Abstract

Editor’s Perspective
What We Already Know about This Topic

Obesity increases the propensity to atelectasis in acute respiratory distress syndrome, but the optimal approach to reversing this atelectasis is uncertain

What This Article Tells Us That Is New

A clinical crossover study comparing three approaches to titrate positive end-expiratory pressure (PEEP; according to a fixed table, according to end-expiratory esophageal pressure, and targeting the best compliance during a decremental PEEP trial) found that a recruitment maneuver followed by decremental PEEP minimized atelectasis and overdistension, and best restored compliance and oxygenation without causing hemodynamic impairment

Background

Obese patients are characterized by normal chest-wall elastance and high pleural pressure and have been excluded from trials assessing best strategies to set positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome (ARDS). The authors hypothesized that severely obese patients with ARDS present with a high degree of lung collapse, reversible by titrated PEEP preceded by a lung recruitment maneuver.

Methods

Severely obese ARDS patients were enrolled in a physiologic crossover study evaluating the effects of three PEEP titration strategies applied in the following order: (1) PEEPARDSNET: the low PEEP/Fio2 ARDSnet table; (2) PEEPINCREMENTAL: PEEP levels set to determine a positive end-expiratory transpulmonary pressure; and (3) PEEPDECREMENTAL: PEEP levels set to determine the lowest respiratory system elastance during a decremental PEEP trial following a recruitment maneuver on respiratory mechanics, regional lung collapse, and overdistension according to electrical impedance tomography and gas exchange.

Results

Fourteen patients underwent the study procedures. At PEEPARDSNET (13 ± 1 cm H2O) end-expiratory transpulmonary pressure was negative (−5 ± 5 cm H2O), lung elastance was 27 ± 12 cm H2O/L, and PaO2/Fio2 was 194 ± 111 mmHg. Compared to PEEPARDSNET, at PEEPINCREMENTAL level (22 ± 3 cm H2O) lung volume increased (977 ± 708 ml), lung elastance decreased (23 ± 7 cm H2O/l), lung collapse decreased (18 ± 10%), and ventilation homogeneity increased thus rising oxygenation (251 ± 105 mmHg), despite higher overdistension levels (16 ± 12%), all values P < 0.05 versus PEEPARDSnet. Setting PEEP according to a PEEPDECREMENTAL trial after a recruitment maneuver (21 ± 4 cm H2O, P = 0.99 vs. PEEPINCREMENTAL) further lowered lung elastance (19 ± 6 cm H2O/l) and increased oxygenation (329 ± 82 mmHg) while reducing lung collapse (9 ± 2%) and overdistension (11 ± 2%), all values P < 0.05 versus PEEPARDSnet and PEEPINCREMENTAL. All patients were maintained on titrated PEEP levels up to 24 h without hemodynamic or ventilation related complications.

Conclusions

Among the PEEP titration strategies tested, setting PEEP according to a PEEPDECREMENTAL trial preceded by a recruitment maneuver obtained the best lung function by decreasing lung overdistension and collapse, restoring lung elastance, and oxygenation suggesting lung tissue recruitment.

ACUTE respiratory distress syndrome (ARDS) is associated with high morbidity and mortality.1  The introduction of lung protective ventilation with a low tidal volume and low airway pressure in patients with ARDS has been shown to improve patient survival.2  Strategies aimed at minimizing alveolar collapse by transiently increasing airway pressure with a recruitment maneuver and titration of positive end-expiratory pressure (PEEP) to optimal respiratory system compliance have failed to provide consistent results.3,4  The use of recruitment maneuvers and high PEEP levels (open lung approach) have been advocated to reestablish lung volume and prevent cyclic opening and closing of small airways while avoiding increases in lung strain.5–8  However, all ARDS patients may not have recruitable lungs,9  making it difficult to predict those patients that benefit most from an open lung approach.

In intubated and mechanically ventilated morbidly obese patients, the chest-wall elastance is not altered.10,11  However, due to the “mass loading” effect of the mass of the thoracoabdominal structures pleural pressure is increased and the chest-wall pressure-volume curve is right-shifted leading to decreased transpulmonary pressure, reduced functional residual capacity, high lung elastance, and formation of atelectasis.10,12  However, the slope of the pressure-volume curve remains essentially unchanged.10  Recent physiologic studies showed that a negative end-expiratory transpulmonary pressure is responsible for alveolar collapse in obese patients.13  In non-ARDS obese patients, setting PEEP to establish a positive end-expiratory transpulmonary pressure is not by itself sufficient to restore lung volume and lung mechanics. However, lung volume and lung mechanics can be optimized by applying lung recruitment maneuvers and then setting PEEP by decremental PEEP trial at the best respiratory system elastance.11 

A body mass index exceeding 35 kg/m2 is a common exclusion criterion in large clinical trials evaluating PEEP in ARDS.14–16  Although a post hoc analysis of the ALVEOLI study demonstrated that obese patients with a body mass index between 30 and 35 kg/m2 assigned to a high PEEP experienced lower mortality compared with those assigned to a low PEEP (18% vs. 32%; P = 0.04), however, severely obese patients (body mass index greater than 35 kg/m2) were not studied.17  The absence of physiologic studies and clinical trials to guide optimal ventilation management in this subset of ARDS patients is particularly worrisome considering that, recently, obesity has become a major health care concern in the United States. Nationally, nearly 38% of adults are obese and 8% have a body mass index greater than 40 kg/m2.18  Large observational studies reported that, among ventilated patients admitted to the intensive care unit, obese patients are much more likely to develop ARDS than nonobese patients.19,20 

We hypothesized that lungs of severely obese patients with ARDS are highly recruitable and that a recruitment maneuver would improve lung mechanics, distribution of ventilation, dead space fraction and oxygenation while avoiding lung overdistention. To test our hypothesis, we designed a clinical crossover physiologic study in severely obese patients (body mass index greater than 35 kg/m2) with ARDS. PEEP strategies evaluated included the low PEEP/Fio2 ARDSnet table,2  PEEP titration to positive end-expiratory transpulmonary pressure without lung recruitment,21  and PEEP titration to the best respiratory system elastance after a recruitment maneuver.22 

Materials and Methods

The study was approved by the Massachusetts General Hospital Institutional Review Board (Boston, Massachusetts; IRB No. 2015P001515) and registered on Clinical Trials (NCT02503241).

Study Population

From April 1, 2016 to July 30, 2017 severely obese adult patients (body mass index greater than 35 kg/m2) admitted to the Medical or Surgical intensive care units of the Massachusetts General Hospital (Boston, Massachusetts) entered the study after written informed consent was obtained. Among patients enrolled in the study, those meeting the Berlin criteria for ARDS23  were included in the present analysis.

Study Procedures

After assessing proper sedation level patients were paralyzed by administration of 0.2 mg/kg of cisatracurium besylate. Patients were ventilated in volume-controlled ventilation at 6 ml/kg of predicted body weight, Fio2 and respiratory rate were maintained as set per clinical management to maintain Spo2 = 88 to 95% and Paco2 less than 50 mmHg, inspiratory to expiratory ratio was set at 1:2 with 0.3 s of inspiratory pause time.

The study protocol had three phases, always performed in the following order (fig. 1):

Fig. 1.

Study protocol maneuvers. The image illustrates the positive end-expiratory pressure (PEEP) levels applied over time during the study protocol. After measurements were obtained at the PEEP level, determined according to the low PEEP/high Fio2 table (PEEPARDSnet), stepwise increases in PEEP by 2 cm H2O every 60 s were performed during the PEEPINCREMENTAL trial in order to reach +2 cm H2O end expiratory transpulmonary pressure ([PLE] (PEEPINCREMENTAL). After a recruitment maneuver a PEEPDECREMENTAL trial was performed by stepwise decrease in PEEP by 2 cm H2O every 60 s. After the second recruitment maneuver, PEEP was set at the level determining the lowest respiratory system elastance during the PEEPDECREMENTAL trial (PEEPDECREMENTAL). All study procedures were performed in volume-controlled ventilation (tidal volume = 6 ml/kg predicted body weight), recruitment maneuvers were performed in pressure-controlled ventilation (driving pressure = 10 cm H2O).

Fig. 1.

Study protocol maneuvers. The image illustrates the positive end-expiratory pressure (PEEP) levels applied over time during the study protocol. After measurements were obtained at the PEEP level, determined according to the low PEEP/high Fio2 table (PEEPARDSnet), stepwise increases in PEEP by 2 cm H2O every 60 s were performed during the PEEPINCREMENTAL trial in order to reach +2 cm H2O end expiratory transpulmonary pressure ([PLE] (PEEPINCREMENTAL). After a recruitment maneuver a PEEPDECREMENTAL trial was performed by stepwise decrease in PEEP by 2 cm H2O every 60 s. After the second recruitment maneuver, PEEP was set at the level determining the lowest respiratory system elastance during the PEEPDECREMENTAL trial (PEEPDECREMENTAL). All study procedures were performed in volume-controlled ventilation (tidal volume = 6 ml/kg predicted body weight), recruitment maneuvers were performed in pressure-controlled ventilation (driving pressure = 10 cm H2O).

  1. PEEP titrated according to the low PEEP/Fio2ARDSnet table2 : (PEEPARDSnet).

  2. Pleural pressure targeted-incremental PEEP (PEEPINCREMENTAL): PEEP progressively increased by 2 cm H2O every 60 s until the end-expiratory transpulmonary pressure equaled 0 to 2 cm H2O representing the optimal incremental PEEP.21 

  3. Optimal Decremental PEEP (PEEPDECREMENTAL): A recruitment maneuver was performed in pressure control ventilation, driving pressure of 10 cm H2O, by stepwise increase in PEEP 5 cm H2O every 30 s targeting a maximum plateau pressure of 50 cm H2O held for 1 min (see Supplemental Digital Content 1, http://links.lww.com/ALN/B878, for details). Following the recruitment maneuver, a PEEPDECREMENTAL trial was performed in volume-controlled ventilation starting at a PEEP level that maintained the plateau pressure less than 50 cm H2O and by decreasing PEEP by 2 cm H2O every 60 s. The PEEP level resulting in the lowest respiratory system elastance identified the optimal PEEPDECREMENTAL.22 

Measurements.

All measurements during PEEPARDSnet, PEEPINCREMENTAL, and PEEPDECREMENTAL were performed at steady state after 10 to 15 min on stable ventilatory settings.24 

Respiratory Mechanics.

A nasogastric tube with esophageal balloon was inserted (AVEA Ventilator Nasogastric Pressure Monitoring Tube Set; CareFusion, USA), and balloon positioning and inflation volume were verified25,26  (see Supplemental Digital Content 1, http://links.lww.com/ALN/B878, and Supplemental Digital Content 2, figure E1, http://links.lww.com/ALN/B879, for details). Airway pressure, flow, esophageal pressure, and capnogram were continuously recorded. To measure the changes in intrathoracic pressures and lung volumes within a breathing cycle a resampling and interpolation process was used and a single “average” respiratory cycle was obtained for each patient at different ventilatory settings. Airway and esophageal pressures at end-inspiration and at end-expiration were obtained at zero flow. Tidal volume was calculated as the integral of the expiratory flow-time waveform.

To describe lung mechanics at different ventilatory settings, absolute esophageal pressure at end-inspiration and end-expiration (after optimizing balloon volume) were recorded and used to calculate lung and chest-wall elastance. As recently reported27  we used the difference between airway opening pressure (PAW) and esophageal pressure (PES) at end expiration to calculate end-expiratory transpulmonary pressure (PLE), reflecting transpulmonary pressure (PL) in the middle to dependent regions of the lung:

 
formula

To determine alveolar tidal stretch at each breath, driving PL was computed as:

 
formula

To describe the contribution of resistive forces on lung mechanics at decreasing lung volumes, airways resistance was calculated by quasi static measurement at the three PEEP study steps while the least square fitting method28  was used throughout the PEEPDECREMENTAL trial to minimize interference with electrical impedance tomography acquisition measurements. Intraabdominal hypertension was excluded by measuring bladder pressure less than 12 cm H2O before initiation of study procedures.29 

Gas Exchange.

Blood gas samples were obtained after ventilating patients for 10 to 15 min at 100% Fio2 with PEEPARDSnet, PEEPINCREMENTAL and PEEPDECREMENTAL. To measure the effects of PEEP on dead space, volumetric capnography was continuously recorded (Respironics NM3; Philips, USA).30  Physiologic dead space was calculated by applying the Enghoff modification of the Bohr equation. Anatomic and alveolar dead-space volumes were determined by calculating the expired gas volume until the inflection point of phase II was reached in the volumetric capnogram.31 

Electrical Impedance Tomography Lung Imaging.

Electrical impedance tomography (Enlight 1800; Timpel SA, Brazil) is a noninvasive, radiation-free, real-time imaging method that measures global and regional changes in lung volumes.32  Lung collapse and overdistension percentages were determined by comparing each electrical impedance tomography pixel-compliance during PEEPARDSnet, PEEPINCREMENTAL, and PEEPDECREMENTAL ventilation.33  Each pixel-compliance was determined by dividing tidal impedance change by the variation in pressure during the respiratory cycle. Therefore, overdistension was identified when, for a given pixel, aeration increased and compliance worsened. On the other hand, reversal of collapse was identified if aeration increased and compliance improved. To compare lung morphology between the PEEP levels obtained during the PEEPINCREMENTAL and PEEPDECREMENTAL titration, all measurement were referenced to the best pixel-compliance obtained during the PEEPDECREMENTAL trial after the recruitment maneuver since the recruitment maneuver allows the measurement of ventilation distribution in all the recruitable pixels. The lung images were divided in four regions, each covering 25% of the ventrodorsal lung area (Supplement Digital Content 2, figure E2, http://links.lww.com/ALN/B879). Homogeneity of ventilation was expressed as percentage of tidal ventilation directed to each region. Changes in end-expiratory lung volume were calculated from changes in end-expiratory lung impedance after linear transformation to volume, expressed in milliliters.34 

Radiologic Imaging.

Routine portable chest radiographs performed within 24 h before and 24 h after the study protocol were reviewed by a board-certified fellowship-trained thoracic radiologist (F.J.F.) blinded to the order of image acquisition. The radiologist evaluated difference in lung volumes based on the number of visible posterior ribs, overinflation defined as flattening of the hemidiaphragms, and presence of atelectasis. The presence of barotrauma (pneumothorax, pneumomediastinum) was also assessed.

Statistical Analysis

We anticipated enrolling 14 patients in this two-treatment crossover study based on an expected decrease in lung elastance of 1.7 ± 1.8 cm H2O/l11 at PEEPDECREMENTALversus PEEPINCREMENTAL, with a power of 90% and a two-sided 0.05 significance level.

The Shapiro–Wilk test was used to assess normality of continuous variables. Data are expressed as mean ± SD or median [interquartile range] as appropriate. Categorical variables are expressed as count (n) and proportion (%). Continuous variables were compared by one-way ANOVA for repeated measure, and whenever a difference between groups was detected, intergroup comparison was performed with paired Student’s t tests. For nonnormally distributed variables, one-way ANOVA for repeated measure on ranks was performed. Post hoc Bonferroni correction was applied for multiple comparisons. Statistical significance was defined as P < 0.05 (two-tailed). Statistical analysis was performed by using SigmaPlot 11.0 software (Systat Software Inc, USA).

Please refer to online Supplemental Digital Content 1, http://links.lww.com/ALN/B878, and Supplemental Digital Content 2, http://links.lww.com/ALN/B879, for details about: inclusion and exclusion criteria, procedures, and data analysis.

Results

Among patients admitted to the participating intensive care units during the study period and requiring mechanical ventilation lasting longer than 24 h (N = 1,053), 117 patients had a body mass index greater than 35 kg/m2. Among the latter cohort, 30 patients met the inclusion criteria, 28 patients were approached to obtain consent (2 patients excluded for logistical reasons), and 24 patients were enrolled and completed the study procedures. Fourteen severely obese patients (body mass index = 58.6 ± 11.0 kg/m2) matched the Berlin definition criteria for ARDS diagnosis. The population characteristics are summarized in table 1 (see Supplemental Digital Content 2, table E1, http://links.lww.com/ALN/B879, for additional details).

Table 1.

Characteristics of the Patients

Characteristics of the Patients
Characteristics of the Patients

At screening, within 6 h after the start of mechanical ventilation, patients were hypoxemic (Pao2/Fio2 = 150 ± 81) on a PEEP greater than or equal to 5 cm H2O and met the Berlin criteria for ARDS. The intensive care unit team treated the patients according to the ARDSnet lung protective ventilation strategy: volume-controlled ventilation with tidal volume 6 ± 1 ml/kg predicted body weight. Selected PEEPARDSnet (13 ± 1 cm H2O) improved Pao2/Fio2 to 194 ± 111 from screening while maintaining plateau pressure less than 28 cm H2O (table 2). A respiratory rate of 26 ± 5 breaths per minute was necessary to maintain normocapnia. In 7 out of 14 patients, ARDS second line therapies were instituted to treat either patients’ uncontrolled respiratory drive or refractory hypoxemia (table 1). Prone positioning was never attempted because it was considered unsafe due to patients’ body habitus and hemodynamic instability. In four patients, extracorporeal membrane oxygenation support was discussed as rescue therapy by the intensive care unit team but initiation of extracorporeal membrane oxygenation was declined due to severe obesity and difficulties associated with cannula placement.

Table 2.

Ventilator Settings, Respiratory Mechanics, Hemodynamic, Gas Exchange

Ventilator Settings, Respiratory Mechanics, Hemodynamic, Gas Exchange
Ventilator Settings, Respiratory Mechanics, Hemodynamic, Gas Exchange

Computed tomography scans of the chest were performed in three patients before the study procedures to rule out pulmonary embolism. Representative images are displayed in Supplement Digital Content 2, figure E3, http://links.lww.com/ALN/B879, showing bilateral parenchymal ground-glass and consolidative opacities with an anteroposterior density gradient characteristic of ARDS.

After consent was obtained, study procedures were started on average 1 [range 0 - 4] day after the initiation of mechanical ventilation. No data was missing on any patient unless specifically reported.

Both PEEP Titration Techniques (PEEPINCREMENTALvs. PEEPDECREMENTAL) Identified Similar Optimal PEEP Levels, Higher than the PEEPARDSnet

The PEEP titration technique did not affect the measured value of end-expiratory transpulmonary pressure (Supplement Digital Content 2, fig. E4, http://links.lww.com/ALN/B879). There was no difference in the titrated PEEP levels obtained: 22 ± 3 cm H2O and 21 ± 4 cm H2O (PEEPINCREMENTALvs. PEEPDECREMENTAL respectively), determining an end-expiratory transpulmonary pressure 1 ± 4 cm H2O and 1 ± 4 cm H2O (PEEPINCREMENTALvs. PEEPDECREMENTAL respectively). At PEEPARDSnet level, the end-expiratory transpulmonary pressure was −5 ± 5 cm H2O (table 2).

Compared to PEEPARDSnet, Titrated PEEP Levels Improved Lung Mechanics by Lowering Driving Pressure, and Increasing End-expiratory Lung Volume and Oxygenation

At PEEPARDSnet, study patients had increased respiratory system elastance, lung elastance and poor oxygenation. Compared to PEEPARDSnet level, lung elastance decreased at PEEPINCREMENTAL level and further decreased after a recruitment maneuver and a PEEPDECREMENTAL trial. At PEEPDECREMENTAL level after a recruitment maneuver, the improvement in respiratory mechanics was mainly attributable to a decrease in lung elastance (fig. 2; table 2). Accordingly, setting PEEP at optimal PEEPDECREMENTAL after a recruitment maneuver resulted in the lowest airways and transpulmonary driving pressure (table 2; fig. 3).

Fig. 2.

Lung mechanics during a positive end-expiratory pressure (PEEP)INCREMENTAL and a PEEPDECREMENTAL trial. Elastance of the respiratory system (ERS), lung (EL), and chest-wall (ECW) through at stepwise increase in PEEP (PEEPINCREMENTAL trial) and stepwise decrease in PEEP after a recruitment maneuver (PEEPDECREMENTAL trial). PEEPINCREMENTAL trial is represented on the left side of the figure while the PEEPDECREMENTAL trial is represented on the right side of the figure. During both the incremental and decremental trial, PEEP settings began on the left and proceeded to the right of each figure. The PEEP levels during the PEEPINCREMENTAL trial are expressed as relative value to the PEEP level at which each patient reached an end-expiratory transpulmonary pressure between 0 and 2 cm H2O (PEEPINCREMENTAL). The PEEP levels during the PEEPDECREMENTAL trial are expressed as relative value to the PEEP level at which each patient reached the lowest ERS (PEEPDECREMENTAL). Data are expressed as mean ± SD.

Fig. 2.

Lung mechanics during a positive end-expiratory pressure (PEEP)INCREMENTAL and a PEEPDECREMENTAL trial. Elastance of the respiratory system (ERS), lung (EL), and chest-wall (ECW) through at stepwise increase in PEEP (PEEPINCREMENTAL trial) and stepwise decrease in PEEP after a recruitment maneuver (PEEPDECREMENTAL trial). PEEPINCREMENTAL trial is represented on the left side of the figure while the PEEPDECREMENTAL trial is represented on the right side of the figure. During both the incremental and decremental trial, PEEP settings began on the left and proceeded to the right of each figure. The PEEP levels during the PEEPINCREMENTAL trial are expressed as relative value to the PEEP level at which each patient reached an end-expiratory transpulmonary pressure between 0 and 2 cm H2O (PEEPINCREMENTAL). The PEEP levels during the PEEPDECREMENTAL trial are expressed as relative value to the PEEP level at which each patient reached the lowest ERS (PEEPDECREMENTAL). Data are expressed as mean ± SD.

Fig. 3.

Oxygenation and driving pressure. Oxygenation (arterial partial pressure of oxygen to inspired fraction of oxygen ratio) and respiratory system stress as airway driving pressure are represented at the three time-points of the study protocol. The stepwise increase in oxygenation together with the decrease in driving pressure are indicative of progressive lung recruitment. Setting positive end-expiratory pressure (PEEP) according to a PEEPDECREMENTAL trial after a recruitment maneuver obtains the highest oxygenation and represents the most protective lung ventilation strategy. *P < 0.05 vs. PEEPARDSnet; #P < 0.05 vs. PEEPINCREMENTAL. Data are expressed as mean ± SD.

Fig. 3.

Oxygenation and driving pressure. Oxygenation (arterial partial pressure of oxygen to inspired fraction of oxygen ratio) and respiratory system stress as airway driving pressure are represented at the three time-points of the study protocol. The stepwise increase in oxygenation together with the decrease in driving pressure are indicative of progressive lung recruitment. Setting positive end-expiratory pressure (PEEP) according to a PEEPDECREMENTAL trial after a recruitment maneuver obtains the highest oxygenation and represents the most protective lung ventilation strategy. *P < 0.05 vs. PEEPARDSnet; #P < 0.05 vs. PEEPINCREMENTAL. Data are expressed as mean ± SD.

Compared to PEEPARDSnet lung volume increased similarly at PEEPINREMENTAL and PEEPDECREMENTAL levels (table 2).

Arterial oxygenation increased at titrated PEEPINCREMENTAL and further improved at titrated PEEPDECREMENTAL after a recruitment maneuver (fig. 3). Dead space fraction was not affected by either titrated PEEP method (table 2).

During the PEEPDECREMENTAL trial, airway resistance increased as PEEP decreased (fig. 4).

Fig. 4.

Airways resistance.  Airways resistance (RAW) throughout a positive end-expiratory pressure (PEEP)DECREMENTAL trial preceded by a recruitment maneuver: RAW increase as the lung volume decreases due to the decreasing levels of PEEP. The PEEP levels during the PEEPDECREMENTAL trial are expressed as relative value to the PEEP level at which each patient reached the lowest lung elastence (EL) (PEEPDECREMENTAL). Data are expressed as mean ± SD.

Fig. 4.

Airways resistance.  Airways resistance (RAW) throughout a positive end-expiratory pressure (PEEP)DECREMENTAL trial preceded by a recruitment maneuver: RAW increase as the lung volume decreases due to the decreasing levels of PEEP. The PEEP levels during the PEEPDECREMENTAL trial are expressed as relative value to the PEEP level at which each patient reached the lowest lung elastence (EL) (PEEPDECREMENTAL). Data are expressed as mean ± SD.

Titrated PEEP Levels Improved Homogeneity of Ventilation Compared to PEEPARDSnet by Minimizing Alveolar Collapse and Overdistension

Compared to PEEPARDSnet, titrated PEEP levels decreased the amount of lung collapse as measured by electrical impedance tomography, with PEEPDECREMENTAL after a recruitment maneuver more beneficial than the PEEPINCREMENTAL strategy (fig. 5A). Conversely the percentage of lung overdistension increased at titrated PEEPINCREMENTAL levels while remaining unchanged at titrated PEEPDECREMENTAL levels after a recruitment maneuver when compared to PEEPARDSnet (fig. 5B). Titrated PEEP levels diverted tidal ventilation to the most dorsal regions of the lung (fig. 5C).

Fig. 5.

Lung collapse, overdistension, and distribution of ventilation measured by the electrical impedance tomography technique at the three time-points of the study protocol. Lung collapse decreases at positive end-expiratory pressure (PEEP)INCREMENTAL levels compared to PEEPARDSnet levels and further decreases at PEEPDECREMENTAL levels after a recruitment maneuver. Lung overdistension increases at PEEPINCREMENTAL levels compared to PEEPARDSnet, while it is unaltered at PEEPDECREMENTAL levels after a recruitment maneuver. Distribution of ventilation is represented as percentage of the tidal volume distributed to four lung regions of interest (ROI), each one covering 25% of total lung volume (ROI 1 to 4 corresponds to the most nondependent to the most dependent areas of the lung). Both PEEPINCREMENTAL and PEEPDECREMENTAL levels redistribute tidal ventilation to the most dependent areas of the lung. *P < 0.05 vs. PEEPARDSnet; # means P < 0.05 vs. PEEPINCREMENTAL. Data are expressed as single values from each patient (lung collapse and overdistension) and mean ± SD.

Fig. 5.

Lung collapse, overdistension, and distribution of ventilation measured by the electrical impedance tomography technique at the three time-points of the study protocol. Lung collapse decreases at positive end-expiratory pressure (PEEP)INCREMENTAL levels compared to PEEPARDSnet levels and further decreases at PEEPDECREMENTAL levels after a recruitment maneuver. Lung overdistension increases at PEEPINCREMENTAL levels compared to PEEPARDSnet, while it is unaltered at PEEPDECREMENTAL levels after a recruitment maneuver. Distribution of ventilation is represented as percentage of the tidal volume distributed to four lung regions of interest (ROI), each one covering 25% of total lung volume (ROI 1 to 4 corresponds to the most nondependent to the most dependent areas of the lung). Both PEEPINCREMENTAL and PEEPDECREMENTAL levels redistribute tidal ventilation to the most dependent areas of the lung. *P < 0.05 vs. PEEPARDSnet; # means P < 0.05 vs. PEEPINCREMENTAL. Data are expressed as single values from each patient (lung collapse and overdistension) and mean ± SD.

During the PEEPDECREMENTAL trial after a recruitment maneuver lung collapse started at approximately 4 ± 3 cm H2O end-expiratory transpulmonary pressure and increased the more end-expiratory transpulmonary pressure decreased (fig. 6). The crossing of the lines in figure 5 represents the PEEP level during the PEEPDECREMENTAL trial where collapse and overdistension were essentially equal. This occurred at an end-expiratory transpulmonary pressure of about +1 cm H2O.

Fig. 6.

Transpulmonary pressure and lung morphology. Percentage of lung collapse (empty circles) and overdistension (squares) during the positive end-expiratory pressure (PEEP)DECREMENTAL trials. End-expiratory transpulmonary pressure (PLE) at each PEEP step is represented at the bottom of the graph. Lung collapse starts at ≈ 3.6 ± 0.9 cmH2O PLE. The PEEP levels during the PEEPDECREMENTAL trial are expressed as relative value to the PEEP level at which each patient reached the lowest respiratory system elastance (PEEPDECREMENTAL). Data are expressed as mean ± SD.

Fig. 6.

Transpulmonary pressure and lung morphology. Percentage of lung collapse (empty circles) and overdistension (squares) during the positive end-expiratory pressure (PEEP)DECREMENTAL trials. End-expiratory transpulmonary pressure (PLE) at each PEEP step is represented at the bottom of the graph. Lung collapse starts at ≈ 3.6 ± 0.9 cmH2O PLE. The PEEP levels during the PEEPDECREMENTAL trial are expressed as relative value to the PEEP level at which each patient reached the lowest respiratory system elastance (PEEPDECREMENTAL). Data are expressed as mean ± SD.

On chest radiograph, low lung volumes were present in 10 out of 14 patients prior to intervention and lung volumes increased in all cases after the intervention by 0.7 [0.2; 1.1] intercostal spaces on average. One postintervention chest radiograph demonstrated mild overinflation (Supplement Digital Content 2, table E2 and fig. E5, http://links.lww.com/ALN/B879).

Titrated PEEP Levels Were Hemodynamically Well Tolerated and Did Not Cause Any Adverse Events

All patients completed the entire study procedures and were ventilated at titrated PEEPDECREMENTAL level for at least 24 h after the study procedures.

At the time of the study procedures nine patients were on vasopressors. Despite the increased level of intrathoracic pressure at titrated PEEP (about 9 cm H2O on average), none of the nine patients required increased vasopressors infusion within 24 h after the study. The remaining five patients remained hemodynamically stable without any requirement of vasopressor drugs neither at the time of the study procedures nor in the following 24 h.

The 24-h fluid balance after the end of the study procedures was negative (less than −1,000 ml) in four patients, even (between −1,000 and +1,000 ml) in seven patients and positive (greater than +1,000 ml) in three patients. During this time period, only one patient received fluid boluses (i.e., 500 ml crystalloids or 250 ml 5% albumin). The fluid boluses were administered for new onset atrial fibrillation (total 24-h fluid balance: +1,300 ml). The arrhythmia resolved within 10 h after amiodarone infusion. For the remaining two patients, the positive fluid balance was secondary to anuria which developed before the study procedures.

Chest radiograph performed within 24 h after the study procedures did not show barotrauma.

Discussion

The main findings of this study are that in severely obese patients with an early diagnosis of ARDS: (1) titration of PEEP according to the low PEEP/Fio2 ARDSnet table is associated with low Pao2/Fio2 levels, lung atelectasis, and nonhomogeneous ventilation; (2) reversible lung collapse contributes substantially to respiratory failure in morbidly obese patients; (3) lung recruitment maneuvers are required to reverse alveolar collapse, despite the use of sufficient PEEP to establish a positive end-expiratory transpulmonary pressure; and (4) setting PEEP by a PEEPDECREMENTAL trial after a recruitment maneuver improves lung mechanics, lung volumes, and oxygenation, minimizing reversible lung collapse and overdistension more than the same PEEP level without lung recruitment.

Since its introduction, the ARDSnet table became synonymous with lung protective ventilation. However, an improved understanding of driving pressure and regional lung ventilation has resulted in an appreciation of the complexity of lung protective ventilation in ARDS, leading us to question a “one-size-fits-all” approach (PEEP/Fio2 table). In the present physiologic study, PEEP levels of obese patients with ARDS were all initially titrated according to the ARDSnet low PEEP/Fio2 table, which resulted in severely low Pao2/Fio2 levels, impaired lung elastance, and nonhomogeneous distribution of ventilation directed mostly to the nondependent regions of the lung, and elevated driving pressure. All study patients met the ARDS Berlin definition. Due to severe refractory hypoxemia and elevated driving pressure, second line therapies were initiated in 7 of the 14 patients, including paralysis and inhaled pulmonary vasodilators. Extracorporeal life support was declined by the cardiac surgery consult team in four patients for technical reasons.

By using the absolute pressure information from an esophageal balloon, we increased PEEP to 9 cmH2O above PEEPARDSnet, targeting an end-expiratory transpulmonary pressure in between 0 and 2 cm H2O (PEEPINCREMENTAL). This maneuver quickly improved oxygenation, respiratory mechanics and reduced driving pressures, confirming the benefits of this strategy, as previously reported by Talmor et al.21  Finally, we demonstrated that a recruitment maneuver followed by a PEEPDECREMENTAL trial based on best respiratory system elastance (i.e., not using esophageal pressure) resulted in equivalent levels of “optimum” PEEP as the PEEPINCREMENTAL approach, but further benefited oxygenation and lung mechanics. When comparing PEEPINCREMENTALversus PEEPDECREMENTAL, we observed additional recruitment of dependent lung collapse, associated with a further reduction in overdistension of nondependent lung, and both contributing to a further reduction in driving pressures (for the same tidal volume), which likely resulted in less injurious mechanical ventilation.35  The observed benefit of PEEPDECREMENTAL over PEEPINCREMENTAL both on lung mechanics and oxygenation suggests that lungs of obese ARDS patients are highly recruitable. As a consequence, driving airway and transpulmonary pressure progressively decreased at PEEPINCREMENTAL levels and was further lowered at PEEPDECREMENTAL levels, implying a more protective ventilator strategy.

When comparing the present results of ARDS obese patients with findings from our previous study in obese patients with acute respiratory failure without ARDS,11  we found intriguing similarities. First, the level of PEEP necessary to counterbalance the increased pleural pressure determining a positive end-expiratory transpulmonary pressure21  corresponds to the PEEP level determining the lowest respiratory system elastance according to a PEEPDECREMENTAL trial following a recruitment maneuver. In the current study, we could also show that this level of PEEP resulted in an optimum compromise between overdistension and lung collapse. Second, severely obese paralyzed and mechanically ventilated patients—with or without ARDS—show similar optimal levels of PEEP. Third, increased respiratory elastance in obesity—with and without ARDS—is attributable exclusively to an increased lung elastance, while chest-wall elastance is unaltered. Consistent with these findings, titration of PEEP by a PEEPDECREMENTAL trial after a recruitment maneuver resulted in a remarkable improvement in lung elastance. All these findings suggest that the lungs of obese patients show a high proportion of recruitable lung collapse, more than the general population of ARDS patients. The high PEEP required in obese patients is mostly needed to counterbalance the increased levels of pleural pressure.

Our physiologic findings are different from what was shown recently in the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial.3 In the latter study, conducted in a non-obese population, patients underwent randomization to the decremental PEEP titration and recruitment maneuver arm without thorough assessment for lung tissue recruitability. Furthermore, the recruitment maneuver procedure, which was associated with cardiac arrest in three patients in the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial required a much longer period to perform at higher airway pressures than used in our study. Our recruitment procedure, does not seem to impair hemodynamics in obese patients, possibly due to their high pleural pressures.

Setting PEEP at PEEPINCREMENTAL and PEEPDECREMENTAL levels raised intrathoracic volume by 977 ± 708 ml and 1,064 ± 813 ml, respectively, corresponding to an increase in end-expiratory esophageal pressure of only 3 ± 2 cm H2O and 3 ± 2 cm H2O, respectively. Accordingly chest wall elastance would have been 4 ± 4 and 3 ± 5 cm H2O/l, values significantly lower than the ones measured according to the standard formula derived form esophageal pressure changes during tidal ventilation. This observation is in line with the hypothesis of a time dependent behavior of the chest-wall36 : higher chest-wall elastance is detected when intrathoracic volume is quickly changed (tidal stretch) while lower values are measured if slow deformation is applied (PEEP related stretch).

As recently shown, when measuring lung tissue recruitment as an increase in end expiratory lung volume promoted by PEEP, the vertical shift of the respiratory system pressure-volume curve above the predicted inflation volume due to PEEP does not allow precise quantification of lung recruitment.37  In the current study, however, the increase in lung volume and aeration of dependent lung regions (electrical impedance tomography data) was followed by an improvement in regional respiratory system elastance, together with a decrease in shunt fraction. Altogether, these findings are indicative of lung tissue recruitment.38  The electrical impedance tomography estimates of lung collapse have been validated against computed tomography33 ; however, these electrical impedance tomography estimates are based on regional compliance, and not on lung density. Thus, they may be theoretically affected by small airways collapse, a potential scenario in obese patients with pleural pressures exceeding airway pressures.39  This phenomenon, if present, might mislead the measurement of regional lung compliance and thus of lung recruitment and collapse by electrical impedance tomography. Airway collapse is sensed as a silent electrical impedance tomographic zone, causing a decrease in the estimates of regional compliance. If airway collapse is not followed by distal alveolar collapse, this phenomenon might cause some overestimation of lung collapse—but not of overdistension. Thus, it is possible that the estimates of lung collapse were slightly overestimated, especially at the PEEPARDSnet, when negative end-expiratory transpulmonary pressure were common. However, they would not cause any bias in the comparison between PEEPINCREMENTALversus PEEPDECREMENTAL, since both reached a positive end-expiratory transpulmonary pressure and both resulted in similar applied PEEP. At the same ventilator PEEP level, we must expect a similar degree of airway closure.39  Although differentiation between the contribution of alveolar collapse and airways closure to the development of respiratory failure was beyond the purpose of this study, our electrical impedance tomography observations, in conjunction with the low oxygenation levels, and computerized tomography showing massive alveolar collapse, suggest that lung collapse plays a major role in this patient population. We further demonstrated that in obese patients reducing PEEP during the PEEPDECREMENTAL trial below end-expiratory transpulmonary pressure level causes a decrease in lung volume large enough to increase airways resistances.40 

Limitations of the Study

There are methodologic limitations to this study. The order of the study procedures was not randomized. Our aim was to differentiate between the effects of titrated PEEP levels alone versus titrated PEEP levels after a recruitment maneuver. Since the high airway pressure reached during the recruitment maneuver may have had a carry-over effect on the values measured at PEEPINCREMENTAL, the order of study procedures was fixed.

Conclusion

In critically-ill obese patients with ARDS, titration of PEEP according to the low PEEP/Fio2 ARDSnet table is associated with low Pao2/Fio2 levels, lung atelectasis and negative transpulmonary pressures. Among the two PEEP titration strategies tested, performing a recruitment maneuver and then applying PEEP according to a PEEPDECREMENTAL trial obtained the best lung function by decreasing lung overdistension and collapse, minimizing driving pressure, and restoring lung elastance and oxygenation, suggesting that lungs of obese patients with ARDS are highly recruitable. The PEEP level required to obtain a positive end-expiratory transpulmonary pressure corresponds to the PEEP level identifying the lowest respiratory system elastance according to a PEEPDECREMENTAL trial after a recruitment maneuver. According to electrical impedance tomography data, PEEPDECREMENTAL levels coincided with the minimum level of both lung collapse and lung overdistension. Further investigation is required to determine if the proposed approach can improve outcomes in this patient population.

Acknowledgments

The authors thank the collaborators (see appendix) who contributed to study design, data collection and data analysis. We also thank the physicians, nurses, respiratory care team and all staff working at the Surgical, Medical and Cardiac intensive care units at Massachusetts General Hospital, Boston, Massachusetts, who permitted the performance of the study.

Research Support

The study was funded by the Departments of Anesthesia, Critical Care and Pain Medicine, and Respiratory Care at Massachusetts General Hospital, Boston, Massachusetts.

Competing Interests

Dr. Amato reports that his research laboratory has received grants in the last 5 yr from the Covidien/Medtronics (Minneapolis, Minnesota; research on mechanical ventilation), Orange Med (Irvine, California; mechanical ventilation), and Timpel S.A. (São Paulo, Brazil; electrical impedance tomography). Dr. Kacmarek is a consultant for Medtronic and Orange Med, and has received research grants from Medtronic and Venner Medical (Dänischenhagen, Germany). Dr. Berra received research grants from Venner Medical and the National Institutes of Health/National Heart, Lung, and Blood Institute (Bethesda, Maryland) grant No. 1 K23 HL128882-01A1 for the project titled “Hemolysis and Nitric Oxide.” The other authors declare no competing interests.

References

References
1.
Bellani
G
,
Laffey
JG
,
Pham
T
,
Fan
E
,
Brochard
L
,
Esteban
A
,
Gattinoni
L
,
van Haren
F
,
Larsson
A
,
McAuley
DF
,
Ranieri
M
,
Rubenfeld
G
,
Thompson
BT
,
Wrigge
H
,
Slutsky
AS
,
Pesenti
A
;
LUNG SAFE Investigators; ESICM Trials Group
:
Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.
JAMA
2016
;
315
:
788
800
2.
Acute Respiratory Distress Syndrome Network
Brower
RG
,
Matthay
MA
,
Morris
A
,
Schoenfeld
D
,
Thompson
BT
,
Wheeler
A
;
Acute Respiratory Distress Syndrome Network
:
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med
2000
;
342
:
1301
8
3.
Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators
Cavalcanti
AB
,
Suzumura
ÉA
,
Laranjeira
LN
,
Paisani
D de M
,
Damiani
LP
,
Guimarães
HP
,
Romano
ER
,
Regenga
M de M
,
Taniguchi
LNT
,
Teixeira
C
,
Pinheiro de Oliveira
R
,
Machado
FR
,
Diaz-Quijano
FA
,
Filho
MS de A
,
Maia
IS
,
Caser
EB
,
Filho
W de O
,
Borges
M de C
,
Martins
P de A
,
Matsui
M
,
Ospina-Tascón
GA
,
Giancursi
TS
,
Giraldo-Ramirez
ND
,
Vieira
SRR
,
Assef
M da GP de L
,
Hasan
MS
,
Szczeklik
W
,
Rios
F
,
Amato
MBP
, et al
Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators
:
Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial.
JAMA
2017
;
318
:
1335
45
4.
Kacmarek
RM
,
Villar
J
,
Sulemanji
D
,
Montiel
R
,
Ferrando
C
,
Blanco
J
,
Koh
Y
,
Soler
JA
,
Martínez
D
,
Hernández
M
,
Tucci
M
,
Borges
JB
,
Lubillo
S
,
Santos
A
,
Araujo
JB
,
Amato
MB
,
Suárez-Sipmann
F
;
Open Lung Approach Network
:
Open lung approach for the acute respiratory distress syndrome: a pilot, randomized controlled trial.
Crit Care Med
2016
;
44
:
32
42
5.
Borges
JB
,
Okamoto
VN
,
Matos
GF
,
Caramez
MP
,
Arantes
PR
,
Barros
F
,
Souza
CE
,
Victorino
JA
,
Kacmarek
RM
,
Barbas
CS
,
Carvalho
CR
,
Amato
MB
:
Reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome.
Am J Respir Crit Care Med
2006
;
174
:
268
78
6.
Muscedere
JG
,
Mullen
JB
,
Gan
K
,
Slutsky
AS
:
Tidal ventilation at low airway pressures can augment lung injury.
Am J Respir Crit Care Med
1994
;
149
:
1327
34
7.
Chiumello
D
,
Carlesso
E
,
Cadringher
P
,
Caironi
P
,
Valenza
F
,
Polli
F
,
Tallarini
F
,
Cozzi
P
,
Cressoni
M
,
Colombo
A
,
Marini
JJ
,
Gattinoni
L
:
Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome.
Am J Respir Crit Care Med
2008
;
178
:
346
55
8.
Caironi
P
,
Cressoni
M
,
Chiumello
D
,
Ranieri
M
,
Quintel
M
,
Russo
SG
,
Cornejo
R
,
Bugedo
G
,
Carlesso
E
,
Russo
R
,
Caspani
L
,
Gattinoni
L
:
Lung opening and closing during ventilation of acute respiratory distress syndrome.
Am J Respir Crit Care Med
2010
;
181
:
578
86
9.
Gattinoni
L
,
Caironi
P
,
Cressoni
M
,
Chiumello
D
,
Ranieri
VM
,
Quintel
M
,
Russo
S
,
Patroniti
N
,
Cornejo
R
,
Bugedo
G
:
Lung recruitment in patients with the acute respiratory distress syndrome.
N Engl J Med
2006
;
354
:
1775
86
10.
Behazin
N
,
Jones
SB
,
Cohen
RI
,
Loring
SH
:
Respiratory restriction and elevated pleural and esophageal pressures in morbid obesity.
J Appl Physiol (1985)
2010
;
108
:
212
8
11.
Pirrone
M
,
Fisher
D
,
Chipman
D
,
Imber
DA
,
Corona
J
,
Mietto
C
,
Kacmarek
RM
,
Berra
L
:
Recruitment maneuvers and positive end-expiratory pressure titration in morbidly obese ICU patients.
Crit Care Med
2016
;
44
:
300
7
12.
Sharp
JT
,
Henry
JP
,
Sweany
SK
,
Meadows
WR
,
Pietras
RJ
:
Effects of mass loading the respiratory system in man.
J Appl Physiol
1964
;
19
:
959
66
13.
Fumagalli
J
,
Berra
L
,
Zhang
C
,
Pirrone
M
,
Santiago
RRS
,
Gomes
S
,
Magni
F
,
Dos Santos
GAB
,
Bennett
D
,
Torsani
V
,
Fisher
D
,
Morais
C
,
Amato
MBP
,
Kacmarek
RM
:
Transpulmonary pressure describes lung morphology during decremental positive end-expiratory pressure trials in obesity.
Crit Care Med
2017
;
45
:
1374
81
14.
Meade
MO
,
Cook
DJ
,
Guyatt
GH
,
Slutsky
AS
,
Arabi
YM
,
Cooper
DJ
,
Davies
AR
,
Hand
LE
,
Zhou
Q
,
Thabane
L
,
Austin
P
,
Lapinsky
S
,
Baxter
A
,
Russell
J
,
Skrobik
Y
,
Ronco
JJ
,
Stewart
TE
;
Lung Open Ventilation Study Investigators
:
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.
JAMA
2008
;
299
:
637
45
15.
Mercat
A
,
Richard
JC
,
Vielle
B
,
Jaber
S
,
Osman
D
,
Diehl
JL
,
Lefrant
JY
,
Prat
G
,
Richecoeur
J
,
Nieszkowska
A
,
Gervais
C
,
Baudot
J
,
Bouadma
L
,
Brochard
L
;
Expiratory Pressure (Express) Study Group
:
Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: A randomized controlled trial.
JAMA
2008
;
299
:
646
55
16.
Brower
RG
,
Lanken
PN
,
MacIntyre
N
,
Matthay
MA
,
Morris
A
,
Ancukiewicz
M
,
Schoenfeld
D
,
Thompson
BT
;
National Heart, Lung, and Blood Institute ARDS Clinical Trials Network
:
Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.
N Engl J Med
2004
;
351
:
327
36
17.
Bime
C
,
Fiero
M
,
Lu
Z
,
Oren
E
,
Berry
CE
,
Parthasarathy
S
,
Garcia
JGN
:
High Positive end-expiratory pressure is associated with improved survival in obese patients with acute respiratory distress syndrome.
Am J Med
2017
;
130
:
207
13
18.
Flegal
KM
,
Kruszon-Moran
D
,
Carroll
MD
,
Fryar
CD
,
Ogden
CL
:
Trends in obesity among adults in the United States, 2005 to 2014.
JAMA
2016
;
315
:
2284
91
19.
Gong
MN
,
Bajwa
EK
,
Thompson
BT
,
Christiani
DC
:
Body mass index is associated with the development of acute respiratory distress syndrome.
Thorax
2010
;
65
:
44
50
20.
Anzueto
A
,
Frutos-Vivar
F
,
Esteban
A
,
Bensalami
N
,
Marks
D
,
Raymondos
K
,
Apezteguía
C
,
Arabi
Y
,
Hurtado
J
,
González
M
,
Tomicic
V
,
Abroug
F
,
Elizalde
J
,
Cakar
N
,
Pelosi
P
,
Ferguson
ND
;
Ventila group
:
Influence of body mass index on outcome of the mechanically ventilated patients.
Thorax
2011
;
66
:
66
73
21.
Talmor
D
,
Sarge
T
,
Malhotra
A
,
O’Donnell
CR
,
Ritz
R
,
Lisbon
A
,
Novack
V
,
Loring
SH
:
Mechanical ventilation guided by esophageal pressure in acute lung injury.
N Engl J Med
2008
;
359
:
2095
104
22.
Suarez-Sipmann
F
,
Böhm
SH
,
Tusman
G
,
Pesch
T
,
Thamm
O
,
Reissmann
H
,
Reske
A
,
Magnusson
A
,
Hedenstierna
G
:
Use of dynamic compliance for open lung positive end-expiratory pressure titration in an experimental study.
Crit Care Med
2007
;
35
:
214
21
23.
Ranieri
VM
,
Rubenfeld
GD
,
Thompson
BT
,
Ferguson
ND
,
Caldwell
E
,
Fan
E
,
Camporota
L
,
Slutsky
AS
;
ARDS Definition Task Force
:
Acute respiratory distress syndrome: The Berlin definition.
JAMA
2012
;
307
:
2526
33
24.
Lim
SC
,
Adams
AB
,
Simonson
DA
,
Dries
DJ
,
Broccard
AF
,
Hotchkiss
JR
,
Marini
JJ
:
Intercomparison of recruitment maneuver efficacy in three models of acute lung injury.
Crit Care Med
2004
;
32
:
2371
7
25.
Baydur
A
,
Behrakis
PK
,
Zin
WA
,
Jaeger
M
,
Milic-Emili
J
:
A simple method for assessing the validity of the esophageal balloon technique.
Am Rev Respir Dis
1982
;
126
:
788
91
26.
Mojoli
F
,
Iotti
GA
,
Torriglia
F
,
Pozzi
M
,
Volta
CA
,
Bianzina
S
,
Braschi
A
,
Brochard
L
:
In vivo calibration of esophageal pressure in the mechanically ventilated patient makes measurements reliable.
Crit Care
2016
;
20
:
98
27.
Yoshida
T
,
Amato
MBP
,
Grieco
DL
,
Chen
L
,
Lima
CAS
,
Roldan
R
,
Morais
CCA
,
Gomes
S
,
Costa
ELV
,
Cardoso
PFG
,
Charbonney
E
,
Richard
JM
,
Brochard
L
,
Kavanagh
BP
:
Esophageal manometry and regional transpulmonary pressure in lung injury.
Am J Respir Crit Care Med
2018
;
197
:
1018
26
28.
Iotti
GA
,
Braschi
A
,
Brunner
JX
,
Smits
T
,
Olivei
M
,
Palo
A
,
Veronesi
R
:
Respiratory mechanics by least squares fitting in mechanically ventilated patients: Applications during paralysis and during pressure support ventilation.
Intensive Care Med
1995
;
21
:
406
13
29.
Malbrain
MLNG
,
Cheatham
ML
,
Kirkpatrick
A
,
Sugrue
M
,
Parr
M
,
Waele
J De
,
Balogh
Z
,
Leppäniemi
A
,
Olvera
C
,
Ivatury
R
,
D’Amours
S
,
Wendon
J
,
Hillman
K
,
Johansson
K
,
Kolkman
K
,
Wilmer
A
:
Results from the International Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. I. Definitions.
Intensive Care Med
2006
;
32
:
1722
32
30.
Doorduin
J
,
Nollet
JL
,
Vugts
MP
,
Roesthuis
LH
,
Akankan
F
,
van der Hoeven
JG
,
van Hees
HW
,
Heunks
LM
:
Assessment of dead-space ventilation in patients with acute respiratory distress syndrome: A prospective observational study.
Crit Care
2016
;
20
:
121
31.
FOWLER
WS
:
Lung function studies; the respiratory dead space.
Am J Physiol
1948
;
154
:
405
16
32.
Victorino
JA
,
Borges
JB
,
Okamoto
VN
,
Matos
GF
,
Tucci
MR
,
Caramez
MP
,
Tanaka
H
,
Sipmann
FS
,
Santos
DC
,
Barbas
CS
,
Carvalho
CR
,
Amato
MB
:
Imbalances in regional lung ventilation: a validation study on electrical impedance tomography.
Am J Respir Crit Care Med
2004
;
169
:
791
800
33.
Costa
EL
,
Borges
JB
,
Melo
A
,
Suarez-Sipmann
F
,
Toufen
C
Jr
,
Bohm
SH
,
Amato
MB
:
Bedside estimation of recruitable alveolar collapse and hyperdistension by electrical impedance tomography.
Intensive Care Med
2009
;
35
:
1132
7
34.
Mauri
T
,
Eronia
N
,
Turrini
C
,
Battistini
M
,
Grasselli
G
,
Rona
R
,
Volta
CA
,
Bellani
G
,
Pesenti
A
:
Bedside assessment of the effects of positive end-expiratory pressure on lung inflation and recruitment by the helium dilution technique and electrical impedance tomography.
Intensive Care Med
2016
;
42
:
1576
87
35.
Amato
MB
,
Meade
MO
,
Slutsky
AS
,
Brochard
L
,
Costa
EL
,
Schoenfeld
DA
,
Stewart
TE
,
Briel
M
,
Talmor
D
,
Mercat
A
,
Richard
JC
,
Carvalho
CR
,
Brower
RG
:
Driving pressure and survival in the acute respiratory distress syndrome.
N Engl J Med
2015
;
372
:
747
55
36.
Stenqvist
O
,
Gattinoni
L
,
Hedenstierna
G
:
What’s new in respiratory physiology? The expanding chest wall revisited!
Intensive Care Med
2015
;
41
:
1110
3
37.
Chiumello
D
,
Marino
A
,
Brioni
M
,
Cigada
I
,
Menga
F
,
Colombo
A
,
Crimella
F
,
Algieri
I
,
Cressoni
M
,
Carlesso
E
,
Gattinoni
L
:
Lung recruitment assessed by respiratory mechanics and computed tomography in patients with acute respiratory distress syndrome. What is the relationship?
Am J Respir Crit Care Med
2016
;
193
:
1254
63
38.
Amato
MB
,
Santiago
RR
:
The Recruitability Paradox.
Am J Respir Crit Care Med
2016
;
193
:
1192
5
39.
Chen
L
,
Sorbo
L Del
,
Grieco
DL
,
Shklar
O
,
Junhasavasdikul
D
,
Telias
I
,
Fan
E
,
Brochard
L
:
Airway closure in acute respiratory distress syndrome: An underestimated and misinterpreted phenomenon.
Am J Respir Crit Care Med
2018
;
197
:
132
136
.
doi:10.1164/rccm.201702-0388LE
40.
Lemyze
M
,
Mallat
J
,
Duhamel
A
,
Pepy
F
,
Gasan
G
,
Barrailler
S
,
Vangrunderbeeck
N
,
Tronchon
L
,
Thevenin
D
:
Effects of sitting position and applied positive end-expiratory pressure on respiratory mechanics of critically ill obese patients receiving mechanical ventilation.
Crit Care Med
2013
;
41
:
2592
9

Appendix

Collaborators:

Sophia Palma, B.Sc., Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts

Grant M. Larson, E.M.T-B., Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts

Shigeru W. Kaneki, B.A., Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts

Daniel Fisher, R.R.T., Respiratory Care Department, Massachusetts General Hospital, Boston, Massachusetts

Emanuele Rezoagli, M.D., Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts

Massimiliano Pirrone, M.D., Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts

Francesco Marrazzo M.D., Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts

Hui Zhang, M.D., Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts

Jing Zhao, M.D., Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts