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Title: - Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome - Insights from the LUNG SAFE Study


Citation: - Bellani G, Laffey JG, Pham T, Madotto F , Fan E, Brochard L, Esteban A , Gattinoni L , Bumbasirevic V, Piquilloud L,Haren FV, Larsson A, McAuley DF, Bauer PR , Arabi YM,Ranieri M, Antonelli M, Rubenfeld GD, Thompson BT, Wrigge H,Slutsky AS, and Pesenti A on behalf of the UNG SAFE Investigators and the ESICM Trials Group. Am J Respir Crit Care Med Vol 195, Iss 1, pp 67–77, Jan 1, 2017.

Aim: -

With this background and no robust multicenter RCT supporting use of NIV in ARDS and in-fact, reporting poor outcome with it, the ESICM lung SAFE group conducted an analysis of their large multicenter survey and reported the result in the above sited paper.


Study Design: -

This was a secondary analysis of the LUNG-SAFE trial (prospective, observational, international, multicenter, cohort study). Patients who received invasive mechanical ventilation (MV) or NIV were enrolled into this trial for 4 consecutive weeks. The enrollment criteria were according to the Berlin criteria for ARDS.

NIV patients were those who received NIV on Day 1 and 2. NIV failure was defined as requirement of invasive MV on day 1 and 2 of NIV. Out of 2831 patients, 436 patients were managed with NIV on days 1 and 2. This cohort of patient constituted the study population. CPAP was used in 28.2% cases and rest of them received pressure cycled modes.


Result/Findings: -

    NIV related data and NIV failure

  • Greater ARDS severity score was associated with significant NIV failure (mild 22.2%, moderate 42.3% or severe 47%, p= 0.008). Interestingly, the use of NIV was similar in all the three severity categories of ARDS.

  • NIV patients received significantly lesser levels of PEEP and higher FiO2 to correct hypoxia. They had a higher tidal volume (>6-8ml/kg), respiratory rate and minute ventilation compared to MV group i.e less control over ventilator drive.

    Invasive MV

  • There was no significant change in tidal or minute ventilation among patients with varying degree of severity of ARDS who had invasive MV. P/F ratio improved more rapidly in patients who had MV.

    NIV Vs invasive MV

  • There was a 30% drop in minute ventilation from NIV to invasive MV. More lung protective ventilation settings were reported when patients were mechanically ventilated.

  • Baseline PaCO2 was higher in MV group with severe ARDS compared to NIV group (52±18 mm Hg vs 43± 14;P<0.001)- more permissive hypercapnia in invasive MV group.

  • After initiation of invasive MV there was a significant increase in PEEP and decrease in respiratory rate and the delivered tidal and minute volume was less.

    Clinical recognition of ARDS

More severe ARDS was associated with increased ability of the clinicians to recognize ARDS and worse outcome measures (mortality, ICU length of stay). The use of NIV was independently associated with lesser possibility of recognition of ARDS on enrollment and also at any given time. Failure of NIV was associated with increased but delayed recognition of ARDS.

    Outcome variables

  • Patients who failed NIV had a significantly poorer outcome (ICU mortality 42.7% vs 10.6%, p<0.001) compared to those who were successfully managed with NIV. After multivariate regression, NIV was associated with significant increase in ICU mortality (hazard ratio of 1.446, 95% CI 1.159-1.805).

  • After propensity matching of 353 NIV and MV patients, there was no significant difference between group mortality. In patients with p/f <150, ICU mortality was higher was 36.2% in NIV group vs 24.7% in MV group (p=0.033).

  • After adjusting for potential confounder, there was 30% increased chance of dying with use of NIV compared to invasive MV.  (though propensity match doesn’t show the same trend)

    Factors for NIV failure

  • NIV failure was associated with higher non-pulmonary SOFA score.

  • A decrease in p/f ratio over two days and increase in PaCO2 on NIV was independently associated with increased mortality.


Conclusion: -

One third of patients with ARDS failed NIV and mortality in this group was high. More sever ARDS (p/f <150) has a worse outcome with NIV compared to invasive MV.


Limitations: -

  • Volumes measured in NIV group may not be accurate.

  • No definite time span (hours) recorded on NIV, the gross enrollment criteria used was use of NIV on day 1 and 2.

  • Patient who received a small NIV trial and then intubated, considered in the invasive MV group which may have under-estimated the NIV failure rate.

  • Type of NIV interface was varying which may potentially decide the success of NIV.

  • Though mortality with severe ARDS who received and failed NIV was higher, it may be due the fact that these patients were relatively sicker between the two groups of patients. Never the less, it needs careful patient selection to consider NIV.


Strengths: -

One of largest prospective data base for NIV use in ARDS.


Relevance to current practice:-

Use of NIV in ARDS is not an uncommon in ICU practice. This study highlights the potential for masking early diagnosis and treatment for ARDS if NIV is used in an inappropriate patient. It may increase the chance of dying (potentially delay intubation).

Evaluation of patient characteristics prior to application of NIV is the most important determinant for success i.e higher non-pulmonary SOFA score and a higher respiratory rate are the factors that lead to poor outcome in ARDS if NIV is used.

Ongoing evaluation of patient is necessary to ensure patient safety on NIV. Failure to response to NIV in terms of increase in PaCO2 or decline in p/f ratio warrants early intubation and mechanical ventilation.

Literature before this study and basis of the current trial:

The use of NIV in type 2 respiratory failure in chronic obstructive pulmonary disease is well established and so as in the management of cardiogenic pulmonary edema. A Cochrane review including 32 studies with 2916 patients found significant reduction in mortality and rate of intubation. Though the same review concluded the significant reduction in mortality is derived from small trials.(1) A meta-analysis prior to this concluded that NIV reduced mortality and probability of intubation in patients with cardiogenic pulmonary edema. It further concluded that at that time CPAP had a higher-level evidence then BiPAP in cardiogenic pulmonary edema but did not find any adverse event when compared both of them.(2)

Initial use of NIV in ARDS is limited to patients with hematologic malignancy who are immunosuppressed. A retrospective observational study conducted across 158 Italian ICUs with 1302 patients demonstrated a decreased mortality rate with initial use of NIV in management of hypoxic respiratory failure in patients with hematologic malignancy even after propensity matching.(3) Mortality was highest among the patient group who failed NIV and receive invasive ventilation followed by the group of patients managed with invasive ventilation at the beginning. The least mortality was reported in the group managed with NIV only. A post HOC analysis of a trial conducted in Belgium and France did not find any difference in mortality when NIV is compared to oxygen only.(4) Two recent meta-analysis reported a significant mortality benefit with early use of NIV in ARDS for immunocompromised population.(5,6)



  1. Vital FMR, Ladeira MT, Atallah ÁN. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD005351. DOI: 10.1002/14651858.CD005351.pub3.

  2. Masip J, Roque M, Sánchez B, Fernández R, Subirana M, Expósito JA. Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA. 2005 Dec 28;294(24):3124-30.

  3. Gristina GR, Antonelli M, Conti G, Ciarlone A, Rogante S, Rossi C, Bertolini G; GiViTI (Italian Group for the Evaluation of Interventions in Intensive Care Medicine). Noninvasive versus invasive ventilation for acute respiratory failure in patients with hematologic malignancies: a 5-year multicenter observational survey. Crit Care Med 2011;39: 2232–2239.

  4. Lemiale V, Resche-Rigon M, Mokart D, Pe`ne F, Rabbat A, Kouatchet A, Vincent F, Bruneel F, Nyunga M, Lebert C. Acute respiratory failure in patients with hematological malignancies: outcomes according to initial ventilation strategy. A Groupe de Recherche RespiratoireenRe ́animationOnco-He ́matologique(Grrr-OH)study. Ann Intensive Care 2015;5:28.

  5. Hui-Bin Huang, Biao Xu, Guang-Yun Liu, Jian-Dong Lin, Bin Du. Use of noninvasive ventilation in immunocompromised patients with acute respiratory failure: a systematic review and meta-analysis. Critical Care (2017) 21:4.

  6. Tao Wang, Lixi Zhang, Kai Luo, Jianqiang He, Yong Ma, Zongru Li, Na Zhao, Qun Xu, Yi Li, Xuezhong Yu. Noninvasive versus invasive mechanical ventilation for immunocompromised patients with acute respiratory failure: a systematic review and meta-analysis. BMC Pulmonary Medicine (2016) 16:129.





Compiled by

DR Sananta K Dash


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