Carrera 2009.

Methods	Country: Spain Design: Prospective multi‐centre double‐blind randomised controlled trial Study site: 7 tertiary hospitals Method of analysis: Results are shown as mean ± SD. Continuous and categorical variables were compared by Student t‐test and Chi2 test. Two‐way analysis of variance (ANOVA) was used to determine the statistical significance of differences between groups and over time. A P value < 0.05 was considered statistically significant. Length of hospital stay data were not normally distributed (Kolmogorov‐Smirnov test), thus Mann‐Whitney U test was performed, and median to represent central measurement of the sample and dispersion was represented as percentiles Aim: To determine whether NIV reduces the need for endotracheal intubation and enhances recovery in patients hospitalised owing to AECOPD
Participants	Eligible for study: Not reported Recruited: 75 patients with AECOPD were recruited from emergency department of 7 tertiary hospitals in Spain: 37 were randomised to NIV group and 38 to control group with sham NIV Completed: 32 participants in NIV group completed study and 5 met intubation criteria (3 were intubated and 2 were continued on NIV off protocol), whereas 25 participants in control group completed the study and 13 met intubation criteria (4 were intubated, 7 were offered NIV, and 2 continued with medical therapy) Age: NIV group: mean (SD) age = 72 (10) years; usual care group: mean (SD) age = 69 (7) years Gender: Not stated Criteria used to define COPD: Not mentioned Inclusion criteria: previous known diagnosis of COPD (not defined by study authors), with symptoms of increasing dyspnoea, cough, and/or sputum production of recent onset (last 2 weeks) in the absence of an alternate diagnosis that leads the attending physician at the emergency department to diagnose AECOPD of sufficient severity as to require hospitalisation according to the following criteria: arterial pH < 7.35 and PaCO2 > 50 mmHg 30 to 60 minutes after intensive medical management (bronchodilator, steroids, oxygen). Recruitment occurred within 24 hours after admission Exclusion criteria: Respiratory rate < 12 bpm or need for immediate intubation for cardiopulmonary resuscitation; arterial pH < 7.25; GCS > 8; administration of sedative drugs within previous 12 hours; neuromuscular disorders; thoracoplasty or kyphoscoliosis; known cause of decompensation requiring specific treatment (pneumothorax, haemoptysis, pneumonia, etc.); medical history of sleep apnoea, asthma, or any severe systemic disease; BMI > 40; facial deformity; history of acute episodes that required NIV treatment; long‐term NIV treatment; history of drug and alcohol abuse or refusal to participate
Interventions	Intervention description: Intervention delivered via NIV; all centres used same BiPAP and facial mask models (Respironics, Inc., Murrysville, PA, USA). EPAP was set at 4 cmH2O, whereas IPAP was adjusted individually to the maximum tolerated (to achieve alleviation of dyspnoea, decreased respiratory rate, and good patient‐ventilator synchrony) in assisted/controlled mode. All participants received conventional treatment with supplementary oxygen to maintain SpO2 ≥ 90%, bronchodilators, steroids, and antibiotics Control description: Sham NIV was delivered via a modified commercially available BiPAP (Respironics, Inc., Murrysville, PA, USA) to provide only controlled oxygen therapy without inspiratory pressure support. To dissipate pressure generated by the machine, investigators drilled a hole in the tube that connects the pressure generator to the patient mask and controlled FiO2 with the oxygen line through this hole, connected to a facial mask of the standard Venturi regulator (Kendall Proclinics, Barcelona, Spain). Sham device was validated and ABGs were indistinguishable from those obtained when a standard Venturi mask was used. All participants received conventional treatment with bronchodilators, steroids, and antibiotics Duration of intervention: First 3 days of hospitalisation for as much time as possible between 3 pm and 8 am for both NIV and sham NIV Intervention delivery by: In the morning (8 am to 3 pm), a respiratory specialist recruited participants and prescribed standard treatment and oxygen. The same physician visited the participant every morning (while patient was off ventilator), decided on treatment modifications, and set the timing for discharge. This physician was not involved in participant care after 3 pm From 3 pm to 8 am, a study investigator (respiratory physician) with experience in NIV, familiar with the BiPAP, who was totally independent of participant care, added BiPAP or sham BiPAP according to the randomisation scheme, and removed device from the room before 8 am the next morning Both NIVs were discontinued on day 4 of hospitalisation Setting: Respiratory ward
Outcomes	Method of outcome data collection: ABG, GCS, force spirometry at discharge, respiratory rate, heart rate, dyspnoea (visual analogue dyspnoea scale). These variables were recorded at inclusion, 1 hour after NIV, and at day 1, day 2, and day 3 Prespecified primary outcomes: Need for endotracheal intubation with presence of 1 or more of the following criteria: cardiorespiratory arrest, arterial pH < 7.20 after 30 minutes on optimal medical treatment or pH between 7.20 and 7.25 on 2 occasions 1 hour apart, pO2 < 45 mmHg despite maximum tolerated oxygen therapy, hypercapnic coma (GCS < 8). Patient fulfilling these criteria were considered failures and were excluded from the study and managed on an open‐label basis and off protocol Prespecified secondary outcomes: Speed of recovery of ABG and length of hospital stay Follow‐up period: From admission until discharge; precise number of follow‐up time points not clearly mentioned
Notes	Primary outcome was need for intubation, not actual intubation. Some participants provided with successful rescue therapy Funder: Supported in part by ABEMAR, Fundación CAUBET‐CIMERA, Programa I3SNS (Línea de Intensificación de la Investigación), SEPAR, Red Respira (ISCII,RTCI 03/11) grants, and CIBERes. These institutions were not involved in study design; in collection, analysis, and interpretation of data; in writing of the manuscript; and in the decision to submit the manuscript for publication
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The randomization scheme was generated by a computer in the coordinating center (HUSD) and sent to the participating centers using sequentially numbered, sealed, opaque envelopes"
Allocation concealment (selection bias)	Low risk	"The randomization scheme was generated by a computer in the coordinating center (HUSD) and sent to the participating centers using sequentially numbered, sealed, opaque envelopes"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo‐controlled intervention (sham NIV) used in control group
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Unclear whether outcomes assessors blinded to group allocation
Incomplete outcome data (attrition bias) All outcomes	High risk	Data analysis included off‐protocol patients; however, anyone who fulfilled the criteria for need for intubation (i.e. 'treatment failure') was excluded from the study
Selective reporting (reporting bias)	Low risk	All specified outcomes were reported
Imbalance of outcome measures at baseline All outcomes	Unclear risk	NIV group had slightly poorer PaO2 (P = 0.05), but the effect of this on study outcomes was not formally evaluated
Comparability of intervention and control group characteristics at baseline	Low risk	No statistically significant differences observed at baseline, but PaO2 levels were slightly worse (lower) in the NIV group than in the control group (P = 0.05)
Protection against contamination All outcomes	Low risk	Control group may have received the intervention, but these individuals were excluded from analyses
Selective recruitment of participants	Low risk	"Consecutive patients" were recruited
Other bias	Low risk	No other sources of bias identified