It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock.OBJECTIVE To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTSMulticenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019.INTERVENTIONS Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. MAIN OUTCOMES AND MEASURESThe primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality.RESULTS Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported. CONCLUSIONS AND RELEVANCEIn patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.

B enite, d the National Referee Centre for Rheumatic and AutoImmune and Systemic diseases in childrEn (RAISE), and

BackgroundPredicting fluid responsiveness may help to avoid unnecessary fluid administration during acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate the diagnostic performance of the following methods to predict fluid responsiveness in ARDS patients under protective ventilation in the prone position: cardiac index variation during a Trendelenburg maneuver, cardiac index variation during an end-expiratory occlusion test, and both pulse pressure variation and change in pulse pressure variation from baseline during a tidal volume challenge by increasing tidal volume (VT) to 8 ml.kg-1.MethodsThis study is a prospective single-center study, performed in a medical intensive care unit, on ARDS patients with acute circulatory failure in the prone position. Patients were studied at baseline, during a 1-min shift to the Trendelenburg position, during a 15-s end-expiratory occlusion, during a 1-min increase in VT to 8 ml.kg-1, and after fluid administration. Fluid responsiveness was deemed present if cardiac index assessed by transpulmonary thermodilution increased by at least 15% after fluid administration.ResultsThere were 33 patients included, among whom 14 (42%) exhibited cardiac arrhythmia at baseline and 15 (45%) were deemed fluid-responsive. The area under the receiver operating characteristic (ROC) curve of the pulse contour-derived cardiac index change during the Trendelenburg maneuver and the end-expiratory occlusion test were 0.90 (95% CI, 0.80–1.00) and 0.65 (95% CI, 0.46–0.84), respectively. An increase in cardiac index ≥ 8% during the Trendelenburg maneuver enabled diagnosis of fluid responsiveness with sensitivity of 87% (95% CI, 67–100), and specificity of 89% (95% CI, 72–100). The area under the ROC curve of pulse pressure variation and change in pulse pressure variation during the tidal volume challenge were 0.52 (95% CI, 0.24–0.80) and 0.59 (95% CI, 0.31–0.88), respectively.ConclusionsChange in cardiac index during a Trendelenburg maneuver is a reliable test to predict fluid responsiveness in ARDS patients in the prone position, while neither change in cardiac index during end-expiratory occlusion, nor pulse pressure variation during a VT challenge reached acceptable predictive performance to predict fluid responsiveness in this setting.Trial registrationClinicalTrials.gov, NCT01965574. Registered on 16 October 2013. The trial was registered 6 days after inclusion of the first patient.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1881-0) contains supplementary material, which is available to authorized users.

KEYWORDSAcute kidney injury Acute respiratory distress syndrome Angiotensin Angiotensin-converting enzyme Sepsis Inflammation Septic shock Renin KEY POINTSActivation of the endocrine renin-angiotensin system (RAS) cascade induces immediate metabolic, hemodynamic, and renal responses, in response to changes in blood pressure and homeostasis. Renin and angiotensin II are upregulated in the setting of sepsis and septic shock. Higher renin and angiotensin II and lower circulating angiotensin-converting enzyme levels are associated with worse survival. Classic and nonclassic RASs modulate the inflammatory and immune responses. The angiotensin II axis stimulates a proinflammatory beneficial antibacterial response. In patients with vasoplegic shock, the infusion of exogenous angiotensin II lowers vasopressor requirements, and improves renal-related outcomes. Experimental evidence supports the direct role of classic RAS in the pathophysiology of acute respiratory distress syndrome, whereas clinical data suggest a lung protective effect of angiotensin-converting enzyme 2 administration.

Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Background The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

The funder had no role in the design and conduct of the study, collection, management, analysis,

Background: Hypotension is a frequent complication of intermittent hemodialysis (IHD) performed in intensive care units (ICUs). Passive leg raising (PLR) combined with continuous measurement of cardiac output is highly reliable to identify preload dependence, and may provide new insights into the mechanisms involved in IHD-related hypotension. The aim of this study was to assess prevalence and risk factors of preload dependence-related hypotension during IHD in the ICU. Methods: A single-center prospective observational study performed on ICU patients undergoing IHD for acute kidney injury and monitored with a PiCCO® device. Primary end points were the prevalence of hypotension (defined as a mean arterial pressure below 65 mm Hg) and hypotension associated with preload dependence. Preload dependence was assessed by the passive leg raising test, and considered present if the systolic ejection volume increased by at least 10 % during the test, as assessed continuously by the PiCCO® device. Results: Forty-seven patients totaling 107 IHD sessions were included. Hypotension was observed in 61 IHD sessions (57 %, CI 95% : 47-66 %) and was independently associated with inotrope administration, higher SOFA score, lower time lag between ICU admission and IHD session, and lower MAP at IHD session onset. Hypotension associated with preload dependence was observed in 19 % (CI 95% : 10-31 %) of sessions with hypotension, and was associated with mechanical ventilation, lower SAPS II, higher pulmonary vascular permeability index (PVPI) and dialysate sodium concentration at IHD session onset. ROC curve analysis identified PVPI and mechanical ventilation as the only variables with significant diagnostic performance to predict hypotension associated with preload dependence (respective AUC: 0.68 (CI 95% : 0.53-0.83) and 0.69 (CI 95% : 0.54-0.85). A PVPI ≥ 1.6 at IHD session onset predicted occurrence of hypotension associated with preload dependence during IHD with a sensitivity of 91 % (CI 95% : 59-100 %), and a specificity of 53 % (CI 95% : 42-63 %). Conclusions: The majority of hypotensive episodes occurring during intermittent hemodialysis are unrelated to preload dependence and should not necessarily lead to reduction of fluid removal by hemodialysis. However, high PVPI at IHD session onset and mechanical ventilation are risk factors of preload dependence-related hypotension, and should prompt reduction of planned fluid removal during the session, and/or an increase in session duration.