Open Lung Approach for the Acute Respiratory Distress Syndrome: A Pilot, Randomized Controlled Trial* Mechanical ventilation guided by esophageal pressure in acute lung injury. Efficacy of positive end-expiratory pressure titration after the alveolar recruitment manoeuvre in patients with acute respiratory distress syndrome A randomised controlled trial of an open lung strategy with staircase recruitment, titrated PEEP and targeted low airway pressures in patients with acute respiratory distress syndrome The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Lung recruitment in patients with the acute respiratory distress syndrome. 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. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: A randomized, controlled trial* Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials.
Objective : The open lung approach is a mechanical ventilation strategy involving lung recruitment and a decremental positive end-expiratory pressure trial . We compared the Acute Respiratory Distress Syndrome network protocol using low levels of positive end-expiratory pressure with open lung approach result ing in moderate to high levels of positive end-expiratory pressure for the management of established moderate/severe acute respiratory distress syndrome . Design : A prospect i ve , multicenter , pilot , r and omized controlled trial . Setting : A network of 20 multidisciplinary ICUs . Patients : Patients meeting the American-European Consensus Conference definition for acute respiratory distress syndrome were considered for the study . Interventions : At 12 - 36 hours after acute respiratory distress syndrome onset , patients were  assessed under st and ardized ventilator setting s ( FIO2≥0.5 , positive end-expiratory pressure ≥10 cm H2O ) . If Pao2/FIO2 ratio remained less than or equal to 200 mm Hg , patients were r and omized to open lung approach or Acute Respiratory Distress Syndrome network protocol . All patients were ventilated with a tidal volume of 4 to 8 ml/kg predicted body weight . Measurements and Main Results : From 1,874 screened patients with acute respiratory distress syndrome , 200 were r and omized : 99 to open lung approach and 101 to Acute Respiratory Distress Syndrome network protocol . Main outcome measures were 60-day and ICU mortalities , and ventilator-free days . Mortality at day-60 ( 29 % open lung approach vs. 33 % Acute Respiratory Distress Syndrome Network protocol , p = 0.18 , log rank test ) , ICU mortality ( 25 % open lung approach vs. 30 % Acute Respiratory Distress Syndrome network protocol , p = 0.53 Fisher ’s exact test ) , and ventilator-free days ( 8 [ 0 - 20 ] open lung approach vs. 7 [ 0 - 20 ] d Acute Respiratory Distress Syndrome network protocol , p = 0.53 Wilcoxon rank test ) were not significantly different . Airway driving pressure ( plateau pressure - positive end-expiratory pressure ) and PaO2/FIO2 improved significantly at 24 , 48 and 72 hours in patients in open lung approach compared with patients in Acute Respiratory Distress Syndrome network protocol . Barotrauma rate was similar in both groups . Conclusions : In patients with established acute respiratory distress syndrome , open lung approach improved oxygenation and driving pressure , without detrimental effects on mortality , ventilator-free days , or barotrauma . This pilot study supports the need for a large , multicenter trial using recruitment maneuvers and a decremental positive end-expiratory pressure trial in persistent acute respiratory distress syndrome BACKGROUND Survival of patients with acute lung injury or the acute respiratory distress syndrome ( ARDS ) has been improved by ventilation with small tidal volumes and the use of positive end-expiratory pressure ( PEEP ) ; however , the optimal level of PEEP has been difficult to determine . In this pilot study , we estimated transpulmonary pressure with the use of esophageal balloon catheters . We reasoned that the use of pleural-pressure measurements , despite the technical limitations to the accuracy of such measurements , would enable us to find a PEEP value that could maintain oxygenation while preventing lung injury due to repeated alveolar collapse or overdistention . METHODS We r and omly assigned patients with acute lung injury or ARDS to undergo mechanical ventilation with PEEP adjusted according to measurements of esophageal pressure ( the esophageal-pressure-guided group ) or according to the Acute Respiratory Distress Syndrome Network st and ard-of-care recommendations ( the control group ) . The primary end point was improvement in oxygenation . The secondary end points included respiratory-system compliance and patient outcomes . RESULTS The study reached its stopping criterion and was terminated after 61 patients had been enrolled . The ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen at 72 hours was 88 mm Hg higher in the esophageal-pressure-guided group than in the control group ( 95 % confidence interval , 78.1 to 98.3 ; P=0.002 ) . This effect was persistent over the entire follow-up time ( at 24 , 48 , and 72 hours ; P=0.001 by repeated- measures analysis of variance ) . Respiratory-system compliance was also significantly better at 24 , 48 , and 72 hours in the esophageal-pressure-guided group ( P=0.01 by repeated- measures analysis of variance ) . CONCLUSIONS As compared with the current st and ard of care , a ventilator strategy using esophageal pressures to estimate the transpulmonary pressure significantly improves oxygenation and compliance . Multicenter clinical trials are needed to determine whether this approach should be widely adopted . ( Clinical Trials.gov number , NCT00127491 . Introduction In acute respiratory distress syndrome ( ARDS ) , adequate positive end-expiratory pressure ( PEEP ) may decrease ventilator-induced lung injury by minimising overinflation and cyclic recruitment-derecruitment of the lung . We evaluated whether setting the PEEP using decremental PEEP titration after an alveolar recruitment manoeuvre ( ARM ) affects the clinical outcome in patients with ARDS . Methods Fifty-seven patients with early ARDS were r and omly assigned to a group given decremental PEEP titration following ARM or a table-based PEEP ( control ) group . PEEP  and  inspired fraction of oxygen ( FiO2 )  in the control group were set according to the table-based combinations of FiO2 and PEEP of the ARDS network , by which we aim ed to achieve a PEEP level compatible with an oxygenation target . In the decremental PEEP titration group , the oxygen saturation and static compliance were monitored as the patients performed the ARM along with the extended sigh method , which is design ed to gradually apply and withdraw a high distending pressure over a prolonged period , and the decremental titration of PEEP . Results The baseline characteristics did not differ significantly between the control and decremental PEEP titration groups . Initial oxygenation improved more in the decremental PEEP titration group than in the control group . However , dynamic compliance , tidal volume and PEEP were similar in the two groups during the first week . The duration of use of paralysing or sedative agents , mechanical ventilation , stay in the intensive care unit and mortality at 28 days did not differ significantly between the decremental PEEP titration and control groups . Conclusions The daily decremental PEEP titration after ARM showed only initial oxygenation improvement compared with the table-based PEEP method . Respiratory mechanics and patient outcomes did not differ between the decremental PEEP titration and control groups . Trial registration Clinical Trials.gov identifier : IS RCT N79027921 Introduction Tidal volume and plateau pressure minimisation are the st and ard components of a protective lung ventilation strategy for patients with acute respiratory distress syndrome ( ARDS ) . Open lung strategies , including higher positive end-expiratory pressure ( PEEP ) and recruitment manoeuvres to date have not proven efficacious . This study examines the effectiveness and safety of a novel open lung strategy , which includes permissive hypercapnia , staircase recruitment manoeuvres ( SRM ) and low airway pressure with PEEP titration . Method Twenty ARDS patients were r and omised to treatment or ARDSnet control ventilation strategies . The treatment group received SRM with decremental PEEP titration and targeted plateau pressure < 30 cm H2O . Gas exchange and lung compliance were measured daily for 7 days and plasma cytokines in the first 24 hours and on days 1 , 3 , 5 and 7 ( mean ± SE ) . Duration of ventilation , ICU stay and hospital stay ( median and interquartile range ) and hospital survival were determined . Results There were significant overall differences between groups when considering plasma IL-8 and TNF-α . For plasma IL-8 , the control group was 41 % higher than the treatment group over the seven-day period ( ratio 1.41 ( 1.11 to 1.79 ) , P = 0.01 ) , while for TNF-α the control group was 20 % higher over the seven-day period ( ratio 1.20 ( 1.01 to 1.42 ) P = 0.05 ) . PaO2/FIO2 ( 204 ± 9 versus 165 ± 9 mmHg , P = 0.005 ) and static lung compliance ( 49.1 ± 2.9 versus 33.7 ± 2.7 mls/cm H2O , P < 0.001 ) were higher in the treatment group than the control group over seven days . There was no difference in duration of ventilation ( 180 ( 87 to 298 ) versus 341 ( 131 to 351 ) hrs , P = 0.13 ) , duration of ICU stay ( 9.9 ( 5.6 to 14.8 ) versus 16.0 ( 8.1 to 19.3 ) days , P = 0.19 ) and duration of hospital stay ( 17.9 ( 13.7 to 34.5 ) versus 24.7 ( 20.5 to 39.8 ) days , P = 0.16 ) between the treatment and control groups . Conclusions This open lung strategy was associated with greater amelioration in some systemic cytokines , improved oxygenation and lung compliance over seven days . A larger trial powered to examine clinical ly-meaningful outcomes is warranted . Trial registration Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND In the acute respiratory distress syndrome ( ARDS ) , positive end-expiratory pressure ( PEEP ) may decrease ventilator-induced lung injury by keeping lung regions open that otherwise would be collapsed . Since the effects of PEEP probably depend on the recruitability of lung tissue , we conducted a study to examine the relationship between the percentage of potentially recruitable lung , as indicated by computed tomography ( CT ) , and the clinical and physiological effects of PEEP . METHODS Sixty-eight patients with acute lung injury or ARDS underwent whole-lung CT during breath-holding sessions at airway pressures of 5 , 15 , and 45 cm of water . The percentage of potentially recruitable lung was defined as the proportion of lung tissue in which aeration was restored at airway pressures between 5 and 45 cm of water . RESULTS The percentage of potentially recruitable lung varied widely in the population , accounting for a mean ( + /-SD ) of 13+/-11 percent of the lung weight , and was highly correlated with the percentage of lung tissue in which aeration was maintained after the application of PEEP ( r2=0.72 , P<0.001 ) . On average , 24 percent of the lung could not be recruited . Patients with a higher percentage of potentially recruitable lung ( greater than the median value of 9 percent ) had greater total lung weights ( P<0.001 ) , poorer oxygenation ( defined as a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ) ( P<0.001 ) and respiratory-system compliance ( P=0.002 ) , higher levels of dead space ( P=0.002 ) , and higher rates of death ( P=0.02 ) than patients with a lower percentage of potentially recruitable lung . The combined physiological variables predicted , with a sensitivity of 71 percent and a specificity of 59 percent , whether a patient 's proportion of potentially recruitable lung was higher or lower than the median . CONCLUSIONS In ARDS , the percentage of potentially recruitable lung is extremely variable and is strongly associated with the response to PEEP CONTEXT 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 . OBJECTIVE 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 . DESIGN AND SETTING R and omized 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 . PATIENTS Nine hundred eighty-three consecutive patients with acute lung injury and a ratio of arterial oxygen tension to inspired oxygen fraction not exceeding 250 . INTERVENTIONS 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 ) . MAIN OUTCOME MEASURE All-cause hospital mortality . RESULTS 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 ) . CONCLUSIONS For patients with acute lung injury and acute respiratory distress syndrome , a multifaceted protocol ized ventilation strategy design ed to recruit and open the lung result ed in no significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocol ized ventilation strategy . This " open-lung " strategy did appear to improve secondary end points related to hypoxemia and use of rescue therapies . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00182195 Objective : It has been shown in a two-center study that high positive end-expiratory pressure ( PEEP ) and low tidal volume ( LTV ) improved outcome in ARDS . However , that study involved patients with underlying diseases unique to the study area , was conducted at only two centers , and enrolled a small number of patients . We similarly hypothesized that a ventilatory strategy based on PEEP above the lower inflection point of the pressure volume curve of the respiratory system ( Pflex ) set on day 1 with a low tidal volume would result in improved outcome in patients with severe and persistent acute respiratory distress syndrome ( ARDS ) . Design : R and omized , controlled clinical trial . Setting : Network of eight Spanish multidisciplinary intensive care units ( ICUs ) under the acronym of ARIES ( Acute Respiratory Insufficiency : España Study ) . Patients : All consecutive patients admitted into participating Spanish ICUs from March 1999 to March 2001 with a diagnosis of ARDS were considered for the study . If 24 hrs after meeting ARDS criteria , the Pao2/Fio2 remained ≤200 mm Hg on st and ard ventilator setting s , patients were r and omized into two groups : control and Pflex/LTV . Interventions : In the control group , tidal volume was 9–11 mL/kg of predicted body weight ( PBW ) and PEEP ≥5 cm H2O . In the Pflex/LTV group , tidal volume was 5–8 mL/kg PBW and PEEP was set on day 1 at Pflex + 2 cm H2O . In both groups , Fio2 was set to maintain arterial oxygen saturation > 90 % and Pao2 70–100 mm Hg , and respiratory rate was adjusted to maintain Paco2 between 35 and 50 mm Hg . Measurements and Main Results : The study was stopped early based on an efficacy stopping rule as described in the methods . Of 103 patients who were enrolled ( 50 control and 53 Pflex ) , eight patients ( five in control , three in Pflex ) were excluded from the final evaluation because the r and om group assignment was not performed in one center according to protocol . Main outcome measures were ICU and hospital mortality , ventilator-free days , and nonpulmonary organ dysfunction . ICU mortality ( 24 of 45 [ 53.3 % ] vs. 16 of 50 [ 32 % ] , p = .040 ) , hospital mortality ( 25 of 45 [ 55.5 % ] vs. 17 of 50 [ 34 % ] , p = .041 )  , and ventilator-free days at day 28 ( 6.02 ± 7.95 in control and 10.90 ± 9.45 in Pflex/LTV , p = .008 ) all favored Pflex/LTV . The mean difference in the number of additional organ failures postr and omization was higher in the control group ( p < .001 ) . Conclusions : A mechanical ventilation strategy with a PEEP level set on day 1 above Pflex and a low tidal volume compared with a strategy with a higher tidal volume and relatively low PEEP has a beneficial impact on outcome in patients with severe and persistent ARDS BACKGROUND Most patients requiring mechanical ventilation for acute lung injury and the acute respiratory distress syndrome ( ARDS ) receive positive end-expiratory pressure ( PEEP ) of 5 to 12 cm of water . Higher PEEP levels may improve oxygenation and reduce ventilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention . We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients . METHODS We r and omly assigned 549 patients with acute lung injury and ARDS to receive mechanical ventilation with either lower or higher PEEP levels , which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen . RESULTS Mean ( + /-SD ) PEEP values on days 1 through 4 were 8.3+/-3.2 cm of water in the lower-PEEP group and 13.2+/-3.5 cm of water in the higher-PEEP group ( P<0.001 ) . The rates of death before hospital discharge were 24.9 percent and 27.5 percent , respectively ( P=0.48 ; 95 percent confidence interval for the difference between groups , -10.0 to 4.7 percent ) . From day 1 to day 28 , breathing was unassisted for a mean of 14.5+/-10.4 days in the lower-PEEP group and 13.8+/-10.6 days in the higher-PEEP group ( P=0.50 ) . CONCLUSIONS These results suggest that in patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water , clinical outcomes are similar whether lower or higher PEEP levels are used BACKGROUND In patients with the acute respiratory distress syndrome , massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury . We determined whether a ventilatory strategy design ed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome . METHODS We r and omly assigned 53 patients with early acute respiratory distress syndrome ( including 28 described previously ) , all of whom were receiving identical hemodynamic and general support , to conventional or protective mechanical ventilation . Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure ( PEEP ) for acceptable oxygenation , with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels ( 35 to 38 mm Hg ) . Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve , a tidal volume of less than 6 ml per kilogram , driving pressures of less than 20 cm of water above the PEEP value , permissive hypercapnia , and preferential use of pressure-limited ventilatory modes . RESULTS After 28 days , 11 of 29 patients ( 38 percent ) in the protective-ventilation group had died , as compared with 17 of 24 ( 71 percent ) in the conventional-ventilation group ( P<0.001 ) . The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group ( P=0.005 ) : the rates of clinical barotrauma were 7 percent and 42 percent , respectively ( P=0.02 ) , despite the use of higher PEEP and mean airway pressures in the protective-ventilation group . The difference in survival to hospital discharge was not significant ; 13 of 29 patients ( 45 percent ) in the protective-ventilation group died in the hospital , as compared with 17 of 24 in the conventional-ventilation group ( 71 percent , P=0.37 ) . CONCLUSIONS As compared with conventional ventilation , the protective strategy was associated with improved survival at 28 days , a higher rate of weaning from mechanical ventilation , and a lower rate of barotrauma in patients with the acute respiratory distress syndrome .  Protective ventilation was not associated with a higher rate of survival to hospital discharge RATIONALE Previous trials of higher positive end-expiratory pressure ( PEEP ) for acute respiratory distress syndrome ( ARDS ) failed to demonstrate mortality benefit , possibly because of differences in lung recruitability among patients with ARDS . OBJECTIVES To determine whether the physiological response to increased PEEP is associated with mortality . METHODS In a secondary analysis of the Lung Open Ventilation Study ( LOVS , n = 983 ) , we examined the relationship between the initial response to changes in PEEP after r and omization and mortality . We sought to corroborate our findings using data from a different trial of higher PEEP ( ExPress , n = 749 ) . MEASUREMENTS AND MAIN RESULTS The oxygenation response ( change in ratio of arterial partial pressure of oxygen to fraction of inspired oxygen : P/F ) after the initial change in PEEP after r and omization varied widely ( median , 9.5 mm Hg ; interquartile range , -16 to 47 ) and was only weakly related to baseline P/F or the magnitude of PEEP change . Among patients in whom  PEEP  was increased after r and omization , an increase in P/F was associated with reduced mortality ( multivariable logistic regression ; adjusted odds ratio , 0.80 [ 95 % confidence interval , 0.72 - 0.89 ] per 25-mm Hg increase in P/F ) , particularly in patients with severe disease ( baseline P/F [ less-than-or-equal-to ] 150 mm Hg ) . Changes in compliance and dead space were not associated with mortality . These findings were confirmed by a similar analysis of data from the ExPress trial . CONCLUSIONS Patients with ARDS who respond to increased PEEP by improved oxygenation have a lower risk of death . The oxygenation response to PEEP might be used to predict whether patients will benefit from higher versus lower PEEP
Rationale : Higher positive end‐expiratory pressure ( PEEP ) levels may reduce atelectrauma , but increase over‐distention lung injury .
Whether higher PEEP improves clinical outcomes among patients with acute respiratory distress syndrome ( ARDS ) is unclear .
Objectives : To compare clinical outcomes of mechanical ventilation strategies using higher PEEP levels versus lower PEEP strategies in patients with ARDS .