Moderate therapeutic hypothermia is currently recommended to improve neurologic outcomes in adults with persistent coma after resuscitated out-of-hospital cardiac arrest. However, the effectiveness ...of moderate therapeutic hypothermia in patients with nonshockable rhythms (asystole or pulseless electrical activity) is debated.
We performed an open-label, randomized, controlled trial comparing moderate therapeutic hypothermia (33°C during the first 24 hours) with targeted normothermia (37°C) in patients with coma who had been admitted to the intensive care unit (ICU) after resuscitation from cardiac arrest with nonshockable rhythm. The primary outcome was survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the Cerebral Performance Category (CPC) scale (which ranges from 1 to 5, with higher scores indicating greater disability). We defined a favorable neurologic outcome as a CPC score of 1 or 2. Outcome assessment was blinded. Mortality and safety were also assessed.
From January 2014 through January 2018, a total of 584 patients from 25 ICUs underwent randomization, and 581 were included in the analysis (3 patients withdrew consent). On day 90, a total of 29 of 284 patients (10.2%) in the hypothermia group were alive with a CPC score of 1 or 2, as compared with 17 of 297 (5.7%) in the normothermia group (difference, 4.5 percentage points; 95% confidence interval CI, 0.1 to 8.9; P = 0.04). Mortality at 90 days did not differ significantly between the hypothermia group and the normothermia group (81.3% and 83.2%, respectively; difference, -1.9 percentage points; 95% CI, -8.0 to 4.3). The incidence of prespecified adverse events did not differ significantly between groups.
Among patients with coma who had been resuscitated from cardiac arrest with nonshockable rhythm, moderate therapeutic hypothermia at 33°C for 24 hours led to a higher percentage of patients who survived with a favorable neurologic outcome at day 90 than was observed with targeted normothermia. (Funded by the French Ministry of Health and others; HYPERION ClinicalTrials.gov number, NCT01994772.).
In patients with acute respiratory distress syndrome (ARDS), the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network recommends a target partial pressure of arterial oxygen (Pao
) ...between 55 and 80 mm Hg. Prospective validation of this range in patients with ARDS is lacking. We hypothesized that targeting the lower limit of this range would improve outcomes in patients with ARDS.
In this multicenter, randomized trial, we assigned patients with ARDS to receive either conservative oxygen therapy (target Pao
, 55 to 70 mm Hg; oxygen saturation as measured by pulse oximetry Spo
, 88 to 92%) or liberal oxygen therapy (target Pao
, 90 to 105 mm Hg; Spo
, ≥96%) for 7 days. The same mechanical-ventilation strategies were used in both groups. The primary outcome was death from any cause at 28 days.
After the enrollment of 205 patients, the trial was prematurely stopped by the data and safety monitoring board because of safety concerns and a low likelihood of a significant difference between the two groups in the primary outcome. Four patients who did not meet the eligibility criteria were excluded. At day 28, a total of 34 of 99 patients (34.3%) in the conservative-oxygen group and 27 of 102 patients (26.5%) in the liberal-oxygen group had died (difference, 7.8 percentage points; 95% confidence interval CI, -4.8 to 20.6). At day 90, 44.4% of the patients in the conservative-oxygen group and 30.4% of the patients in the liberal-oxygen group had died (difference, 14.0 percentage points; 95% CI, 0.7 to 27.2). Five mesenteric ischemic events occurred in the conservative-oxygen group.
Among patients with ARDS, early exposure to a conservative-oxygenation strategy with a Pao
between 55 and 70 mm Hg did not increase survival at 28 days. (Funded by the French Ministry of Health; LOCO
ClinicalTrials.gov number, NCT02713451.).
Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear.
In this phase 3, multicenter, ...double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days.
A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval CI, 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment.
Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).
Monitoring of residual gastric volume is recommended to prevent ventilator-associated pneumonia (VAP) in patients receiving early enteral nutrition. However, studies have challenged the reliability ...and effectiveness of this measure.
To test the hypothesis that the risk of VAP is not increased when residual gastric volume is not monitored compared with routine residual gastric volume monitoring in patients receiving invasive mechanical ventilation and early enteral nutrition.
Randomized, noninferiority, open-label, multicenter trial conducted from May 2010 through March 2011 in adults requiring invasive mechanical ventilation for more than 2 days and given enteral nutrition within 36 hours after intubation at 9 French intensive care units (ICUs); 452 patients were randomized and 449 included in the intention-to-treat analysis (3 withdrew initial consent).
Absence of residual gastric volume monitoring. Intolerance to enteral nutrition was based only on regurgitation and vomiting in the intervention group and based on residual gastric volume greater than 250 mL at any of the 6 hourly measurements and regurgitation or vomiting in the control group.
Proportion of patients with at least 1 VAP episode within 90 days after randomization, as assessed by an adjudication committee blinded to patient group. The prestated noninferiority margin was 10%.
In the intention-to-treat population, VAP occurred in 38 of 227 patients (16.7%) in the intervention group and in 35 of 222 patients (15.8%) in the control group (difference, 0.9%; 90% CI, -4.8% to 6.7%). There were no significant between-group differences in other ICU-acquired infections, mechanical ventilation duration, ICU stay length, or mortality rates. The proportion of patients receiving 100% of their calorie goal was higher in the intervention group (odds ratio, 1.77; 90% CI, 1.25-2.51; P = .008). Similar results were obtained in the per-protocol population.
Among adults requiring mechanical ventilation and receiving early enteral nutrition, the absence of gastric volume monitoring was not inferior to routine residual gastric volume monitoring in terms of development of VAP.
clinicaltrials.gov Identifier: NCT01137487.
Patients who are treated with targeted temperature management after out-of-hospital cardiac arrest with shockable rhythm are at increased risk for ventilator-associated pneumonia. The benefit of ...preventive short-term antibiotic therapy has not been shown.
We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving adult patients (>18 years of age) in intensive care units (ICUs) who were being mechanically ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management at 32 to 34°C. Patients with ongoing antibiotic therapy, chronic colonization with multidrug-resistant bacteria, or moribund status were excluded. Either intravenous amoxicillin-clavulanate (at doses of 1 g and 200 mg, respectively) or placebo was administered three times a day for 2 days, starting less than 6 hours after the cardiac arrest. The primary outcome was early ventilator-associated pneumonia (during the first 7 days of hospitalization). An independent adjudication committee determined diagnoses of ventilator-associated pneumonia.
A total of 198 patients underwent randomization, and 194 were included in the analysis. After adjudication, 60 cases of ventilator-associated pneumonia were confirmed, including 51 of early ventilator-associated pneumonia. The incidence of early ventilator-associated pneumonia was lower with antibiotic prophylaxis than with placebo (19 patients 19% vs. 32 34%; hazard ratio, 0.53; 95% confidence interval, 0.31 to 0.92; P = 0.03). No significant differences between the antibiotic group and the control group were observed with respect to the incidence of late ventilator-associated pneumonia (4% and 5%, respectively), the number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days if patients were discharged and 7 days and 7 days if patients had died), and mortality at day 28 (41% and 37%). At day 7, no increase in resistant bacteria was identified. Serious adverse events did not differ significantly between the two groups.
A 2-day course of antibiotic therapy with amoxicillin-clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator-associated pneumonia than placebo. No significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28. (Funded by the French Ministry of Health; ANTHARTIC ClinicalTrials.gov number, NCT02186951.).
COVID-19 pneumonia typically begins with subpleural ground glass opacities with progressive extension on computerized tomography studies. Lung ultrasound is well suited to this interstitial, ...subpleural involvement, and it is now broadly used in intensive care units (ICUs). The extension and severity of lung infiltrates can be described numerically with a reproducible and validated lung ultrasound score (LUSS). We hypothesized that LUSS might be useful as a tool to non-invasively monitor the evolution of COVID-19 pneumonia at the bedside. LUSS monitoring was rapidly implemented in the management of our COVID-19 patients with RT-PCR-documented COVID-19. The LUSS was evaluated repeatedly at the bedside. We present a graphic description of the course of LUSS during COVID-19 in 10 consecutive patients admitted in our intensive care unit with moderate to severe ARDS between March 15 and 30th. LUSS appeared to be closely related to the disease progression. In successfully extubated patients, LUSS decreased and was lower than at the time of intubation. LUSS increased inexorably in a patient who died from refractory hypoxemia. LUSS helped with the diagnosis of ventilator-associated pneumonia (VAP), showing an increased score and the presence of new lung consolidations in all 5 patients with VAPs. There was also a good agreement between CT-scans and LUSS as for the presence of lung consolidations. In conclusion, our early experience suggests that LUSS monitoring accurately reflect disease progression and indicates potential usefulness for the management of COVID-19 patients with ARDS. It might help with early VAP diagnosis, mechanical ventilation weaning management, and potentially reduce the need for X-ray and CT exams. LUSS evaluation is easy to use and readily available in ICUs throughout the world, and might be a safe, cheap and simple tool to optimize critically ill COVID-19 patients care during the pandemic.
The French Society of Intensive Care Medicine (SRLF), jointly with the French-Speaking Group of Paediatric Emergency Rooms and Intensive Care Units (GFRUP) and the French-Speaking Association of ...Paediatric Surgical Intensivists (ADARPEF), worked out guidelines for the management of central venous catheters (CVC), arterial catheters and dialysis catheters in intensive care unit.
For adult patients
: Using GRADE methodology, 36 recommendations for an improved catheter management were produced by the 22 experts. Recommendations regarding catheter-related infections’ prevention included the preferential use of subclavian central vein (GRADE 1), a one-step skin disinfection(GRADE 1) using 2% chlorhexidine (CHG)-alcohol (GRADE 1), and the implementation of a quality of care improvement program. Antiseptic- or antibiotic-impregnated CVC should likely not be used (GRADE 2, for children and adults). Catheter dressings should likely not be changed before the 7th day, except when the dressing gets detached, soiled or impregnated with blood (GRADE 2− adults). CHG dressings should likely be used (GRADE 2+). For adults and children, ultrasound guidance should be used to reduce mechanical complications in case of internal jugular access (GRADE 1), subclavian access (Grade 2) and femoral venous, arterial radial and femoral access (Expert opinion). For children, an ultrasound-guided supraclavicular approach of the brachiocephalic vein was recommended to reduce the number of attempts for cannulation and mechanical complications. Based on scarce publications on diagnostic and therapeutic strategies and on their experience (expert opinion), the panel proposed definitions, and therapeutic strategies.
To assess whether early thrombocytopenia during septic shock is associated with an increased risk of death at day 28 and to identify risk factors associated with a low platelet count.
Prospective, ...multicenter, observational cohort study.
Fourteen ICUs from 10 French university teaching and nonacademic hospitals.
Consecutive adult patients with septic shock admitted between November 2009 and September 2011 were eligible.
None.
Of the 1,495 eligible patients, 1,486 (99.4%) were included. Simplified Acute Physiology Score II score of greater than or equal to 56, immunosuppression, age of more than 65 years, cirrhosis, bacteremia (p ≤ 0.001 for each), and urinary sepsis (p = 0.005) were globally associated with an increased risk of thrombocytopenia within the first 24 hours following the onset of septic shock. Survival at day 28 estimated by the Kaplan-Meier method was lower in patients with thrombocytopenia and decreased with thrombocytopenia severity. By multivariate Cox regression, a platelet count of less than or equal to 100,000/mm3 was independently associated with a significantly increased risk of death within the 28 days following septic shock onset. The risk of death increased with the severity of thrombocytopenia (hazard ratio, 1.65; 95% CI, 1.31-2.08 for a platelet count below 50,000/mm3 vs > 150,000/mm3; p < 0.0001).
This is the first study to investigate thrombocytopenia within the first 24 hours of septic shock onset as a prognostic marker of survival at day 28 in a large cohort of ICU patients. Measuring platelet count is inexpensive and easily feasible for the physician in routine practice, and thus, it could represent an easy "alert system" among patients in septic shock.
COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. ...The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19).
Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared.
COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1β concentrations.
CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach.
ClinicalTrials.gov, NCT03955887.
Mitochondria have emerged as key actors of innate and adaptive immunity. Mitophagy has a pivotal role in cell homeostasis, but its contribution to macrophage functions and host defense remains to be ...delineated. Here, we showed that lipopolysaccharide (LPS) in combination with IFN-γ inhibited PINK1-dependent mitophagy in macrophages through a STAT1-dependent activation of the inflammatory caspases 1 and 11. In addition, we demonstrated that the inhibition of mitophagy triggered classical macrophage activation in a mitochondrial ROS-dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation, which favored bactericidal clearance and led to a better survival rate. Reciprocally, mitochondrial uncouplers that promote mitophagy reversed LPS/IFN-γ-mediated activation of macrophages and led to immunoparalysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy was inhibited in blood monocytes of patients with sepsis as compared with nonseptic patients. Overall, this work demonstrates that the inhibition of mitophagy is a physiological mechanism that contributes to the activation of myeloid cells and improves the outcome of sepsis.
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