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      Multivariable fractional polynomial interaction to investigate continuous effect modifiers in a meta-analysis on higher versus lower PEEP for patients with ARDS

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          Abstract

          Objectives

          A recent individual patient data (IPD) meta-analysis suggested that patients with moderate or severe acute respiratory distress syndrome (ARDS) benefit from higher positive end-expiratory pressure (PEEP) ventilation strategies. However, thresholds for continuous variables (eg, hypoxaemia) are often arbitrary and linearity assumptions in regression approaches may not hold; the multivariable fractional polynomial interaction (MFPI) approach can address both problems. The objective of this study was to apply the MFPI approach to investigate interactions between four continuous patient baseline variables and higher versus lower PEEP on clinical outcomes.

          Setting

          Pooled data from three randomised trials in intensive care identified by a systematic review.

          Participants

          2299 patients with acute lung injury requiring mechanical ventilation.

          Interventions

          Higher (N=1136) versus lower PEEP (N=1163) ventilation strategy.

          Outcome measures

          Prespecified outcomes included mortality, time to death and time-to-unassisted breathing. We examined the following continuous baseline characteristics as potential effect modifiers using MFPI: PaO 2/FiO 2 (arterial partial oxygen pressure/ fraction of inspired oxygen), oxygenation index, respiratory system compliance (tidal volume/(inspiratory plateau pressure−PEEP)) and body mass index (BMI).

          Results

          We found that for patients with PaO 2/FiO 2 below 150 mm Hg, but above 100 mm Hg or an oxygenation index above 12 (moderate ARDS), higher PEEP reduces hospital mortality, but the beneficial effect appears to level off for patients with very severe ARDS. Patients with mild ARDS (PaO 2/FiO 2 above 200 mm Hg or an oxygenation index below 10) do not seem to benefit from higher PEEP and might even be harmed. For patients with a respiratory system compliance above 40 mL/cm H 2O or patients with a BMI above 35 kg/m 2, we found a trend towards reduced mortality with higher PEEP, but there is very weak statistical confidence in these findings.

          Conclusions

          MFPI analyses suggest a nonlinear effect modification of higher PEEP ventilation by PaO 2/FiO 2 and oxygenation index with reduced mortality for some patients suffering from moderate ARDS.

          Study registration number

          CRD42012003129.

          Related collections

          Most cited references16

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          Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.

          The need for lung protection is universally accepted, but the optimal level of positive end-expiratory pressure (PEEP) in patients with acute lung injury (ALI) or acute respiratory distress syndrome remains debated. To compare the effect on outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI. A multicenter randomized controlled trial of 767 adults (mean [SD] age, 59.9 [15.4] years) with ALI conducted in 37 intensive care units in France from September 2002 to December 2005. Tidal volume was set at 6 mL/kg of predicted body weight in both strategies. Patients were randomly assigned to a moderate PEEP strategy (5-9 cm H(2)O) (minimal distension strategy; n = 382) or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H(2)O (increased recruitment strategy; n = 385). The primary end point was mortality at 28 days. Secondary end points were hospital mortality at 60 days, ventilator-free days, and organ failure-free days at 28 days. The 28-day mortality rate in the minimal distension group was 31.2% (n = 119) vs 27.8% (n = 107) in the increased recruitment group (relative risk, 1.12 [95% confidence interval, 0.90-1.40]; P = .31). The hospital mortality rate in the minimal distension group was 39.0% (n = 149) vs 35.4% (n = 136) in the increased recruitment group (relative risk, 1.10 [95% confidence interval, 0.92-1.32]; P = .30). The increased recruitment group compared with the minimal distension group had a higher median number of ventilator-free days (7 [interquartile range {IQR}, 0-19] vs 3 [IQR, 0-17]; P = .04) and organ failure-free days (6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = .04). This strategy also was associated with higher compliance values, better oxygenation, less use of adjunctive therapies, and larger fluid requirements. A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality. However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure. clinicaltrials.gov Identifier: NCT00188058.
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            Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.

            Low-tidal-volume ventilation reduces mortality in critically ill patients with acute lung injury and acute respiratory distress syndrome. Instituting additional strategies to open collapsed lung tissue may further reduce mortality. To compare an established low-tidal-volume ventilation strategy with an experimental strategy based on the original "open-lung approach," combining low tidal volume, lung recruitment maneuvers, and high positive-end-expiratory pressure. Randomized controlled trial with concealed allocation and blinded data analysis conducted between August 2000 and March 2006 in 30 intensive care units in Canada, Australia, and Saudi Arabia. Nine hundred eighty-three consecutive patients with acute lung injury and a ratio of arterial oxygen tension to inspired oxygen fraction not exceeding 250. The control strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau airway pressures not exceeding 30 cm H2O, and conventional levels of positive end-expiratory pressure (n = 508). The experimental strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau pressures not exceeding 40 cm H2O, recruitment maneuvers, and higher positive end-expiratory pressures (n = 475). All-cause hospital mortality. Eighty-five percent of the 983 study patients met criteria for acute respiratory distress syndrome at enrollment. Tidal volumes remained similar in the 2 groups, and mean positive end-expiratory pressures were 14.6 (SD, 3.4) cm H2O in the experimental group vs 9.8 (SD, 2.7) cm H2O among controls during the first 72 hours (P < .001). All-cause hospital mortality rates were 36.4% and 40.4%, respectively (relative risk [RR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .19). Barotrauma rates were 11.2% and 9.1% (RR, 1.21; 95% CI, 0.83-1.75; P = .33). The experimental group had lower rates of refractory hypoxemia (4.6% vs 10.2%; RR, 0.54; 95% CI, 0.34-0.86; P = .01), death with refractory hypoxemia (4.2% vs 8.9%; RR, 0.56; 95% CI, 0.34-0.93; P = .03), and previously defined eligible use of rescue therapies (5.1% vs 9.3%; RR, 0.61; 95% CI, 0.38-0.99; P = .045). For patients with acute lung injury and acute respiratory distress syndrome, a multifaceted protocolized ventilation strategy designed to recruit and open the lung resulted in no significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocolized ventilation strategy. This "open-lung" strategy did appear to improve secondary end points related to hypoxemia and use of rescue therapies. clinicaltrials.gov Identifier: NCT00182195.
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              • Article: not found

              Dangers of using "optimal" cutpoints in the evaluation of prognostic factors.

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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2016
                8 September 2016
                : 6
                : 9
                : e011148
                Affiliations
                [1 ]Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel , Basel, Switzerland
                [2 ]Institute of Medical Biometrics and Medical Informatics, Freiburg University Medical Centre , Freiburg, Germany
                [3 ]MRC Clinical Trials Unit, Hub for Trials Methodology Research , University College London , London, UK
                [4 ]University Hospital Angers , Angers, France
                [5 ]Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital; & University of Toronto , Toronto, Ontario, Canada
                [6 ]Institute for Clinical Epidemiology and Biostatistics, McMaster University , Hamilton, Ontario, Canada
                [7 ]Keenan Research Centre for Biomedical Science of St. Michael's Hospital , Toronto, Ontario, Canada
                [8 ]Interdepartmental Division of Critical Care Medicine, University of Toronto , Toronto, Ontario, Canada
                [9 ]Emergency and Intensive Care Department, General Hospital Annecy France, INSERM Unit 955 Eq13 , Paris, France
                [10 ]Niagara Health System , St. Catharines, Ontario, Canada
                Author notes
                [Correspondence to ] Dr Benjamin Kasenda; benjamin.kasenda@ 123456gmail.com
                Article
                bmjopen-2016-011148
                10.1136/bmjopen-2016-011148
                5020750
                27609843
                3f7826a7-25ba-42d7-bc9d-b4806119535e
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 13 January 2016
                : 30 May 2016
                : 18 July 2016
                Categories
                Intensive Care
                Research
                1506
                1707
                1731

                Medicine
                ards,acute lung injury,treatment interaction,multivariable fractional polynomials,ipd meta-analysis

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