This was a prospective observational clinical study (ClinicalTrials.gov NCT04445961) conducted in intensive care units (ICUs) at three hospitals of Sechenov University (Moscow, Russia) from May 1 to August 14, 2020. The study was approved by the Institutional Ethics Committee (reference number: 16-20). Written informed consent was waived owing to the observational nature of the study.
All mechanically ventilated patients (both invasive and non-invasive) were daily screened for eligibility. We included patients with COVID-19-associated respiratory failure requiring invasive mechanical ventilation after noninvasive ventilation (NIV) failure. Exclusion criteria were: 1)peripheral oxygen saturation (SpO2) > 93%, no visible work of auxiliary respiratory muscles (sternocleidomastoid and scalene), no fatigue on conventional oxygen therapy (oxygen flow < 15 l/min) or non-invasive ventilation; 2) life-threatening heart rhythm abnormalities and/or systolic blood pressure < 80 mmHg despite norepinephrine at a dose > 2 µg/kg/min; 3) ICU stay less than 24 hours for any reason; 4) primary lung diseases (e.g. interstitial lung diseases, lung emphysema) or tumour metastases in lungs; 5) chronic decompensated diseases with extrapulmonary organ dysfunction (tumour progression, liver cirrhosis, congestive heart failure); 6) atonic coma.
At the start of the study all patients were on mechanical ventilation in the assisted pressure-controlled volume-guaranteed mode in supine position with the tidal volume (VT) set at 6-8 ml/kg of the predicted body weight (PBW) and positive end-expiratory pressure set at 8 cmH2O, inspiratory time 0,8-1,1 s to prevent air trapping at exhalation, respiratory rate (RR) set at 16-28 to reach arterial carbon dioxide tension (PaCO2) 35-50 mmHg and inspiratory fraction of oxygen (FiO2) set at minimal level to reach SpO2 93-96%. Patients were sedated with a propofol infusion up to the Richmond Agitation-Sedation Score (RASS) -3-4 points and paralyzed if they had inspiratory swings on pressure-time curve and/or visible work of auxiliary respiratory muscles besides RASS-4.
We measured plateau pressure (Pplat) with the inspiratory hold maneuver for 3 seconds at PEEP levels of 14, 12, 10 and 8 cmH2O and calculated driving pressure (DP) as Pplat-PEEP and static respiratory system compliance (CRS) on Days 1, 3, 5, 7, 10, 14, 21 and 28 (if applicable) («PEEP trial»). We set the PEEP level at mentioned time points at the balance point of the lowest DP and the highest SpO2. After the PEEP setting, we increased tidal volume by 100 ml and 200 ml in 2 steps, respectively, and measured Pplat on each step with DP and CRS calculation (on Days 1 and 7 as part of recruitment maneuver)(«volume trial»). For the correct calculation of CRS during a volume increase we computed the «normalized» CRS by dividing the tidal volume in ml/kg of the predicted body weight to driving pressure.
Also, on Days 1 and 7, we used the recruitment maneuver (RM) doubling tidal the volume for 15 respiratory cycles at a preset PEEP level (the doubled tidal volume was reached by several steps of 100 ml each). Before the maneuver we set FiO2 that corresponds to SpO2 90%. Prior to and at the end of the maneuver we measured the plethysmography variability index (PVI) by Radical-7 monitor (Masimo Corp, Irvine, CA, USA). We defined RM as effective if SpO2 rose to 95% and higher in 5 minutes after RM.
Patients were placed in the prone position for at least 16 hours per day if it led to an increase in SpO2 by more than 5% except for patients with body mass index > 40 kg/m2 (they were placed in lateral positions) and patients in whom the prone position led to an increase in driving pressure. The ventilation mode was switched to the Pressure Support mode if a patient was conscious or sedated up to RASS 0-2, had a stable respiratory and hemodynamic state, no visible work of auxiliary respiratory muscles and a stable respiratory pattern after switching. The pressure support level was set according to Pplat and corrected to achieve the Tobin index (respiratory rate/VT) of less than 70. Tracheostomy was performed on the 3rd day of mechanical ventilation.
Before the PEEP and volume trials we measured partial pressure of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide in arterial blood (PaCO2), arterial pH, and end-expiratory carbon dioxide tension (PetCO2), and calculated PaO2/FiO2 ratio, alveolar dead space (VDalv/VT) according to Bohr-Enghoff equation and ventilatory ratio (VR) (19).
Routine blood examinations included 1) complete blood count, 2) coagulation profile - fibrinogen, activated partial thromboplastin time, international normalized ratio and D-dimers, 3) serum biochemical tests (C-reactive protein, albumin, creatinine, blood urea nitrogen, total bilirubin, alanine transaminase and aspartate transaminase, lactate dehydrogenase, electrolytes and serum ferritin). The frequency of tests was determined by the attending physician (everyday, as usual).
Endpoints and statistical analysis
The primary endpoints were: 1. «Optimum» PEEP level on Days 1 and 7 of mechanical ventilation balanced between the lowest DP and the highest SpO2; 2. Number of patients with recruitable lung defined as SpO2 changed from 90% to 95% and more after recruitment maneuver on Days 1 and 7 of mechanical ventilation.
Secondary endpoints included: 1. «Optimum» PEEP level on Days 3, 5, 10, 14 and 21 (set as described above); 2. Driving pressure at different PEEP levels (8, 10, 12, 14 mbar) and different tidal volumes (initial, +100 ml and + 200 ml) at a set PEEP level on Days 1, 3, 5, 7, 10, 14, 21 of the mechanical ventilation; 3. Alveolar dead space on Days 1, 3, 5, 7, 10, 14, 21 of the mechanical ventilation; 4. Plethysmography variation index before PEEP and volume trials and at the end of the recruitment maneuver on Days 1 and 7 of the mechanical ventilation or during the volume trial on Days 3, 5,10 and 21; 5. PaO2/FiO2 ratio and ventilatory ratio on Days 1, 3, 5, 7, 10, 14, 21 of the mechanical ventilation.
Descriptive statistics included proportions for categorical and median (interquartile range) for continuous variables. No imputation was made for missing data. To assess differences between survivors and non-survivors, we performed the Mann-Whitney U test for continuous variables, and Chi-square or Fisher exact test for categorical variables. The Friedman test was used for variable dynamics within group. A two-sided p< 0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics version 19.0 (IBM, Armonk, NY, USA).