High-Dose Steroids for Nonresolving Acute Respiratory Distress Syndrome in Critically Ill COVID-19 Patients Treated With Dexamethasone: A Multicenter Cohort Study.

OBJECTIVES: To determine the impact of high doses of corticosteroids (HDCT) in critically ill COVID-19 patients with nonresolving acute respiratory distress syndrome (ARDS) who had been previously treated with dexamethasone as a standard of care. DESIGN: Prospective observational cohort study. Eligible patients presented nonresolving ARDS related to severe acute respiratory syndrome coronavirus 2 infection and had received initial treatment with dexamethasone. We compared patients who had received or not HDCT during ICU stay, consisting of greater than or equal to 1 mg/kg of methylprednisolone or equivalent for treatment of nonresolving ARDS. The primary outcome was 90-day mortality. We assessed the impact of HDCT on 90-day mortality using univariable and multivariable Cox regression analysis. Further adjustment for confounding variables was performed using overlap weighting propensity score. The association between HDCT and the risk of ventilator-associated pneumonia was estimated using multivariable cause-specific Cox proportional hazard model adjusting for pre-specified confounders. SETTING: We included consecutive patients admitted in 11 ICUs of Great Paris area from September 2020 to February 2021. PATIENTS: Three hundred eighty-three patients were included (59 in the HDCT group, 324 in the no HDCT group). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At day 90, 30 of 59 patients (51%) in the HDCT group and 116 of 324 patients (35.8%) in the no HDCT group had died. HDCT was significantly associated with 90-day mortality in unadjusted (hazard ratio [HR], 1.60; 95% CI, 1.04-2.47; p = 0.033) and adjusted analysis with overlap weighting (adjusted HR, 1.65; 95% CI, 1.03-2.63; p = 0.036). HDCT was not associated with an increased risk of ventilator-associated pneumonia (adjusted cause-specific HR, 0.42; 95% CI, 0.15-1.16; p = 0.09). CONCLUSIONS: In critically ill COVID-19 patients with nonresolving ARDS, HDCT result in a higher 90-day mortality.

SARS-CoV-2 variants and mutational patterns: relationship with risk of ventilator-associated pneumonia in critically ill COVID-19 patients in the era of dexamethasone.

We aimed to explore the relationships between specific viral mutations/mutational patterns and ventilator-associated pneumonia (VAP) occurrence in COVID-19 patients admitted in intensive care units between October 1, 2020, and May 30, 2021. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing. In this prospective multicentre cohort study, 259 patients were included. 222 patients (47%) had been infected with pre-existing ancestral variants, 116 (45%) with variant α, and 21 (8%) with other variants. 153 patients (59%) developed at least one VAP. There was no significant relationship between VAP occurrence and a specific SARS CoV-2 lineage/sublineage or mutational pattern.

Use of high-flow nasal cannula oxygen and risk factors for high-flow nasal cannula oxygen failure in critically-ill patients with COVID-19.

BACKGROUND: High-flow nasal oxygen therapy (HFNC) may be an attractive first-line ventilatory support in COVID-19 patients. However, HNFC use for the management of COVID-19 patients and risk factors for HFNC failure remain to be determined. METHODS: In this retrospective study, we included all consecutive COVID-19 patients admitted to our intensive care unit (ICU) in the first (Mars-May 2020) and second (August 2020- February 202) French pandemic waves. Patients with limitations for intubation were excluded. HFNC failure was defined as the need for intubation after ICU admission. The impact of HFNC use was analyzed in the whole cohort and after constructing a propensity score. Risk factors for HNFC failure were identified through a landmark time-dependent cause-specific Cox model. The ability of the 6-h ROX index to detect HFNC failure was assessed by generating receiver operating characteristic (ROC) curve. RESULTS: 200 patients were included: HFNC was used in 114(57%) patients, non-invasive ventilation in 25(12%) patients and 145(72%) patients were intubated with a median delay of 0 (0-2) days after ICU admission. Overall, 78(68%) patients had HFNC failure. Patients with HFNC failure had a higher ICU mortality rate (34 vs. 11%, p = 0.02) than those without. At landmark time of 48 and 72 h, SAPS-2 score, extent of CT-Scan abnormalities > 75% and HFNC duration (cause specific hazard ratio (CSH) = 0.11, 95% CI (0.04-0.28), per + 1 day, p < 0.001 at 48 h and CSH = 0.06, 95% CI (0.02-0.23), per + 1 day, p < 0.001 at 72 h) were associated with HFNC failure. The 6-h ROX index was lower in patients with HFNC failure but could not reliably predicted HFNC failure with an area under ROC curve of 0.65 (95% CI(0.52-0.78), p = 0.02). In the matched cohort, HFNC use was associated with a lower risk of intubation (CSH = 0.32, 95% CI (0.19-0.57), p < 0.001). CONCLUSIONS: In critically-ill COVID-19 patients, while HFNC use as first-line ventilatory support was associated with a lower risk of intubation, more than half of patients had HFNC failure. Risk factors for HFNC failure were SAPS-2 score and extent of CT-Scan abnormalities > 75%. The risk of HFNC failure could not be predicted by the 6-h ROX index but decreased after a 48-h HFNC duration.

Auto-antibodies against type I IFNs in > 10% of critically ill COVID-19 patients: a prospective multicentre study.

BACKGROUND: Auto-antibodies (auto-Abs) neutralizing type I interferons (IFN) have been found in about 15% of critical cases COVID-19 pneumonia and less than 1% of mild or asymptomatic cases. Determining whether auto-Abs influence presentation and outcome of critically ill COVID-19 patients could lead to specific therapeutic interventions. Our objectives were to compare the severity at admission and the mortality of patients hospitalized for critical COVID-19 in ICU with versus without auto-Abs. RESULTS: We conducted a prospective multicentre cohort study including patients admitted in 11 intensive care units (ICUs) from Great Paris area hospitals with proven SARS-CoV-2 infection and acute respiratory failure. 925 critically ill COVID-19 patients were included. Auto-Abs neutralizing type I IFN-α2, ß and/or ω were found in 96 patients (10.3%). Demographics and comorbidities did not differ between patients with versus without auto-Abs. At ICU admission, Auto-Abs positive patients required a higher FiO2 (100% (70-100) vs. 90% (60-100), p = 0.01), but were not different in other characteristics. Mortality at day 28 was not different between patients with and without auto-Abs (18.7 vs. 23.7%, p = 0.279). In multivariable analysis, 28-day mortality was associated with age (adjusted odds ratio (aOR) = 1.06 [1.04-1.08], p < 0.001), SOFA score (aOR = 1.18 [1.12-1.23], p < 0.001) and immunosuppression (aOR = 1.82 [1.1-3.0], p = 0.02), but not with the presence of auto-Abs (aOR = 0.69 [0.38-1.26], p = 0.23). CONCLUSIONS: In ICU patients, auto-Abs against type I IFNs were found in at least 10% of patients with critical COVID-19 pneumonia. They were not associated with day 28 mortality.

SARS-CoV-2 Genomic Characteristics and Clinical Impact of SARS-CoV-2 Viral Diversity in Critically Ill COVID-19 Patients: A Prospective Multicenter Cohort Study.

The SARS-CoV-2 variant of concern, α, spread worldwide at the beginning of 2021. It was suggested that this variant was associated with a higher risk of mortality than other variants. We aimed to characterize the genetic diversity of SARS-CoV-2 variants isolated from patients with severe COVID-19 and unravel the relationships between specific viral mutations/mutational patterns and clinical outcomes. This is a prospective multicenter observational cohort study. Patients aged ≥18 years admitted to 11 intensive care units (ICUs) in hospitals in the Greater Paris area for SARS-CoV-2 infection and acute respiratory failure between 1 October 2020 and 30 May 2021 were included. The primary clinical endpoint was day-28 mortality. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing (Illumina COVIDSeq). In total, 413 patients were included, 183 (44.3%) were infected with pre-existing variants, 197 (47.7%) were infected with variant α, and 33 (8.0%) were infected with other variants. The patients infected with pre-existing variants were significantly older (64.9 ± 11.9 vs. 60.5 ± 11.8 years; p = 0.0005) and had more frequent COPD (11.5% vs. 4.1%; p = 0.009) and higher SOFA scores (4 [3-8] vs. 3 [2-4]; 0.0002). The day-28 mortality was no different between the patients infected with pre-existing, α, or other variants (31.1% vs. 26.2% vs. 30.3%; p = 0.550). There was no association between day-28 mortality and specific variants or the presence of specific mutations. At ICU admission, the patients infected with pre-existing variants had a different clinical presentation from those infected with variant α, but mortality did not differ between these groups. There was no association between specific variants or SARS-CoV-2 genome mutational pattern and day-28 mortality.

Impact of COVID-19 on the association between pulse oximetry and arterial oxygenation in patients with acute respiratory distress syndrome.

Managing patients with acute respiratory distress syndrome (ARDS) requires frequent changes in mechanical ventilator respiratory settings to optimize arterial oxygenation assessed by arterial oxygen partial pressure (PaO2) and saturation (SaO2). Pulse oxymetry (SpO2) has been suggested as a non-invasive surrogate for arterial oxygenation however its accuracy in COVID-19 patients is unknown. In this study, we aimed to investigate the influence of COVID-19 status on the association between SpO2 and arterial oxygenation. We prospectively included patients with ARDS and compared COVID-19 to non-COVID-19 patients, regarding SpO2 and concomitant arterial oxygenation (SaO2 and PaO2) measurements, and their association. Bias was defined as mean difference between SpO2 and SaO2 measurements. Occult hypoxemia was defined as a SpO2 ≥ 92% while concomitant SaO2 < 88%. Multiple linear regression models were built to account for confounders. We also assessed concordance between positive end-expiratory pressure (PEEP) trial-induced changes in SpO2 and in arterial oxygenation. We included 55 patients, among them 26 (47%) with COVID-19. Overall, SpO2 and SaO2 measurements were correlated (r = 0.70; p < 0.0001), however less so in COVID-19 than in non-COVID-19 patients (r = 0.55, p < 0.0001 vs. r = 0.84, p < 0.0001, p = 0.002 for intergroup comparison). Bias was + 1.1%, greater in COVID-19 than in non-COVID-19 patients (2.0 vs. 0.3%; p = 0.02). In multivariate analysis, bias was associated with COVID-19 status (unstandardized ß = 1.77, 95%CI = 0.38-3.15, p = 0.01), ethnic group and ARDS severity. Occult hypoxemia occurred in 5.5% of measurements (7.7% in COVID-19 patients vs. 3.4% in non-COVID-19 patients, p = 0.42). Concordance rate between PEEP trial-induced changes in SpO2 and SaO2 was 84%, however less so in COVID-19 than in non-COVID-19 patients (69% vs. 97%, respectively). Similar results were observed for PaO2 regarding correlations, bias, and concordance with SpO2 changes. In patients with ARDS, SpO2 was associated with arterial oxygenation, but COVID-19 status significantly altered this association.

Single-cell RNA sequencing of blood antigen-presenting cells in severe COVID-19 reveals multi-process defects in antiviral immunity.

COVID-19 can lead to life-threatening respiratory failure, with increased inflammatory mediators and viral load. Here, we perform single-cell RNA-sequencing to establish a high-resolution map of blood antigen-presenting cells (APCs) in 15 patients with moderate or severe COVID-19 pneumonia, at day 1 and day 4 post admission to intensive care unit or pulmonology department, as well as in 4 healthy donors. We generated a unique dataset of 81,643 APCs, including monocytes and rare dendritic cell (DC) subsets. We uncovered multi-process defects in antiviral immune defence in specific APCs from patients with severe disease: (1) increased pro-apoptotic pathways in plasmacytoid DCs (pDCs, key effectors of antiviral immunity), (2) a decrease of the innate sensors TLR9 and DHX36 in pDCs and CLEC9a+ DCs, respectively, (3) downregulation of antiviral interferon-stimulated genes in monocyte subsets and (4) a decrease of major histocompatibility complex (MHC) class II-related genes and MHC class II transactivator activity in cDC1c+ DCs, suggesting viral inhibition of antigen presentation. These novel mechanisms may explain patient aggravation and suggest strategies to restore the defective immune defence.

Use of Venovenous Extracorporeal Membrane Oxygenation in Critically-Ill Patients With COVID-19.

Acute respiratory distress syndrome (ARDS) related to Coronavirus disease (COVID-19) is associated with high mortality. It has been suggested that venovenous extracorporeal membrane oxygenation (ECMO) was suitable in this indication, albeit the effects of ECMO on the mechanical respiratory parameters have been scarcely described. In this case-series, we prospectively described the use of venovenous ECMO and its effects on mechanical respiratory parameters in eleven COVID-19 patients with severe ARDS. Implantation of ECMO occurred 6 [3-11] days after the onset of mechanical ventilation. At the time of ECMO implantation, all patients received neuromuscular blocking agents, three (27%) received inhaled nitric oxide and prone positioning was performed in all patients with 4 [3-5] sessions of PP per patient. Under ECMO, the tidal volume was significantly decreased from 6.1 [4.0-6.3] to 3.4 [2.5-3.6] mL/kg of predicted body weight and the positive end-expiratory pressure level was increased by 25 ± 27% whereas the driving pressure and the mechanical power decreased by 33 ± 25% and 71 ± 27%, respectively. The PaO2/FiO2 ratio significantly increased from 68 [58-89] to 168 [137-218] and the oxygenation index significantly decreased from 28 [26-35] to 13 [10-15]. The duration of ECMO was 12 [8-25] days. Nine (82%) patients experienced ECMO-related complications and the main complication was major bleeding requiring blood transfusions. Intensive care unit mortality rate was 55% but no patient died from ECMO-related complications. In COVID-19 patients with severe ARDS, venovenous ECMO allowed ultra-protective ventilation, improved oxygenation and should be considered in highly selected patients with the most severe ARDS.

How to detect a positive response to a fluid bolus when cardiac output is not measured?

BACKGROUND: Volume expansion is aimed at increasing cardiac output (CO), but this variable is not always directly measured. We assessed the ability of changes in arterial pressure, pulse pressure variation (PPV) and heart rate (HR) or of a combination of them to detect a positive response of cardiac output (CO) to fluid administration. METHODS: We retrospectively included 491 patients with circulatory failure. Before and after a 500-mL normal saline infusion, we measured CO (PiCCO device), HR, systolic (SAP), diastolic (DAP), mean (MAP) and pulse (PP) arterial pressure, PPV, shock index (HR/SAP) and the PP/HR ratio. RESULTS: The fluid-induced changes in HR were not correlated with the fluid-induced changes in CO. The area under the receiver operating characteristic curve (AUROC) for changes in HR as detectors of a positive fluid response (CO increase ≥ 15%) was not different from 0.5. The fluid-induced changes in SAP, MAP, PP, PPV, shock index (HR/SAP) and the PP/HR ratio were correlated with the fluid-induced changes in CO, but with r < 0.4. The best detection was provided by increases in PP, but it was rough (AUROC = 0.719 ± 0.023, best threshold: increase ≥ 10%, sensitivity = 72 [66-77]%, specificity = 64 [57-70]%). Neither the decrease in shock index nor the changes in other indices combining changes in HR, shock index, PPV and PP provided a better detection of a positive fluid response than changes in PP. CONCLUSION: A positive response to fluid was roughly detected by changes in PP and not detected by changes in HR. Changes in combined indices including the shock index and the PP/HR ratio did not provide a better diagnostic accuracy.

Long term renal recovery in survivors after OHCA.

BACKGROUNDS: In survivors of out-of-hospital cardiac arrest (OHCA), acute kidney injury (AKI) is frequent and is associated with numerous factors of definitive renal injury. We made the hypothesis that AKI after OHCA was a strong risk factor of long-term chronic kidney disease (CKD). We aimed to evaluate long-term renal outcome of OHCA survivors according the occurrence of AKI in ICU. METHODS: We used prospectively collected data from consecutive OHCA patients admitted between 2007 and 2012 in a tertiary medical ICU. AKI was defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Long-term creatinine level was the last blood creatinine assessment we were able to retrieve. The main outcome was the occurrence of CKD, defined by an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73m2 according to the MDRD equation. Long-term mortality was evaluated as well. Factors associated with CKD occurrence were evaluated by competing risk survival analysis (Fine Gray and Cox cause specific models). RESULTS: Among the 246 OHCA patients who were discharged alive, outcome of 133 patients was available (median age 55 [iqr 46, 68], 75.2% of male). During a median follow-up time of 1.8 [0.8-2.5] years, CKD occurred in 17 (12.7%) patients and 24 (18%) patients died. A previous history of arterial hypertension (sHR = 3.28[1.15;9.39], p = 0.027; CSH = 4.83 [1.57;14.9], p = 0.006), AKI during ICU stay (sHR = 3.72[1.40;9.84], p = 0.008; CSH = 5.41[1.79;16.3], p = 0.003) and an age higher than 55 (sHR = 6.13[1.55;24.3], p = 0.009; CSH = 2.16[1.72;43.8], p = 0.006) were independently associated with CKD occurrence. AKI was not associated with long-term mortality (sHR = 0.73 [0.27;1.99], p = 0.55; CSH = 0.75 [0.28;2.01], p = 0.57). CONCLUSION: In OHCA survivors, CKD was a frequent long-term complication. AKI during ICU stay was a strong determinant of long-term CKD occurrence.

A retrospective comparison between delayed and early hip fracture surgery in patients taking clopidogrel: same total bleeding but different timing of blood transfusion.

PURPOSE: Managing hip fracture surgery in patients taking clopidogrel is challenging. The optimal timing for surgery remains unclear. Early surgery in such patients potentially increases peri-operative bleeding, whereas delayed surgery has been shown to be associated with worse postoperative outcomes. The aim of this study was to investigate whether a delay to surgery affects total blood loss, bleeding kinetics, blood transfusion requirements, or post-operative outcomes. METHODS: A retrospective monocentric study including all hip fracture patients treated with clopidogrel between 2011 and 2016 (39 patients) was carried out. Patients who underwent delayed surgery after withholding clopidogrel for five days or more, from 2011 to 2013, were compared to patients who benefited from earlier surgical procedures (within 48 hours of admission) from 2014 to 2016. RESULTS: Total blood loss, amount of blood transfusion and rate of postoperative complications did not differ between the two groups. However, the timing of bleeding was significantly different; blood loss occurred during the pre-operative phase in the delayed surgery group (p < 0.0001), whereas it occurred during the intra-operative phase in the early surgery group (p = 0.005). The length of the hospital stay was significantly shorter for the early surgery group than for the delayed surgery group: 11 ± three versus 15 ± four days (p = 0.004). CONCLUSIONS: Early surgical treatment of hip fracture in patients receiving clopidogrel does not increase the overall red blood cell loss or the transfusion requirement, but may affect the timing of blood transfusion. Hip fracture surgery should preferably be performed without delay in patients taking clopidogrel.