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Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. OBJECTIVE To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. DESIGN, SETTING, AND PARTICIPANTS The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 10 9 /L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. INTERVENTIONS Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days. MAIN OUTCOME AND MEASURES The primary end point was 28-day all-cause mortality. RESULTS Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, −3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. CONCLUSIONS AND RELEVANCE Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality.

In patients with acute hypoxemic respiratory failure breathing spontaneously, the respiratory rate was a predictor of intubation under standard oxygen, but not under high-flow nasal cannula oxygen or noninvasive ventilation. A PaO2/FIO2 below 200 mm Hg and a high tidal volume greater than 9 mL/kg were the two strong predictors of intubation under noninvasive ventilation.

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BackgroundAdrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial.MethodsAdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock.ResultsCirculating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5–148.1 pg/ml]. Initial SOFA score was 7 [IQR 5–10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9–2.9]; adjusted HR 1.6 [CI 1.1–2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5–9.8).ConclusionsAdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial.Trial registrationClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2243-2) contains supplementary material, which is available to authorized users.

Background The COVID-19 outbreak requires a permanent adaptation of practices. Cardiopulmonary resuscitation (CPR) is also involved and we evaluated these changes in the management of out-of-hospital cardiac arrest (OHCA). Methods OHCA of medical origins identified from the French National Cardiac Arrest Registry between March 1st and April 31st 2020 (COVID-19 period), were analysed. Different resuscitation characteristics were compared with the same period from the previous year (non-COVID-19 period). Results Overall, 1005 OHCA during the COVID-19 period and 1620 during the non-COVID-19 period were compared. During the COVID-19 period, bystanders and first aid providers initiated CPR less frequently (49.8% versus 54.9%; difference, − 5.1 percentage points [95% CI, − 9.1 to − 1.2]; and 84.3% vs. 88.7%; difference, − 4.4 percentage points [95% CI, − 7.1 to − 1.6]; respectively) as did mobile medical teams (67.3% vs. 75.0%; difference, − 7.7 percentage points [95% CI, − 11.3 to − 4.1]). First aid providers used defibrillators less often (66.0% vs. 74.1%; difference, − 8.2 percentage points [95% CI, − 11.8 to − 4.6]). Return of spontaneous circulation (ROSC) and D30 survival were lower during the COVID-19 period (19.5% vs. 25.3%; difference, − 5.8 percentage points [95% CI, − 9.0 to − 2.5]; and 2.8% vs. 6.4%; difference, − 3.6 percentage points [95% CI, − 5.2 to − 1.9]; respectively). Conclusions During the COVID-19 period, we observed a decrease in CPR initiation regardless of whether patients were suspected of SARS-CoV-2 infection or not. In the current atmosphere, it is important to communicate good resuscitation practices to avoid drastic and lasting reductions in survival rates after an OHCA.

IntroductionSepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)—a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay—for kidney events in sepsis and septic shock.MethodsThe Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality.ResultsMedian age was 66 years (interquartile range 55–75), and 28-day mortality was 22% (95% confidence interval [CI] 19%−25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median = 65 [IQR = 45–106] vs. 179 [114–242]; 53 [39–70] vs. 133 [79–196] pmol/l; and 70 [47–121] vs. 174 [93–242] pmol/l, all P < 0.0001), also after adjustment for confounding factors (adjusted odds ratio = 3.3 [95% CI = 1.8–6.0], 3.9 [95% CI = 2.1–7.2], and 3.4 [95% CI = 1.9–6.2], all P < 0.0001). Penkid increase preceded elevation of serum creatinine with WRF and was low in renal recovery.ConclusionAdmission penkid concentration was associated with MAKEs, AKI, and WRF in a timely manner in septic patients.