The COVID-19 Driving Force: How It Shaped the Evidence of Non-Invasive Respiratory Support.

During the COVID-19 pandemic, the use of non-invasive respiratory support (NIRS) became crucial in treating patients with acute hypoxemic respiratory failure. Despite the fear of viral aerosolization, non-invasive respiratory support has gained attention as a way to alleviate ICU overcrowding and reduce the risks associated with intubation. The COVID-19 pandemic has led to an unprecedented increased demand for research, resulting in numerous publications on observational studies, clinical trials, reviews, and meta-analyses in the past three years. This comprehensive narrative overview describes the physiological rationale, pre-COVID-19 evidence, and results of observational studies and randomized control trials regarding the use of high-flow nasal oxygen, non-invasive mechanical ventilation, and continuous positive airway pressure in adult patients with COVID-19 and associated acute hypoxemic respiratory failure. The review also highlights the significance of guidelines and recommendations provided by international societies and the need for further well-designed research to determine the optimal use of NIRS in treating this population.

Differences in clinical characteristics and outcomes between COVID-19 and influenza in critically ill adult patients: A national database study.

OBJECTIVE: Prior to the coronavirus disease 2019 (COVID-19) pandemic, influenza was the most frequent cause of viral respiratory pneumonia requiring intensive care unit (ICU) admission. Few studies have compared the characteristics and outcomes of critically ill patients with COVID-19 and influenza. METHODS: This was a French nationwide study comparing COVID-19 (March 1, 2020-June 30, 2021) and influenza patients (January 1, 2014-December 31, 2019) admitted to an ICU during pre-vaccination era. Primary outcome was in-hospital death. Secondary outcome was need for mechanical ventilation. RESULTS: 105,979 COVID-19 patients were compared to 18,763 influenza patients. Critically ill patients with COVID-19 were more likely to be men with more comorbidities. Patients with influenza required more invasive mechanical ventilation (47 vs. 34%, p < 0·001), vasopressors (40% vs. 27, p < 0·001) and renal-replacement therapy (22 vs. 7%, p < 0·001). Hospital mortality was 25% and 21% (p < 0·001) in patients with COVID-19 and influenza, respectively. In the subgroup of patients receiving invasive mechanical ventilation, ICU length of stay was significantly longer in patients with COVID-19 (18 [10-32] vs. 15 [8-26] days, p < 0·001). Adjusting for age, gender, comorbidities, and modified SAPS II score, in-hospital death was higher in COVID-19 patients (adjusted sub-distribution hazard ratio [aSHR]=1.69; 95%CI=1.63-1.75) compared with influenza patients. COVID-19 was also associated with less invasive mechanical ventilation (aSHR=0.87; 95%CI=0.85-0.89) and a higher likelihood of death without invasive mechanical ventilation (aSHR=2.40; 95%CI=2.24-2.57). CONCLUSION: Despite younger age and lower SAPS II score, critically ill COVID-19 patients had a longer hospital stay and higher mortality than patients with influenza.

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia: The ANTICOVID Randomized Clinical Trial.

Importance: Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative. Objectives: To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies. Design, Settings, and Participants: The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis-114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023. Interventions: Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days. Main Outcomes and Measures: A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death). Results: Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95% CI, 39.9% to 54.8%] vs 52.7% [95% CI, 45.2% to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95% CI, 43.4% to 58.3%] vs 49.1% [95% CI, 41.7% to 56.6%]; P = .82) and TA compared with HD-PA (53.5% [95% CI 45.8% to 60.9%] vs 46.5% [95% CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2% thrombosis, 2.6% bleeding, 14.0% death), 16.4% receiving HD-PA (5.5% thrombosis, 3.6% bleeding, 11.8% death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7% death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, -14.7 [95% CI -6.2 to -23.2] and -14.7 [95% CI -6.2 to -23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, -13.5; 95% CI -2.6 to -24.3). Conclusions and Relevance: This randomized clinical trial found that compared with SD-PA, neither HD-PA nor TA use improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemic COVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04808882.

Trends in clinical characteristics and outcomes of all critically ill COVID-19 adult patients hospitalized in France between March 2020 and June 2021: a national database study.

INTRODUCTION: Studies regarding coronavirus disease 2019 (COVID-19) were mainly performed in the initial wave, but some small-scale data points to prognostic differences for patients in successive waves. We therefore aimed to study the impact of time on prognosis of ICU-admitted COVID-19 patients. METHOD: We performed a national retrospective cohort study, including all adult patients hospitalized in French ICUs from March 1, 2020 to June 30, 2021, and identified three surge periods. Primary and secondary outcomes were in-hospital mortality and need for invasive mechanical ventilation, respectively. RESULTS: 105,979 critically ill ICU-admitted COVID-19 patients were allocated to the relevant three surge periods. In-hospital mortality for surges 1, 2, and 3 was, respectively, 24%, 27%, and 24%. Invasive mechanical ventilation was the highest level of respiratory support for 42%, 32%, and 31% (p < 0.001) over the whole period, with a decline in the use of vasopressors over time. Adjusted for age, sex, comorbidities, and modified Simplified Acute Physiology Score II at ICU admission, time period was associated with less invasive mechanical ventilation and a high risk of in-hospital death. Vaccination against COVID-19 was associated with a lower likelihood of invasive mechanical ventilation (adjusted sub-hazard ratio [aSHR] = 0.64 [0.53-0.76]) and intra-hospital death (aSHR = 0.80, [0.68-0.95]). CONCLUSION: In this large database of ICU patients admitted for COVID-19, we observed a decline in invasive mechanical ventilation, vasopressors, and RRT use over time but a high risk of in-hospital death. Vaccination was identified as protective against the risk of invasive mechanical ventilation and in-hospital death.

Low dose of morphine to relieve dyspnea in acute respiratory failure (OpiDys): protocol for a double-blind randomized controlled study.

BACKGROUND: Dyspnea is common and severe in intensive care unit (ICU) patients managed for acute respiratory failure. Dyspnea appears to be associated with impaired prognosis and neuropsychological sequels. Pain and dyspnea share many similarities and previous studies have shown the benefit of morphine on dyspnea in patients with end-stage onco-hematological disease and severe heart or respiratory disease. In these populations, morphine administration was safe. Here, we hypothesize that low-dose opioids may help to reduce dyspnea in patients admitted to the ICU for acute respiratory failure. The primary objective of the trial is to determine whether the administration of low-dose titrated opioids, compared to placebo, in patients admitted to the ICU for acute respiratory failure with severe dyspnea decreases the mean 24-h intensity of dyspnea score. METHODS: In this single-center double-blind randomized controlled trial with 2 parallel arms, we plan to include 22 patients (aged 18-75 years) on spontaneous ventilation with either non-invasive ventilation, high flow oxygen therapy or standard oxygen therapy admitted to the ICU for acute respiratory failure with severe dyspnea. They will be assigned after randomization with a 1:1 allocation ratio to receive in experimental arm administration of low-dose titrated morphine hydrochloride for 24 h consisting in an intravenous titration relayed subcutaneously according to a predefined protocol, or a placebo (0.9% NaCl) administered according to the same protocol in the control arm. The primary endpoint is the mean 24-h dyspnea score assessed by a visual analog scale of dyspnea. DISCUSSION: To our knowledge, this study is the first to evaluate the benefit of opioids on dyspnea in ICU patients admitted for acute respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT04358133 . Registered on 24 April 2020.

Specialized Weaning Unit in the Trajectory of SARS-CoV-2 ARDS: Influence of Limb Muscle Strength on Decannulation and Rehabilitation.

BACKGROUND: Patients with ARDS due to COVID-19 may require tracheostomy and transfer to a weaning center. To date, data on the outcome of these patients are scarce. The objectives of this study were to determine the factors associated with time to decannulation and limb-muscle strength recovery. METHODS: This was an observational retrospective study of subjects with COVID-19-related ARDS requiring tracheostomy after prolonged ventilation, who were subsequently transferred to a weaning center from April 4, 2020-May 30, 2020. RESULTS: Forty-three subjects were included. Median age (interquartile range) was 61 (48-66) y; 81% were men, and median body mass index (BMI) was 30 (26-35) kg/m2. Tracheostomy was performed after a median of 19 (12-27) d of mechanical ventilation, and the median ICU length of stay prior to transfer to the weaning center was 30 (21-46) d. On admission to the weaning center, the median Medical Research Council (MRC) score was 36 (27-44). Time to decannulation was 9 (7-18) d after admission to the weaning center. The only factor independently associated with early decannulation was the MRC score on admission to the weaning center (odds ratio 1.16 [95% CI 1.06-1.31], P = .005). Two factors were independently associated with MRC gain ≥ 10: BMI (odds ratio 0.88 [95% CI 0.76-0.99], P = .045) and MRC on admission (odds ratio 0.91 [95% CI 0.82-0.98], P = .03. Three months after admission to the weaning center, 40 subjects (93%) were weaned from mechanical ventilation and 36 (84%) had returned home. CONCLUSIONS: MRC score at weaning center admission predicted both early decannulation and limb-muscle strength recovery.

Comparison of standard prophylactic, intermediate prophylactic and therapeutic anticoagulation in patients with severe COVID-19: protocol for the ANTICOVID multicentre, parallel-group, open-label, randomised controlled trial.

INTRODUCTION: COVID-19 induces venous, arterial and microvascular thrombosis, involving several pathophysiological processes. In patients with severe COVID-19 without macrovascular thrombosis, escalating into high-dose prophylactic anticoagulation (HD-PA) or therapeutic anticoagulation (TA) could be beneficial in limiting the extension of microvascular thrombosis and forestalling the evolution of lung and multiorgan microcirculatory dysfunction. In the absence of data from randomised trials, clinical practice varies widely. METHODS AND ANALYSIS: This is a French multicentre, parallel-group, open-label, randomised controlled superiority trial to compare the efficacy and safety of three anticoagulation strategies in patients with COVID-19. Patients with oxygen-treated COVID-19 showing no pulmonary artery thrombosis on computed tomography with pulmonary angiogram will be randomised to receive either low-dose PA, HD-PA or TA for 14 days. Patients attaining the extremes of weight and those with severe renal failure will not be included. We will recruit 353 patients. Patients will be randomised on a 1:1:1 basis, and stratified by centre, use of invasive mechanical ventilation, D-dimer levels and body mass index. The primary endpoint is a hierarchical criterion at day 28 including all-cause mortality, followed by the time to clinical improvement defined as the time from randomisation to an improvement of at least two points on the ordinal clinical scale. Secondary outcomes include thrombotic and major bleeding events at day 28, individual components of the primary endpoint, number of oxygen-free, ventilator-free and vasopressor-free days at day 28, D-dimer and sepsis-induced coagulopathy score at day 7, intensive care unit and hospital stay at day 28 and day 90, and all-cause death and quality of life at day 90. ETHICS AND DISSEMINATION: The study has been approved by an ethical committee (Ethics Committee, Ile de France VII, Paris, France; reference 2020-A03531-38). Patients will be included after obtaining their signed informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04808882.

Spike Gene Evolution and Immune Escape Mutations in Patients with Mild or Moderate Forms of COVID-19 and Treated with Monoclonal Antibodies Therapies.

We explored the molecular evolution of the spike gene after the administration of anti-spike monoclonal antibodies in patients with mild or moderate forms of COVID-19. Four out of the 13 patients acquired a mutation during follow-up; two mutations (G1204E and E406G) appeared as a mixture without clinical impact, while the Q493R mutation emerged in two patients (one receiving bamlanivimab and one receiving bamlanivimab/etesevimab) with fatal outcomes. Careful virological monitoring of patients treated with mAbs should be performed, especially in immunosuppressed patients.

Evolving outcomes of extracorporeal membrane oxygenation support for severe COVID-19 ARDS in Sorbonne hospitals, Paris.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) was frequently used to treat patients with severe coronavirus disease-2019 (COVID-19)-associated acute respiratory distress (ARDS) during the initial outbreak. Care of COVID-19 patients evolved markedly during the second part of 2020. Our objective was to compare the characteristics and outcomes of patients who received ECMO for severe COVID-19 ARDS before or after July 1, 2020. METHODS: We included consecutive adults diagnosed with COVID-19 in Paris-Sorbonne University Hospital Network ICUs, who received ECMO for severe ARDS until January 28, 2021. Characteristics and survival probabilities over time were estimated during the first and second waves. Pre-ECMO risk factors predicting 90-day mortality were assessed using multivariate Cox regression. RESULTS: Characteristics of the 88 and 71 patients admitted, respectively, before and after July 1, 2020, were comparable except for older age, more frequent use of dexamethasone (18% vs. 82%), high-flow nasal oxygenation (19% vs. 82%) and/or non-invasive ventilation (7% vs. 37%) after July 1. Respective estimated probabilities (95% confidence intervals) of 90-day mortality were 36% (27-47%) and 48% (37-60%) during the first and the second periods. After adjusting for confounders, probability of 90-day mortality was significantly higher for patients treated after July 1 (HR 2.27, 95% CI 1.02-5.07). ECMO-related complications did not differ between study periods. CONCLUSIONS: 90-day mortality of ECMO-supported COVID-19-ARDS patients increased significantly after July 1, 2020, and was no longer comparable to that of non-COVID ECMO-treated patients. Failure of prolonged non-invasive oxygenation strategies before intubation and increased lung damage may partly explain this outcome.

Correction to: Effect of PEEP decremental on respiratory mechanics, gas exchange, pulmonary regional ventilation, and hemodynamics in patients with SARS-Cov-2-associated Acute Respiratory Distress Syndrome.

An amendment to this paper has been published and can be accessed via the original article.

COVID-19 ARDS is characterized by higher extravascular lung water than non-COVID-19 ARDS: the PiCCOVID study.

BACKGROUND: In acute respiratory distress syndrome (ARDS), extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPI) measured by transpulmonary thermodilution reflect the degree of lung injury. Whether EVLWi and PVPI are different between non-COVID-19 ARDS and the ARDS due to COVID-19 has never been reported. We aimed at comparing EVLWi, PVPI, respiratory mechanics and hemodynamics in patients with COVID-19 ARDS vs. ARDS of other origin. METHODS: Between March and October 2020, in an observational study conducted in intensive care units from three university hospitals, 60 patients with COVID-19-related ARDS monitored by transpulmonary thermodilution were compared to the 60 consecutive non-COVID-19 ARDS admitted immediately before the COVID-19 outbreak between December 2018 and February 2020. RESULTS: Driving pressure was similar between patients with COVID-19 and non-COVID-19 ARDS, at baseline as well as during the study period. Compared to patients without COVID-19, those with COVID-19 exhibited higher EVLWi, both at the baseline (17 (14-21) vs. 15 (11-19) mL/kg, respectively, p = 0.03) and at the time of its maximal value (24 (18-27) vs. 21 (15-24) mL/kg, respectively, p = 0.01). Similar results were observed for PVPI. In COVID-19 patients, the worst ratio between arterial oxygen partial pressure over oxygen inspired fraction was lower (81 (70-109) vs. 100 (80-124) mmHg, respectively, p = 0.02) and prone positioning and extracorporeal membrane oxygenation (ECMO) were more frequently used than in patients without COVID-19. COVID-19 patients had lower maximal lactate level and maximal norepinephrine dose than patients without COVID-19. Day-60 mortality was similar between groups (57% vs. 65%, respectively, p = 0.45). The maximal value of EVLWi and PVPI remained independently associated with outcome in the whole cohort. CONCLUSION: Compared to ARDS patients without COVID-19, patients with COVID-19 had similar lung mechanics, but higher EVLWi and PVPI values from the beginning of the disease. This was associated with worse oxygenation and with more requirement of prone positioning and ECMO. This is compatible with the specific lung inflammation and severe diffuse alveolar damage related to COVID-19. By contrast, patients with COVID-19 had fewer hemodynamic derangement. Eventually, mortality was similar between groups. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: ClinicalTrials.gov (NCT04337983). Registered 30 March 2020-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04337983 .

Characteristics, management, and prognosis of elderly patients with COVID-19 admitted in the ICU during the first wave: insights from the COVID-ICU study : Prognosis of COVID-19 elderly critically ill patients in the ICU.

BACKGROUND: The COVID-19 pandemic is a heavy burden in terms of health care resources. Future decision-making policies require consistent data on the management and prognosis of the older patients (> 70 years old) with COVID-19 admitted in the intensive care unit (ICU). METHODS: Characteristics, management, and prognosis of critically ill old patients (> 70 years) were extracted from the international prospective COVID-ICU database. A propensity score weighted-comparison evaluated the impact of intubation upon admission on Day-90 mortality. RESULTS: The analysis included 1199 (28% of the COVID-ICU cohort) patients (median [interquartile] age 74 [72-78] years). Fifty-three percent, 31%, and 16% were 70-74, 75-79, and over 80 years old, respectively. The most frequent comorbidities were chronic hypertension (62%), diabetes (30%), and chronic respiratory disease (25%). Median Clinical Frailty Scale was 3 (2-3). Upon admission, the PaO2/FiO2 ratio was 154 (105-222). 740 (62%) patients were intubated on Day-1 and eventually 938 (78%) during their ICU stay. Overall Day-90 mortality was 46% and reached 67% among the 193 patients over 80 years old. Mortality was higher in older patients, diabetics, and those with a lower PaO2/FiO2 ratio upon admission, cardiovascular dysfunction, and a shorter time between first symptoms and ICU admission. In propensity analysis, early intubation at ICU admission was associated with a significantly higher Day-90 mortality (42% vs 28%; hazard ratio 1.68; 95% CI 1.24-2.27; p < 0·001). CONCLUSION: Patients over 70 years old represented more than a quarter of the COVID-19 population admitted in the participating ICUs during the first wave. Day-90 mortality was 46%, with dismal outcomes reported for patients older than 80 years or those intubated upon ICU admission.

Co-infection of SARS-CoV-2 with other respiratory viruses and performance of lower respiratory tract samples for the diagnosis of COVID-19.

OBJECTIVES: This study was performed during the early outbreak period of coronavirus disease 2019 (COVID-19) and the seasonal epidemics of other respiratory viral infections, in order to describe the extent of co-infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with other respiratory viruses. It also compared the diagnostic performances of upper respiratory tract (URT) and lower respiratory tract (LRT) samples for SARS-CoV-2 infection. METHODS: From 25 January to 29 March 2020, all URT and LRT samples collected from patients with suspected COVID-19 received in the virology laboratory of Pitié-Salpêtrière University Hospital (Paris, France) were simultaneously tested for SARS-CoV-2 and other respiratory viruses. RESULTS: A total of 1423 consecutive patients were tested: 677 (47.6%) males, 746 (52.4%) females, median age 50 (range, 1-103) years. Twenty-one (1.5%) patients were positive for both SARS-CoV-2 and other respiratory viruses. The detection rate of SARS-CoV-2 was significantly higher in LRT than in URT (53.6% vs. 13.4%; p<0.0001). The analysis of paired samples from 117 (8.2%) patients showed that SARS-CoV-2 load was lower in URT than in LRT samples in 65% of cases. CONCLUSION: The detection of other respiratory viruses in patients during this epidemic period could not rule out SARS-CoV-2 co-infection. Furthermore, LRT samples increased the accuracy of diagnosis of COVID-19.

Focus on renal blood flow in mechanically ventilated patients with SARS-CoV-2: a prospective pilot study.

Mechanically ventilated patients with ARDS due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seem particularly susceptible to AKI. Our hypothesis was that the renal blood flow could be more compromised in SARS-CoV-2 patients than in patients with "classical" ARDS. We compared the renal resistivity index (RRI) and the renal venous flow (RVF) in ARDS patients with SARS-CoV-2 and in ARDS patients due to other etiologies. Prospective, observational pilot study performed on 30 mechanically ventilated patients (15 with SARS-COV-2 ARDS and 15 with ARDS). Mechanical ventilation settings included constant-flow controlled ventilation, a tidal volume of 6 ml/kg of ideal body weight and the PEEP level titrated to the lowest driving pressure. Ultrasound Doppler measurements of RRI and RVF pattern were performed in each patient. Patients with SARS-COV-2 ARDS had higher RRI than patients with ARDS (0.71[0.67-0.78] vs 0.64[0.60-0.74], p = 0.04). RVF was not-continuous in 9/15 patients (71%) in the SARS-COV-2 ARDS group and in and 5/15 (33%) in the ARDS group (p = 0.27). A linear correlation was found between PEEP and RRI in patients with SARS-COV-2 ARDS (r2 = 0.31; p = 0.03) but not in patients with ARDS. Occurrence of AKI was 53% in patients with SARS-COV-2 ARDS and 33% in patients with ARDS (p = 0.46). We found a more pronounced impairment in renal blood flow in mechanically ventilated patients with SARS-COV-2 ARDS, compared with patients with "classical" ARDS.