Optimal Dosing and Timing of High-Dose Corticosteroid Therapy in Hospitalized Patients With COVID-19: Study Protocol for a Retrospective Observational Multicenter Study (SELECT).

BACKGROUND: In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19. OBJECTIVE: Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19. METHODS: This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand. RESULTS: As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024. CONCLUSIONS: This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48183.

Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial.

PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality.

INTRODUCTION: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) show limited systemic hyperinflammation, but immunomodulatory treatments are effective. Little is known about the inflammatory response in the lungs and if this could be targeted using high-dose steroids (HDS). We aimed to characterise the alveolar immune response in patients with COVID-19-related ARDS, to determine its association with mortality, and to explore the association between HDS treatment and the alveolar immune response. METHODS: In this observational cohort study, a comprehensive panel of 63 biomarkers was measured in repeated bronchoalveolar lavage (BAL) fluid and plasma samples of patients with COVID-19 ARDS. Differences in alveolar-plasma concentrations were determined to characterise the alveolar inflammatory response. Joint modelling was performed to assess the longitudinal changes in alveolar biomarker concentrations, and the association between changes in alveolar biomarker concentrations and mortality. Changes in alveolar biomarker concentrations were compared between HDS-treated and matched untreated patients. RESULTS: 284 BAL fluid and paired plasma samples of 154 patients with COVID-19 were analysed. 13 biomarkers indicative of innate immune activation showed alveolar rather than systemic inflammation. A longitudinal increase in the alveolar concentration of several innate immune markers, including CC motif ligand (CCL)20 and CXC motif ligand (CXCL)1, was associated with increased mortality. Treatment with HDS was associated with a subsequent decrease in alveolar CCL20 and CXCL1 levels. CONCLUSIONS: Patients with COVID-19-related ARDS showed an alveolar inflammatory state related to the innate host response, which was associated with a higher mortality. HDS treatment was associated with decreasing alveolar concentrations of CCL20 and CXCL1.

Closed-loop ventilation in COVID-19 patients with acute hypoxemic respiratory failure-A case series.

BACKGROUND: INTELLiVENT-adaptive support ventilation (ASV) is an automated closed-loop mode of invasive ventilation for use in critically ill patients. INTELLiVENT-ASV automatically adjusts, without the intervention of the caregiver, ventilator settings to achieve the lowest work and force of breathing. AIMS: The aim of this case series is to describe the specific adjustments of INTELLiVENT-ASV in patients with acute hypoxemic respiratory failure, who were intubated for invasive ventilation. STUDY DESIGN: We describe three patients with severe acute respiratory distress syndrome (ARDS) because of COVID-19 who received invasive ventilation in our intensive care unit (ICU) in the first year of the COVID-19 pandemic. RESULTS: INTELLiVENT-ASV could be used successfully, but only after certain adjustments in the settings of the ventilator. Specifically, the high oxygen targets that are automatically chosen by INTELLiVENT-ASV when the lung condition 'ARDS' is ticked had to be lowered, and the titration ranges for positive end expiratory pressure (PEEP) and inspired oxygen fraction (FiO2 ) had to be narrowed. CONCLUSION: The challenges taught us how to adjust the ventilator settings so that INTELLiVENT-ASV could be used in successive COVID-19 ARDS patients, and we experienced the benefits of this closed-loop ventilation in clinical practice. RELEVANCE TO CLINICAL PRACTICE: INTELLiVENT-ASV is attractive to use in clinical practice. It is safe and effective in providing lung-protective ventilation. A closely observing user always remains needed. INTELLiVENT-ASV has a strong potential to reduce the workload associated with ventilation because of the automated adjustments.

Incidence of Air Leaks in Critically Ill Patients with Acute Hypoxemic Respiratory Failure Due to COVID-19.

Subcutaneous emphysema, pneumothorax and pneumomediastinum are well-known complications of invasive ventilation in patients with acute hypoxemic respiratory failure. We determined the incidences of air leaks that were visible on available chest images in a cohort of critically ill patients with acute hypoxemic respiratory failure due to coronavirus disease of 2019 (COVID-19) in a single-center cohort in the Netherlands. A total of 712 chest images from 154 patients were re-evaluated by a multidisciplinary team of independent assessors; there was a median of three (2-5) chest radiographs and a median of one (1-2) chest CT scans per patient. The incidences of subcutaneous emphysema, pneumothoraxes and pneumomediastinum present in 13 patients (8.4%) were 4.5%, 4.5%, and 3.9%. The median first day of the presence of an air leak was 18 (2-21) days after arrival in the ICU and 18 (9-22)days after the start of invasive ventilation. We conclude that the incidence of air leaks was high in this cohort of COVID-19 patients, but it was fairly comparable with what was previously reported in patients with acute hypoxemic respiratory failure in the pre-COVID-19 era.

Oxygen Consumption with High-Flow Nasal Oxygen versus Mechanical Ventilation- An International Multicenter Observational Study in COVID-19 Patients (PROXY-COVID).

The COVID-19 pandemic led to local oxygen shortages worldwide. To gain a better understanding of oxygen consumption with different respiratory supportive therapies, we conducted an international multicenter observational study to determine the precise amount of oxygen consumption with high-flow nasal oxygen (HFNO) and with mechanical ventilation. A retrospective observational study was conducted in three intensive care units (ICUs) in the Netherlands and Spain. Patients were classified as HFNO patients or ventilated patients, according to the mode of oxygen supplementation with which a patient started. The primary endpoint was actual oxygen consumption; secondary endpoints were hourly and total oxygen consumption during the first two full calendar days. Of 275 patients, 147 started with HFNO and 128 with mechanical ventilation. Actual oxygen use was 4.9-fold higher in patients who started with HFNO than in patients who started with ventilation (median 14.2 [8.4-18.4] versus 2.9 [1.8-4.1] L/minute; mean difference = 11.3 [95% CI 11.0-11.6] L/minute; P < 0.01). Hourly and total oxygen consumption were 4.8-fold (P < 0.01) and 4.8-fold (P < 0.01) higher. Actual oxygen consumption, hourly oxygen consumption, and total oxygen consumption are substantially higher in patients that start with HFNO compared with patients that start with mechanical ventilation. This information may help hospitals and ICUs predicting oxygen needs during high-demand periods and could guide decisions regarding the source of distribution of medical oxygen.

Prognostication using SpO2/FiO2 in invasively ventilated ICU patients with ARDS due to COVID-19 - Insights from the PRoVENT-COVID study.

BACKGROUND: The SpO2/FiO2 is a useful oxygenation parameter with prognostic capacity in patients with ARDS. We investigated the prognostic capacity of SpO2/FiO2 for mortality in patients with ARDS due to COVID-19. METHODS: This was a post-hoc analysis of a national multicenter cohort study in invasively ventilated patients with ARDS due to COVID-19. The primary endpoint was 28-day mortality. RESULTS: In 869 invasively ventilated patients, 28-day mortality was 30.1%. The SpO2/FiO2 on day 1 had no prognostic value. The SpO2/FiO2 on day 2 and day 3 had prognostic capacity for death, with the best cut-offs being 179 and 199, respectively. Both SpO2/FiO2 on day 2 (OR, 0.66 [95%-CI 0.46-0.96]) and on day 3 (OR, 0.70 [95%-CI 0.51-0.96]) were associated with 28-day mortality in a model corrected for age, pH, lactate levels and kidney dysfunction (AUROC 0.78 [0.76-0.79]). The measured PaO2/FiO2 and the PaO2/FiO2 calculated from SpO2/FiO2 were strongly correlated (Spearman's r = 0.79). CONCLUSIONS: In this cohort of patients with ARDS due to COVID-19, the SpO2/FiO2 on day 2 and day 3 are independently associated with and have prognostic capacity for 28-day mortality. The SpO2/FiO2 is a useful metric for risk stratification in invasively ventilated COVID-19 patients.

Biomarkers of alveolar epithelial injury and endothelial dysfunction are associated with scores of pulmonary edema in invasively ventilated patients.

BACKGROUND: Pulmonary edema is a central hallmark of Acute Respiratory Distress Syndrome (ARDS). Endothelial dysfunction and epithelial injury contribute to permeability but their differential contribution to pulmonary edema development remains understudied. METHODS: Plasma levels of surfactant protein-D (SP-D), soluble receptor for advanced glycation end products (sRAGE) and angiopoietin-2 (Ang-2) were measured in a prospective, multicenter cohort of invasively ventilated patients. Pulmonary edema was quantified using the radiographic assessment of lung edema (RALE) and global lung ultrasound (LUS) score. Variables were collected within 48 hours after intubation. Linear regression was used to examine the association of the biomarkers with pulmonary edema. RESULTS: In 362 patients, higher SP-D, sRAGE and Ang-2 concentrations were significantly associated with higher RALE and global LUS scores. After stratification by ARDS subgroups (pulmonary, non-pulmonary, COVID, non-COVID), the positive association of SP-D levels with pulmonary edema remained, while sRAGE and Ang-2 showed less consistent associations throughout the subgroups. In a multivariable analysis, SP-D levels were most strongly associated with pulmonary edema when combined with sRAGE (RALE score: ßSP-D = 6.79 units/log10 pg/mL, ßsRAGE = 3.84 units/log10 pg/mL, R2 = 0.23; global LUS score: ßSP-D = 3.28 units/log10 pg/mL, ßsRAGE = 2.06 units/log10 pg/mL, R2 = 0.086), while Ang-2 did not further improve the model. CONCLUSION: Biomarkers of epithelial injury and endothelial dysfunction were associated with pulmonary edema in invasively ventilated patients. SP-D and sRAGE showed the strongest association, suggesting that epithelial injury may form a final common pathway in the alveolar-capillary barrier dysfunction underlying pulmonary edema.

Prognostic Value of the Radiographic Assessment of Lung Edema Score in Mechanically Ventilated ICU Patients.

INTRODUCTION: The Radiographic Assessment of Lung Edema (RALE) score provides a semi-quantitative measure of pulmonary edema. In patients with acute respiratory distress syndrome (ARDS), the RALE score is associated with mortality. In mechanically ventilated patients in the intensive care unit (ICU) with respiratory failure not due to ARDS, a variable degree of lung edema is observed as well. We aimed to evaluate the prognostic value of RALE in mechanically ventilated ICU patients. METHODS: Secondary analysis of patients enrolled in the 'Diagnosis of Acute Respiratory Distress Syndrome' (DARTS) project with an available chest X-ray (CXR) at baseline. Where present, additional CXRs at day 1 were analysed. The primary endpoint was 30-day mortality. Outcomes were also stratified for ARDS subgroups (no ARDS, non-COVID-ARDS and COVID-ARDS). RESULTS: 422 patients were included, of which 84 had an additional CXR the following day. Baseline RALE scores were not associated with 30-day mortality in the entire cohort (OR: 1.01, 95% CI: 0.98-1.03, p = 0.66), nor in subgroups of ARDS patients. Early changes in RALE score (baseline to day 1) were only associated with mortality in a subgroup of ARDS patients (OR: 1.21, 95% CI: 1.02-1.51, p = 0.04), after correcting for other known prognostic factors. CONCLUSIONS: The prognostic value of the RALE score cannot be extended to mechanically ventilated ICU patients in general. Only in ARDS patients, early changes in RALE score were associated with mortality.

Practice of Awake Prone Positioning in Critically Ill COVID-19 Patients-Insights from the PRoAcT-COVID Study.

We describe the incidence, practice and associations with outcomes of awake prone positioning in patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19) in a national multicenter observational cohort study performed in 16 intensive care units in the Netherlands (PRoAcT−COVID-study). Patients were categorized in two groups, based on received treatment of awake prone positioning. The primary endpoint was practice of prone positioning. Secondary endpoint was 'treatment failure', a composite of intubation for invasive ventilation and death before day 28. We used propensity matching to control for observed confounding factors. In 546 patients, awake prone positioning was used in 88 (16.1%) patients. Prone positioning started within median 1 (0 to 2) days after ICU admission, sessions summed up to median 12.0 (8.4−14.5) hours for median 1.0 day. In the unmatched analysis (HR, 1.80 (1.41−2.31); p < 0.001), but not in the matched analysis (HR, 1.17 (0.87−1.59); p = 0.30), treatment failure occurred more often in patients that received prone positioning. The findings of this study are that awake prone positioning was used in one in six COVID-19 patients. Prone positioning started early, and sessions lasted long but were often discontinued because of need for intubation.

Prone Positioning Decreases Inhomogeneity and Improves Dorsal Compliance in Invasively Ventilated Spontaneously Breathing COVID-19 Patients-A Study Using Electrical Impedance Tomography.

BACKGROUND: We studied prone positioning effects on lung aeration in spontaneously breathing invasively ventilated patients with coronavirus disease 2019 (COVID-19). METHODS: changes in lung aeration were studied prospectively by electrical impedance tomography (EIT) from before to after placing the patient prone, and back to supine. Mixed effect models with a random intercept and only fixed effects were used to evaluate changes in lung aeration. RESULTS: fifteen spontaneously breathing invasively ventilated patients were enrolled, and remained prone for a median of 19 [17 to 21] hours. At 16 h the global inhomogeneity index was lower. At 2 h, there were neither changes in dorsal nor in ventral compliance; after 16 h, only dorsal compliance (ßFe +18.9 [95% Confidence interval (CI): 9.1 to 28.8]) and dorsal end-expiratory lung impedance (EELI) were increased (ßFe, +252 [95% CI: 13 to 496]); at 2 and 16 h, dorsal silent spaces was unchanged (ßFe, -4.6 [95% CI: -12.3 to +3.2]). The observed changes induced by prone positioning disappeared after turning patients back to supine. CONCLUSIONS: in this cohort of spontaneously breathing invasively ventilated COVID-19 patients, prone positioning decreased inhomogeneity, increased lung volumes, and improved dorsal compliance.

Longitudinal respiratory subphenotypes in patients with COVID-19-related acute respiratory distress syndrome: results from three observational cohorts.

BACKGROUND: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) have been postulated to present with distinct respiratory subphenotypes. However, most phenotyping schema have been limited by sample size, disregard for temporal dynamics, and insufficient validation. We aimed to identify respiratory subphenotypes of COVID-19-related ARDS using unbiased data-driven approaches. METHODS: PRoVENT-COVID was an investigator-initiated, national, multicentre, prospective, observational cohort study at 22 intensive care units (ICUs) in the Netherlands. Consecutive patients who had received invasive mechanical ventilation for COVID-19 (aged 18 years or older) served as the derivation cohort, and similar patients from two ICUs in the USA served as the replication cohorts. COVID-19 was confirmed by positive RT-PCR. We used latent class analysis to identify subphenotypes using clinically available respiratory data cross-sectionally at baseline, and longitudinally using 8-hourly data from the first 4 days of invasive ventilation. We used group-based trajectory modelling to evaluate trajectories of individual variables and to facilitate potential clinical translation. The PRoVENT-COVID study is registered with ClinicalTrials.gov, NCT04346342. FINDINGS: Between March 1, 2020, and May 15, 2020, 1007 patients were admitted to participating ICUs in the Netherlands, and included in the derivation cohort. Data for 288 patients were included in replication cohort 1 and 326 in replication cohort 2. Cross-sectional latent class analysis did not identify any underlying subphenotypes. Longitudinal latent class analysis identified two distinct subphenotypes. Subphenotype 2 was characterised by higher mechanical power, minute ventilation, and ventilatory ratio over the first 4 days of invasive mechanical ventilation than subphenotype 1, but PaO2/FiO2, pH, and compliance of the respiratory system did not differ between the two subphenotypes. 185 (28%) of 671 patients with subphenotype 1 and 109 (32%) of 336 patients with subphenotype 2 had died at day 28 (p=0·10). However, patients with subphenotype 2 had fewer ventilator-free days at day 28 (median 0, IQR 0-15 vs 5, 0-17; p=0·016) and more frequent venous thrombotic events (109 [32%] of 336 patients vs 176 [26%] of 671 patients; p=0·048) compared with subphenotype 1. Group-based trajectory modelling revealed trajectories of ventilatory ratio and mechanical power with similar dynamics to those observed in latent class analysis-derived trajectory subphenotypes. The two trajectories were: a stable value for ventilatory ratio or mechanical power over the first 4 days of invasive mechanical ventilation (trajectory A) or an upward trajectory (trajectory B). However, upward trajectories were better independent prognosticators for 28-day mortality (OR 1·64, 95% CI 1·17-2·29 for ventilatory ratio; 1·82, 1·24-2·66 for mechanical power). The association between upward ventilatory ratio trajectories (trajectory B) and 28-day mortality was confirmed in the replication cohorts (OR 4·65, 95% CI 1·87-11·6 for ventilatory ratio in replication cohort 1; 1·89, 1·05-3·37 for ventilatory ratio in replication cohort 2). INTERPRETATION: At baseline, COVID-19-related ARDS has no consistent respiratory subphenotype. Patients diverged from a fairly homogenous to a more heterogeneous population, with trajectories of ventilatory ratio and mechanical power being the most discriminatory. Modelling these parameters alone provided prognostic value for duration of mechanical ventilation and mortality. FUNDING: Amsterdam UMC.

The RALE Score Versus the CT Severity Score in Invasively Ventilated COVID-19 Patients-A Retrospective Study Comparing Their Prognostic Capacities.

BACKGROUND: Quantitative radiological scores for the extent and severity of pulmonary infiltrates based on chest radiography (CXR) and computed tomography (CT) scan are increasingly used in critically ill invasively ventilated patients. This study aimed to determine and compare the prognostic capacity of the Radiographic Assessment of Lung Edema (RALE) score and the chest CT Severity Score (CTSS) in a cohort of invasively ventilated patients with acute respiratory distress syndrome (ARDS) due to COVID-19. METHODS: Two-center retrospective observational study, including consecutive invasively ventilated COVID-19 patients. Trained scorers calculated the RALE score of first available CXR and the CTSS of the first available CT scan. The primary outcome was ICU mortality; secondary outcomes were duration of ventilation in survivors, length of stay in ICU, and hospital-, 28-, and 90-day mortality. Prognostic accuracy for ICU death was expressed using odds ratios and Area Under the Receiver Operating Characteristic curves (AUROC). RESULTS: A total of 82 patients were enrolled. The median RALE score (22 [15-37] vs. 26 [20-39]; p = 0.34) and the median CTSS (18 [16-21] vs. 21 [18-23]; p = 0.022) were both lower in ICU survivors compared to ICU non-survivors, although only the difference in CTSS reached statistical significance. While no association was observed between ICU mortality and RALE score (OR 1.35 [95%CI 0.64-2.84]; p = 0.417; AUC 0.50 [0.44-0.56], this was noticed with the CTSS (OR, 2.31 [1.22-4.38]; p = 0.010) although with poor prognostic capacity (AUC 0.64 [0.57-0.69]). The correlation between the RALE score and CTSS was weak (r2 = 0.075; p = 0.012). CONCLUSIONS: Despite poor prognostic capacity, only CTSS was associated with ICU mortality in our cohort of COVID-19 patients.

Upcoming and urgent challenges in critical care research based on COVID-19 pandemic experience.

While the coronavirus disease 2019 (COVID-19) pandemic placed a heavy burden on healthcare systems worldwide, it also induced urgent mobilisation of research teams to develop treatments preventing or curing the disease and its consequences. It has, therefore, challenged critical care research to rapidly focus on specific fields while forcing critical care physicians to make difficult ethical decisions. This narrative review aims to summarise critical care research -from organisation to research fields- in this pandemic setting and to highlight opportunities to improve research efficiency in the future, based on what is learned from COVID-19. This pressure on research revealed, i.e., (i) the need to harmonise regulatory processes between countries, allowing simplified organisation of international research networks to improve their efficiency in answering large-scale questions; (ii) the importance of developing translational research from which therapeutic innovations can emerge; (iii) the need for improved triage and predictive scores to rationalise admission to the intensive care unit. In this context, key areas for future critical care research and better pandemic preparedness are artificial intelligence applied to healthcare, characterisation of long-term symptoms, and ethical considerations. Such collaborative research efforts should involve groups from both high and low-to-middle income countries to propose worldwide solutions. As a conclusion, stress tests on healthcare organisations should be viewed as opportunities to design new research frameworks and strategies. Worldwide availability of research networks ready to operate is essential to be prepared for next pandemics. Importantly, researchers and physicians should prioritise realistic and ethical goals for both clinical care and research.

Low tidal volume ventilation is associated with mortality in COVID-19 patients-Insights from the PRoVENT-COVID study.

PURPOSE: Low tidal volume ventilation (LTVV) is associated with mortality in patients with acute respiratory distress syndrome. We investigated the association of LTVV with mortality in COVID-19 patients. METHODS: Secondary analysis of a national observational study in COVID-19 patients in the first wave of the pandemic. We compared COVID-19 patients that received LTVV, defined as controlled ventilation with a median tidal volume ≤ 6 mL/kg predicted body weight over the first 4 calendar days of ventilation, with patients that did not receive LTVV. The primary endpoint was 28-day mortality. In addition, we identified factors associated with use of LTVV. RESULTS: Of 903 patients, 294 (32.5%) received LTVV. Disease severity scores and ARDS classification was not different between the two patient groups. The primary endpoint, 28-day mortality, was met in 68 out of 294 patients (23.1%) that received LTVV versus in 193 out of 609 patients (31.7%) that did not receive LTVV (P < 0.001). LTVV was independently associated with 28-day mortality (HR, 0.68 (0.45 to 0.95); P = 0.025). Age, height, the initial tidal volume and continuous muscle paralysis was independently associated with use of LTVV. CONCLUSIONS: In this cohort of invasively ventilated COVID-19 patients, approximately a third of patients received LTVV. Use of LTVV was independently associated with reduced 28-day mortality. The initial tidal volume and continuous muscle paralysis were potentially modifiable factors associated with use of LTVV. These findings are important as they could help clinicians to recognize patients who are at risk of not receiving LTVV.

Closed-loop oxygen control improves oxygen therapy in acute hypoxemic respiratory failure patients under high flow nasal oxygen: a randomized cross-over study (the HILOOP study).

BACKGROUND: We aimed to assess the efficacy of a closed-loop oxygen control in critically ill patients with moderate to severe acute hypoxemic respiratory failure (AHRF) treated with high flow nasal oxygen (HFNO). METHODS: In this single-centre, single-blinded, randomized crossover study, adult patients with moderate to severe AHRF who were treated with HFNO (flow rate ≥ 40 L/min with FiO2 ≥ 0.30) were randomly assigned to start with a 4-h period of closed-loop oxygen control or 4-h period of manual oxygen titration, after which each patient was switched to the alternate therapy. The primary outcome was the percentage of time spent in the individualized optimal SpO2 range. RESULTS: Forty-five patients were included. Patients spent more time in the optimal SpO2 range with closed-loop oxygen control compared with manual titrations of oxygen (96.5 [93.5 to 98.9] % vs. 89 [77.4 to 95.9] %; p < 0.0001) (difference estimate, 10.4 (95% confidence interval 5.2 to 17.2). Patients spent less time in the suboptimal range during closed-loop oxygen control, both above and below the cut-offs of the optimal SpO2 range, and less time above the suboptimal range. Fewer number of manual adjustments per hour were needed with closed-loop oxygen control. The number of events of SpO2 < 88% and < 85% were not significantly different between groups. CONCLUSIONS: Closed-loop oxygen control improves oxygen administration in patients with moderate-to-severe AHRF treated with HFNO, increasing the percentage of time in the optimal oxygenation range and decreasing the workload of healthcare personnel. These results are especially relevant in a context of limited oxygen supply and high medical demand, such as the COVID-19 pandemic. Trial registration The HILOOP study was registered at www. CLINICALTRIALS: gov under the identifier NCT04965844 .

Clinical characteristics, physiological features, and outcomes associated with hypercapnia in patients with acute hypoxemic respiratory failure due to COVID-19---insights from the PRoVENT-COVID study.

PURPOSE: We determined the incidence of hypercapnia and associations with outcome in invasively ventilated COVID-19 patients. METHODS: Posthoc analysis of a national, multicenter, observational study in 22 ICUs. Patients were classified as 'hypercapnic' or 'normocapnic' in the first three days of invasive ventilation. Primary endpoint was prevalence of hypercapnia. Secondary endpoints were ventilator parameters, length of stay (LOS) in ICU and hospital, and mortality in ICU, hospital, at day 28 and 90. RESULTS: Of 824 patients, 485 (58.9%) were hypercapnic. Hypercapnic patients had a higher BMI and had COPD, severe ARDS and venous thromboembolic events more often. Hypercapnic patients were ventilated with lower tidal volumes, higher respiratory rates, higher driving pressures, and with more mechanical power of ventilation. Hypercapnic patients had comparable minute volumes but higher ventilatory ratios than normocapnic patients. In hypercapnic patients, ventilation and LOS in ICU and hospital was longer, but mortality was comparable to normocapnic patients. CONCLUSION: Hypercapnia occurs often in invasively ventilated COVID-19 patients. Main differences between hypercapnic and normocapnic patients are severity of ARDS, occurrence of venous thromboembolic events, and a higher ventilation ratio. Hypercapnia has an association with duration of ventilation and LOS in ICU and hospital, but not with mortality.