Neurologic Outcomes of Survivors of COVID-19-Associated Acute Respiratory Distress Syndrome Requiring Intubation.

OBJECTIVES: To describe 3-6-month neurologic outcomes of survivors of COVID-19-associated acute respiratory distress syndrome, invasively ventilated in the ICU. DESIGN: A bicentric prospective study during the two first waves of the pandemic (March to May and September to December, 2020). SETTING: Two academic hospital ICUs, Paris, France. PATIENTS: Adult COVID-19-associated acute respiratory distress syndrome survivors, invasively ventilated in the ICU, were eligible for a neurologic consultation between 3 and 6 months post ICU discharge. INTERVENTIONS: Follow-up by face-to-face neurologic consultation. MEASURES AND MAIN RESULTS: The primary endpoint was favorable functional outcome defined by a modified Rankin scale score less than 2, indicating survival with no significant disability. Secondary endpoints included mild cognitive impairment (Montreal Cognitive Assessment score < 26), ICU-acquired weakness (Medical Research Council score < 48), anxiety and depression (Hospital Anxiety and Depression score > 7), and posttraumatic stress disorder (posttraumatic stress disorder checklist for Diagnostic and Statistical Manual of Mental Disorders 5 score > 30). Of 54 eligible survivors, four non-French-speaking patients were excluded, eight patients were lost-to-follow-up, and one died during follow-up. Forty-one patients were included. Time between ICU discharge and neurologic consultation was 3.8 months (3.6-5.9 mo). A favorable functional outcome was observed in 16 patients (39%) and mild cognitive impairment in 17 of 33 patients tested (52%). ICU-acquired weakness, depression or anxiety, and posttraumatic stress disorder were reported in six of 37 cases (16%), eight of 31 cases (26%), and two of 27 cases (7%), respectively. Twenty-nine patients (74%) required rehabilitation (motor, cognitive, or psychologic). ICU and hospital lengths of stay, tracheostomy, and corticosteroids were negatively associated with favorable outcome. By contrast, use of alpha-2 agonists during ICU stay was associated with favorable outcome. CONCLUSIONS: COVID-19-associated acute respiratory distress syndrome requiring intubation led to slight-to-severe functional disability in about 60% of survivors 4 months after ICU discharge. Cognitive impairment, muscle weakness, and psychologic symptoms were frequent. A large multicenter study is warranted to allow identification of modifiable factors for improving long-term outcome.

Oropharyngeal and intestinal concentrations of opportunistic pathogens are independently associated with death of SARS-CoV-2 critically ill adults.

BACKGROUND: The composition of the digestive microbiota may be associated with outcome and infections in patients admitted to the intensive care unit (ICU). The dominance by opportunistic pathogens (such as Enterococcus) has been associated with death. However, whether this association remains all throughout the hospitalization are lacking. METHODS: We performed a single-center observational prospective cohort study in critically ill patients admitted with severe SARS-CoV-2 infection. Oropharyngeal and rectal swabs were collected at admission and then twice weekly until discharge or death. Quantitative cultures for opportunistic pathogens were performed on oropharyngeal and rectal swabs. The composition of the intestinal microbiota was assessed by 16S rDNA sequencing. Oropharyngeal and intestinal concentrations of opportunistic pathogens, intestinal richness and diversity were entered into a multivariable Cox model as time-dependent covariates. The primary outcome was death at day 90. RESULTS: From March to September 2020, 95 patients (765 samples) were included. The Simplified Acute Physiology Score 2 (SAPS 2) at admission was 33 [24; 50] and a Sequential Organ Failure Assessment score (SOFA score) at 6 [4; 8]. Day 90 all-cause mortality was 44.2% (42/95). We observed that the oropharyngeal and rectal concentrations of Enterococcus spp., Staphylococcus aureus and Candida spp. were associated with a higher risk of death. This association remained significant after adjustment for prognostic covariates (age, chronic disease, daily antimicrobial agent use and daily SOFA score). A one-log increase in Enterococcus spp., S. aureus and Candida spp. in oropharyngeal or rectal swabs was associated with a 17% or greater increase in the risk of death. CONCLUSION: We found that elevated oropharyngeal/intestinal Enterococcus spp. S. aureus and Candida spp. concentrations, assessed by culture, are associated with mortality, independent of age, organ failure, and antibiotic therapy, opening prospects for simple and inexpensive microbiota-based markers for the prognosis of critically ill SARS-CoV-2 patients.

Passive leg raising-induced changes in pulse pressure variation to assess fluid responsiveness in mechanically ventilated patients: a multicentre prospective observational study.

BACKGROUND: Passive leg raising-induced changes in cardiac index can be used to predict fluid responsiveness. We investigated whether passive leg raising-induced changes in pulse pressure variation (ΔPPVPLR) can also predict fluid responsiveness in mechanically ventilated patients. METHODS: In this multicentre prospective observational study, we included 270 critically ill patients on mechanical ventilation in whom volume expansion was indicated because of acute circulatory failure. We did not include patients with cardiac arrythmias. Cardiac index and PPV were measured before/during a passive leg raising test and before/after volume expansion. A volume expansion-induced increase in cardiac index of >15% defined fluid responsiveness. To investigate whether ΔPPVPLR can predict fluid responsiveness, we determined areas under the receiver operating characteristic curves (AUROCs) and grey zones for relative and absolute ΔPPVPLR. RESULTS: Of the 270 patients, 238 (88%) were on controlled mechanical ventilation with no spontaneous breathing activity and 32 (12%) were on pressure support ventilation. The median tidal volume was 7.1 (inter-quartile range [IQR], 6.6-7.6) ml kg-1 ideal body weight. One hundred sixty-four patients (61%) were fluid responders. Relative and absolute ΔPPVPLR predicted fluid responsiveness with an AUROC of 0.92 (95% confidence interval [95% CI], 0.88-0.95; P<0.001) each. The grey zone for relative and absolute ΔPPVPLR included 4.8% and 22.6% of patients, respectively. These results were not affected by ventilatory mode and baseline characteristics (type of shock, centre, vasoactive treatment). CONCLUSIONS: Passive leg raising-induced changes in pulse pressure variation accurately predict fluid responsiveness with a small grey zone in critically ill patients on mechanical ventilation. CLINICAL TRIAL REGISTRATION: NCT03225378.

Impact of rapid multiplex PCR on management of antibiotic therapy in COVID-19-positive patients hospitalized in intensive care unit.

Because the diagnosis of co/superinfection in COVID-19 patients is challenging, empirical antibiotic therapy is frequently initiated until microbiological analysis results. We evaluated the performance and the impact of the BioFire® FilmArray® Pneumonia plus Panel on 112 respiratory samples from 67 COVID-19 ICU patients suspected of co/superinfections. Globally, the sensitivity and specificity of the test were 89.3% and 99.1%, respectively. Positive tests led to antibiotic initiation or adaptation in 15% of episodes and de-escalation in 4%. When negative, 28% of episodes remained antibiotic-free (14% no initiation, 14% withdrawal). Rapid multiplex PCRs can help to improve antibiotic stewardship by administering appropriate antibiotics earlier and avoiding unnecessary prescriptions.

Comparison of high-flow nasal therapy, noninvasive ventilation, and continuous positive airway pressure on outcomes in critically ill patients admitted for COVID-19 with acute respiratory failure.

BACKGROUND: The optimal first-line noninvasive respiratory support (NIRS) to improve outcome in patients affected by COVID-19 pneumonia admitted to ICU is still debated. METHODS: We conducted a retrospective study in seven French ICUs, including all adults admitted between July and December 2020 with documented SARS-CoV-2 acute respiratory failure (PaO2/FiO2<300 mmHg), and treated with either high-flow nasal therapy (HFNT) alone, noninvasive ventilation alone or in combination with HFNT (NIV), or continuous positive airway pressure alone or in combination with HFNT (CPAP). The primary outcome was NIRS failure at day 28, defined as the need for endotracheal intubation (ETI) or death without ETI. RESULTS: Among the 355 patients included, 160 (45%) were treated with HFNT alone, 115 (32%) with NIV and 80 (23%) with CPAP. The primary outcome occurred in 65 (41%), 69 (60%), and 25 (31%) patients among those treated with HFNT alone, NIV, and CPAP, respectively (P<0.001). After univariate analysis, patients treated with CPAP had a trend for a lower incidence of the primary outcome, whereas patients treated with NIV had a significant higher incidence of the primary outcome, both compared to those treated with HFNT alone (unadjusted Hazard ratio 0.67; 95% CI [0.42-1.06], and 1.58; 95% CI [1.12-2.22]; P=0.09 and 0.008, respectively). CONCLUSIONS: Among ICU patients admitted for severe COVID-19 pneumonia and managed with NIRS, the outcome seems to differ according to the initial chosen strategy. Prospective randomized controlled studies are warranted to identify the optimal strategy.

Augmented renal clearance in the ICU: estimation, incidence, risk factors and consequences-a retrospective observational study.

BACKGROUND: Augmented renal clearance (ARC) remains poorly evaluated in ICU. The objective of this study is to provide a full description of ARC in ICU including prevalence, evolution profile, risk factors and outcomes. METHODS: This was a retrospective, single-center, observational study. All the patients older than 18 years admitted for the first time in Medical ICU, Bichat, University Hospital, APHP, France, between January 1, 2017, and November 31, 2020 and included into the Outcomerea database with an ICU length of stay longer than 72 h were included. Patients with chronic kidney disease were excluded. Glomerular filtration rate was estimated each day during ICU stay using the measured creatinine renal clearance (CrCl). Augmented renal clearance (ARC) was defined as a 24 h CrCl greater than 130 ml/min/m2. RESULTS: 312 patients were included, with a median age of 62.7 years [51.4; 71.8], 106(31.9%) had chronic cardiovascular disease. The main reason for admission was acute respiratory failure (184(59%)) and 196(62.8%) patients had SARS-COV2. The median value for SAPS II score was 32[24; 42.5]; 146(44%) and 154(46.4%) patients were under vasopressors and invasive mechanical ventilation, respectively. The overall prevalence of ARC was 24.6% with a peak prevalence on Day 5 of ICU stay. The risk factors for the occurrence of ARC were young age and absence of cardiovascular comorbidities. The persistence of ARC during more than 10% of the time spent in ICU was significantly associated with a lower risk of death at Day 30. CONCLUSION: ARC is a frequent phenomenon in the ICU with an increased incidence during the first week of ICU stay. Further studies are needed to assess its impact on patient prognosis.

Mid-Regional Pro-Adrenomedullin as a Prognostic Factor for Severe COVID-19 ARDS.

Mid-regional proadrenomedullin (MR-proADM) protects against endothelial permeability and has been associated with prognosis in bacterial sepsis. As endothelial dysfunction is central in the pathophysiology of severe SARS-CoV-2 infection, we sought to evaluate MR-proADM both as a prognostic biomarker and as a marker of bacterial superinfection. Consecutive patients admitted to the ICU for severe SARS-CoV-2 pneumonia were prospectively included and serum was bio-banked on days 1, 3, and 7. MR-proADM levels were measured blindly from clinical outcomes in batches at the end of follow-up. Among the 135 patients included between April 2020 and May 2021, 46 (34.1%) had died at day 60. MR-proADM levels on days 1, 3, and 7 were significantly higher in day-60 non-survivors. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve (0.744, p < 0.001) of day-1 MR-proADM compared favorably with the AUC ROC curve of day-1 procalcitonin (0.691, p < 0.001). Serial MR-proADM measurements on days 3 and 7 may add prognostic information. After adjusting for CRP, LDH, and lymphocyte values, day-1 MR-proADM remained significantly associated with day-60 mortality. MR-proADM concentrations were significantly higher in patients with respiratory superinfections (on days 3 and 7) and bloodstream infections (on days 1, 3, and 7) than in patients without infection. Our results suggest that MR-proADM is a good predictor of outcome in severe SARS-CoV-2 infection and could be a useful tool to assess bacterial superinfection in COVID-19 patients.

High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial.

Importance: The benefit of high-dose dexamethasone and oxygenation strategies vs standard of care for patients with severe acute hypoxemic respiratory failure (AHRF) caused by COVID-19 pneumonia is debated. Objectives: To assess the benefit of high-dose dexamethasone compared with standard of care dexamethasone, and to assess the benefit of high-flow nasal oxygen (HFNo2) or continuous positive airway pressure (CPAP) compared with oxygen support standard of care (o2SC). Design, Setting, and Participants: This multicenter, placebo-controlled randomized clinical trial was conducted in 19 intensive care units (ICUs) in France from April 2020 to January 2021. Eligible patients were consecutive ICU-admitted adults with COVID-19 AHRF. Randomization used a 2 × 3 factorial design for dexamethasone and oxygenation strategies; patients not eligible for at least 1 oxygenation strategy and/or already receiving invasive mechanical ventilation (IMV) were only randomized for dexamethasone. All patients were followed-up for 60 days. Data were analyzed from May 26 to July 31, 2021. Interventions: Patients received standard dexamethasone (dexamethasone-phosphate 6 mg/d for 10 days [or placebo prior to RECOVERY trial results communication]) or high-dose dexamethasone (dexamethasone-phosphate 20 mg/d on days 1-5 then 10 mg/d on days 6-10). Those not requiring IMV were additionally randomized to o2SC, CPAP, or HFNo2. Main Outcomes and Measures: The main outcomes were time to all-cause mortality, assessed at day 60, for the dexamethasone interventions, and time to IMV requirement, assessed at day 28, for the oxygenation interventions. Differences between intervention groups were calculated using proportional Cox models and expressed as hazard ratios (HRs). Results: Among 841 screened patients, 546 patients (median [IQR] age, 67.4 [59.3-73.1] years; 414 [75.8%] men) were randomized between standard dexamethasone (276 patients, including 37 patients who received placebo) or high-dose dexamethasone (270 patients). Of these, 333 patients were randomized among o2SC (109 patients, including 56 receiving standard dexamethasone), CPAP (109 patients, including 57 receiving standard dexamethasone), and HFNo2 (115 patients, including 56 receiving standard dexamethasone). There was no difference in 60-day mortality between standard and high-dose dexamethasone groups (HR, 0.96 [95% CI, 0.69-1.33]; P = .79). There was no significant difference for the cumulative incidence of IMV criteria at day 28 among o2 support groups (o2SC vs CPAP: HR, 1.08 [95% CI, 0.71-1.63]; o2SC vs HFNo2: HR, 1.04 [95% CI, 0.69-1.55]) or 60-day mortality (o2SC vs CPAP: HR, 0.97 [95% CI, 0.58-1.61; o2SC vs HFNo2: HR, 0.89 [95% CI, 0.53-1.47]). Interactions between interventions were not significant. Conclusions and Relevance: In this randomized clinical trial among ICU patients with COVID-19-related AHRF, high-dose dexamethasone did not significantly improve 60-day survival. The oxygenation strategies in patients who were not initially receiving IMV did not significantly modify 28-day risk of IMV requirement. Trial Registration: ClinicalTrials.gov Identifier: NCT04344730; EudraCT: 2020-001457-43.

Prevalence of anxiety and depressive symptoms among medical residents in Tunisia: a cross-sectional survey.

OBJECTIVE: To assess the prevalence of anxiety and depressive symptoms and the associated risk factors among Tunisian medical residents. DESIGN: Cross-sectional survey. SETTING: Faculty of Medicine, Tunis. PARTICIPANTS: All Tunisian medical residents brought together between 14 and 22 December 2015 to choose their next 6-month rotation. INTERVENTION: The items of the Hospital Anxiety and Depression (HAD) questionnaire were employed to capture the prevalence of anxiety and/or depression among the residents. The statistical relationships between anxiety and depression (HAD score) and sociodemographic and work-related data were explored by Poisson regression. RESULTS: 1700 out of 2200 (77%) medical residents (mean age: 28.5±2 years, female: 60.8%) answered the questionnaire. The mean working hours per week was 62±21 hours; 73% ensured a mean of 5.4±3 night shifts per month; and only 8% of them could benefit from a day of safety rest. Overall, 74.1% of the participating residents had either definite (43.6%) or probable (30.5%) anxiety, while 62% had definite (30.5%) or probable (31.5%) depression symptoms, with 20% having both definite anxiety and definite depression. The total HAD score was significantly associated with the resident's age (OR=1.014, 95% CI 1.006 to 1.023, p=0.001); female gender (OR=1.114, 95% CI 1.083 to 1.145, p<0.0001); and the heavy burden of work imposed on a weekly or monthly basis, as reflected by the number of night shifts per month (OR=1.048, 95% CI 1.016 to 1.082, p=0.03) and the number of hours worked per week (OR=1.008, 95% CI 1.005 to 1.011, p<0.0001). Compared with medical specialties, the generally accepted difficult specialties (surgical or medical-surgical) were associated with a higher HAD score (OR=1.459, 95% CI 1.172 to 1.816, p=0.001). CONCLUSION: Tunisian residents experience a rate of anxiety/depression substantially higher than that reported at the international level. This phenomenon is worrying as it has been associated with an increase in medical errors, work dissatisfaction and attrition. The means of improving the well-being of Tunisian medical residents are explored, emphasising those requiring immediate implementation.