Rationale: Whether patients with coronavirus disease (COVID-19) may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. Objectives: To estimate the effect of ECMO on 90-day mortality versus IMV only. Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO versus no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 < 80 or PaCO2 ⩾ 60 mm Hg). We controlled for confounding using a multivariable Cox model on the basis of predefined variables. Measurements and Main Results: A total of 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability on Day 7 from the onset of eligibility criteria (87% vs. 83%; risk difference, 4%; 95% confidence interval, 0–9%), which decreased during follow-up (survival on Day 90: 63% vs. 65%; risk difference, −2%; 95% confidence interval, −10 to 5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand and when initiated within the first 4 days of IMV and in patients who are profoundly hypoxemic. Conclusions: In an emulated trial on the basis of a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and regions with ECMO capacities specifically organized to handle high demand.
Abstract Background Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19. Methods All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgium and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score. Results Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay and 491 (23%) during the first 24 h following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO 2 /FiO 2 ratio > 150 mmHg when prone positioning was initiated. Among non-early PP group patients, 1013 (47.4%) patients had finally been placed in PP within a median delay of 3 days after ICU admission. Day-60 mortality in non-early PP group was 34.2% versus 39.3% in the early PP group ( p = 0.038). Day-28 and Day-90 mortality as well as the need for adjunctive therapies was more important in patients with early PP. After propensity score adjustment, no significant difference in survival at Day-60 was found between the two study groups (HR 1.34 [0.96–1.68], p = 0.09 and HR 1.19 [0.998–1.412], p = 0.053 in complete case analysis or in multiple imputation analysis, respectively). Conclusions In a large multicentric international cohort of intubated ICU patients with ARDS due to COVID-19, PP has been used frequently as a main treatment. In this study, our data failed to show a survival benefit associated with early PP started within 24 h after ICU admission compared to PP after day-1 for all COVID-19 patients requiring invasive mechanical ventilation regardless of their severity.
To evaluate the respective impact of standard oxygen, high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) on oxygenation failure rate and mortality in COVID-19 patients admitted to intensive care units (ICUs). Multicenter, prospective cohort study (COVID-ICU) in 137 hospitals in France, Belgium, and Switzerland. Demographic, clinical, respiratory support, oxygenation failure, and survival data were collected. Oxygenation failure was defined as either intubation or death in the ICU without intubation. Variables independently associated with oxygenation failure and Day-90 mortality were assessed using multivariate logistic regression. From February 25 to May 4, 2020, 4754 patients were admitted in ICU. Of these, 1491 patients were not intubated on the day of ICU admission and received standard oxygen therapy (51%), HFNC (38%), or NIV (11%) (P < 0.001). Oxygenation failure occurred in 739 (50%) patients (678 intubation and 61 death). For standard oxygen, HFNC, and NIV, oxygenation failure rate was 49%, 48%, and 60% (P < 0.001). By multivariate analysis, HFNC (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.36-0.99, P = 0.013) but not NIV (OR 1.57, 95% CI 0.78-3.21) was associated with a reduction in oxygenation failure). Overall 90-day mortality was 21%. By multivariable analysis, HFNC was not associated with a change in mortality (OR 0.90, 95% CI 0.61-1.33), while NIV was associated with increased mortality (OR 2.75, 95% CI 1.79-4.21, P < 0.001). In patients with COVID-19, HFNC was associated with a reduction in oxygenation failure without improvement in 90-day mortality, whereas NIV was associated with a higher mortality in these patients. Randomized controlled trials are needed.
Abstract Background Ventilator-associated pneumonia (VAP) causes increased mortality, prolonged hospital stay and increased healthcare costs. Prevention of VAP in intensive care units (ICUs) is currently based on several measures, and application of noble metal coating on medical devices has been shown to inhibit the bacterial adherence of microorganisms to the surface. The objective of this study was to evaluate the potential benefit of noble metal coating of endotracheal tubes for the prevention of VAP. Methods This was a multi-center, randomized, controlled, double-blind, prospective study including ventilated patients from nine ICUs from four hospital sites in Belgium. Patients were randomly intubated with identical appearing noble metal alloy (NMA) coated (NMA-coated group) or non-coated (control group) endotracheal tubes (ETT). Primary endpoint was the incidence of VAP. Secondary endpoints were the proportion of antibiotic days during ICU stay and tracheal colonization by pathogenic bacteria. Results In total, 323 patients were enrolled, 168 in the NMA-coated group and 155 in the control group. During ventilation, VAP occurred in 11 patients (6.5%) in the NMA-coated group and in 18 patients (11.6%) in the control group ( p = 0.11). A higher delay in VAP occurrence was observed in the NMA-coated group compared with the control group by Cox proportional hazards regression analysis (HR 0.41, 95% CI 0.19–0.88, p = 0.02). The number of antibiotic days was 58.8% of the 1,928 ICU days in the NMA-coated group and 65.4% of the 1774 ICU days in the control group ( p = 0.06). Regarding tracheal colonization, bacteria occurred in 38 of 126 patients in the NMA-coated group (30.2%) and in 37 of 109 patients in the control group (33.9%) ( p = 0.57). Conclusions This study provides preliminary evidence to support the benefit of noble metal coating in the prevention of VAP. A confirmatory study in a larger population would be valuable. Trial registration : Clinical trial number: NCT04242706 ( http://www.clinicaltrials.gov )
Abstract Background Previous retrospective research has shown that maintaining prone positioning (PP) for an average of 40 h is associated with an increase of survival rates in intubated patients with COVID-19-related acute respiratory distress syndrome (ARDS). This study aims to determine whether a cumulative PP duration of more than 32 h during the first 2 days of intensive care unit (ICU) admission is associated with increased survival compared to a cumulative PP duration of 32 h or less. Methods This study is an ancillary analysis from a previous large international observational study involving intubated patients placed in PP in the first 48 h of ICU admission in 149 ICUs across France, Belgium and Switzerland. Given that PP is recommended for a 16-h daily duration, intensive PP was defined as a cumulated duration of more than 32 h during the first 48 h, whereas standard PP was defined as a duration equal to or less than 32 h. Patients were followed-up for 90 days. The primary outcome was mortality at day 60. An Inverse Probability Censoring Weighting (IPCW) Cox model including a target emulation trial method was used to analyze the data. Results Out of 2137 intubated patients, 753 were placed in PP during the first 48 h of ICU admission. The intensive PP group ( n = 79) had a median PP duration of 36 h, while standard PP group ( n = 674) had a median of 16 h during the first 48 h. Sixty-day mortality rate in the intensive PP group was 39.2% compared to 38.7% in the standard PP group ( p = 0.93). Twenty-eight-day and 90-day mortality as well as the ventilator-free days until day 28 were similar in both groups. After IPCW, there was no significant difference in mortality at day 60 between the two-study groups (HR 0.95 [0.52–1.74], p = 0.87 and HR 1.1 [0.77–1.57], p = 0.61 in complete case analysis or in multiple imputation analysis, respectively). Conclusions This secondary analysis of a large multicenter European cohort of intubated patients with ARDS due to COVID-19 found that intensive PP during the first 48 h did not provide a survival benefit compared to standard PP.
We report a case of ceftriaxone-induced encephalopathy correlated with high cerebrospinal fluid concentration. Neurotoxicity of cephalosporin is increasingly reported, especially regarding fourth-generation cephalosporins. The factors influencing the corticospinal fluid (CSF) concentration are plasma concentration, liposolubility, ionization, molecular weight, protein binding and efflux. In our patient, high levels of ceftriaxone (27.9 mg/l) were found in the CSF. β-lactam associated neurotoxicity is mainly related to similarities between GABA and β-lactam ring. Because of disparate CSF/plasma ratio and blood-brain barrier efflux among patients, plasmatic drug monitoring probably cannot be used as a surrogate of CSF concentration. This is, as we know, the first case of described ceftriaxone-induced encephalopathy associated with an objective excessive cerebrospinal concentration.
In order to decrease the incidence of ventilator-associated pneumonia (VAP) in Belgium, a national campaign for implementing a VAP bundle involving assessment of sedation, cuff pressure control, oral care with chlorhexidine and semirecumbent position, was launched in 2011–2012. This report will document the impact of this campaign. On 1 day, once a year from 2010 till 2016, except in 2012, Belgian ICUs were questioned about their ventilated patients. For each of these, data about the application of the bundle and the possible treatment for VAP were recorded. Between 36.6 and 54.8% of the 120 Belgian ICUs participated in the successive surveys. While the characteristics of ventilated patients remained similar throughout the years, the percentage of ventilated patients and especially the duration of ventilation significantly decreased before and after the national VAP bundle campaign. Ventilator care also profoundly changed: Controlling cuff pressure, head positioning above 30° were obtained in more than 90% of cases. Oral care was more frequently performed within a day, using more concentrated solutions of chlorhexidine. Subglottic suctioning also was used but in only 24.7% of the cases in the last years. Regarding the prevalence of VAP, it significantly decreased from 28% of ventilated patients in 2010 to 10.1% in 2016 (p ≤ 0.0001). Although a causal relationship cannot be inferred from these data, the successive surveys revealed a potential impact of the VAP bundle campaign on both the respiratory care of ventilated patients and the prevalence of VAP in Belgian ICUs encouraging them to follow the guidelines.
Background Several randomised clinical trials have studied convalescent plasma for coronavirus disease 2019 (COVID-19) using different protocols, with different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralising antibody titres, at different time-points and severities of illness. Methods In the prospective multicentre DAWn-plasma trial, adult patients hospitalised with COVID-19 were randomised to 4 units of open-label convalescent plasma combined with standard of care (intervention group) or standard of care alone (control group). Plasma from donors with neutralising antibody titres (50% neutralisation titre (NT 50 )) ≥1/320 was the product of choice for the study. Results Between 2 May 2020 and 26 January 2021, 320 patients were randomised to convalescent plasma and 163 patients to the control group according to a 2:1 allocation scheme. A median (interquartile range) volume of 884 (806–906) mL) convalescent plasma was administered and 80.68% of the units came from donors with neutralising antibody titres (NT 50 ) ≥1/320. Median time from onset of symptoms to randomisation was 7 days. The proportion of patients alive and free of mechanical ventilation on day 15 was not different between both groups (convalescent plasma 83.74% (n=267) versus control 84.05% (n=137)) (OR 0.99, 95% CI 0.59–1.66; p=0.9772). The intervention did not change the natural course of antibody titres. The number of serious or severe adverse events was similar in both study arms and transfusion-related side-effects were reported in 19 out of 320 patients in the intervention group (5.94%). Conclusions Transfusion of 4 units of convalescent plasma with high neutralising antibody titres early in hospitalised COVID-19 patients did not result in a significant improvement of clinical status or reduced mortality.
Abstract Background: Considering the high mortality rate of severe Covid-19 patients, it is necessary to identify prognostic factors and therapies which could be valuable in this setting. Methods: The method consisted in a multicentric retrospective analysis in all consecutive Covid-19 patients admitted to intensive care unit (ICU) and mechanically ventilated for more than 24 hours from March 1 to April 25, 2020.Admission date, age, sex, body mass index, underlying conditions, treatments, physiological values, use of vasopressors, renal replacement therapy and extracorporeal membrane oxygenation, duration of mechanical ventilation, length of ICU stay, ICU and ventilator-free days at day 42 were collected. Primary outcome was survival. Simple and multiple time-dependent Cox regression models were used to assess the effects of factors on survival. Results: Out of 2003 patients hospitalized for SARS-CoV-2, 361 were admitted to the participating ICUs, 257 were ventilated for more than 24 hours and 247 were included in the study. The length of stay in ICU was 21 (12-32) days and the mortality rate was 45%. Using multiple regression, risk factors for mortality were age, high serum creatinine value, low mean arterial pressure, low lymphocytes count on day 0 and the absence of corticosteroid therapy during the first week of mechanical ventilation. The mortality rate of the patients who received corticosteroids was 34% and 48% for patients who did not (p = 0.01). Conclusion: In this multicenter cohort, the mortality of patients with SARS-CoV-2 pneumonia treated with mechanical ventilation was high. The risk factors for mortality included age, renal and circulatory dysfunction, lymphopenia and the absence of corticosteroid therapy during the first week of mechanical ventilation.
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