Effect of noninvasive ventilation on mortality and clinical outcomes among patients with severe hypoxemic COVID-19 pneumonia after high-flow nasal oxygen failure: a multicenter retrospective French cohort with propensity score analysis.

BACKGROUND: We assessed the effect of noninvasive ventilation (NIV) on mortality and length of stay after high flow nasal oxygenation (HFNO) failure among patients with severe hypoxemic COVID-19 pneumonia. METHODS: In this multicenter, retrospective study, we enrolled COVID-19 patients admitted in intensive care unit (ICU) for severe COVID-19 pneumonia with a HFNO failure from December 2020 to January 2022. The primary outcome was to compare the 90-day mortality between patients who required a straight intubation after HFNO failure and patients who received NIV after HFNO failure. Secondary outcomes included ICU and hospital length of stay. A propensity score analysis was performed to control for confounding factors between groups. Exploratory outcomes included a subgroup analysis for 90-day mortality. RESULTS: We included 461 patients with HFNO failure in the analysis, 233 patients in the straight intubation group and 228 in the NIV group. The 90-day mortality did not significantly differ between groups, 58/228 (25.4%) int the NIV group compared with 59/233 (25.3%) in the straight intubation group, with an adjusted hazard ratio (HR) after propensity score weighting of 0.82 [95%CI, 0.50-1.35] (p = 0.434). ICU length of stay was significantly shorter in the NIV group compared to the straight intubation group, 10.0 days [IQR, 7.0-19.8] versus 18.0 days [IQR,11.0-31.0] with a propensity score weighted HR of 1.77 [95%CI, 1.29-2.43] (p < 0.001). A subgroup analysis showed a significant increase in mortality rate for intubated patients in the NIV group with 56/122 (45.9%), compared to 59/233 (25.3%) for patients in the straight intubation group (p < 0.001). CONCLUSIONS: In severely hypoxemic COVID-19 patients, no significant differences were observed on 90-day mortality between patients receiving straight intubation and those receiving NIV after HFNO failure. NIV strategy was associated with a significant reduction in ICU length of stay, despite an increase in mortality in the subgroup of patients finally intubated.

Impact of prone position on dead-space fraction in COVID-19 related acute respiratory distress syndrome.

INTRODUCTION: COVID-19 Related Acute Respiratory Syndrome (C-ARDS) is characterized by a mismatch between respiratory mechanics and hypoxemia, suggesting increased dead-space fraction (DSF). Prone position is a cornerstone treatment of ARDS under invasive mechanical ventilation reducing mortality. We sought to investigate the impact of prone position on DSF in C-ARDS in a cohort of patients receiving invasive mechanical ventilation. METHODS: we retrospectively analysed data from 85 invasively mechanically ventilated patients with C-ARDS in supine and in prone positions, hospitalized in Intensive Care Unit (Reims University Hospital), between November, 1st 2020 and November, 1st 2022. DSF was estimated via 3 formulas usable at patients' bedside, based on partial pressure of carbon dioxide (PaCO2) and end-tidal carbon dioxide (EtCO2). RESULTS: there was no difference of DSF between supine and prone position, using the 3 formulas. According to Enghoff, Frankenfield and Gattinoni equations, DSF in supine vs. prone position was in median respectively [IQR]: 0.29 [0.13-0.45] vs. 0.31 [0.19-0.51] (p = 0.37), 0.5 [0.48-0.52] vs. 0.51 [0.49-0.53] (p = 0.43), and 0.71 [0.55-0.87] vs. 0.69 [0.57-0.81], (p = 0.32). CONCLUSION: prone position did not change DSF in C-ARDS.

Impact of sex differences on cardiac injury in critically ill patients with COVID-19.

BACKGROUND: COVID-19 infections are associated with accrued inflammatory responses which may result in cardiac injury. Immune response to infection appears different between men and women, suggesting that COVID-19 patients' outcomes may differ according to biological sex. However, the impact of biological sex on the occurrence of cardiac injury during intensive care unit (ICU) stay in COVID-19 patients remain unclear. METHODS: In this multicenter and prospective study, we included consecutive patients admitted to ICU for severe COVID-19 pneumonia, during the first two pandemic waves. Biological, electrocardiogram (ECG) and echocardiographic variables were collected on ICU admission. Cardiac injury was defined by increased troponin above 99th percentile of upper norm value and newly diagnosed ECG and/or echocardiographic abnormalities. The primary endpoint was the proportion of patients with cardiac injury during ICU stay according to biological sex. The impact of biological sex on other subsequent clinical outcomes was also evaluated. RESULTS: We included 198 patients with a median age of 66 (56-73) years, 147 (74%) patients were men and 51 (26%) were women. Overall, 119 (60%) patients had cardiac injury during ICU stay and the proportion of patients with cardiac injury during ICU stay was not different between men and women (60% vs. 61%, p = 1.00). Patients with cardiac injury during ICU stay showed more cardiovascular risk factors and chronic cardiac disease and had a higher ICU mortality rate. On ICU admission, they had a more marked lymphopenia (0.70 (0.40-0.80) vs. 0.80 (0.50-1.10) × 109/L, p < 0.01) and inflammation (C-Reactive Protein (155 (88-246) vs. 111 (62-192) mg/L, p = 0.03); D-Dimers (1293 (709-2523) vs. 900 (560-1813) µg/L, p = 0.03)). Plasmatic levels of inflammatory biomarkers on ICU admission correlated with SAPS-2 and SOFA scores but not with the different echocardiographic variables. Multivariate analysis confirmed cardiovascular risk factors (OR = 2.31; 95%CI (1.06-5.02), p = 0.03) and chronic cardiac disease (OR = 8.58; 95%CI (1.01-73.17), p = 0.04) were independently associated with the occurrence of cardiac injury during ICU stay, whereas biological sex (OR = 0.88; 95%CI (0.42-1.84), p = 0.73) was not. Biological sex had no impact on the occurrence during ICU stay of other clinical outcomes. CONCLUSIONS: Most critically ill patients with COVID-19 were men and experienced cardiac injury during ICU stay. Nevertheless, biological sex had no impact on the occurrence of cardiac injury during ICU stay or on other clinical outcomes. Clinical trial registration NCT04335162.

Excess Soluble fms-like Tyrosine Kinase 1 Correlates With Endothelial Dysfunction and Organ Failure in Critically Ill Coronavirus Disease 2019 Patients.

Excess soluble fms-like tyrosine kinase 1 (sFlt-1), a soluble inhibitor of vascular endothelial growth factor pathway, has been demonstrated to promote endothelial dysfunction. Here, we demonstrate that sFlt-1 plasma levels correlate with respiratory symptom severity, expression of endothelial dysfunction biomarker, and incidence of organ failure in coronavirus disease 2019 patients. Clinical Trials Registration: NCT04394195.

Deletion of receptor for advanced glycation end products exacerbates lymphoproliferative syndrome and lupus nephritis in B6-MRL Fas lpr/j mice.

The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3(+)B220(+)CD4(-)CD8(-) autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE(-/-) mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE(-/-) mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) (p = 0.02). We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3(+)B220(+)CD4(-)CD8(-) T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional.

The Eight Unanswered and Answered Questions about the Use of Vasopressors in Septic Shock.

Septic shock is mainly characterized-in addition to hypovolemia-by vasoplegia as a consequence of a release of inflammatory mediators. Systemic vasodilatation due to depressed vascular tone results in arterial hypotension, which induces or worsens organ hypoperfusion. Accordingly, vasopressor therapy is mandatory to correct hypotension and to reverse organ perfusion due to hypotension. Currently, two vasopressors are recommended to be used, norepinephrine and vasopressin. Norepinephrine, an α1-agonist agent, is the first-line vasopressor. Vasopressin is suggested to be added to norepinephrine in cases of inadequate mean arterial pressure instead of escalating the doses of norepinephrine. However, some questions about the bedside use of these vasopressors remain. Some of these questions have been well answered, some of them not clearly addressed, and some others not yet answered. Regarding norepinephrine, we firstly reviewed the arguments in favor of the choice of norepinephrine as a first-line vasopressor. Secondly, we detailed the arguments found in the recent literature in favor of an early introduction of norepinephrine. Thirdly, we reviewed the literature referring to the issue of titrating the doses of norepinephrine using an individualized resuscitation target, and finally, we addressed the issue of escalation of doses in case of refractory shock, a remaining unanswered question. For vasopressin, we reviewed the rationale for adding vasopressin to norepinephrine. Then, we discussed the optimal time for vasopressin administration. Subsequently, we addressed the issue of the optimal vasopressin dose, and finally we discussed the best strategy to wean these two vasopressors when combined.

Left atrial dissection after a supra-annular mitral valve replacement for endocarditis.

BACKGROUND: Left atrial dissection is a rare and a potentially fatal complication of cardiac surgery. Multi-modal imagery is helpful for the diagnosis and to guide the treatment. CASE PRESENTATION: We report the case of a 66-year-old female patient who underwent a combined mitral and aortic valve replacement for degenerative valvular disease. She presented an infectious endocarditis revealed by a third-degree atrioventricular bloc and had a redo mitral- and aortic valve replacement. Mitral valve was inserted in supra-annular position due to annular destruction. Post-operative course was marked by a refractory acute heart failure explained by a left atrial wall dissection confirmed by transoesophageal echocardiography and synchronized cardiac CT-scan. Surgical treatment was theoretically indicated but considering the high risk of a third surgery, a palliative care support was collegially decided. CONCLUSIONS: Left atrial dissection can occur after a redo surgery and supra-annular mitral valve implantation. Multi-modal imagery including transoesophageal echocardiography and cardiac CT-scan is helpful for the diagnosis.

Post-Intensive Care Syndrome Prevalence Six Months after Critical Covid-19: Comparison between First and Second Waves.

OBJECTIVE: To explore the impact of improved intensive care for COVID-19 patients on the prevalence of post-intensive care syndrome (PICS). DESIGN: Ambispective cohort study. PATIENTS: Post-intensive care unit COVID-19 patients from the first and second waves of COVID-19. METHODS: Patients were evaluated at 6 months after infection. PICS was defined as the presence of a 1-min sit-to-stand test (1STS) score < 2.5th percentile or a Symbol Digit Modalities Test (SDMT) below the 2 standard deviation cut-off, or a Hospital Anxiety and Depression Scale score ≥ 11. RESULTS: A total of 60 patients were included (34 from wave 1 and 26 from wave 2). Intensive care unit management improved between waves, with shorter duration of orotracheal intubation (7 vs 23.5 days, p = 0.015) and intensive care unit stay (6 vs 9.5 days, p = 0.006) in wave 2. PICS was present in 51.5% of patients after wave 1 and 52% after wave 2 (p = 0.971). Female sex and diabetes were significantly associated with PICS by multivariate analysis. CONCLUSION: Approximately half of post-intensive care unit COVID-19 patients have 1 or more impairments consistent with PICS at 6 months, with an impact on quality of life and participation. Improved intensive care unit management was not associated with a decrease in the prevalence of PICS. Identification of patients at risk, particularly women and diabetic patients, is essential. Further studies of underlying mechanisms and the need for rehabilitation are essential to reduce the risk of PICS.

Management and outcomes of pregnant women admitted to intensive care unit for severe pneumonia related to SARS-CoV-2 infection: the multicenter and international COVIDPREG study.

PURPOSE: Management and outcomes of pregnant women with coronavirus disease 2019 (COVID-19) admitted to intensive care unit (ICU) remain to be investigated. METHODS: A retrospective multicenter study conducted in 32 ICUs in France, Belgium and Switzerland. Maternal management as well as maternal and neonatal outcomes were reported. RESULTS: Among the 187 pregnant women with COVID-19 (33 ± 6 years old and 28 ± 7 weeks' gestation), 76 (41%) were obese, 12 (6%) had diabetes mellitus and 66 (35%) had pregnancy-related complications. Standard oxygenation, high-flow nasal oxygen therapy (HFNO) and non-invasive ventilation (NIV) were used as the only oxygenation technique in 41 (22%), 55 (29%) and 18 (10%) patients, respectively, and 73 (39%) were intubated. Overall, 72 (39%) patients required several oxygenation techniques and 15 (8%) required venovenous extracorporeal membrane oxygenation. Corticosteroids and tocilizumab were administered in 157 (84%) and 25 (13%) patients, respectively. Awake prone positioning or prone positioning was performed in 49 (26%) patients. In multivariate analysis, risk factors for intubation were obesity (cause-specific hazard ratio (CSH) 2.00, 95% CI (1.05-3.80), p = 0.03), term of pregnancy (CSH 1.07, 95% CI (1.02-1.10), per + 1 week gestation, p = 0.01), extent of computed tomography (CT) scan abnormalities > 50% (CSH 2.69, 95% CI (1.30-5.60), p < 0.01) and NIV use (CSH 2.06, 95% CI (1.09-3.90), p = 0.03). Delivery was required during ICU stay in 70 (37%) patients, mainly due to maternal respiratory worsening, and improved the driving pressure and oxygenation. Maternal and fetal/neonatal mortality rates were 1% and 4%, respectively. The rate of maternal and/or neonatal complications increased with the invasiveness of maternal respiratory support. CONCLUSION: In ICU, corticosteroids, tocilizumab and prone positioning were used in few pregnant women with COVID-19. Over a third of patients were intubated and delivery improved the driving pressure.

Algorithm for rational use of Film Array Pneumonia Panel in bacterial coinfections of critically ill ventilated COVID-19 patients.

The FilmArray Pneumonia Panel has proven to be an effective tool for rapid detection of main respiratory pathogens. However, its rational use needs appropriate knowledge and formation regarding its indication and interpretation. Herein, we provide some advices to help with success of its daily routine use, particularly in critically ill ventilated COVID-19 patients. Clinical Trial registration number: NCT04453540.

Plasma procalcitonin may be an early predictor of liver injury in acetaminophen poisoning: A prospective cohort study.

BACKGROUND AND AIMS: Acetaminophen is a common cause of poisoning and liver injury worldwide; however, patient stratification is suboptimal. We aimed to assess the contribution of admission plasma procalcitonin concentration (PCT) to better identify acetaminophen-poisoned patients likely to develop liver injury. METHODS: We conducted a prospective observational cohort study including all acetaminophen-poisoned patients requiring N-acetylcysteine admitted in a toxicological intensive care unit between 2012 and 2017. Multivariate analysis was performed using a Cox regression model to investigate factors associated with liver injury, defined as an increase in alanine aminotransferase (ALT) >100 IU/L. RESULTS: One hundred seventeen patients (age, 32 years (21-53), median [25th-75th percentiles]) were included after self-ingesting 16 g (9-30) acetaminophen and received N-acetylcysteine infusion administered within a median 6 h-delay (4-12) from exposure. Co-ingestions were reported in 77% of patients. Rumack-Matthew nomogram was non-interpretable in 47% cases. Liver injury occurred in 38 patients (32%) with a median peak ALT of 2020 IU/L (577-4248). In liver injury patients, admission PCT was significantly increased in comparison to patients without liver injury (21.5 ng/ml (3.2-44.9) versus 0.1 ng/ml (0-0.4), respectively, p < 0.01). The increase in PCT preceded the increase in ALT by 33 h (10-74). In a multivariate analysis, PCT > 1 ng/ml was significantly associated with liver injury (hazard ratio, 7.2 [95% confidence interval, 2.3-22.6; p < 0.001]). PCT (area under the receiver-operating characteristics curve, 0.91 [95%CI: 0.84-0.97]) predicted liver injury with sensitivity, specificity, negative, and positive predictive values of 0.92, 0.84, 0.96, and 0.73, respectively. CONCLUSION: PCT on admission is associated with liver injury in acetaminophen poisoning. PCT might be used as a predictive tool of liver injury to improve clinical decision-making.

Acquired decrease of the C3b/C4b receptor (CR1, CD35) and increased C4d deposits on erythrocytes from ICU COVID-19 patients.

In order to study the mechanisms of COVID-19 damage following the complement activation phase occurring during the innate immune response to SARS-CoV-2, CR1 (the regulating complement activation factor, CD35, the C3b/C4b receptor), C4d deposits on Erythrocytes (E), and the products of complement activation C3b/C3bi, were assessed in 52 COVID-19 patients undergoing O2 therapy or assisted ventilation in ICU units in Rheims France. An acquired decrease of CR1 density on E from COVID-19 patients was observed (Mean = 418, SD = 162, N = 52) versus healthy individuals (Mean = 592, SD = 287, N = 400), Student's t-test p < 10-6, particularly among fatal cases, and in parallel with several parameters of clinical severity. Large deposits of C4d on E in patients were well above values observed in normal individuals, mostly without concomitant C3 deposits, in more than 80% of the patients. This finding is reminiscent of the increased C4d deposits on E previously observed to correlate with sub endothelial pericapillary deposits in organ transplant rejection, and with clinical SLE flares. Conversely, significant C3 deposits on E were only observed among » of the patients. The decrease of CR1/E density, deposits of C4 fragments on E and previously reported detection of virus spikes or C3 on E among COVID-19 patients, suggest that the handling and clearance of immune complex or complement fragment coated cell debris may play an important role in the pathophysiology of SARS-CoV-2. Measurement of C4d deposits on E might represent a surrogate marker for assessing inflammation and complement activation occurring in organ capillaries and CR1/E decrease might represent a cumulative index of complement activation in COVID-19 patients. Taken together, these original findings highlight the participation of complement regulatory proteins and indicate that E are important in immune pathophysiology of COVID-19 patients. Besides a potential role for monitoring the course of disease, these observations suggest that novel therapies such as the use of CR1, or CR1-like molecules, in order to down regulate complement activation and inflammation, should be considered.

Dismal Survival in COVID-19 Patients Requiring ECMO as Rescue Therapy after Corticosteroid Failure.

(1) Background: COVID-19 may lead to refractory hypoxemia requiring venovenous extracorporeal membrane oxygenation (ECMO). Survival rate if ECMO is implemented as rescue therapy after corticosteroid failure is unknown. We aimed to investigate if ECMO implemented after failure of the full-recommended 10-day corticosteroid course can improve outcome. (2) Methods: We conducted a three-center cohort study including consecutive dexamethasone-treated COVID-19 patients requiring ECMO between 03/2020 and 05/2021. We compared survival at hospital discharge between patients implemented after (ECMO-after group) and before the end of the 10-day dexamethasone course (ECMO-before group). (3) Results: Forty patients (28M/12F; age, 57 years (51-62) (median (25th-75th percentiles)) were included, 28 (70%) in the ECMO-before and 12 (30%) in the ECMO-after group. In the ECMO-before group, 9/28 patients (32%) received the 6 mg/day dexamethasone regimen versus 12/12 (100%) in the ECMO-after group (p < 0.0001). The rest of the patients received an alternative dexamethasone regimen consisting of 20 mg/day during 5 days followed by 10 mg/day during 5 days. Patients in the ECMO-before group tended to be younger (57 years (51-59) versus 62 years (57-67), p = 0.053). In the ECMO-after group, no patient (0%) survived while 12 patients (43%) survived in the ECMO-before group (p = 0.007). (4) Conclusions: Survival is poor in COVID-19 patients requiring ECMO implemented after the full-recommended 10-day dexamethasone course. Since these patients may have developed a particularly severe presentation, new therapeutic strategies are urgently required.

Targeted temperature management using the "Esophageal Cooling Device" after cardiac arrest (the COOL study): A feasibility and safety study.

BACKGROUND: Targeted temperature management (TTM) between 32 and 36°C is recommended after out-of-hospital cardiac arrest (OHCA). We aimed to assess the feasibility and safety of the "Esophageal Cooling Device" (ECD) in performing TTM. PATIENTS AND METHODS: This single-centre, prospective, interventional study included 17 comatose OHCA patients. Main exclusion criteria were: delay between OHCA and return of spontaneous circulation (ROSC)>60min, delay between sustained ROSC and inclusion >360min, known oesophageal disease. A TTM between 32 and 34°C was performed using the ECD (Advanced Cooling Therapy, USA) connected to a heat exchanger console (Meditherm III®, Gaymar, France), without cold fluids' use. Primary endpoint was feasibility of inducing, maintaining TTM, and rewarming using the ECD alone. Secondary endpoints were adverse events, focusing on potential digestive damages. Results were expressed as median (interquartiles 25-75). RESULTS: Cooling rate to reach the Target Temperature (33°C-TT) was 0.26°C/h [0.19-0.36]. All patients reached the 32-34°C range with a time spent within the range of 26h [21-28] (3 patients did not reach 33°C). Temperature deviation outside the TT during TTM-maintenance was 0.10°C [0.03-0.20]. Time with deviation >1°C was 0h. Rewarming rate was 0.20°C/h [0.18-0.22]. Among the 16 gastrointestinal endoscopy procedures performed, 10 (62.5%) were normal. Minor oeso-gastric injuries (37.5% and 19%, respectively) were similar to usual orogastric tube injuries. One patient experienced severe oesophagitis mimicking peptic lesions, not cooling-related. No patient among the 9 alive at 3-month follow-up had gastrointestinal complains. CONCLUSION: ECD seems an interesting, safe, accurate, semi-invasive cooling method in OHCA patients treated with 33°C-TTM, particularly during the maintenance phase.