Ultra-low tidal volume ventilation for COVID-19-related ARDS in France (VT4COVID): a multicentre, open-label, parallel-group, randomised trial.

BACKGROUND: COVID-19-related acute respiratory distress syndrome (ARDS) is associated with a high mortality rate and longer mechanical ventilation. We aimed to assess the effectiveness of ventilation with ultra-low tidal volume (ULTV) compared with low tidal volume (LTV) in patients with COVID-19-related ARDS. METHODS: This study was a multicentre, open-label, parallel-group, randomised trial conducted in ten intensive care units in France. Eligible participants were aged 18 years or older, received invasive mechanical ventilation for COVID-19 (confirmed by RT-PCR), had ARDS according to the Berlin definition, a partial pressure of arterial oxygen to inspiratory oxygen fraction (PaO2/FiO2) ratio of 150 mm Hg or less, a tidal volume (VT) of 6·0 mL/kg predicted bodyweight or less, and received continuous intravenous sedation. Patients were randomly assigned (1:1) using randomisation blocks to receive ULTV (intervention group) aiming for VT of 4·0 mL/kg predicted bodyweight or LTV (control group) aiming for VT 6·0 mL/kg predicted bodyweight. Participants, investigators, and outcome assessors were not masked to group assignment. The primary outcome was a ranked composite score based on all-cause mortality at day 90 as the first criterion and ventilator-free days among patients alive at day 60 as the second criterion. Effect size was computed with the unmatched win ratio, on the basis of pairwise prioritised comparison of primary outcome components between every patient in the ULTV group and every patient in the LTV group. The unmatched win ratio was calculated as the ratio of the number of pairs with more favourable outcome in the ULTV group over the number of pairs with less favourable outcome in the ULTV group. Primary analysis was done in the modified intention-to-treat population, which included all participants who were randomly assigned and not lost to follow-up. This trial is registered with ClinicalTrials.gov, NCT04349618. FINDINGS: Between April 15, 2020, and April 13, 2021, 220 patients were included and five (2%) were excluded. 215 patients were randomly assigned (106 [49%] to the ULTV group and 109 [51%] to the LTV group). 58 (27%) patients were female and 157 (73%) were male. The median age was 68 years (IQR 60-74). 214 patients completed follow-up (one lost to follow-up in the ULTV group) and were included in the modified intention-to-treat analysis. The primary outcome was not significantly different between groups (unmatched win ratio in the ULTV group 0·85 [95% CI 0·60 to 1·19]; p=0·38). 46 (44%) of 105 patients in the ULTV group and 43 (39%) of 109 in the LTV group died by day 90 (absolute difference 4% [-9 to 18]; p=0·52). The rate of severe respiratory acidosis in the first 28 days was higher in the ULTV group than in the LTV group (35 [33%] vs 14 [13%]; absolute difference 20% [95% CI 9 to 31]; p=0·0004). INTERPRETATION: In patients with moderate-to-severe COVID-19-related ARDS, there was no significant difference with ULTV compared with LTV in the composite score based on mortality and ventilator-free days among patients alive at day 60. These findings do not support the systematic use of ULTV in patients with COVID-19-related ARDS. FUNDING: French Ministry of Solidarity and Health and Hospices Civils de Lyon.

Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.

Atrophy of Diaphragm and Pectoral Muscles in Critically Ill Patients.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Muscle atrophy is common in the critically ill, and diaphragm atrophy occurs during mechanical ventilation. It is not known whether wasting of diaphragm and nondiaphragm muscle is related. WHAT THIS ARTICLE TELLS US THAT IS NEW: Ultrasound was used for serial assessment of diaphragm and pectoral muscle in 97 critically ill patients. Diaphragm and pectoral atrophy occurred in 48% and 29%, respectively, and was associated with septic shock (diaphragm) and steroid use (pectoral); atrophy of the two muscle types appears unrelated. BACKGROUND: Muscle atrophy occurs early during critical illnesses. Although diffuse, this atrophy may specifically affect the diaphragm under artificial inactivity accompanying invasive mechanical ventilation. The primary objective of this study was to highlight diaphragm atrophy during the first 5 days of critical illness. Monitoring of pectoral thickness (a nonpostural muscle with mainly phasic function) served as a control. METHODS: Diaphragm and pectoral thicknesses were measured by ultrasound within the first 24 h of admission in 97 critically ill patients, including 62 on mechanical ventilation. Thirty-five patients were reexamined at day 5. RESULTS: Baseline median (interquartile) values of diaphragm and pectoral thicknesses at day 1 were 2.4 (2.0, 2.9) and 5.9 (4.7, 7.2) mm, respectively (n = 97). Higher values of diaphragm thickness at baseline were positively associated with male sex, chronic obstructive pulmonary disease, and diabetes. Diaphragm and pectoral atrophies (defined as a decrease of 10% or more between day 1 and day 5) were detected in 48% (17 of 35) and 29% (10 of 34) respectively, and were uncorrelated with each other. Diaphragm atrophy was significantly more frequent in patients with septic shock and in those with mechanical ventilation, as compared with their respective counterparts (71% [10 of 14] vs. 33% [7 of 21], P = 0.027 and 71% [17 of 28] vs. 0% [0 of 7], P = 0.004, respectively), whereas pectoral atrophy was more common in patients treated with steroids as compared with their counterparts (58% [7 of 12] vs. 14% [3 of 22], P = 0.006). A statistically significant association between diaphragm atrophy and outcome was not found. Pectoral atrophy seemed associated with less successful weaning from mechanical ventilation at day 14 (12% [1 of 8] vs. 58% [11 of 19], P = 0.043). CONCLUSIONS: Ultrasound enables identification of specific early diaphragm atrophy that affects the majority of mechanically ventilated patients and septic shock patients. Diaphragm atrophy and pectoral muscle atrophy seem to be two unrelated processes.

Inability of Diaphragm Ultrasound to Predict Extubation Failure: A Multicenter Study.

BACKGROUND: Diaphragmatic dysfunction may promote weaning difficulties in patients who are mechanically ventilated. OBJECTIVE: The goal of this study was to assess whether diaphragm dysfunction detected by ultrasound prior to extubation could predict extubation failure in the ICU. METHODS: This multicenter prospective study included patients at high risk of reintubation: those aged > 65 years, with underlying cardiac or respiratory disease, or intubated > 7 days. All patients had successfully undergone a spontaneous breathing trial. Diaphragmatic function was assessed by ultrasound prior to extubation while breathing spontaneously on a T-piece. Bilateral diaphragmatic excursion and apposition thickening fraction were measured, and diaphragmatic dysfunction was defined as excursion < 10 mm or thickening < 30%. Cough strength was clinically assessed by physiotherapists. Extubation failure was defined as reintubation or death within the 7 days following extubation. RESULTS: Over a 20-month period, 191 at-risk patients were studied. Among them, 33 (17%) were considered extubation failures. The proportion of patients with diaphragmatic dysfunction was similar between those whose extubation succeeded and those whose extubation failed: 46% vs 51% using excursion (P = .55), and 71% vs 68% using thickening (P = .73), respectively. Values of excursion and thickening did not differ between the success and the failure groups: at right, excursion was 14 ± 7 mm vs 11 ± 8 (P = .13), and thickening was 29 ± 29% vs 38 ± 48% (P = .83), respectively. Extubation failure rates were 7%, 22%, and 46% in patients with effective, moderate, and ineffective cough (P < .01). Ineffective cough was the only variable independently associated with extubation failure. CONCLUSIONS: Diaphragmatic dysfunction assessed by ultrasound was not associated with an increased risk of extubation failure.

Sigmoidal equation for lung and chest wall volume-pressure curves in acute respiratory failure.

To assess incidence and magnitude of the "lower inflection point" of the chest wall, the sigmoidal equation was used in 36 consecutive patients intubated and mechanically ventilated with acute lung injury (ALI). They were 21 primary and 5 secondary ALI, 6 unilateral pneumonia, and 4 cardiogenic pulmonary edema. The lower inflection point was estimated as the point of maximal compliance increase. The low constant flow inflation method and esophageal pressure were used to partition the volume-pressure curves into their chest wall and lung components on zero end-expiratory pressure. The sigmoidal equation had an excellent fit with coefficients of determination >0.90 in all instances. The point of maximal compliance increase of the chest wall ranged from 0 to 8.3 cmH2O (median 1 cmH2O) with no difference between ALI groups. The chest wall significantly contributed to the lower inflection point of the respiratory system in eight patients only. The occurrence of a significant contribution of the chest wall to the lower inflection point of the respiratory system is lower than anticipated. The sigmoidal equation is able to determine precisely the point of the maximal compliance increase of lung and chest wall.