about one-day reduction in ICU length of study with NPPV compared to SMC, and CPAP, in particular, compared to SMC. These differences were not supported in comparisons of bilevel NPPV to SMC and CPAP to bilevel NPPV. Some studies such as Holt 1994 have shown a reduction in hospital length of stay in ACPE patients using CPAP. We postulate that the reductions in ICU length of stay may be related to the reduction in intubation, as Wysocki 1995 related the smaller intubation rate to shorter hospital stay in a post-hoc analysis. Although our review found NPPV and CPAP to be better tolerated than SMC, future studies should assess whether a trade-off exists between treatment intolerance and other important outcomes such as mortality. In Crane 2004, while a large number of CPAP treated patients were intolerant of treatment, patients in this group also had lower mortality compared to bilevel NPPV and SMC.

NPPV was introduced to emergency departments in the early 1990s and became a relatively common place by approximately 2001 (Bersten 1991). In our review we noted similar reductions in mortality in patients treated with NPPV in the emergency department (RR 0.55, 95% CI 0.36 to 0.86; Analysis 5.2) and in the ICU (RR 0.48, 95% CI 0.28 to 0.83; Analysis 5.3). This finding supports initiation of NPPV in patients with ACPE in the emergency department. Additionally in our analysis, a cross-over RCTof 124 patients with out-of-hospital diagnosis of ACPE and use of CPAP demonstrated faster improvements in dyspnoea, faster improvements in PaO2, lower intubation rates, lower use of dobutamine, and lower hospital mortality (Plaisance 2007). These results reinforce the positive pressure concept considered as non-pharmacologic treatment and not a simple measure of support in ACPE cases.

We did find consistent effects of NPPV compared SMC and bilevel NPPV compared CPAP on PaO2 in patients with ACPE in first hour. However, it would be interesting if future studies analyse the existence of a direct relation among an early PaO2 improvements with outcomes such as mortality and need for intubation.

Some studies have postulated that patients with ACPE and hypercapnia (increased amount of carbon dioxide in the blood > 45 mmHg) may benefit to a greater extent from bilevel NPPV treatment (Hoffmann 1999; Rusterholtz 1999; Wysocki 1995; Wysocki 1999). In a post-hoc analysis, we pooled studies including ACPE patients with hypercapnia at admission (mean values of PaCO2) and compared NPPV to SMC on the outcomes of mortality and endotracheal intubation. Compared to all population with ACPE patients, we found significant reductions in mortality (RR 0.60, 95% CI 0.40 to 0.88; Analysis 1.5 and ETI rate (RR 0.44, 95% CI 0.25 to 0.77; Analysis 2.3) favouring hypercapnic patients although the between-group differences were not statistically significant. Similarly, we found favourable reductions in mortality and intubation in among patients treated with bilevel NPPV versus standard medical care (RR 0.59, 95% CI 0.34 to 1.02 and RR 0.47, 95% CI 0.22 to 0.97, respectively; Analysis 1.10 and Analysis 2.8) and no difference in mortality (RR 0.98, 95% CI 0.45 to 2.14; Analysis 1.13 ) or intubation (RR 1.17, 95% CI 0.58 to 2.33; Analysis 2.11) in hypercapnic patients compared with all population with ACPE patients treated with bilevel NPPV versus CPAP; although the between group differences are not statistically significant. These analysis are reinforced by the meta-analysis studies by Agmy 2008, Moritz 2007; Nava 2003 and Masip 2000 who realised the mortality analysis and/or endotracheal intubation rate in the subgroup of hypercapnics patients and the results were more favourable to the use of bilevel compared to SMC in mortality and intubation (RR 0.20, 95% CI 0.04 to 0.86 and RR 0.28, 95% CI 0.12 to 0.69, respectively; Analysis 1.11 and Analysis 2.9), but no significant differences between CPAP and bilevel (RR 1.06, 95% CI 0.33 to 3.37 and RR 0.92, 95% CI 0.26 to 3.21, respectively; Analysis 1.14 and Analysis 2.12). Though these comparisons didn't report significant difference to the meta-analysis results conducted in patients with ACPE in general. Our analyses have demonstrated that patients with ACPE and hypercapnia seem to benefit even more from the usage of NPPV, particularly from bilevel NPPV.

Once the benefits of NPPV have been demonstrated, cost-benefit analyses, like the one conducted by Newberry et al. showing that NPPV cost less than mechanical ventilation (Newberry 1995), are important. In another study, the cost of respiratory services were lower with NPPV compared with SMC, but total cost with NPPV was higher than in the SMC group (Kramer 1995).

Overall completeness and applicability of evidence

In this review, we pooled the results of 32 RCTs (27 comparing NPPV and SMC and 14 comparing CPAP and bilevel NPPV) in patients with ACPE on important clinical outcomes, or eleven studies additional than the first version of this systematic review. This update maintains the results of the previous version where both NPPV and CPAP reduce hospital mortality, endotracheal intubation, ICU length of stay and respiratory rate compared to SMC. We did not observe the same beneficial effects on important clinical outcomes among studies comparing bilevel NPPV to SMC and CPAP to bilevel NPPV, though these results were similar in their effect size yet more imprecise. We also found that NPPV, CPAP and bilevel NPPV were better tolerated than SMC alone. Importantly, compared to SMC, use of NPPV, bilevel NPPV and CPAP in patients with ACPE did not increase the incidence of acute myocardial infarction during or after intervention. However this update identified a lower incidence of important adverse events in patients receiving NPPV plus SMC, as lower risk of progression of respiratory failure and coma. If we consider only CPAP, also a lower risk of cardiorespiratory arrest is also demonstrated. Among the studies that made the direct comparison between CPAP and bilevel NPPV a significantly lower incidence of arrhythmias with CPAP was observed. The only adverse event significantly unfavourable to the use of NPPV identified was skin damage. Our results demonstrate the effectiveness and safety of NPPV, especially CPAP, as adjuvant therapy to SMC in patients with ACPE.

Quality of the evidence

We considered the quality of the evidence to be moderate, although there may be some potential for publication bias. We defined seven relevant outcomes in order to assess the quality of evidence by GRADE (Guyatt 2008; Higgins 2011), and the primary outcome of mortality was considered to supported by quality evidence, where incidence of acute myocardial infarction during intervention and intolerance to the allocated treatment were considered to supported by only moderate quality of evidence. The remaining (endotracheal intubation rate and ICU length of stay, incidence of acute myocardial infarction after intervention and hospital length of stay) were unsupported by adequate evidence.

Potential biases in the review process

The major weakness of our review is the comparatively small number of events within trials comparing bilevel NPPV to SMC and CPAP to bilevel NPPV, thus limiting the inferences that can be made from them. It is important to note that SMC varied widely among the studies and included different drugs at different dosages. This disparity may have influenced treatment effect across studies. For example, Sharon 2000 used high doses of isosorbide dinitrate, which was related to better results in important outcomes such as acute myocardial infarction incidence and need for intubations when compared with low doses of isosorbide. Another potential source of bias is the variable inclusion criteria across studies. Disparities in baseline characteristics may have influenced patient response to treatment. A final source of bias may be the different thresholds or criteria used for reintubation in the included studies.

Strengths of this review include methods to reduce bias (multimodal search strategy without language restrictions, duplicate independent screening and data abstraction and prespecified criteria for appraising methodologic quality) with the quantitative differential of the Cochrane reviews (Jadad 2000; McKibbon 2004). To this end, we obtained additional information from 17 authors (Agmy 2008; Bautin 2005; Bersten 1991; Bellone 2005; Crane 2004; Delclaux 2000; Ferrari 2007; Gray 2008; Kelly 2002; Martin-Bermudez 2002; Masip 2000; Nava 2003; Park 2004; Räsänen 1985; Takeda 1998; Thys 2002; Weitz 2007). As a result, our meta-analysis includes the largest number of trials exploring the role of NPPV in ACPE and consequently had increased power in pooling outcomes (Potts 2009). We analysed the impact of NPPV on a broad set of physiological and clinical outcomes. Although there was heterogeneity in some analyses, it was possible to observe that the exclusion of low quality studies did not influence the results (Bersten 1991; Weitz 2007). The generalisability of our findings is enhanced by the diverse nature of the trials included in our review, representing international experience with NPPV use for ACPE.

Agreements and disagreements with other studies or reviews

The first systematic review on the role of NPPV for ACPE reported a lower intubation rate with CPAP Pang 1998. Hess 2004 subsequently suggested that bilevel NPPV may benefit patients with ACPE with hypercapnia. Nadar 2005 then found that bilevel NPPV decreased intubation, improved oxygenation, and was better tolerated compared to CPAP in patients with ACPE. However, because of the concern regarding the potential for acute myocardial infarction, bilevel NPPV could not be recommended for treatment of ACPE. Our review supports the use of NPPV, and especially CPAP, in the treatment of ACPE. These findings are important as current ACPE management guidelines do not recommend NPPV use in the absence of A level of evidence (Nieminen 2005). The results of our review could make this recommendation possible.

However, newer meta-analyses have found results similar to ours (Collins 2006; Ho 2006; Masip 2005; Peter 2006;Weng 201O; Winck 2006), although with small differences in methodological and included studies, all conclude that NPPV is effective in reducing mortality in patients with ACPE. However, a mega-trial conducted in patients with ACPE was published and concluded that NPPV does not reduce mortality compared to SMC (Gray 2008); however, it is possible to observe several important differences in this study that differ from the others included in systematic reviews and meta-analysis as: mortality was evaluated after 7 or 30 days from the beginning of the intervention, while other studies have analysed mortality during the period of hospitalisation. Gray 2008 excluded patients who were more seriously ill. Approximately one in five patients in the SMC arm crossed over to NPPV within two hours of randomisation in Gray 2008, suggesting contamination that would attenuate the apparent effect of NPPV on mortality. Gray 2008 also had a 40% lower event rate than found in our meta-analysis, which may be due to differences in patient characteristics, SMC, or other unmeasured differences that could influence the size of the treatment effect of NPPV. The quality of the studies that had evaluated the primary outcome mortality was high, as of can be visualised in Summary of findings for the main comparison, which strengthens our inference of the benefit of NPPV in reducing mortality in patients with ACPE.

Authors' conclusions

Implications for practice

Data from RCTs have demonstrated that NPPV (CPAP and bilevel NPPV) is effective in reducing hospital mortality, intubation rate and ICU length of stay. In addition, NPPV resulted in faster improvement and was better tolerated than SMC. Further, our meta-analysis did not demonstrate an increase in the incidence of acute myocardial infarction during and after NPPV application. We show a lower risk of progressive respiratory distress and neurological failure (coma) when compare NPPV to SMC and cardiorespiratory arrest when compare only CPAP to SMC as well as a lower risk of arrhythmia when comparing CPAP to bilevel NPPV. CPAP can be considered the first option in selection of NPPV due to more robust evidence for its effectiveness and safety and lower costs compared with bilevel NPPV.

Implications for research

Further studies are required to reduce uncertainty regarding length of hospital stay, long-term mortality, costs and the time required to manage NPPV. Additional research is required to elucidate if hypercapnic patients with ACPE may benefit to a greater extent than non-hypercapnic patients and if bilevel NPPV confers similar benefit or risks compared to CPAP.

Acknowledgements

We are grateful to the authors of the studies we reviewed and who kindly answered our e-mails or correspondence regarding additional data (Räsänen, Bersten, Kelly, Nava, Park, Takeda, Thys, Masip, Bellone, Crane, Delclaux, Ferrari, Bautin, Agmy, Gray and Weitz). We are also thankful for the critical evaluation of the professors Dr. Velasco IT, Dr. Scalabrini Neto A, Dr. Gonçalves AJ, Dr. Godoy MF and by the collaboration of the following co-authors in the first version of the publication of this systematic review: Burns K, Saconato H, Sen A, Hawkes CA and Soares B. We thank Joey Kwong by Chinese translation paper. Finally the Cochrane heart group for suggested improvements.

Data and analyses

Download statistical data

Comparison 1. Hospital mortality
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) x SMC201107Risk Ratio (M-H, Random, 95% CI)0.66 [0.48, 0.89]
2 NPPV (CPAP and BILEVEL) X SMC - sensitivity analysis181023Risk Ratio (M-H, Random, 95% CI)0.65 [0.46, 0.91]
3 NPPV (CPAP and BILEVEL) X SMC- ED place9717Risk Ratio (M-H, Random, 95% CI)0.55 [0.36, 0.86]
4 NPPV (CPAP and BILEVEL) X SMC - ICU place7365Risk Ratio (M-H, Random, 95% CI)0.48 [0.28, 0.83]
5 NPPV (CPAP and BILEVEL) X SMC - in patients hypercanics - baseline9603Risk Ratio (M-H, Random, 95% CI)0.60 [0.40, 0.88]
6 CPAP x SMC13699Risk Ratio (M-H, Random, 95% CI)0.60 [0.39, 0.94]
7 CPAP X SMC - sensitivity analysis12659Risk Difference (M-H, Random, 95% CI)-0.12 [-0.19, -0.04]
8 BILEVEL X SMC11506Risk Ratio (M-H, Random, 95% CI)0.65 [0.39, 1.09]
9 BILEVEL X SMC - sensitivity analysis9458Risk Ratio (M-H, Random, 95% CI)0.63 [0.37, 1.09]
10 BILEVEL X SMC - in patients hypercanics - baseline7401Risk Ratio (M-H, Random, 95% CI)0.59 [0.34, 1.02]
11 BILEVEL X SMC - in patients hypercanics2104Risk Ratio (M-H, Random, 95% CI)0.20 [0.04, 0.86]
12 CPAP X BILEVEL12694Risk Ratio (M-H, Random, 95% CI)1.10 [0.61, 1.97]
13 CPAP X BILEVEL - in patients hypercanics - baseline9518Risk Ratio (M-H, Random, 95% CI)0.98 [0.45, 2.14]
14 CPAP X BILEVEL - in patients hypercanics298Risk Ratio (M-H, Random, 95% CI)1.06 [0.33, 3.37]
Analysis 1.1.

Comparison 1 Hospital mortality, Outcome 1 NPPV (CPAP and BILEVEL) x SMC.

Analysis 1.2.

Comparison 1 Hospital mortality, Outcome 2 NPPV (CPAP and BILEVEL) X SMC - sensitivity analysis.

Analysis 1.3.

Comparison 1 Hospital mortality, Outcome 3 NPPV (CPAP and BILEVEL) X SMC- ED place.

Analysis 1.4.

Comparison 1 Hospital mortality, Outcome 4 NPPV (CPAP and BILEVEL) X SMC - ICU place.

Analysis 1.5.

Comparison 1 Hospital mortality, Outcome 5 NPPV (CPAP and BILEVEL) X SMC - in patients hypercanics - baseline.

Analysis 1.6.

Comparison 1 Hospital mortality, Outcome 6 CPAP x SMC.

Analysis 1.7.

Comparison 1 Hospital mortality, Outcome 7 CPAP X SMC - sensitivity analysis.

Analysis 1.8.

Comparison 1 Hospital mortality, Outcome 8 BILEVEL X SMC.

Analysis 1.9.

Comparison 1 Hospital mortality, Outcome 9 BILEVEL X SMC - sensitivity analysis.

Analysis 1.10.

Comparison 1 Hospital mortality, Outcome 10 BILEVEL X SMC - in patients hypercanics - baseline.

Analysis 1.11.

Comparison 1 Hospital mortality, Outcome 11 BILEVEL X SMC - in patients hypercanics.

Analysis 1.12.

Comparison 1 Hospital mortality, Outcome 12 CPAP X BILEVEL.

Analysis 1.13.

Comparison 1 Hospital mortality, Outcome 13 CPAP X BILEVEL - in patients hypercanics - baseline.

Analysis 1.14.

Comparison 1 Hospital mortality, Outcome 14 CPAP X BILEVEL - in patients hypercanics.

Comparison 2. EETI rate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC221261Risk Ratio (M-H, Random, 95% CI)0.52 [0.36, 0.75]
2 NPPV (CPAP and BILEVEL) X SMC - sensitivity analysis201195Risk Ratio (M-H, Random, 95% CI)0.53 [0.37, 0.78]
3 NPPV (CPAP and BILEVEL) X SMC - in patients hypercapnics - baseline9621Risk Ratio (M-H, Random, 95% CI)0.44 [0.25, 0.77]
4 CPAP X SMC14825Risk Ratio (M-H, Random, 95% CI)0.47 [0.33, 0.67]
5 CPAP X SMC - sensitivity analysis13785Risk Ratio (M-H, Random, 95% CI)0.48 [0.34, 0.67]
6 BILEVEL X SMC12536Risk Ratio (M-H, Random, 95% CI)0.55 [0.26, 1.17]
7 BILEVEL X SMC - sensitivity analysis10470Risk Ratio (M-H, Random, 95% CI)0.45 [0.26, 0.80]
8 BILEVEL X SMC - in patients hypercapnics - baseline7401Risk Ratio (M-H, Random, 95% CI)0.47 [0.22, 0.97]
9 BILEVEL X SMC - in patients hypercapnics3120Risk Ratio (M-H, Random, 95% CI)0.28 [0.12, 0.69]
10 CPAP X BILEVEL13721Risk Ratio (M-H, Random, 95% CI)1.04 [0.55, 1.97]
11 CPAP X BILEVEL - in patients hypercapnics - baseline9518Risk Ratio (M-H, Random, 95% CI)1.17 [0.58, 2.33]
12 CPAP X BILEVEL - in patients hypercapnics298Risk Ratio (M-H, Random, 95% CI)0.92 [0.26, 3.21]
Analysis 2.1.

Comparison 2 EETI rate, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 2.2.

Comparison 2 EETI rate, Outcome 2 NPPV (CPAP and BILEVEL) X SMC - sensitivity analysis.

Analysis 2.3.

Comparison 2 EETI rate, Outcome 3 NPPV (CPAP and BILEVEL) X SMC - in patients hypercapnics - baseline.

Analysis 2.4.

Comparison 2 EETI rate, Outcome 4 CPAP X SMC.

Analysis 2.5.

Comparison 2 EETI rate, Outcome 5 CPAP X SMC - sensitivity analysis.

Analysis 2.6.

Comparison 2 EETI rate, Outcome 6 BILEVEL X SMC.

Analysis 2.7.

Comparison 2 EETI rate, Outcome 7 BILEVEL X SMC - sensitivity analysis.

Analysis 2.8.

Comparison 2 EETI rate, Outcome 8 BILEVEL X SMC - in patients hypercapnics - baseline.

Analysis 2.9.

Comparison 2 EETI rate, Outcome 9 BILEVEL X SMC - in patients hypercapnics.

Analysis 2.10.

Comparison 2 EETI rate, Outcome 10 CPAP X BILEVEL.

Analysis 2.11.

Comparison 2 EETI rate, Outcome 11 CPAP X BILEVEL - in patients hypercapnics - baseline.

Analysis 2.12.

Comparison 2 EETI rate, Outcome 12 CPAP X BILEVEL - in patients hypercapnics.

Comparison 3. Incidence of acute myocardial infarction (during intervention)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC8461Risk Ratio (M-H, Random, 95% CI)1.24 [0.79, 1.95]
2 CPAP X SMC3152Risk Ratio (M-H, Random, 95% CI)0.91 [0.37, 2.24]
3 BILEVEL X SMC7356Risk Ratio (M-H, Random, 95% CI)1.40 [0.78, 2.49]
4 CPAP X BILEVEL7409Risk Ratio (M-H, Random, 95% CI)0.66 [0.39, 1.10]
5 BILEVEL X SMC - heterogeneity analysis6316Risk Ratio (M-H, Random, 95% CI)1.14 [0.69, 1.88]
Analysis 3.1.

Comparison 3 Incidence of acute myocardial infarction (during intervention), Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 3.2.

Comparison 3 Incidence of acute myocardial infarction (during intervention), Outcome 2 CPAP X SMC.

Analysis 3.3.

Comparison 3 Incidence of acute myocardial infarction (during intervention), Outcome 3 BILEVEL X SMC.

Analysis 3.4.

Comparison 3 Incidence of acute myocardial infarction (during intervention), Outcome 4 CPAP X BILEVEL.

Analysis 3.5.

Comparison 3 Incidence of acute myocardial infarction (during intervention), Outcome 5 BILEVEL X SMC - heterogeneity analysis.

Comparison 4. Incidence of acute myocardial infarction (after intervention)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC4154Risk Ratio (M-H, Random, 95% CI)0.70 [0.11, 4.26]
2 CPAP X SMC299Risk Ratio (M-H, Random, 95% CI)1.08 [0.11, 10.23]
3 BILEVEL X SMC365Risk Ratio (M-H, Random, 95% CI)0.52 [0.02, 11.54]
4 CPAP X BILEVEL268Risk Ratio (M-H, Random, 95% CI)1.57 [0.57, 4.32]
Analysis 4.1.

Comparison 4 Incidence of acute myocardial infarction (after intervention), Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 4.2.

Comparison 4 Incidence of acute myocardial infarction (after intervention), Outcome 2 CPAP X SMC.

Analysis 4.3.

Comparison 4 Incidence of acute myocardial infarction (after intervention), Outcome 3 BILEVEL X SMC.

Analysis 4.4.

Comparison 4 Incidence of acute myocardial infarction (after intervention), Outcome 4 CPAP X BILEVEL.

Comparison 5. Intolerance to allocated treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC131848Risk Ratio (M-H, Random, 95% CI)0.47 [0.29, 0.77]
2 NPPV (CPAP and BILEVEL) X SMC - heterogeneity analysis12692Risk Ratio (M-H, Random, 95% CI)0.42 [0.30, 0.58]
3 CPAP X SMC91304Risk Ratio (M-H, Random, 95% CI)0.55 [0.36, 0.85]
4 BILEVEL X SMC7995Risk Ratio (M-H, Random, 95% CI)0.58 [0.24, 1.42]
5 CPAP X BILEVEL3894Risk Ratio (M-H, Random, 95% CI)0.94 [0.35, 2.53]
Analysis 5.1.

Comparison 5 Intolerance to allocated treatment, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 5.2.

Comparison 5 Intolerance to allocated treatment, Outcome 2 NPPV (CPAP and BILEVEL) X SMC - heterogeneity analysis.

Analysis 5.3.

Comparison 5 Intolerance to allocated treatment, Outcome 3 CPAP X SMC.

Analysis 5.4.

Comparison 5 Intolerance to allocated treatment, Outcome 4 BILEVEL X SMC.

Analysis 5.5.

Comparison 5 Intolerance to allocated treatment, Outcome 5 CPAP X BILEVEL.

Comparison 6. Hospital length of stay
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC10542Mean Difference (IV, Random, 95% CI)-0.80 [-2.10, 0.51]
2 NPPV (CPAP and BILEVEL) X SMC - heterogeneity analysis9519Mean Difference (IV, Random, 95% CI)-0.38 [-1.35, 0.58]
3 CPAP X SMC5337Mean Difference (IV, Random, 95% CI)-0.51 [-1.69, 0.67]
4 BILEVEL X SMC7311Mean Difference (IV, Random, 95% CI)-1.38 [-3.38, 0.62]
5 CPAP X BILEVEL6402Mean Difference (IV, Random, 95% CI)-0.46 [-1.99, 1.07]
Analysis 6.1.

Comparison 6 Hospital length of stay, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 6.2.

Comparison 6 Hospital length of stay, Outcome 2 NPPV (CPAP and BILEVEL) X SMC - heterogeneity analysis.

Analysis 6.3.

Comparison 6 Hospital length of stay, Outcome 3 CPAP X SMC.

Analysis 6.4.

Comparison 6 Hospital length of stay, Outcome 4 BILEVEL X SMC.

Analysis 6.5.

Comparison 6 Hospital length of stay, Outcome 5 CPAP X BILEVEL.

Comparison 7. ICU length of stay
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC6222Mean Difference (IV, Random, 95% CI)-0.89 [-1.33, -0.45]
2 CPAP X SMC3169Mean Difference (IV, Random, 95% CI)-1.09 [-1.63, -0.56]
3 BILEVEL X SMC353Std. Mean Difference (IV, Random, 95% CI)-0.65 [-1.37, 0.06]
4 CPAP X BILEVEL3159Mean Difference (IV, Random, 95% CI)0.31 [-0.78, 1.40]
Analysis 7.1.

Comparison 7 ICU length of stay, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 7.2.

Comparison 7 ICU length of stay, Outcome 2 CPAP X SMC.

Analysis 7.3.

Comparison 7 ICU length of stay, Outcome 3 BILEVEL X SMC.

Analysis 7.4.

Comparison 7 ICU length of stay, Outcome 4 CPAP X BILEVEL.

Comparison 8. Breath rate after one hour
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC9438Mean Difference (IV, Random, 95% CI)-2.86 [-3.85, -1.87]
2 CPAP X SMC7300Mean Difference (IV, Random, 95% CI)-2.39 [-3.70, -1.07]
3 BILEVEL X SMC6254Mean Difference (IV, Random, 95% CI)-3.52 [-4.80, -2.23]
4 CPAP X BILEVEL5218Mean Difference (IV, Random, 95% CI)0.57 [1.00, 2.13]
Analysis 8.1.

Comparison 8 Breath rate after one hour, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 8.2.

Comparison 8 Breath rate after one hour, Outcome 2 CPAP X SMC.

Analysis 8.3.

Comparison 8 Breath rate after one hour, Outcome 3 BILEVEL X SMC.

Analysis 8.4.

Comparison 8 Breath rate after one hour, Outcome 4 CPAP X BILEVEL.

Comparison 9. Heart rate after one hour
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC9438Mean Difference (IV, Random, 95% CI)-4.01 [-8.16, 0.15]
2 NPPV (CPAP and BILEVEL) X SMC - heterogeneity analysis7329Mean Difference (IV, Random, 95% CI)-3.79 [-6.88, -0.70]
3 CPAP X SMC7300Mean Difference (IV, Random, 95% CI)-4.45 [-10.81, 1.92]
4 CPAP X SMC - heterogeneity analysis5191Mean Difference (IV, Random, 95% CI)-4.10 [-8.93, 0.72]
5 BILEVEL X SMC6254Mean Difference (IV, Random, 95% CI)-4.21 [-7.77, -0.65]
6 CPAP X BILEVEL4182Mean Difference (IV, Random, 95% CI)-0.56 [-5.22, 4.11]
Analysis 9.1.

Comparison 9 Heart rate after one hour, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 9.2.

Comparison 9 Heart rate after one hour, Outcome 2 NPPV (CPAP and BILEVEL) X SMC - heterogeneity analysis.

Analysis 9.3.

Comparison 9 Heart rate after one hour, Outcome 3 CPAP X SMC.

Analysis 9.4.

Comparison 9 Heart rate after one hour, Outcome 4 CPAP X SMC - heterogeneity analysis.

Analysis 9.5.

Comparison 9 Heart rate after one hour, Outcome 5 BILEVEL X SMC.

Analysis 9.6.

Comparison 9 Heart rate after one hour, Outcome 6 CPAP X BILEVEL.

Comparison 10. Sistolic blood pressure after one hour
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC6182Mean Difference (IV, Random, 95% CI)-1.64 [-7.83, 4.56]
2 CPAP X SMC6211Mean Difference (IV, Random, 95% CI)0.12 [-6.56, 6.81]
3 BILEVEL X SMC487Mean Difference (IV, Random, 95% CI)1.93 [-7.94, 11.80]
4 CPAP X BILEVEL4182Mean Difference (IV, Random, 95% CI)-1.17 [-10.79, 8.44]
5 CPAP X BILEVEL - heterogeneity analysis3136Mean Difference (IV, Random, 95% CI)2.57 [-4.30, 9.44]
Analysis 10.1.

Comparison 10 Sistolic blood pressure after one hour, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 10.2.

Comparison 10 Sistolic blood pressure after one hour, Outcome 2 CPAP X SMC.

Analysis 10.3.

Comparison 10 Sistolic blood pressure after one hour, Outcome 3 BILEVEL X SMC.

Analysis 10.4.

Comparison 10 Sistolic blood pressure after one hour, Outcome 4 CPAP X BILEVEL.

Analysis 10.5.

Comparison 10 Sistolic blood pressure after one hour, Outcome 5 CPAP X BILEVEL - heterogeneity analysis.

Comparison 11. Diastolic blood pressure after one hour
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC5138Mean Difference (IV, Random, 95% CI)-1.49 [-6.43, 3.45]
2 CPAP X SMC5167Mean Difference (IV, Random, 95% CI)-0.92 [-9.10, 7.27]
3 CPAP X SMC - heterogeneity analysis3107Mean Difference (IV, Random, 95% CI)-7.32 [-12.79, -1.86]
4 BILEVEL X SMC487Mean Difference (IV, Random, 95% CI)-0.96 [-6.09, 4.16]
5 CPAP X BILEVEL4182Mean Difference (IV, Random, 95% CI)-2.60 [-9.58, 4.37]
6 CPAP X BILEVEL - heterogeneity analysis262Mean Difference (IV, Random, 95% CI)-7.86 [-13.03, -2.70]
Analysis 11.1.

Comparison 11 Diastolic blood pressure after one hour, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 11.2.

Comparison 11 Diastolic blood pressure after one hour, Outcome 2 CPAP X SMC.

Analysis 11.3.

Comparison 11 Diastolic blood pressure after one hour, Outcome 3 CPAP X SMC - heterogeneity analysis.

Analysis 11.4.

Comparison 11 Diastolic blood pressure after one hour, Outcome 4 BILEVEL X SMC.

Analysis 11.5.

Comparison 11 Diastolic blood pressure after one hour, Outcome 5 CPAP X BILEVEL.

Analysis 11.6.

Comparison 11 Diastolic blood pressure after one hour, Outcome 6 CPAP X BILEVEL - heterogeneity analysis.

Comparison 12. Mean blood pressure after one hour
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC3256Mean Difference (IV, Random, 95% CI)-2.41 [-8.27, 3.45]
2 CPAP X SMC189Mean Difference (IV, Random, 95% CI)3.00 [-5.31, 11.31]
3 BILEVEL X SMC2167Mean Difference (IV, Random, 95% CI)-5.42 [-11.60, 0.76]
4 CPAP X BILEVEL180Mean Difference (IV, Random, 95% CI)-4.40 [-13.25, 4.45]
Analysis 12.1.

Comparison 12 Mean blood pressure after one hour, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 12.2.

Comparison 12 Mean blood pressure after one hour, Outcome 2 CPAP X SMC.

Analysis 12.3.

Comparison 12 Mean blood pressure after one hour, Outcome 3 BILEVEL X SMC.

Analysis 12.4.

Comparison 12 Mean blood pressure after one hour, Outcome 4 CPAP X BILEVEL.

Comparison 13. PaO2 (mmHg) after one hour
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC4140Mean Difference (IV, Random, 95% CI)10.04 [1.09, 19.00]
2 CPAP X SMC5177Mean Difference (IV, Random, 95% CI)-2.64 [-25.87, 20.59]
3 CPAP X SMC - heterogeneity analysis3117Mean Difference (IV, Random, 95% CI)-22.09 [-34.35, -9.83]
4 BILEVEL X SMC379Mean Difference (IV, Random, 95% CI)4.79 [-11.11, 20.69]
5 CPAP X BILEVEL3136Mean Difference (IV, Random, 95% CI)-27.00 [-44.75, -9.25]
Analysis 13.1.

Comparison 13 PaO2 (mmHg) after one hour, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 13.2.

Comparison 13 PaO2 (mmHg) after one hour, Outcome 2 CPAP X SMC.

Analysis 13.3.

Comparison 13 PaO2 (mmHg) after one hour, Outcome 3 CPAP X SMC - heterogeneity analysis.

Analysis 13.4.

Comparison 13 PaO2 (mmHg) after one hour, Outcome 4 BILEVEL X SMC.

Analysis 13.5.

Comparison 13 PaO2 (mmHg) after one hour, Outcome 5 CPAP X BILEVEL.

Comparison 14. Adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC1511329Risk Ratio (M-H, Random, 95% CI)0.85 [0.63, 1.16]
1.1 Skin damage11594Risk Ratio (M-H, Random, 95% CI)6.62 [1.20, 36.55]
1.2 Pneumonia3232Risk Ratio (M-H, Random, 95% CI)0.35 [0.05, 2.20]
1.3 Pulmonary aspiration51255Risk Ratio (M-H, Random, 95% CI)1.58 [0.06, 38.61]
1.4 Gastrointestinal Bleeding3192Risk Ratio (M-H, Random, 95% CI)1.37 [0.27, 6.89]
1.5 Gastric distention8484Risk Ratio (M-H, Random, 95% CI)13.26 [0.82, 215.12]
1.6 Vomiting51229Risk Ratio (M-H, Random, 95% CI)1.06 [0.46, 2.47]
1.7 Asphyxia2170Risk Ratio (M-H, Random, 95% CI)3.0 [0.12, 72.31]
1.8 Pneumothorax61474Risk Ratio (M-H, Random, 95% CI)0.72 [0.08, 6.89]
1.9 Conjunctivitis2147Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.10 Sinusitis2219Risk Ratio (M-H, Random, 95% CI)3.0 [0.12, 72.31]
1.11 Disconfort with mask7512Risk Ratio (M-H, Random, 95% CI)5.39 [0.97, 30.09]
1.12 Hypotension11030Risk Ratio (M-H, Random, 95% CI)0.82 [0.58, 1.16]
1.13 Arrhythmia11027Risk Ratio (M-H, Random, 95% CI)0.83 [0.50, 1.38]
1.14 Progressive respiratory distress21122Risk Ratio (M-H, Random, 95% CI)0.58 [0.37, 0.89]
1.15 Cardiorespiratory arrest31252Risk Ratio (M-H, Random, 95% CI)0.60 [0.29, 1.26]
1.16 Neurological failure (coma)190Risk Ratio (M-H, Random, 95% CI)0.10 [0.01, 0.71]
1.17 Eye irritation140Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.18 Stroke1130Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.19 Seizures1130Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.03]
2 NPPV (CPAP and BILEVEL) X SMC - AFTER 20001110703Risk Ratio (M-H, Random, 95% CI)0.87 [0.63, 1.19]
2.1 Skin damage8492Risk Ratio (M-H, Random, 95% CI)6.62 [1.20, 36.55]
2.2 Pneumonia2152Risk Ratio (M-H, Random, 95% CI)0.35 [0.05, 2.20]
2.3 Pulmonary aspiration21095Risk Ratio (M-H, Random, 95% CI)1.58 [0.06, 38.61]
2.4 Gastrointestinal Bleeding2170Risk Ratio (M-H, Random, 95% CI)2.32 [0.35, 15.42]
2.5 Gastric distention4302Risk Ratio (M-H, Random, 95% CI)13.26 [0.82, 215.12]
2.6 Vomiting51229Risk Ratio (M-H, Random, 95% CI)1.06 [0.46, 2.47]
2.7 Asphyxia1130Risk Ratio (M-H, Random, 95% CI)3.0 [0.12, 72.31]
2.8 Pneumothorax51434Risk Ratio (M-H, Random, 95% CI)0.72 [0.08, 6.89]
2.9 Conjunctivitis2147Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.10 Sinusitis2219Risk Ratio (M-H, Random, 95% CI)3.0 [0.12, 72.31]
2.11 Disconfort with mask7512Risk Ratio (M-H, Random, 95% CI)5.39 [0.97, 30.09]
2.12 Hypotension11030Risk Ratio (M-H, Random, 95% CI)0.82 [0.58, 1.16]
2.13 Arrhythmia11027Risk Ratio (M-H, Random, 95% CI)0.83 [0.50, 1.38]
2.14 Progressive respiratory distress21122Risk Ratio (M-H, Random, 95% CI)0.58 [0.37, 0.89]
2.15 Cardiorespiratory arrest31252Risk Ratio (M-H, Random, 95% CI)0.60 [0.29, 1.26]
2.16 Neurological failure (coma)190Risk Ratio (M-H, Random, 95% CI)0.10 [0.01, 0.71]
2.17 Eye irritation140Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.18 Stroke1130Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.19 Seizures1130Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.03]
3 CPAP X SMC107133Risk Ratio (M-H, Random, 95% CI)0.63 [0.45, 0.87]
3.1 Skin damage7343Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 69.52]
3.2 Pneumonia180Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.3 Pulmonary aspiration5908Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.4 Gastrointestinal Bleeding122Risk Ratio (M-H, Random, 95% CI)0.33 [0.02, 7.39]
3.5 Gastric distention7447Risk Ratio (M-H, Random, 95% CI)11.00 [0.64, 189.65]
3.6 Vomiting3785Risk Ratio (M-H, Random, 95% CI)0.93 [0.34, 2.54]
3.7 Asphyxia140Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.8 Pneumothorax5998Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.9 Conjunctivitis2147Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.10 Sinusitis189Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.11 Disconfort with mask3265Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.12 Hypotension1684Risk Ratio (M-H, Random, 95% CI)0.83 [0.55, 1.25]
3.13 Arrhythmia1682Risk Ratio (M-H, Random, 95% CI)0.55 [0.28, 1.09]
3.14 Progressive respiratory distress2776Risk Ratio (M-H, Random, 95% CI)0.53 [0.31, 0.92]
3.15 Cardiorespiratory arrest2777Risk Ratio (M-H, Random, 95% CI)0.41 [0.18, 0.91]
3.16 Neurological failure (coma)190Risk Ratio (M-H, Random, 95% CI)0.10 [0.01, 0.71]
4 BILEVEL X SMC86823Risk Ratio (M-H, Random, 95% CI)1.05 [0.76, 1.46]
4.1 Skin damage6296Risk Ratio (M-H, Random, 95% CI)7.16 [1.27, 40.50]
4.2 Nosocomial pneumonia2152Risk Ratio (M-H, Random, 95% CI)0.35 [0.05, 2.20]
4.3 Disconfort with mask5274Risk Ratio (M-H, Random, 95% CI)5.39 [0.97, 30.09]
4.4 Gastrointestinal bleeding2170Risk Ratio (M-H, Random, 95% CI)2.32 [0.35, 15.42]
4.5 Gastric dilatation264Risk Ratio (M-H, Random, 95% CI)15.87 [0.96, 262.30]
4.6 Vomiting5848Risk Ratio (M-H, Random, 95% CI)1.21 [0.47, 3.11]
4.7 Claustrophobia1130Risk Ratio (M-H, Random, 95% CI)3.0 [0.12, 72.31]
4.8 Pneumothorax2832Risk Ratio (M-H, Random, 95% CI)1.01 [0.11, 9.63]
4.9 Eye irritation140Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.10 Sinusitis1130Risk Ratio (M-H, Random, 95% CI)3.0 [0.12, 72.31]
4.11 Cardiac arrest2830Risk Ratio (M-H, Random, 95% CI)0.96 [0.25, 3.61]
4.12 Stroke1130Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.13 Seizures1130Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.03]
4.14 Gastric aspiration1704Risk Ratio (M-H, Random, 95% CI)3.09 [0.13, 75.50]
4.15 Hypotension1698Risk Ratio (M-H, Random, 95% CI)0.82 [0.54, 1.23]
4.16 Arrhythmia1695Risk Ratio (M-H, Random, 95% CI)1.10 [0.64, 1.90]
4.17 Progressive respiratory distress1700Risk Ratio (M-H, Random, 95% CI)0.61 [0.36, 1.03]
5 CPAP X BILEVEL57593Risk Ratio (M-H, Random, 95% CI)1.18 [0.94, 1.48]
5.1 Skin damage5790Risk Ratio (M-H, Random, 95% CI)0.64 [0.19, 2.16]
5.2 Pneumothorax2715Risk Ratio (M-H, Random, 95% CI)2.89 [0.12, 70.63]
5.3 Pulmonary aspiration3796Risk Ratio (M-H, Random, 95% CI)2.88 [0.12, 70.43]
5.4 Gastric distension3172Risk Ratio (M-H, Random, 95% CI)1.49 [0.56, 4.00]
5.5 Vomiting4857Risk Ratio (M-H, Random, 95% CI)0.97 [0.43, 2.19]
5.6 Disconfort with mask4735Risk Ratio (M-H, Random, 95% CI)1.03 [0.53, 2.00]
5.7 Increased breathing discomfort1576Risk Ratio (M-H, Random, 95% CI)1.42 [0.67, 3.02]
5.8 Hypotension2758Risk Ratio (M-H, Random, 95% CI)0.98 [0.65, 1.48]
5.9 Arrhythmia1677Risk Ratio (M-H, Random, 95% CI)2.00 [1.02, 3.92]
5.10 Progressive respiratory distress1679Risk Ratio (M-H, Random, 95% CI)1.19 [0.64, 2.21]
5.11 Cardiorespiratory arrest1678Risk Ratio (M-H, Random, 95% CI)1.61 [0.59, 4.38]
5.12 Pharyngeal damage180Risk Ratio (M-H, Random, 95% CI)0.95 [0.06, 14.69]
5.13 Cough180Risk Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.57]
Analysis 14.1.

Comparison 14 Adverse events, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Analysis 14.2.

Comparison 14 Adverse events, Outcome 2 NPPV (CPAP and BILEVEL) X SMC - AFTER 2000.

Analysis 14.3.

Comparison 14 Adverse events, Outcome 3 CPAP X SMC.

Analysis 14.4.

Comparison 14 Adverse events, Outcome 4 BILEVEL X SMC.

Analysis 14.5.

Comparison 14 Adverse events, Outcome 5 CPAP X BILEVEL.

Comparison 15. Hospital or 7-day mortality
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC212263Risk Ratio (M-H, Random, 95% CI)0.72 [0.55, 0.94]
Analysis 15.1.

Comparison 15 Hospital or 7-day mortality, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Comparison 16. Hospital or 30-day mortality
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC222387Risk Ratio (M-H, Random, 95% CI)0.75 [0.60, 0.95]
Analysis 16.1.

Comparison 16 Hospital or 30-day mortality, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Comparison 17. General or 7-day ETI rate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NPPV (CPAP and BILEVEL) X SMC232417Risk Ratio (M-H, Random, 95% CI)0.55 [0.38, 0.78]
Analysis 17.1.

Comparison 17 General or 7-day ETI rate, Outcome 1 NPPV (CPAP and BILEVEL) X SMC.

Appendices

Appendix 1. Search strategies 2009

MEDLINE (Ovid)

1 exp Heart Failure/ (66770)
2 exp Myocardial Infarction/ (126033)
3 cardiogenic oedema$.tw. (7)
4 cardiogenic edema$.tw. (39)
5 pulmonary oedema.tw. (2354)
6 pulmonary edema.tw. (9499)
7 cardiac failure.tw. (9005)
8 heart failure.tw. (73909)
9 cardiac insufficiency.tw. (3578)
10 Pulmonary Edema/ (13680)
11 heart insufficiency.tw. (672)
12 Ventricular Dysfunction, Left/ (14770)
13 wet lung.tw. (307)
14 or/1-13 (245334)
15 exp Respiration, Artificial/ (49052)
16 exp Ventilators, Mechanical/ (7535)
17 mechanical ventilation.tw. (17741)
18 artificial ventilation.tw. (2502)
19 assisted ventilation.tw. (1817)
20 artificial respiration.tw. (1465)
21 (respirator or respirators).tw. (3713)
22 bipap.tw. (366)
23 nippv.tw. (262)
24 nppv.tw. (290)
25 niv.tw. (750)
26 niav.tw. (0)
27 cpap.tw. (3643)
28 aprv.tw. (61)
29 ippb.tw. (267)
30 ippv.tw. (628)
31 peep.tw. (3253)
32 positive pressure ventilation.tw. (3426)
33 pulmonary ventilation.tw. (2151)
34 non invasive ventilation.tw. (573)
35 noninvasive ventilation.tw. (747)
36 pressure support ventilation.tw. (571)
37 positive end expiratory pressure.tw. (3381)
38 bi-level positive airway pressure.tw. (93)
39 bilevel positive airway pressure.tw. (169)
40 or/15-39 (69840)
41 14 and 40 (3618)
42 randomized controlled trial.pt. (283687)
43 controlled clinical trial.pt. (81002)
44 Randomized controlled trials/ (64251)
45 random allocation/ (66529)
46 double blind method/ (104848)
47 single-blind method/ (13580)
48 or/42-47 (478246)
49 exp animal/ not humans/ (3476457)
50 48 not 49 (445629)
51 clinical trial.pt. (461395)
52 exp Clinical Trials as Topic/ (224000)
53 (clin$ adj25 trial$).ti,ab. (168562)
54 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab. (101838)
55 placebos/ (28620)
56 placebo$.ti,ab. (120725)
57 random$.ti,ab. (467107)
58 research design/ (58374)
59 or/51-58 (1009730)
60 59 not 49 (935775)
61 50 or 60 (966076)
62 61 and 41 (369)
63 (2005$ or 2006$ or 2007$ or 2008$ or 2009$).em. (3387916)
64 63 and 62 (160)

CENTRAL (The Cochrane Library)

#1 MeSH descriptor Heart Failure explode all trees 4000
#2 MeSH descriptor Myocardial Infarction explode all trees 6778
#3 myocardial next infarction in All Text 12934
#4 (cardiogenic in All Text near/6 edema in All Text) 64
#5 (cardiogenic in All Text near/6 oedema in All Text) 24
#6 (pulmonary in All Text near/6 edema in All Text) 389
#7 (pulmonary in All Text near/6 oedema in All Text) 210
#8 heart next failure in All Text 8265
#9 cardiac next failure in All Text 768
#10 cardiac next insufficiency in All Text 187
#11 heart next insufficiency in All Text 27
#12 left next ventricular next insufficiency in All Text 8
#13 left next ventricular next dysfunction in All Text 764
#14 wet next lung in All Text 3
#15 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14) 20230
#16 MeSH descriptor Respiration, Artificial explode all trees 3377
#17 MeSH descriptor Ventilators, Mechanical explode all trees 211
#18 mechanical next ventilation in All Text 3047
#19 artificial next ventilation in All Text 483
#20 assisted next ventilation in All Text 413
#21 artificial next respiration in All Text 52
#22 (positive in All Text near/6 pressure in All Text near/6 ventilation in All Text) 982
#23 (respirator in All Text or respirators in All Text) 8427
#24 pulmonary next ventilat* in All Text 782
#25 non next invasive next ventilation in All Text 164
#26 noninvasive next ventilation in All Text 127
#27 non-invasive next ventilation in All Text 164
#28 positive next airway next pressure in All Text 1088
#29 positive next pressure next respiration in All Text 1056
#30 pressure next support next ventilation in All Text 219
#31 mask next ventilation in All Text 120
#32 bipap in All Text 135
#33 nippv in All Text 66
#34 nppv in All Text 78
#35 niv in All Text 152
#36 cpap in All Text 1007
#37 niav in All Text 3
#38 aprv in All Text 11
#39 ippb in All Text 59
#40 ippv in All Text 133
#41 peep in All Text 375
#42 positive next end next expiratory next pressure in All Text 464
#43 (#16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25) 11353
#44 (#26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35) 2260
#45 (#36 or #37 or #38 or #39 or #40 or #41 or #42) 1632
#46 (#43 or #44 or #45) 12336
#47 (#15 and #46) 536

EMBASE (Ovid)

1 exp Congestive Heart Failure/ (29823)
2 exp Heart Infarction/ (124630)
3 cardiogenic oedema$.tw. (8)
4 cardiogenic edema$.tw. (29)
5 pulmonary oedema.tw. (1856)
6 pulmonary edema.tw. (7171)
7 cardiac failure.tw. (6888)
8 heart failure.tw. (66554)
9 cardiac insufficiency.tw. (1235)
10 Lung Edema/ (15202)
11 heart insufficiency.tw. (254)
12 heart left ventricle function/ (14936)
13 wet lung.tw. (246)
14 or/1-13 (220649)
15 exp Ventilator/ (5189)
16 exp Artificial Ventilation/ (56813)
17 mechanical ventilation.tw. (16434)
18 artificial ventilation.tw. (1731)
19 assisted ventilation.tw. (1491)
20 artificial respiration.tw. (477)
21 (respirator or respirators).tw. (2181)
22 bipap.tw. (343)
23 nippv.tw. (233)
24 nppv.tw. (282)
25 niv.tw. (653)
26 niav.tw. (0)
27 cpap.tw. (3121)
28 aprv.tw. (64)
29 ippb.tw. (138)
30 ippv.tw. (465)
31 peep.tw. (3010)
32 positive pressure ventilation.tw. (2867)
33 pulmonary ventilation.tw. (1053)
34 non invasive ventilation.tw. (571)
35 noninvasive ventilation.tw. (774)
36 pressure support ventilation.tw. (579)
37 positive end expiratory pressure.tw. (3039)
38 bi-level positive airway pressure.tw. (82)
39 bilevel positive airway pressure.tw. (180)
40 or/15-39 (68033)
41 14 and 40 (4482)
42 controlled clinical trial/ (67441)
43 random$.tw. (410939)
44 randomized controlled trial/ (174578)
45 follow-up.tw. (369197)
46 double blind procedure/ (74328)
47 placebo$.tw. (113396)
48 placebo/ (132301)
49 factorial$.ti,ab. (8626)
50 (crossover$ or cross-over$).ti,ab. (40537)
51 (double$ adj blind$).ti,ab. (86993)
52 (singl$ adj blind$).ti,ab. (7707)
53 assign$.ti,ab. (112821)
54 allocat$.ti,ab. (35785)
55 volunteer$.ti,ab. (101863)
56 Crossover Procedure/ (21843)
57 Single Blind Procedure/ (8587)
58 or/42-57 (1066875)
59 (exp animals/ or nonhuman/) not human/ (2748065)
60 58 not 59 (974762)
61 60 and 41 (561)
62 (2005$ or 2006$ or 2007$ or 2008$ or 2009$).em. (2870201)
63 61 and 62 (300)

CINAHL (EBCSO)

( (MH "Ventilators, Mechanical") or (MH "Positive Pressure Ventilation+") or ventilat* or CPAP or NPPV or bipap or nippv or aprv or ippb or ippv or peep ) and S4 and ( (MH "Clinical Trials+") or random$ or trial or clinical study or group$ or placebo$ )  

Appendix 2. Search strategies 2011

CENTRAL and DARE (The Cochrane Library)

#1 MeSH descriptor Heart Failure explode all trees
#2 MeSH descriptor Myocardial Infarction explode all trees
#3 myocardial next infarction in All Text
#4 (cardiogenic in All Text near/6 edema in All Text)
#5 (cardiogenic in All Text near/6 oedema in All Text)
#6 (pulmonary in All Text near/6 edema in All Text)
#7 (pulmonary in All Text near/6 oedema in All Text)
#8 heart next failure in All Text
#9 cardiac next failure in All Text
#10 cardiac next insufficiency in All Text
#11 heart next insufficiency in All Text
#12 left next ventricular next insufficiency in All Text
#13 left next ventricular next dysfunction in All Text
#14 wet next lung in All Text
#15 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14)
#16 MeSH descriptor Respiration, Artificial explode all trees
#17 MeSH descriptor Ventilators, Mechanical explode all trees
#18 mechanical next ventilation in All Text
#19 artificial next ventilation in All Text
#20 assisted next ventilation in All Text
#21 artificial next respiration in All Text
#22 (positive in All Text near/6 pressure in All Text near/6 ventilation in All Text)
#23 (respirator in All Text or respirators in All Text)
#24 pulmonary next ventilat* in All Text
#25 non next invasive next ventilation in All Text
#26 noninvasive next ventilation in All Text
#27 non-invasive next ventilation in All Text
#28 positive next airway next pressure in All Text
#29 positive next pressure next respiration in All Text
#30 pressure next support next ventilation in All Text
#31 mask next ventilation in All Text
#32 bipap in All Text
#33 nippv in All Text
#34 nppv in All Text
#35 niv in All Text
#36 cpap in All Text
#37 niav in All Text
#38 aprv in All Text
#39 ippb in All Text
#40 ippv in All Text
#41 peep in All Text
#42 positive next end next expiratory next pressure in All Text
#43 (#16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25)
#44 (#26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35)
#45 (#36 or #37 or #38 or #39 or #40 or #41 or #42)
#46 (#43 or #44 or #45)
#47 (#15 and #46)

MEDLINE (Ovid)

1. exp Heart Failure/
2. exp Myocardial Infarction/
3. cardiogenic edema$.tw.
4. cardiogenic oedema$.tw.
5. pulmonary oedema.tw.
6. pulmonary edema.tw.
7. cardiac failure.tw.
8. heart failure.tw.
9. cardiac insufficiency.tw.
10. Pulmonary Edema/
11. heart insufficiency.tw.
12. Ventricular Dysfunction, Left/
13. wet lung.tw.
14. or/1-13
15. exp Respiration, Artificial/
16. exp Ventilators, Mechanical/
17. mechanical ventilation.tw.
18. artificial ventilation.tw.
19. assisted ventilation.tw.
20. artificial respiration.tw.
21. (respirator or respirators).tw.
22. bipap.tw.
23. nippv.tw.
24. nppv.tw.
25. niv.tw.
26. niav.tw.
27. cpap.tw.
28. aprv.tw.
29. ippb.tw.
30. ippv.tw.
31. peep.tw.
32. positive pressure ventilation.tw.
33. pulmonary ventilation.tw.
34. non invasive ventilation.tw.
35. noninvasive ventilation.tw.
36. pressure support ventilation.tw.
37. positive end expiratory pressure.tw.
38. bi-level positive airway pressure.tw.
39. bilevel positive airway pressure.tw.
40. or/15-39
41. 14 and 40
42. randomized controlled trial.pt.
43. controlled clinical trial.pt.
44. randomized.ab.
45. placebo.ab.
46. drug therapy.fs.
47. randomly.ab.
48. trial.ab.
49. groups.ab.
50. 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49
51. exp animals/ not humans.sh.
52. 50 not 51
53. 41 and 52
54. ((2001009* or 201010* or 201011* or 201012* or 2011*) not ("20100921" or "20100922" or "20100923" or "20100924" or "20100925" or "20100926" or "20100927" or "20100928" or "20100929" or "20100930")).ed.
55. 53 and 54

EMBASE (Ovid)

1. exp Congestive Heart Failure/
2. exp Heart Infarction/
3. cardiogenic oedema$.tw.
4. cardiogenic edema$.tw.
5. pulmonary oedema.tw.
6. pulmonary edema.tw.
7. cardiac failure.tw.
8. heart failure.tw.
9. cardiac insufficiency.tw.
10. Lung Edema/
11. heart insufficiency.tw.
12. heart left ventricle function/
13. wet lung.tw.
14. or/1-13
15. exp Ventilator/
16. exp Artificial Ventilation/
17. mechanical ventilation.tw.
18. artificial ventilation.tw.
19. assisted ventilation.tw.
20. artificial respiration.tw.
21. (respirator or respirators).tw.
22. bipap.tw.
23. nippv.tw.
24. nppv.tw.
25. niv.tw.
26. niav.tw.
27. cpap.tw.
28. aprv.tw.
29. ippb.tw.
30. ippv.tw.
31. peep.tw.
32. positive pressure ventilation.tw.
33. pulmonary ventilation.tw.
34. non invasive ventilation.tw.
35. noninvasive ventilation.tw.
36. pressure support ventilation.tw.
37. positive end expiratory pressure.tw.
38. bi-level positive airway pressure.tw.
39. bilevel positive airway pressure.tw.
40. or/15-39
41. 14 and 40
42. random$.tw.
43. factorial$.tw.
44. crossover$.tw.
45. cross over$.tw.
46. cross-over$.tw.
47. placebo$.tw.
48. (doubl$ adj blind$).tw.
49. (singl$ adj blind$).tw.
50. assign$.tw.
51. allocat$.tw.
52. volunteer$.tw.
53. crossover procedure/
54. double blind procedure/
55. randomized controlled trial/
56. single blind procedure/
57. 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56
58. (animal/ or nonhuman/) not human/
59. 57 not 58
60. 41 and 59
61. ("201038" or "201039" or "201040" or "201041" or "201042" or "201043" or "201044" or "201045" or "201046" or "201047" or "201048" or "201049" or "201050" or "201051" or "201052" or 2011*).em.
62. 60 and 61

CINAHL

S47 S43 and S46
S46 S44 or S45
S45 EM 2010
S44 EM 2009
S43 S14 and S39 and S42
S42 S40 or S41
S41 TI (random* or trial or clinical study or group* or placebo*) or AB (random* or trial or clinical study or group* or placebo*)
S40 (MH "Clinical Trials+")
S39 S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38
S38 TI (bi-level positive airway pressure) or AB (bi-level positive airway pressure)
S37 TI (positive end expiratory pressure) or AB (positive end expiratory pressure)
S36 TI (pressure support ventilation) or AB (pressure support ventilation)
S35 TI (noninvasive ventilation) or AB (noninvasive ventilation)
S34 TI (non invasive ventilation) or AB (non invasive ventilation)
S33 TI (pulmonary ventilation) or AB (pulmonary ventilation)
S32 TI (positive pressure ventilation) or AB (positive pressure ventilation)
S31 TI (peep) or AB (peep)
S30 TI (ippv) or AB (ippv)
S29 TI (ippb) or AB (ippb)
S28 TI (aprv) or AB (aprv)
S27 TI (cpap) or AB (cpap)
S26 TI (niav) or AB (niav)
S25 TI (niv) or AB (niv)
S24 TI (nppv) or AB (nppv)
S23 TI (nippv) or AB (nippv)
S22 TI (bipap) or AB (bipap)
S21 TI (respirator or respirators) or AB (respirator or respirators)
S20 TI (artificial respiration) or AB (artificial respiration)
S19 TI (assisted ventilation) or AB (assisted ventilation)
S18 TI (artificial ventilation) or AB (artificial ventilation)
S17 TI (mechanical ventilation) or AB (mechanical ventilation)
S16 (MH "Ventilation, Mechanical, Differentiated")
S15 (MH "Ventilators, Mechanical")
S14 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13
S13 TI (wet lung) or AB (wet lung)
S12 (MH "Ventricular Dysfunction, Left")
S11 TI (heart insufficiency) or AB (heart insufficiency)
S10 (MH "Pulmonary Edema")
S9 TI (cardiac insufficiency) or AB (cardiac insufficiency)
S8 TI (heart failure) or AB (heart failure)
S7 TI (cardiac failure) or AB (cardiac failure)
S6 TI (pulmonary edema*) or AB (pulmonary edema*)
S5 TI (pulmonary oedema*) or AB (pulmonary oedema*)
S4 TI (cardiogenic edema*) or AB (cardiogenic edema*)
S3 TI (cardiogenic oedema*) or AB (cardiogenic oedema*)
S2 (MH "Myocardial Infarction+")
S1 (MH "Heart Failure, Congestive+")

What's new

DateEventDescription
12 November 2012New search has been performedNew search in April 2011 found 11 new studies
1 December 2011New citation required and conclusions have changed

Eleven new studies have been included in this review update.

Background section has been updated.

No changes have been made to the methodology. The search strategies have been modified in MEDLINE and EMBASE, and the dates over which the databases were searched were updated.

The conclusions have been amended slightly. The use of CPAP produces fewer adverse events compared to the standard treatment or compared the Bilevel NPPV, but the main thrust of the review has not changed.

History

Protocol first published: Issue 3, 2005
Review first published: Issue 3, 2008

DateEventDescription
17 April 2008AmendedConverted to new review format.

Contributions of authors

Flávia Vital did the protocol conceiving, designing, coordinating and writing and did the following tasks: selection of studies, quality evaluation, extraction and analysis data, final report and completion of the Cochrane publication and updating.

Álvaro Atallah did the protocol writing and did the following tasks: data analysis, final report and completion of the Cochrane publication and updating. Expertise advice.

Magdaline Ladeira did the protocol writing and the following tasks: selection of studies, quality evaluation, completion of the Cochrane publication and updating.

Declarations of interest

None known.

Sources of support

Internal sources

  • Department of Urgency Medicine, Universidade Federal de São Paulo, Brazil.

  • Brazilian Cochrane Centre, Brazil.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Agmy 2008

MethodsSingle centre randomised controlled trial, parallel design, unblinded, using ITT approach. No patients were lost to follow up. Setting: RICU or CCU.
Participants129 participants. Causes: systolic, diastolic or valvular heart failure.
InterventionsCPAP group. N=44.
BILEVEL group. N=44.
Control group: standard medical care+O2 mask (High flow facemask - 60%). N= 41.
Co-intervention: morphine, diuretics, ACE and nitrates.
Outcomes
  1. Mortality

  2. Need for tracheal intubation

  3. Arterial blood gases (PaO2, PaCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Length of hospital stay

  6. Length of ICU stay

  7. Intrapulmonary shunt

  8. A-aoxygengradient

  9. Cardiac output

  10. Intolerance

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Bautin 2005

MethodsRandomised controlled trial, parallel design, unblinded, using ITT approach. No patients were lost to follow up. Setting: ICU.
Participants22 participants, with age 63.4±4.6 years in BILEVEL group and 64.3±5.6 in standard medical care group. All patients underwent cardiosurgery procedure (6 - CABG, 16 - valves replacement). Causes: HF, Mitral valve dysfunction and arrhythmias.
InterventionsBILEVEL group: EPAP=5.1±0.3 cm H2O; e IPAP= 9.8±1.1 cmH2O. N=11.
Control group: standard medical care + O2 mask. N= 11.
Co-intervention: not related.
Outcomes
  1. Mortality

  2. Need tracheal intubation

  3. Arterial blood gases (PaO2, PaCO2) and pH

  4. Vital signs (BR, BP, HR)

  5. Length of hospital stay

  6. Length of ICU stay

  7. Incidence of acute myocardial infarction (follow-up)

  8. Droupouts/ withdrawal

  9. Side effects

  10. Treatment failure

NotesMask: full face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Bellone 2004

MethodsSingle centre randomised controlled trial (used a computer-generated random number sequence in closed envelopes with identification numbers that were stored in emergency room), parallel design, unblinded, using ITT approach. No patients were lost to follow up. Written consent was obtained from the patients' relatives at the start of the protocol. Setting: emergency department.
Participants46 participants (23 males and 23 females), with age 77.3±7.3 years in BILEVEL group and 76.8±7 in CPAP group. Diagnosis criteria: bilateral rales , and typical findings of congestion on chest radiograph, without a history suggesting pulmonary aspiration or pneumonia, SaO2<90% with O2 mask>5l/min via reservoir face mask, dyspnoea, BR>30b/min, use accessory muscles or paradoxical abdominal motion in association with tachycardia, HR>100b/min, cardiac gallops. History: heart failure, coronary artery disease, diabetes, hypertension, COPD, chronic atrial fibrillation and chronic kidney failure. Causes: respiratory infections, hypertension, tachyarrhythmia, other. Excluded patients: patients required endotracheal intubation immediately or already intubated, presenting a respiratory or cardiac arrest, cardiogenic shock (SBP<90mmHg), or at the time of admission had an acute coronary syndrome, patients unresponsive, with diagnosis of pneumonia, agitated, and unable to cooperate or if they had any condition that precluded application of a face mask.
InterventionsCPAP group: PEEP=10 cmH2O. N=22, TIME=103±45 minutes.
BILEVEL group: EPAP=5 cm H2O; e IPAP= 15 cm H2O initially, and then adjusted to obtain a tidal volume of more than 400ml, without leakage. N=24, time= 98±39 minutes.
Co-intervention: morphine sulfate, furosemide, sodium nitroprusside, glyceryl trinitrate,digoxin, oxygen therapy to obtain SaO2>90%.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases (PaCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Incidence of acute myocardial infarction (follow-up)

  6. Droupouts/ withdrawal

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported
Adherence to the intention-to-treat principleLow risk 

Bellone 2005

MethodsSingle centre randomised controlled trial (used a computer-generated random number sequence in closed envelopes with identification numbers that were stored in emergency room), parallel design, unblinded, using ITT approach. No losses to follow up. Written consent was obtained from the patients' relatives at the start of the protocol. Setting: Niguarda Hospital Emergency Department - Milan - Italy.
Participants36 participants (12 males and 24 females), with age 76.8±6.6 years in BILEVEL group and 76.8±6.9 in CPAP group. Diagnosis criteria: typical findings of congestion on chest radiograph and widespread rales without a history suggesting pulmonary aspiration or pneumonia, SaO2<90% with O2 mask >5l/min, dyspnoea, BR >30b/min, use accessory muscles or paradoxical abdominal motion in association with tachycardia, HR>100b/min, cardiac gallop. History: heart failure, acute myocardial infarction, diabetes, hypertension. Causes : respiratory infections, hypertension, tachyarrhythmia, myocardial infarction, others. Excluded patients: patients with PaCO2 <45mmHg, required endotracheal intubation or already intubated, presenting a respiratory or cardiac arrest, cardiogenic shock (SBP<90mmHg), severe renal failure, presenting clinical and history findings of chronic obstructive pulmonary disease or previously enrolled in other studies.
InterventionsCPAP group: PEEP=10 cmH2O. N=18, TIME=220±82 minutes.
BILEVEL group: EPAP=5 cm H2O; e IPAP= 15 cm H2O initially, and then adjusted to obtain a tidal volume of more than 400ml, without leakage. N=18, time= 205±68 minutes.
Co-intervention: morphine, furosemide, sodium nitroprusside, glyceryl trinitrate,digoxin, oxygen therapy to obtain SaO2>90%.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases (PCO2, pH)

  4. Vital signs (BR)

  5. Droupouts/ withdrawals

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Bersten 1991

MethodsSingle centre randomised controlled trial (random selection of a coloured cap), parallel design, unblinded, lack of intention-to-treat analysis confirmed on study assessment. Loss to follow up: no patients in standard medical care group and one patient in CPAP group. Patients or next-of-kin were aware through informed consent. Setting: emergency department or ward to the intensive care unit (ICU).
Participants40 participants (13 males and 27 females), with age 75±6 years in standard medical care group and 76±6 in CPAP group. Diagnosis criteria: dyspnoea of sudden onset with typical finds on chest radiographs and widespread rales without a history suggesting pulmonary aspiration or infection, jugular venous pressure elevated and third heart sound. Causes: acute myocardial infarction, myocardial ischaemia, congestive heart failure. Excluded patients: acute myocardial infarction with shock, SBP<90mmHg, severe stenotic valvular disease, chronic airflow obstruction with known carbon dioxide retention.
InterventionsCPAP group: PEEP= 10 cmH2O. N=19, TIME=9.3±4.9 hours.
Control group: O2 mask + standard medical care. N= 20.
Co-intervention: furosemide, morphine, diazepam, nitroglycerin.
Outcomes
  1. Mortality,

  2. Tracheal intubation rate

  3. Arterial blood gases ( PaO2, PaCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Treatment failure

  6. Side-effects

  7. Droupouts/ withdrawals

  8. Length of hospital stay

  9. Length of ICU stay

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk 
Allocation concealment (selection bias)High risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported
Adherence to the intention-to-treat principleHigh risk 

Crane 2004

MethodsMulticenter randomised controlled trial (2 university hospitals). Randomization procedure: random numbers produced by Microsoft Excel, assignments were concealed in an opaque envelope. Parallel design, unblinded, using ITT approach. No reported loss to follow up. Patients or next-of-kin were aware through informed consent, but in 17 cases, the patient gave verbal consent. Setting: emergency department.
Participants60 participants (23 males and 37 females), with age 74.6±11.1 years in standard medical care group, 74.9±12.2 in CPAP group and 76±8.4 in BILEVEL group. Diagnosis criteria: BR >23 bpm, Rx consistent with pulmonary oedema, pH <7,35, widespread pulmonary crepitations and diaphoresis. History: heart failure, ischaemic heart disease, DM, Hypertension, COPD. Excluded patients: Hypotension (SBP<90mmHg), T>38oC, patients requiring thrombolysis for myocardial infarction or dialysis for renal impairment, patients with impaired consciousness or with dementia.
InterventionsCPAP group: PEEP=10 cm H2O. N=20.
BILEVEL group: EPAP=5 cm H2O; e IPAP= 15 cmH2O. N=20.
Control group: standard medical care+O2 mask (To maintain SaO2 >90%). N= 20.
Co-intervention: furosemide, nitrates and diamorphine (without restriction)
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases ( PaO2, PCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Incidence of acute myocardial infarction (follow-up)

  6. Compliance of patient

  7. Treatment failure

  8. Side-effects

NotesMask: full face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported
Adherence to the intention-to-treat principleLow risk 

Delclaux 2000

MethodsMulticenter randomised controlled trial (6 centres). Randomization procedure: randomisation computer-generated; sealed envelopes were used to randomly assign patients to their treatment group. Parallel design, using ITT approach. Blindness only of the investigators. No patient were lost to follow-up. Informed consent was obtained of the all patients. Setting: intensive care unit (ICU).
Participants123 participants, but only a subgroup with 42 participants had CPO. Diagnosis criteria: acute respiratory insufficiency (PaO2/FiO2<300 with O2 =10l/min, bilateral lung infiltrates on a posteroanterior chest radiograph, randomisation within 3 hours after the criteria were first fulfilled. Because a cardiogenic mechanism contributing to the pulmonary oedema might have had a substantial influence on the study results, the randomisation was stratified based on whether there was an underlying cardiac disease. Causes: ischaemia, arrhythmias, fluid overload, hypertension, valvular disease, pneumonia, aspiration, systemic inflammatory response syndrome (SIRS), shock, other. Excluded patients: younger than 18 years, intubation was refused or contraindicated, history of COPD, acute respiratory acidosis (defined as a pH<7,30 and PaCO2 > 50 mmHg, systolic blood pressure less than 90 mmHg under optimal therapy (fluid repletion), ventricular arrhythmias, coma or seizures, life-threatening hypoxaemia, use of epinephrine or norepinephrine, and the inability to clear copious airway secretions.
InterventionsCPAP group: PEEP= 7,5 cmH2O with increase or decrease 2,5 cmH2O. N=22, TIME=6 hours or more.
Control group: standard medical care+O2 mask. N= 20.
Co-intervention: diuretics, antibiotics.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

NotesMask: full face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasLow risk 
Adherence to the intention-to-treat principleLow risk 

Ferrari 2007

MethodsSingle centre randomised controlled trial (according to a random sequence previously generated from a table of random numbers, the assignments were placed in closed boxes, with identification numbers, stored in the HDU), parallel design, unblinded, lack of intention-to-treat analysis. Two patients were lost (Two patients refused) to follow up. Written consent was obtained from the patients. Setting: High Dependency Unit (HDU) of the Emergency Department.
Participants52 participants (23 males and 29 females), with age 74.2±9.7 years in BILEVEL group and 76.7±9.2 in CPAP group. Diagnosis criteria: rapid onset of symptoms,severe dyspnoea at rest, respiratory rate 30 breaths/min, use of accessory respiratory muscles, oxygen saturation by pulse oximetry (Spo2) 90% with a fraction of inspired oxygen (Fio2) of 60% via a Venturi mask, radiologic findings of ACPE. Causes : hypertensive crisis, tachyarrhythmia, chronic Ischaemic cardiomyopathy, dilated cardiomyopathy and valvular heart disease. Excluded patients: acute coronary syndrome on hospital admission,18 haemodynamic instability (systolic BP 90 mm Hg with dopamine or dobutamine infusion 5 g/kg/min) or life-threatening arrhythmias, need for immediate endotracheal intubation (respiratory arrest, bradypnoea, or gasping for air), inability to protect the airways, impaired sensorium (unconsciousness or agitation), inability to clear secretions, respiratory tract infection, recent oesophageal/gastric surgery, GI bleeding, facial deformities, hematologic malignancy or cancer with an Eastern Cooperative Oncology Group performance status 2, chronic respiratory failure necessitating long-term oxygen therapy, diagnosis of myocardial infarction, pulmonary embolism, pneumonia, exacerbation of COPD, pneumothorax in the previous 3 months, and denial or refusal of intubation.
InterventionsCPAP group: PEEP = 8.8±1.9 cmH2O. N = 27, TIME= 8.1±8.3 hours.
BILEVEL group: EPAP = 7±1.2 cm H2O e IPAP= 15±3.1 cmH2O . N=25, TIME= 6.0±4.7 hours.
Co-intervention:
Outcomes
  1. Rate of acute myocardial infarction

  2. Mortality

  3. ETI

  4. Duration of ventilatory assistance

  5. HDU length of stay

  6. Hospital length of stay

  7. Arterial blood gases (PaCO2, pH, PaO2/FiO2, SaO2)

  8. Vital signs (BR, HR)

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported
Adherence to the intention-to-treat principleHigh risk 

Ferrari 2010

MethodsMulticenter (3 - Italy) randomised controlled trial (according to a random sequence previously generated from a table of random numbers, the assignments were placed in closed boxes, each with an identification number and were stored in the ED), parallel design, unblinded, using intention-to-treat analysis. Written consent was obtained from patients’ next of kin if patients were unable to give informed consent due to the severity of their disease. Setting: Emergency Department.
Participants80 adults participants with age 76.55±9.48 years in BILEVEL group and 77.25±9,17 in CPAP group, with acute respiratory failure due to severe ACPE. Diagnosis criteria: severe dyspnoea at rest, respiratory rate > 30 breaths/min, use of accessory respiratory muscles, PaO2/FiO2 < 200 despite oxygen via Venturi mask with a FiO2 of 60%, radiologic findings of ACPE. Causes : hypertensive crisis, dysrhythmias, UA/NSTEMI, respiratory infections. Exclusion criteria: STEMI (patients with unstable angina/Non-ST elevation MI were included in the study protocol),haemodynamic instability (systolic arterial pressure 90 mmHg), need for immediate ETI (respiratory arrest, bradypnoea), Inability to protect the airways, impaired sensorium (severe agitation or unconsciousness), COPD, exacerbation, pulmonary embolism, pneumonia, recent oesophageal-gastric surgery, gastrointestinal bleeding, facial deformities, hematological malignancy or cancer with ECOG performance status > 2.
InterventionsCPAP group: PEEP = 8.88±1.77 cmH2O. N = 40, TIME = 8.46±7.14 hours.
BILEVEL group: EPAP = 6.75±1.44 cmH2O e IPAP= 14±3.11 cmH2O . N=40, TIME = 5.91±4.01 hours.
Co-intervention: furosemide, glycerol trinitrate, sodium nitroprusside, morphine hydrochloride.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Duration of ventilatory assistance

  4. Hospital length of stay

  5. Arterial blood gases (PaCO2, PaO2/FiO2, SaO2) and pH

  6. Vital signs (BP, BR, HR)

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot reported if there were drop-outs over the monitoring of patients.
Selective reporting (reporting bias)High risk 
Detection biasUnclear riskNot reported
Adherence to the intention-to-treat principleLow risk 

Ferrer 2003

MethodsMulticenter (3 - Spain), prospective, randomised (randomly allocated within 24-hours, using a computer-generated table for each centre), controlled trial, parallel-group, using intention-to-treat analysis. No patient were lost to follow-up. Informed consent was obtained in all cases. Setting: ICU.
ParticipantsGroup of patients with acute hypoxaemic respiratory failure whose sub-group contained 30 patients with pulmonary oedema cardiogenic (10 males and 20 females), with age 76±9 years in standard medical care group and 71±13 in BILEVEL group. Diagnosis criteria: dyspnoea of sudden onset with physical findings consistent with pulmonary oedema, such as widespread rales with or without third heart sound, and typical findings of congestion on a chest x-ray. Exclusion criteria: hypercapnia (PaCO2 of more than 45 mm Hg) on admission; need for emergency intubation; recent oesophageal, facial, or cranial trauma or surgery; severely decreased consciousness (a Glasgow coma score of 11 or less); severe haemodynamic instability despite fluid repletion and use of vasoactive agents; a lack of cooperation; tracheotomy or other upper airway disorders; severe ventricular arrhythmia or myocardial ischaemia; active upper gastrointestinal bleeding; an inability to clear respiratory secretions; and more than one severe organ dysfunction in addition to respiratory failure.
InterventionsBILEVEL group. N=15.
Control group: standard medical care + O2 mask (To maintain SaO2 >92%). N= 15.
Outcomes
  1. Tracheal intubation rate

  2. Mortality

  3. ICU length of stay

  4. Hospital length of stay

  5. Droupouts/ withdrawals

  6. Side-effects

  7. Treatment failure

  8. Arterial blood gases (PaCO2, pH, PaO2/FiO2, SaO2)

  9. Vital signs (BR, BP, HR)

NotesMask: face mask or nasal mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Unclear riskNot submitted multiple planning outcomes reported on results.
Detection biasUnclear riskNot reported
Adherence to the intention-to-treat principleLow risk 

Fontanella 2010

MethodsRandomised controlled trial. Losses to follow up not reported. Informed consent not described. Setting: Cardiac Care Unit (CCU).
Participants40 participants with age 80±7 in CPAP group and 76±9 in BILEVEL group.Diagnosis criteria: patients with acute cardiogenic pulmonary oedema.
InterventionsCPAP group: PEEP = 8±2 cmH2O. N = 21.
BILEVEL group: EPAP = 10±2 cmH2O e IPAP= 18±3 cmH2O . N=19.
Co-intervention: ?
Outcomes
  1. Tracheal intubation rate

  2. Mortality

  3. ICU length of stay

  4. Arterial blood gases (PaO2, pH, PaO2/FiO2, SaO2)

  5. Vital signs (BR, BP, HR)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot reported if there were drop-outs over the monitoring of patients.
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Frontin 2010

MethodsSingle centre (France) randomised controlled trial (by balanced blocks of random numbers was provided by telephone using sealed opaque envelopes), parallel design, unblinded, not using ITT approach by Cochrane - All patients after randomisation. Two patients (in the CPAP group) refused the ongoing use of their data once their condition stabilised and were not analysed. Informed consent was obtained from patients or their surrogates. Setting: out-of-hospital medical emergencies is the responsibility of the "Service d'Aide Médicale Urgente" (SAMU) and continued on ICU.
Participants124 participants randomised, 122 analysed (52 males and 70 females), with age 79.3±10.5 years in standard medical care group and 79.4±10.7 in CPAP group. Inclusion criteria: 18 years or older with clinical symptoms of ACPE such as orthopnoea, diffuse crackles without evidence of pulmonary aspiration or infection, pulse oximetry (SpO2) less than 90% and a respiratory rate greater than 25 breaths per minute. Excluded patients: cardiovascular collapse or an impaired level of consciousness, acute myocardial infarction, or if they had an immediate need for intubation. Patient with a history of gastric surgery (b8 days) and patients vomiting were also excluded
InterventionsCPAP group: PEEP= 10 cmH2O. N=60.
Control group: standard medical care+O2 mask. N= 62.
Co-intervention: furosemide - 1mg/Kg, morphine pre-hospital, isosorbide dinitrate injections was 4 (range, 3-5) in both groups.
Outcomes
  1. Mortality 30 days

  2. Tracheal intubation rate

  3. Arterial blood gases (PaO2, PaCO2)

  4. Vital signs (BR, BP, HR)

  5. Side-effects

  6. Intensive care unit (ICU) length of stay

  7. Length of hospital stay

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleHigh risk 

Gray 2008

MethodsMulticenter, open, prospective, randomised, controlled trial, parallel-group trial with three treatment groups:
standard oxygen therapy, CPAP, and bilevel NIPPV. Patients were randomly assigned to one of the three treatments at a 1:1:1 ratio with the use of a 24 hour telephone randomisation service. The randomisation sequence was stratified according to centre, with variable block length. Lack of intention-to-treat analysis. Eighty-seven patients were excluded after randomisation because of ineligibility or previous recruitment into the trial. Informed written or witnessed oral consent from the patient or relative was obtained. Setting: emergency department.
Participants1156 participants, 56.9% were women, with age 79±9 years in standard medical care group and 78±10 in CPAP group and 77±10 in BILEVEL group. Diagnosis criteria: age of more than 16 years, a clinical diagnosis of acute cardiogenic pulmonary oedema, pulmonary oedema shown by a chest radiograph, a respiratory rate of more than 20 breaths per minute, and an arterial hydrogen ion concentration of greater than 45 nmol per litre (pH <7.35). Excluded patients: patients requirement for a lifesaving or emergency intervention, such as primary percutaneous coronary intervention; inability to give consent; or previous recruitment into the trial.
InterventionsCPAP group: PEEP= 10±4 cmH2O. N=346. Time = 2.2±1.5hours.
Bilevel NPPV group: EPAP= 7±3 cm H2O e IPAP= 14±5 cmH2O. N=356. Time= 2.0±1.3 hours.
Control group: standard medical care + O2 mask with a reservoir. N= 367.
Co-intervention: nitrates, diuretics and opioids.
Outcomes
  1. 7-day mortality

  2. 7-day tracheal intubation rate

  3. 30-day mortality

  4. Admission to the critical care unit

  5. Arterial blood gases ( PaO2, PaCO2, pH)

  6. Vital signs (BR, BP, HR)

  7. Incidence of acute myocardial infarction

  8. Compliance of patients with NPPV

  9. Side-effects and complications

  10. Length of hospital stay

  11. PEEP levels, PS levels and bilevel NPPV vs CPAP.

  12. Duration of therapy.

NotesAlthough the study reports that held ITT, analyses submitted have not included all randomised patients (follow-up bias), as well as, it was not described as the total distribution of randomisation by group. Results were presented in the format completely different from other studies included, making impossible their inclusion in meta-analyses (variables dicotômicas acute myocardial infarction and Intolerance to the allocated treatment not possessed N total to perform ITT or were analysed in times different from those envisaged in this review - mortality and intubation in 7 or 30 days). Continuous variables were presented just as mean value of the difference between 0 and 1 hour after the intervention and not as mean and standard deviation. However the author, although asked, did not send the data in the format required to include in Meta-analysis.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasLow risk 
Adherence to the intention-to-treat principleHigh risk 

Kelly 2002

MethodsSingle centre randomised controlled trial (by balanced blocks using sealed envelopes), parallel design, unblinded, using ITT approach. No patients were lost to follow up. Informed consent was obtained of the patients. Setting: emergency department and continued in the high dependency unit.
Participants58 participants (26 males and 32 females), with age 78±2 years in standard medical care group and 77±2 in CPAP group. Diagnosis criteria: acute onset of breathlessness, BR>20bpm, bilateral basal crackles or chest auscultation, Rx typical of pulmonary oedema. Causes: left ventricular systolic dysfunction and hypertensive crisis; the CPAP group had more severe disease with a slightly greater acidosis and hypercapnia. Excluded patients: patients with radiograph consistent with pneumonia or pneumothorax, or if they had received pre-hospital treatment with intervention other than oxygen, diuretics or opiates.
InterventionsCPAP group: PEEP= 7.5 cmH2O. N=27, TIME= minimum of 6 hours.
Control group: standard medical care+O2 mask. N= 31. (FiO2=60%).
Co-intervention: furosemide, morphine sulfate, nitrate.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases ( PaO2, PaCO2)

  4. Vital signs (BR, BP, HR)

  5. Incidence of acute myocardial infarction (follow-up)

  6. Treatment failure

  7. Side-effects

  8. Droupouts/ withdrawals

  9. Length of hospital stay

NotesMask: full face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported
Adherence to the intention-to-treat principleLow risk 

L'Her 2004

MethodsMulticenter randomised controlled trial, in three teaching hospitals in France. The randomisation protocol was computer generated and equalised in groups of 10 patients, parallel design, unblinded, using ITT approach. No patients were lost to follow up. Patients or their next of kin gave written informed consent. Setting: emergency department.
Participants89 participants (37 males and 51 females), with age 84±6 years in standard medical care group and 84±6 in CPAP group. Diagnosis criteria: Age similar or more than 75 year, acute hypoxaemic respiratory failure (PaO2/ FiO2<300 despite O2> 8l/min for 15 minutes), BR> 25bpm, contraction of accessory muscles, clinical examination: systolic and/or diastolic hypertension, widespread crackles or wheezing; medical record : previous cardiomyopathy, and/or acute dyspnoea with progressive orthopnoea; electrocardiographic tracing (Q waves and/or abnormalities in the T wave and ST segment; left ventricular hypertrophy, bundle branch block, atrial fibrillation); and chest radiography ( cardiac enlargement with a cardiothoracic ratio>50%, and/or pulmonary congestion with Kerley B lines, alveolar filing, pleural effusions) compatible with a diagnosis of cardiogenic pulmonary oedema. Causes: Tachyarrythymia, acute Ischaemic heart disease, hypertensive crises, respiratory tract infection, undiagnosed. Exclusion criteria: Glasgow Coma Scale less or similar 7, SpO2 similar or less 85% despite oxygen, haemodynamic instability, chronic respiratory insufficiency.
InterventionsCPAP group: PEEP= 7.5 cmH2O. N=43, TIME=8±6 hours.
Control group: standard medical care+O2 mask. N= 46.
Co-intervention: furosemide, nitroglycerin, glyceryl-trinitrate, morphine, isosorbide dinitrate.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases ( PCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Treatment failure

  6. Side-effects

  7. Droupouts/ withdrawals

  8. Length of hospital stay

  9. Compliance of patient

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)High risk 
Detection biasUnclear riskNot reported
Adherence to the intention-to-treat principleLow risk 

Levitt 2001

MethodsSingle centre randomised controlled trial (from a previously computer-generated list), parallel design, unblinded, lack of intention-to-treat analysis confirmed on study assessment. Four patients were lost to follow up. Informed consent was obtained of the patients. Setting: emergency department.
Participants42 patients were randomised, but 4 patients did not meet inclusion criteria following randomisation. Therefore, study entry 38 participants (13 males and 25 females), with age 68.5±15 years in standard medical care group and 67.4±15 in BILEVEL group. Diagnosis criteria: tachypnoea, BR>30bpm, diaphoresis or accessory muscle use, pulmonary rales, distended neck veins, peripheral oedema, history CHF (congestive heart failure) and radiograph findings of the pulmonary oedema. Causes: acute congestive heart failure. Excluded patients: patients with radiograph were found not to have CHF or required immediate intubation.
InterventionsBILEVEL group: EPAP= cm H2O e IPAP= cmH2O. N=21, time= 2 hours.
Control group: standard medical care+O2 mask. N= 17.
Co-intervention: morphine,furosemide, nitroglycerin.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Treatment failure

  4. Incidence of acute myocardial infarction (follow-up)

  5. Length of hospital stay

NotesMask:nasal or face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasHigh risk 
Adherence to the intention-to-treat principleHigh risk 

Liesching 2003

MethodsSingle centre randomised controlled trial, parallel design, unblinded, using ITT approach. Losses to follow up not reported. Informed consent not described.
Participants27 participants. Diagnosis criteria: patients with acute cardiogenic pulmonary oedema. Patients with myocardial infarction at presentation were excluded.
InterventionsCPAP group: PEEP=10 cmH2O. N=14.
BILEVEL group: EPAP=4 cm H2O e IPAP= 12cmH2O. N=13.
Co-intervention: medical treatment..
Outcomes
  1. Tracheal intubation rate

  2. Incidence of acute myocardial infarction (follow-up)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot reported if there were drop-outs over the monitoring of patients.
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Lin 1991

MethodsSingle centre randomised controlled trial, parallel design, unblinded, lack of intention-to-treat analysis confirmed on study assessment. 15 patients in CPAP group and 10 patients in O2 group were lost to follow up. Infomed consent was obtained of the patients. Setting: intensive care unit. Wash out of 30 minutes.
Participants80 patients were randomised, but 25 patients did not meet inclusion criteria following randomisation. Therefore, study entry 55 patients (50 males and 5 females), with age 74.1±8.8 years in standard medical care group and 73.4±8.2 in CPAP group. Diagnosis criteria: Radiologic evidence of acute interstitial or alveolar oedema of cardiac origin, tachypnoea, BR>22bpm, intercostal or suprasternal retractions, PaO2/FiO2 > 200, P(A-a)O2>200. Causes: CHF, dilated cardiomyopathy, Ischaemic heart disease, hypertensive cardiovascular disease, acute myocardial infarction. Excluded patients: patients unresponsive to speech or unable to maintain a patent airway and who had cardiogenic shock, signs of lung infection, evidence pulmonary embolism, chronic lung disease with CO2 retention at rest.
InterventionsCPAP group: PEEP=3.75±1.76 cmH2O in first hour (pressure was applied by connecting a serial CPAP valve -2,5 cm, 5 cm, 7,5 cm, 10 cm, 12,5 cm - to the face mask at each 30 min interval. N=25, TIME=6 hours.
Control group: standard medical care+O2 mask. N= 30.
Co-intervention: medical treatment of pulmonary oedema was not restricted.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases ( PaO2, PCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Droupouts/ withdrawals

  6. Treatment failure

NotesMask: face mask.
FiO2=100% full time.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
High risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleHigh risk 

Lin 1995

MethodsSingle centre randomised controlled trial, parallel design, unblinded, using ITT approach. No losses to follow up were reported. Informed consent not reported. Setting: emergency department or the patient was recruited during hospitalisation. Wash out of 30 minutes.
Participants100 participants (90 males and 10 females), with age 73±9 years in standard medical care group and 72±8 in CPAP group. Diagnosis criteria: dyspnoea and tachypnoea, BR>22bpm, use of accessory respiratory muscles, PaO2/FiO2 between 200 and 400, P(A-a)O2< 250. Rx bilateral diffuse interstitial or alveolar oedema and most rales, and without history aspiration or infection. Causes: CHF, dilated cardiomyopathy, Ischaemic heart disease, hypertensive crisis, acute myocardial infarction. Excluded patients: patients unresponsive, unable to maintain a patent airway and who had cardiogenic shock, ventricular septal rupture, any severe stenotic valvular disease or chronic lung disease.
InterventionsCPAP group: PEEP=3.75±1.7 cmH2O in first hour (pressure was applied by connecting a serial CPAP valve -2,5 cm, 5 cm, 7,5 cm, 10 cm, 12,5 cm - to the face mask at each 30 min interval. N=41, TIME=6 hours.
Control group: standard medical care+O2 mask. N= 33.
Co-intervention: Isosorbide dinitrate, morphine, furosemide, nitroprusside, nitroglycerin, dopamine.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases (PaO2, PCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Droupouts/ withdrawals

  6. Length of hospital stay

  7. Length of ICU stay

  8. Treatment failure

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Unclear riskNot submitted multiple planning outcomes reported on results.
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Martin-Bermudez 2002

MethodsRandomised controlled trial. Losses to follow up not reported. Informed consent not described.
Participants84 consecutive patients with respiratory failure due to severe cardiogenic pulmonary oedema were randomly assigned to receive either pressure support ventilation plus positive end expiratory pressure or continuous positive airway pressure. Lack of intention-to-treat analysis confirmed on study assessment. 3 patients in CPAP group and 1 patients in BILEVEL group were lost after randomisation (a case of respiratory failure by aspiration pneumonia, a re-acute CPE and two declined to continue participating in the study).
InterventionsCPAP group: time= 107±57 min. N=42.
BILEVEL group: time= 76±50 min . N=42.
Co-intervention: ?
Outcomes
  1. Mortality

  2. Length of hospital stay

  3. Length of ICU stay

  4. Arterial blood gases (pH, PaCO2, PaO2/FiO2,)

  5. Vital signs (BR, BP, HR)

  6. Incidence of acute myocardial infarction (follow-up)

  7. Dyspnea score

  8. Tidal volume

NotesMask: face mask
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Unclear riskNot submitted multiple planning outcomes reported on results.
Detection biasLow risk 
Adherence to the intention-to-treat principleHigh risk 

Masip 2000

MethodsSingle centre randomised controlled trial (the randomisation sequence was generated by a table of random numbers, the assignments were placed in closed envelopes with identification numbers that were stored in the intensive-care unit), parallel design, unblinded, lack of intention-to-treat analysis confirmed on study assessment. Two patients in standard medical care group and one patient in BILEVEL group were lost to follow up. Patients or next-of-kin were aware through informed consent. Setting: emergency department or ward to the intensive care unit (ICU).
Participants40 participants went randomised, but 3 patients were excluded from the analysis. Therefore, study entry 37 patients (19 males and 18 females), with age 78.5±5 years in standard medical care group, 75.3±11 in BILEVEL group. Diagnosis criteria: dyspnoea of sudden onset with physical findings consistent with pulmonary oedema (widespread rales with or without third heart sound) and typical findings of congestion on a chest radiograph. History: heart failure, acute myocardial infarction, Hypertension, diabetes mellitus, chronic obstructive pulmonary disease. Causes: acute myocardial infarction, hypertensive crisis, hypervolaemia,unstable angina, tachyarrhythmia, respiratory-tract infection, treatment non-compliance. Excluded patients: cardiogenic shock (SBP < 90mmHg), severe acute or chronic airflow obstruction without evidence of cardiogenic pulmonary oedema, severe chronic renal failure, neurological impairment, acute myocardial infarction necessitating thrombolysis, evidence of pneumonia, immediate need for intubation, and absence of pulmonary oedema on a first chest radiograph.
InterventionsBILEVEL group: EPAP= 5 cm H2O e IPAP= 15.2±2.4 cmH2O. N=19, time= 254±90 min.
Control group: standard medical care+O2 mask (FiO2 > or = 50%). N= 26
Co-intervention: morphine, furosemide, glyceryl trinitrate, digoxin.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases (pH)

  4. Vital signs (BR, BP, HR)

  5. Incidence of acute myocardial infarction (follow-up)

  6. Dropouts/ withdrawals

  7. Side-effects

  8. Length of hospital

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Unclear riskNot reported.
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleHigh risk 

Mehta 1997

MethodsSingle centre randomised controlled trial (computer random number sequence), parallel design, double-blind, lack of intention-to-treat analysis confirmed on study assessment. 4 patients in CPAP group and 5 patients in BILEVEL group were lost to follow up. Patients or next-of-kin were aware through informed consent. Single blind. Setting: emergency department and ICU.
Participants36 participants (11 males and 25 females), with age 76±7 years in CPAP group and 77±12 in BILEVEL group. Diagnosis criteria: moderate-to-severe dyspnoea, BR>30bpm, use of accessory respiratory muscles or paradoxical abdominal motion in combination with tachycardia (heart rate of >100 bpm), cardiac gallops, bilateral rales, and typical findings of congestion on a chest radiograph, without a history suggesting pulmonary aspiration or infection. Causes: acute myocardial infarction, left bundle-branch block, coronary artery disease. Excluded patients: already intubated, suffering a respiratory or cardiac arrest, had an unstable cardiac rhythm, or a systolic blood pressure (BP)<90mmHg, patients unresponsive, agitated, and unable to cooperate, or if they had any condition that precluded application of a face mask.
InterventionsCPAP group: PEEP=10 cmH2O. N=13, TIME= 6.4±5.8 hours.
BILEVEL group: EPAP=5 cm H2O and IPAP= 15cmH2O. N=14, TIME = 7.1±4.7 hours.
Co-intervention: morphine, furosemide, isosorbide dinitrate.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Incidence of acute myocardial infarction (follow-up)

  4. Dropouts/ withdrawals

  5. Side-effects

  6. Length of hospital stay

  7. Length of ICU stay

NotesMask: nasal mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
High risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleHigh risk 

Moritz 2007

MethodsMulticenter randomised controlled trial (3 centres), randomisation procedure: allocation to treatment was stratified for centre and based on block randomisation of 10 consecutive study numbers. Parallel design, single blind. Lack of intention-to-treat analysis confirmed on study assessment, eleven patients were withdrawn because no informed consent was obtained (n7) or because they were lost to follow-up. Patients or next-of-kin gave written informed consent. Setting: emergency department.
Participants109 participants (57 males and 52 females), with age 77.6±9.4 years in CPAP group and 77.7±9.2 in BILEVEL group. Diagnosis criteria: association of sudden onset of dyspnoea; presence of bilateral rales on auscultation, with no medical history suggesting pulmonary aspiration or infection; or congestion found on chest radiograph. Furthermore, patients had to present 2 of the following severity criteria of respiratory failure: respiratory frequency greater than 30 breaths/min; pulse oxymetry saturation (SpO2) below 90%, with oxygen at greater than 5 L per minute through reservoir facemask; and use of accessory muscles (Patrick scale 3). Causes: acute myocardial infarction, treatment noncompliance, respiratory tract infection, myocardial ischaemia, hypertensive emergency, previous pulmonary oedema. Excluded patients: out-of-hospital use CPAP or BILEVEL, temperature above 39°C, altered mental state, severe acute or chronic airflow obstruction, with no evidence of pulmonary oedema, chronic renal failure, evidence of pneumonia, acute myocardial infarction necessitating thrombolysis or primary angioplasty, immediate indication for tracheal intubation, respiratory or cardiac arrest, SpO2 < 85% with 100% FiO2, decreased alertness or major agitation requiring sedation, clinical signs of exhaustion: active contraction of the respiratory accessory muscles, with paradoxic abdominal or thoracic motion.
InterventionsCPAP group: PEEP=7.7±2.1 cmH2O. N=59, TIME= 2.3 hours.
BILEVEL group: EPAP=4.9±0.9 cm H2O and IPAP= 12±3.2cmH2O. N=50, time= 2.8 hours.
Co-intervention: morphine sulfate, furosemide, nitroprusside, sublingual or topical or intravenous nitroglycerin.
Outcomes
  1. Hospital mortality

  2. ETI

  3. Incidence of acute myocardial infarction

  4. Vital signs (pulse rate, systolic and diastolic blood pressure, BR)

  5. Arterial blood gases (PaO2, PCO2, pH)

  6. Acessory muscle use evaluated with Patrick Scale

  7. SpO2

  8. Duration of the ventilation period

  9. Length of hospital stay

NotesMask: full face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasLow risk 
Adherence to the intention-to-treat principleHigh risk 

Nava 2003

MethodsMulticenter randomised controlled trial (5 centres), randomisation procedure: the randomisation schedule had a block design for each centre and was generated by an independent statistician who used random numbers (because the level of PaCO2 might have a substantial influence on the study results, the randomisation was balanced according to whether the patients had an admission PaCO2< or >45mmHg), parallel design, unblinded, using ITT approach. No patients were lost to follow up. Patients or next-of-kin were aware through informed consent. Setting: emergency department.
Participants130 participants (101 males and 29 females), with age 73.1±8.3 years in standard medical care group and 72.1±9.1 in BILEVEL group. Diagnosis criteria: dyspnoea of sudden onset with BR>30bpm, PaO2/FiO2<250, typical finds on chest radiographs (congestion) and physical signs of pulmonary oedema (widespread rales) without a history suggesting pulmonary aspiration or infection. Causes: acute acute myocardial infarction, hypertension, hyperthermia (but not showing any signs of pulmonary infection), arrhythmia, aortic stenosis, mitral regurgitation. Excluded patients: immediate need for endotracheal intubation, severe sensorial impairment, shock, ventricular arrhythmias, life threatening hypoxia (SaO2<80%), acute myocardial infarction necessitating thrombolysis, severe chronic renal failure and pneumothorax.
InterventionsBILEVEL group: EPAP=6.1±3.2 cm H2O e IPAP= 14.5±21,1cmH2O. N=65, time= 11.4±3.6 hours.
Control group: standard medical care+O2 mask (to maintain an SpO2>90%). N= 65
Co-intervention: morphine sulfate, furosemide, glyceryl trinitrate.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases (PaO2, PCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Incidence of acute myocardial infarction (follow-up)

  6. Compliance of patient

  7. Side-effects

  8. Length of hospital stay

NotesMask: full face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Park 2001

MethodsSingle centre randomised controlled trial (computer random number sequence in closed envelopes), parallel design, unblinded, not using ITT approach. Loss to follow up not reported. Patients or guardians were aware through informed consent. Setting: in hospital.
Participants26 participants (10 males and 16 females), with mean age 69±7 years. Diagnosis criteria: dyspnoea of acute onset or worsening, respiration rate more or similar 25 bpm, Rx compatible with pulmonary congestion. Causes: acute myocardial infarction, hypertensive emergencies, acute ischaemic heart disease, infectious endocarditis or undetermined. Excluded patients: SBP less than 90mmHg, arrhythmias requiring electric cardioversion, decreased consciousness level, bradypnoea, lack of cooperation or agitation, repetitive vomiting, upper digestive haemorrhage, facial deformities or any other decompensated respiratory disease.
InterventionsCPAP group: PEEP= 7.5 cmH2O. N=9, TIME=170±90min.
BILEVEL group: EPAP=4 cm H2O e IPAP= 12cmH2O. N=7, time= 155±38min.
Control group: standard medical care+O2 mask (15l/min). N= 10.
Co-intervention: Isosorbide dinitrate (5mg) + standard medication
Outcomes
  1. Mortality,

  2. Traqueal intubation rate,

  3. Arterial blood gases ( PaO2, PaCO2, pH),

  4. Vital signs (BR, BP, HR),

  5. Incidence of acute myocardial infarction (follow-up),

  6. Compliance of patient,

  7. Dropouts/ withdrawals.

NotesOutcome 6 was poorly reported as a brief comment: BILEVEL group more cooperated and related less dyspnoea.
Mask: CPAP: closed face mask, BILEVEL: nasal mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot reported.
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleHigh risk 

Park 2004

MethodsSingle centre randomised controlled trial (the patients were randomised with sealed envelopes - nine per envelope - using a 3:3:3 assignment scheme), parallel design, lack of intention-to-treat analysis confirmed on study assessment. Two patients in BILEVEL group and one patients in O2 group were lost to follow up. Patients or guardians were aware through informed consent. Setting: in emergency department. Wash out of 6 minutes.
Participants83 participants went randomised, but 3 patients did not meet inclusion criteria for study entry. Therefore, study entry 80 patients (34 males and 46 females), with age 65±15 years in standard medical care group, 61±17 in CPAP group and 66+/-14 in BILEVEL group. Diagnosis criteria: More than 16 years, acute onset of severe respiratory distress (BR>25rpm), associated tachycardia and diaphoresis and findings of pulmonary congestion on physical examination and chest Rx 2 hours after randomisation. Causes: acute myocardial infarction, myocardial ischaemia, crisis hypertensive, progressive heart failure, hypervolaemia (20%with CPO severe). Excluded patients: SBP < 90mmHg, decrease consciousness level, intractable vomiting, acute myocardial infarction with persistent ST segment elevation, pulmonary embolism, COPD, pneumonia or pneumothorax .
InterventionsCPAP group: PEEP=11±2 cmH2O. N=27, TIME=102±41min.
BILEVEL group: EPAP=11±2 cm H2O e IPAP= 17±2cmH2O. N=7, time= 124±62min.
Control group: standard medical care+O2 mask (FiO2 > or = 50%). N=26
Co-intervention: Isosorbide dinitrate, morphine, furosemide, nitroprusside, nitroglycerin
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Incidence of acute myocardial infarction (follow-up)

  4. Compliance of patient

  5. Dropouts/ withdrawals

  6. Treatment failure

  7. Side-effects

  8. Length of hospital stay

NotesMask: face mask. CPAP or BILEVEL with FiO2=50%.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleHigh risk 

Räsänen 1985

MethodsSingle centre randomised controlled trial. The patients were randomly assigned to 1 of 2 group by opening 1 of 40 sealed envelopes. Parallel design, unblinded, using ITT approach. Loss to follow up not reported. Informed consent not described. Wash out of 10 minutes. Setting: intensive care unit (ICU).
Participants40 participants (13 males and 17 females), with age 73±9 years in standard medical care group and 74±9 in CPAP group. Diagnosis criteria: respiratory failure and clinical and radiologic evidence of acute alveolar pulmonary oedema of cardiac origin, dyspnoea, signs increase respiratory work (intercostal and suprasternal retractions or use of accessory respiration muscles), respiratory rate of more than 25 bpm. PaO2/FiO2<200. Causes: severe heart failure primarily after acute myocardial infarction, acute exacerbation of chronic left ventricular dysfunction, ventricular arrhythmia or acute valve incompetence. Excluded patients: patients unresponsive to speech or unable to maintain patent airway, with lung infection, pulmonary embolism, chronic lung disease with CO2 retention at rest or after treatment PaO2<50mmHg, PaCO2>55mmHg, BR>35bpm.
InterventionsCPAP group: PEEP= 10 cmH2O. N=20, TIME=180min.
Control group: standard medical care+O2 mask (FiO2=28-30%). N= 20.
Co-intervention: furosemide, morphine, diazepam, chlorpromazine, nitroglycerin, nitroprusside, digitalis, dopamine and dobutamine.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Arterial blood gases ( PaO2, PCO2, pH)

  4. Vital signs (BR, BP, HR)

  5. Incidence of acute myocardial infarction (follow-up)

  6. Treatment failure

  7. Side-effects

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Unclear riskNot submitted multiple planning outcomes reported on results.
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Sharon 2000

MethodsSingle centre randomised controlled trial (according to their numerical order on list that had been predetermined by lot), parallel design, unblinded, using ITT approach. No losses to follow up. Informed consent was obtained. Setting: mobile intensive care unit teams in the patient's home or during delivery to the emergency department.
Participants40 patients went randomised (19 males and 21 females), with age 73±7 years in standard medical care group and 72+/-6 in BILEVEL group. Diagnosis criteria: symptoms and signs of pulmonary oedema accompanied by oxygen saturation of < 90% measured by pulse oximetry, prior to oxygen administration. Echocardiographics findings: moderate aortic stenosis, moderate mitral regurgitation, ejection fraction. Excluded patients: previous treatment with nitrates above 40 mg/d, or mononitrate or long-acting trinitrates administered more than twice daily or short acting trinitrates administered more than three times a day; previous treatment with furosemide> 80 mg/d; hypotension (blood pressure <110/70 mmHg); previous adverse effect of nitrates; ST elevations consistent with acute myocardial infarction on baseline ECG; and absence of pulmonary oedema on chest radiograph obtained on arrival to the emergency department.
InterventionsBILEVEL group: EPAP= 4.2±3,.cm H2O, e IPAP=9.3±2.3 cmH2O + ISDN = 3.5±2.5mg. N=20, time=at least 50 minutes.
Control group: O2 mask + high dose IV ISDN =10.8±5.7mg . N= 20.
Co-intervention: IV ISDN (Isorsobide-dinitrate), furosemide and morphine
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Incidence of acute myocardial infarction (follow-up)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk 
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Takeda 1997

MethodsSingle centre randomised controlled trial, parallel design, unblinded, using ITT approach. Loss to follow up not reported. Patients or guardians were aware through informed consent. Setting: intensive care unit (ICU).
Participants30 participants (22 males and 8 females), with age 64±9 years in standard medical care group and 69+/-10 in CPAP group. Diagnosis criteria: dyspnoea of sudden onset, PaO2<80mmHg with FiO2>ou= 50%, typical finds on chest radiographs, and widespread rales without a history suggesting pulmonary aspiration or infection. Causes: acute myocardial infarction, prior myocardial infarction, cardiomyopathy, mitral valve regurgitation. Exclusion criteria: complicated with aspiration and/or pneumonia, immediate need for endotracheal intubation, shock, and life-threatening hypoxia at study entry.
InterventionsCPAP group: PEEP= 7±3 cmH2O. N=15, TIME=11.9±8.4hours.
Control group: standard medical care+O2 mask. N=15.
Co-intervention: furosemide, morphine, nitroglycerin, digitalis, dopamine, dobutamine, norepinephrine.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Length of ICU stay

NotesMask: nasal mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Unclear riskThe method used was not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Unclear riskNot submitted multiple planning outcomes reported on results.
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Takeda 1998

MethodsSingle centre randomised controlled trial (by envelope method), parallel design, unblinded, using ITT approach. No patients were lost after randomisation. Patient's next of kin were aware through informed consent. Setting: coronary care unit (CCU).
Participants22 participants (17 males and 5 females), with age 75±10 years in standard medical care group and 74±11 in CPAP group. Diagnosis criteria: dyspnoea of sudden onset, PaO2<80mmHg with FiO2= 50%, typical finds on chest radiographs and widespread rales without a history suggesting pulmonary aspiration or infection, typical chest pain 30 minutes creatine kinase twice a least the normal, ECG changes consistent with acute myocardial infarction. Causes: Acute myocardial infarction. Exclusion criteria: complicated with aspiration and/or pneumonia, immediate need for endotracheal intubation, shock, and life-threatening hypoxia at study entry.
InterventionsCPAP group: PEEP= 7±3 cmH2O. N=11, TIME=48hours.
Control group: standard medical care+O2 mask. N= 11.
Co-intervention: furosemide, morphine, nitroglycerin, dopamine, dobutamine, norepinephrine, epinephrine.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

NotesMask: nasal mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Thys 2002

MethodsSingle centre randomised controlled trial (through opaque and sealed envelopes by batches of 20 envelopes), parallel design with placebo, single blind, using ITT approach. None patient went lost. Informed consent was obtained of the patients. Setting: emergency department and intensive care unit (ICU).
Participants8 participants (5 males and 3 females), with age 77.5±8.38 years. Diagnosis criteria: orthopnoea, bibasilar crackles, bilateral perihilar infiltrates on chest radiograph with cardiomegaly and a compatible clinical history; age more than 18 years, acute onset of moderate-to-severe dyspnoea, BR>30 or < 10bpm, hypoxaemia (PaO2 <55mmHg) or need for O2 supplementation, pH<7,33. Excluded patients: immediate indication for endotracheal intubation, major unrest, haemodynamic instability, facial or thoracic trauma, lack of cooperation, difficult adaptation of a facial mask, pulmonary embolism, retrosternal pain suggestive of a acute myocardial infarction.
InterventionsBILEVEL group: EPAP= 6.1±1.5 cmH2O e IPAP= 16.5±1.5 cmH2O. N=3, time= 77.33±16.25 minutes.
Control group: standard medical care+O2 with similar mask (placebo). N= 5.
Co-intervention: furosemide, isosorbide dinitrate.
Outcomes
  1. Mortality

  2. Tracheal intubation rate

  3. Incidence of acute myocardial infarction (follow-up)

  4. Side-effects

  5. Length of hospital stay

  6. Length of ICU stay

NotesMask: face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method used was not reported.
Allocation concealment (selection bias)Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleLow risk 

Weitz 2007

  1. a

    ITT - intention to treat; SaO2 - arterial saturation of oxygen; O2 - oxygen; l/min - litre per minute;
    BR - breath rate; b/min - breaths per minute; HR - heart rate; b/min - beats per minute; Rx - radiograph;
    CHF - congestive heart failure; CPO - cardiogenic pulmonary oedema; ISDN - isosorbide dinitrate; FiO2 - fraction of inspired oxygen; P(A-a)O2 - alveolar-arterial oxygen gradient; PaCO2 - carbon dioxide tension of arterial blood; PaO2 - partial pressure of oxygen in arterial blood; CO2 - carbon dioxide; pH - potential of hydrogen; BP - blood pressure; ICU - intensive care unit; SBP - systolic blood pressure; N - number; IPAP - inspiratory positive airway pressure; EPAP - expiratory positive airway pressure; BILEVEL - bilevel positive airway pressure; PEEP - positive expiratory end pressure; CPAP - continuous positive airway pressure; SMC - standard medical care; STEMI - ST segment elevation myocardial infarction.

MethodsSingle centre randomised controlled trial, parallel design, unblinded, not using ITT approach. Three patients allocated to the standard group were not followed up because it was obvious on admission that these patients did not suffer from an acute cardiogenic pulmonary oedema. Informed consent was obtained. Setting: mobile intensive care unit teams in the patient's home or during delivery to the emergency department.
Participants23 participants (12 males and 11 females), with age 72-92 years in standard medical care group and 54-86 in BILEVEL group. Diagnosis criteria: severe dyspnoea and consecutively showed additional clinical signs of ACPE (SaO2< 90% and basal rales). Excluded patients: severe uncontrolled agitation, angina, obvious ST elevation in the ECG, emesis and aspiration, cardiogenic shock, life threatening arrhythmias, coma or any obvious need for intubation.
InterventionsBILEVEL group: EPAP= 5 cm H2O e IPAP= 12.5±1.2 cmH2O. N=10.
Control group: standard medical care+O2 with similar mask (placebo). N= 5.
Co-intervention: furosemide, isosorbide dinitrate.
Outcomes
  1. SaO2 at the time of the hospital admission

  2. Measure the brain natriuretic peptide (BNP)

  3. Mortality

  4. Length of hospital stay

  5. Length of ICU stay

  6. Vital signs (BR, BP, HR)

  7. Dyspnea scale

  8. Tracheal intubation rate

  9. Incidence of acute myocardial infarction (follow-up)

  10. Side-effects

NotesMask: Face mask.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk 
Allocation concealment (selection bias)High riskInadequate
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Unclear riskNot submitted multiple planning outcomes reported on results.
Detection biasUnclear riskNot reported.
Adherence to the intention-to-treat principleHigh risk 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    108 excluded.

Acosta 2000The clinical situation is different.
Albert 2000The clinical situation is different.
Alper 2007It is not a RCT or QRCT.
Alper 2008It is not a RCT or QRCT.
Andrade 1998The clinical situation is different.
Antonelli 2001It is not a RCT or QRCT.
Aronow 2007It is not a RCT or QRCT.
Barach 1938It is not a RCT or QRCT.
Baratz 1992It is not a RCT or QRCT.
Bavry 2008It is not a RCT or QRCT.
Bellone 2002The outcomes did not meet the inclusion criteria.
Blomqvist 1991Study with dogs.
Bollaert 2002Study involve other kind of ventilatory support (PAV)
Bouquin 1998It is not a RCT or QRCT.
Bradley 2000The clinical situation is different.
Brezins 1993Study involve other kind of ventilatory support (invasive mechanical ventilation).
Brijker 1999It is not a RCT or QRCT.
Brochard 1998It is a letter commenting the L'Her's article.
Chadda 2002The outcomes did not meet the inclusion criteria.
Chen 2008Compare NPPV vs. mechanical ventilation.
Crane 2002It is not a RCT or QRCT.
Craven 2000It is not a RCT or QRCT.
Cross 2000It is not a RCT or QRCT.
Cross 2003This is study is in patients with acute respiratory failure and include a subgroup with pulmonary edema (inclusion criteria not clear for cardiogenic pulmonary edema). However, although the author have been contected, he is not replay.
Cydulka 2005It is a letter commenting the Nava's article.
Domenighetti 2002It is not a RCT or QRCT.
Du Cailar 1975It is not a RCT or QRCT.
Eaton 2002The clinical situation is different.
Evans 2001It is not a RCT or QRCT.
Fromm 1995It is not a RCT or QRCT.
Giacomini 2003It is not a RCT or QRCT.
Girou 2003The clinical situation is different.
Gorbunova 2005The end point doesn't similar commended in protocol.
Gray 2009It is the same study published in New England in 2008 by Gray et al.
Guerra 2005It is not a RCT or QRCT.
Guntupalli 1984It is not a RCT or QRCT.
Gust 1998It is a letter to the editor.
Hao 2002It is not a RCT or QRCT.
Hess 2004It is not a RCT or QRCT.
Hilberg 1997It is not a RCT or QRCT.
Hipona 1996It is a letter to the editor.
Hoffman B 1999It is not a RCT or QRCT.
Hoffmann 1999It is not a RCT or QRCT.
Holt 1994It is not a RCT or QRCT.
Hotchkiss 1998It is not a RCT or QRCT.
Hubble 2006It is not a RCT or QRCT.
Hughes 1999It is a letter to the editor.
Iapichino 2004It is not a RCT or QRCT.
Jackson 2000It is not a RCT or QRCT.
Jackson 2001It is not a RCT or QRCT.
Jackson R 2001It is not a RCT or QRCT.
Kallio 2003It is not a RCT or QRCT.
Keenan 2004It is not a RCT or QRCT.
Kelly 2001It is a letter to the editor.
Kiely 1998The outcomes did not meet the inclusion criteria.
Kindgen-Milles 2000It is not a RCT or QRCT.
Kosowsky 2000It is not a RCT or QRCT.
Kosowsky 2001It is not a RCT or QRCT.
Kramer 1995This is study is in acute respiratory failure and include only two patients with cardiogenic pulmonary edema that received NPPV and nobody received CPAP or SMC.
L'Her 1998It is not a RCT or QRCT.
L'Her E 1998It is not a RCT or QRCT.
Lal 1969The study test only different oxygen masks.
Lapinsky 1994It is not a RCT or QRCT.
Leman 2005It is a RCT, but only compared two different brands of CPAP equipment.
Lenique 1997It is not a RCT or QRCT.
Li 2004It is a RCT, it is Chinese paper  whose data was translated by Cochrane, but dichotomous variables advocated not were analyzed and the continuous variables analysis happened in different period of advocated - 2hs and 24hs after the start of the intervention.
Liesching T 2003It is not a RCT or QRCT.
Lo Coco 1997It is not a RCT or QRCT.
Mackay CA 2000It is a Poster of Congress. Did not assess relevant outcomes.
Masip 2008It is not a RCT or QRCT.
Massaria 1976It is not a RCT or QRCT.
Meduri 1991The clinical situation is different. It was conducted in patients with COPD or asthma.
Mehta 2000The outcomes did not meet the inclusion criteria.
Mehta 2004It is not a RCT or QRCT.
Mehta 2005It is not a RCT or QRCT.
Minuto 2003It is not a RCT or QRCT.
Mollica 2001It is not a RCT or QRCT.
Moritz 2003The outcomes did not meet the inclusion criteria.
Murray 2002It is not a RCT or QRCT.
Murray 2003It is not a RCT or QRCT.
Nadar 2005It is not a RCT or QRCT.
Nava 2002It is not a RCT or QRCT.
Newberry 1995It is not a RCT or QRCT.
Newby 2007It is a brief presentation of RCT published in The New England in 2008 by Gray et al.
Nikki 1982The study compares CPAP vs. mechanical ventilation.
Niranjan 1998It is a letter to the editor with comment about noninvasive ventilation.
Panacek 2002It is not a RCT or QRCT.
Pang 1998It is not a RCT or QRCT.
Park 2005It is not a RCT or QRCT.
Park 2006It is an article of review.
Perel 1983It is not a RCT or QRCT.
Perkins 2006It is not a RCT or QRCT.
Philip-joet 1999The clinical situation is different.
Plaisance 2007It is a RCT, but this study cross-over, the groups were compared in different times were different from those described in this review.
Pollack 1996It is not a RCT or QRCT.
Poponick 1999It is not a RCT or QRCT.
Popova 2010The outcomes did not meet the inclusion criteria.
Poulton 1936It is not a RCT or QRCT.
Rabatin 1999It is not a RCT or QRCT.
Rasanen J 1985It is not a RCT or QRCT.
Rizk 1982It is not a RCT or QRCT.
Roche 2003The clinical situation is different.
Rusterholtz 1999It is not a RCT or QRCT.
Rutherholtz 2008It is a RCT, but compared CPAP vs.PAV.
Sacchetti 2001It is a letter to the editor .
Sachetti 1995It is not a RCT or QRCT.
Salvucci A 2001It is not a RCT or QRCT.
Sarullo 2004It is not a RCT or QRCT.
Schettino 2008It is not a RCT or QRCT.
Severinghaus 2002It is not a RCT or QRCT.
Simonds 2000It is not a RCT or QRCT.
Sinuff 2000It is not a RCT or QRCT.
Somauroo 2000The clinical situation is different. It was conducted in patients with chronic congestive heart failure.
Sutton 2002It is a letter to the editor.
Trevisan 2008It is a RCT, but compared It is a RCT, but compared NPPV as a method of weaning.
Uy 2003The study compares CPAP vs. mechanical ventilation.
Uy 2004It is a RCT, but compared It is a RCT, but compared CPAP vs.invasive mechanical ventilation
Vaisanen 1987The outcomes did not meet the inclusion criteria.
Valipour 2004It is not a RCT or QRCT.
Werdan 1999It is not a RCT or QRCT.
Widger 2001It is not a RCT or QRCT.
Wood 1998This is study is in acute respiratory failure and include a subgroup with cardiogenic pulmonary oedema. However, although the author have been contected, he is not replay.
Wright 2001It is a letter to the editor.
Wysocki 1995This is study is in acute respiratory failure and include a subgroup with cardiogenic pulmonary oedema. However, although the author have been contected, he is not replay.
Wysocki 1999It is not a RCT or QRCT.
Zhang 2008The end point doesn’t similar commended in protocol.

Characteristics of ongoing studies [ordered by study ID]

NCT00554580

Trial name or titleEffect of Continuous Positive Airway Pressure on Short Term Inhospital Prognosis for Acute Pulmonary Edema
MethodsAllocation: Randomised
Endpoint classification: Efficacy Study
Intervention model: Parallel Assignment
Masking: Open label
Primary purpose: Treatment
ParticipantsAdults with acute cardiogenic pulmonary oedema
Interventions
  • A: Active comparator

    • usual care of pulmonary acute oedema

    • Intervention: usual care of acute pulmonary oedema

  • B: Experimental

    • CPAP + usual care of pulmonary acute oedema

    • Intervention: continuous positive airway pressure (CPAP)

Outcomes

Death, tracheal intubation and mechanical ventilation rates, persistence of inclusion criteria for respiratory distress and shock until H2, reappearance of inclusion criteria after H2. [ Time Frame: 48 hours ]

Brain natriuretic factor value curves from H0, H6 and H24; composite criteria without intubation rate; clinical and biological parameters evolution during the first 48 hours, myocardial infarction rate, CPAP non tol [ Time Frame: H0, H6, H24, H48 ]

Starting dateNovember 6, 2007
Contact information 
Noteshttp://clinicaltrials.gov/ct2/show/NCT00554580

NCT00912158

Trial name or titleNoninvasive Mechanical Ventilation in Acute Cardiogenic Pulmonary Edema
MethodsAllocation: Randomised
Endpoint classification: Safety/efficacy study
Intervention model: Parallel assignment
Masking: Open label
Primary purpose: Treatment
ParticipantsAdults with acute cardiogenic pulmonary oedema
InterventionsOther: standard therapy (ST)
Device: CPAP and BIPAP
OutcomesNumber of patients who were intubated, arterial blood gases, respiratory rate, blood pressure, cardiac output, intrapulmonary shunt, A-a oxygen gradient, heart rate, and dyspnoea duration of hospital and ICU stay and mortality [ Time Frame: Hospital stay ]
Starting dateApril 8, 2009
Contact informationmahaghanem@hotmail.com
Noteshttp://clinicaltrials.gov/ct2/show/NCT00912158