The protocol was approved by an Ethics Committee and the National Agency for drug safety in France and registered (NCT02939963 in clinical.trial.gov).
Patients
Patients were eligible if they met all the following inclusion criteria: (1) age ≥ 18 years; (2) intubated and mechanically ventilated for acute respiratory failure for at least 24 consecutive hours; (3) able to tolerate PS 10–15 cmH2O with total respiratory rate 25–35 breaths/min and expired tidal volume 6–8 ml/kg predicted body weight; (4) meeting criteria for SBT (see Additional file 1); (5) under EVITA XL ICU ventilator (Dräger, Germany); (6) agreement to participate from the patient or her/his next of kin. The list of non-inclusion criteria is provided in Additional file 1.
Measurement set-up
We measured airflow by using a linear pneumotachograph (3700 series, Hans Rudolph, Shawnee, Kansas) and airway pressure (Paw) at the proximal tip of the endotracheal tube. We measured esophageal pressure (Pes) by using a 5Fr specific catheter balloon (CooperSurgical, Inc., Trumbull, CT) descended down to the lower third of esophagus through the nostril. We assessed the proper position of the Pes device [15] and the amount of nonstressed air volume into the esophageal balloon [16]. Paw and Pes were connected to pressure transducers (Gabarith PMSET 1DT-XX, Becton-Dickinson, Singapore). Pressure transducers and pneumotachograph were calibrated using a manometer (717 1G, Fluke Biomedical, Everett, Washington) and a precision rotameter (Houdec Glass, Martin Medical, Lyon, France), respectively, at room temperature in each experiment. The set-up had a flow-resistance of 0.79 cmH2O/l/s and a dead space of 20 ml. During the experiment the heated-humidifier was working on and the pneumotachograph was not warmed to avoid any risk of endotracheal tube obstruction.
We wrapped the thorax at the 5–6th intercostal space with a 16-electrode electrical impedance tomography (EIT) belt. The belt was connected to an EIT monitor (Pulmovista 500, Dräger, Lubeck, Germany). EIT device measured changes in impedance across the thorax from the measurement of surface potential differences resulting from the application of a low-intensity alternate electrical current generated by pairs of electrodes and rotating around the thorax at a rate of 20 Hz.
Protocol
This was a crossover study with two treatment arms. Each included patient received both arms in a computer-generated random order. In the ATC arm, the ventilator was set at PS 0 cmH2O, with the shortest rising time, cycling-off 25% of maximal inspiratory flow, PEEP 4 cmH2O and ATC on with 100% inspiratory compensation for the patient’s endotracheal tube size. Expiratory ATC was not activated because it was not available in the ventilators used in present study. In the low-PS arm, settings were the same except for 7 cmH2O PS and ATC off. Each treatment period was applied during 30 min and was separated by a 30-min period during which baseline ventilator settings were resumed. If the patient did not tolerate SBT (see Additional file 1 for criteria) he/she was switched back to the baseline ventilator settings and qualified as SBT failure.
During the last 2 min of each treatment period, Paw, Pes and airflow analog signals were continuously recorded at 200 Hz by using a data logger (Biopac MP150, Biopac, Inc., Goleta, CA). We obtained Paw at 100 ms (P0.1) by activating a specific function built into the ventilator. Five brief end-expiratory occlusions were automatically generated by the ventilator after manually pushing on a specific button at random during the 2 min of the recording. In the same time, EIT signals were continuously recorded. Paw, Pes, airflow signals were stored for off-line analysis by using Acqknowledge 4.0 version (Biopac, Inc., Goletta, CA). The same was done for the EIT signals by using a specific software (EITDataAnalysisTool 6.1, Dräger, Lubeck, Germany).
Data analysis
Over each recorded breath the measurements were automatically performed under an in-house software developed with the Matlab scripting language. Tidal volume (VT) and respiratory rate were obtained from the flow signal. Inspiration was defined as the flow crossing zero. Resistive (R) and elastic (E) components of WOB done by the patient were obtained from the Campbell diagram and the total WOB was the sum of the R and E components. Muscular pressure (Pmus) was computed as the difference between Pes and VT times chest wall elastance in each breath (Fig. 1). Chest wall elastance was computed as the change in Pes over the breath divided by 4% vital capacity expected for gender, age and height [17]. The R and E components of breathing power were the product of each WOB component to respiratory rate and expressed as J/min. The total breathing power was the sum of its R and E components. The pressure–time product of inspiratory muscles (PTPmus) was the area of Pmus over the inspiration in each breath multiplied by the respiratory rate. Intrinsic PEEP was measured as the Pes deflection from the onset of inspiratory effort to the first zero flow. No correction was made for gastric pressure.
P0.1 was measured on the Paw tracings recorded in the data logger at 100 ms after the first zero flow. The values of the 5 measurements per condition were averaged.
We assessed the functioning of the ventilator in each mode by measuring PEEP, maximal deflection in Paw at the time of inspiratory effort (DPtrig), time delay between onset of inspiratory effort to return to baseline PEEP (DTtrig), maximal inspiratory pressure and maximal inspiratory flow (see Additional file 1).
The EIT signals were processed with the EIT and diffuse optical tomography reconstruction software (EIDORS) [18] licensed under the GNU general public (http://eidors3d.sourceforge.net/) associated with the Matlab scripting language (see Additional file 1).
The pressure drop across the endotracheal tube was evaluated from general mechanical law as described [19]. This pressure drop is a function of the instantaneous flow rate and the endotracheal tube geometry (length and diameter). We measured the pressure generated by the ventilator and we computed the ideal pressure that would only be needed to compensate for RET. The difference between this ideal pressure and effective Paw was computed by summing the instantaneous difference (see Additional file 1 for more details).
Statistical analysis
The primary end-point was the total breathing power generated by the patient’s respiratory muscles and was used to power the study. We set total breathing power to 10 J/min in the low-PS arm reference group [7], and a 4 J/min clinically relevant increase in total breathing power with ATC with a 4 J/min standard deviation [7]. At first and second risk orders of 5% and 20%, respectively, 16 patients were needed (Epi-Info software). Assuming a 10% rate of patients with missing data a total of 20 patients should be enrolled in the study.
The values were expressed as median (1st–3rd quartiles) and compared by non-parametric Wilcoxon signed rank test between the two arms. For the primary end-point, we furthermore tested the period effect and the treatment–period interaction [20]. If the period has a significant effect the analysis would be adjusted for the period. If the interaction between treatment and period is significant only the first period will be used. Correlation between variables was assessed by using Spearman rank correlation. The statistical analysis was performed by using the R software 3.5.2 version [21]. P value < 0.05 was taken as the statistical significant threshold. No correction for multiple comparisons was done.