(i) Purpose. The fluid challenge (FC) is a well-established test of preload reserve. Only limited data exist in regard to the FC efficacy based on infusion time. Slow administration may be associated with lack of effect based on fluid redistribution and external conditions changes. On the contrary, fast administration may lead to brisk fluid overload and damage to the endothelium and endothelial glycocalyx (EG). The aim of this trial was to compare the FC infusion time on its hemodynamic effects and EG. (ii) Methods. Prospective randomized single-center trial of fast (5-10 minutes) versus slow (20-30 minutes) administration of 500ml balanced crystalloid FC in spinal surgery (cohort OR) and septic shock (cohort SEP) patients. Hemodynamic response was assessed using standard monitoring and blood flow measurements; damage to EG was assessed using the perfused boundary region (PBR) via intravital microscopy monitoring in the sublingual region within relevant time points ranging up to 120 minutes. (iii) Results. Overall, 66 FCs in 50 surgical and 16 septic patients were assessed. Fluid administration was associated with increase of PBR in general (1.9 (1.8-2.1) vs. 2.0 (1.8-2.2); p= 0.008). These changes were transient in OR cohort whereas they were long-lasting in septic fluid responders. The rate of fluid responsiveness after fast versus slow administration was comparable in global population (15 (47%) vs. 17 (50%); p=0.801) as well as in both cohorts. (iv) Conclusions. Fluid challenge administration was associated with increased PBR (and presumable EG volume changes) which normalized within the next 60 minutes in surgical patients but remained impeded in septic fluid responders. The fluid responsiveness rate after fast and slow FC was comparable, but fast administration tended to induce higher, though transient, response in blood pressure.

BackgroundThe use of goal directed fluid protocols in intermediate risk patients undergoing hip or knee replacement was studied in few trials using invasive monitoring. For this reason we have implemented two different fluid management protocols, both based on a novel totally non-invasive arterial pressure monitoring device and compared them to the standard (no-protocol) treatment applied before the transition in our academic institution.MethodsThree treatment groups were compared in this prospective study: the observational (CONTROL, N = 40) group before adoption of fluid protocols and two randomized groups after the transition to protocol fluid management with the use of the continuous non-invasive blood pressure monitoring (CNAP®) device. In the PRESSURE group (N = 40) standard variables were used for restrictive fluid therapy. Goal directed fluid therapy using pulse pressure variation was used in the GDFT arm (N = 40). The influence on the rate of postoperative complications, on the hospital length of stay and other parameters was assessed.ResultsBoth protocols were associated with decreased fluid administration and maintained hemodynamic stability. Reduced rate of postoperative infection and organ complications (22 (55 %) vs. 33 (83 %) patients; p = 0.016; relative risk 0.67 (0.49–0.91)) was observed in the GDFT group compared to CONTROL. Lower number of patients receiving transfusion (4 (10 %) in GDFT vs. 17 (43 %) in CONTROL; p = 0.005) might contribute to this observation. No significant differences were observed in other end-points.ConclusionIn our study, the use of the fluid protocol based on pulse pressure variation assessed using continuous non-invasive arterial pressure measurement seems to be associated with a reduction in postoperative complications and transfusion needs as compared to standard no-protocol treatment.Trial registrationACTRN12612001014842Electronic supplementary materialThe online version of this article (doi:10.1186/s12871-015-0131-8) contains supplementary material, which is available to authorized users.

The endothelial glycocalyx (EG) is the thin sugar-based lining on the apical surface of endothelial cells. It has been linked to the physiological functioning of the microcirculation and has been found to be damaged in critical illness and after acute care surgery. This review aims to describe the role of EG in severely injured patients undergoing surgery, discuss specific situations (e.G. major trauma, hemorrhagic shock, trauma induced coagulopathy) as well as specific interventions commonly applied in these patients (e.g. fluid therapy, transfusion) and specific drugs related to perioperative medicine with regard to their impact on EG.EG in acute care surgery is exposed to damage due to tissue trauma, inflammation, oxidative stress and inadequate fluid therapy. Even though some interventions (transfusion of plasma, human serum albumin, hydrocortisone, sevoflurane) are described as potentially EG protective there is still no specific treatment for EG protection and recovery in clinical medicine.The most important principle to be adopted in routine clinical practice at present is to acknowledge the fragile structure of the EG and avoid further damage which is potentially related to worsened clinical outcome.

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The laboratory analysis provides accurate, but time consuming hemoglobin level estimation especially in the emergency setting. The reliability of time-sparing point of care devices (POCT) remains uncertain. We tested two POCT devices accuracy (HemoCue201 and GemPremier™3000) in routine emergency department workflow. Blood samples taken from patients admitted to the emergency department were analyzed for hemoglobin concentration using a laboratory reference Beckman Coulter LH 750 (HB), the HemoCue (HB) and the Gem Premier 3000 (HB). Pairwise comparison for each device and Hb was performed using correlation and the Bland-Altman methods. The reliability of transfusion decision was assessed using three-zone error grid. A total of 292 measurements were performed in 99 patients. Mean hemoglobin level were 115 ± 33, 110 ± 28 and 111 ± 30 g/l for Hb, Hb and Hb respectively. A significant correlation was observed for both devices: Hb versus Hb (r = 0.93, p < 0.001) and HB versus HB (r = 0.86, p < 0.001). The Bland-Altman method revealed bias of -3.7 g/l (limits of agreement -20.9 to 13.5) for HB and HB and 2.5 g/l (-18.6 to 23.5) for HB and HB, which significantly differed between POCT devices (p < 0.001). Using the error grid methodology: 94 or 91 % of values (Hb and Hb) fell in the zone of acceptable difference (A), whereas 0 and 1 % (Hb and Hb) were unacceptable (zone C). The absolute accuracy of tested POCT devices was low though reaching a high level of correlation with laboratory measurement. The results of the Morey´s error grid were unfavorable for both POCT devices.

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Objectives The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. Trial design REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. Participants The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. Inclusion criteria Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria:  • Moderate – PaO2/FiO2 100–200 mmHg;  • Severe – PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. Exclusion criteria Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history:  a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days;  b) Systemic corticosteroid use before hospitalization;  c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment;  d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g.  • intractable hyperglycaemia;  • active gastrointestinal bleeding;  • adrenal gland disorders;  • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. Intervention and comparator Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1–5, followed by dexamethasone 10 mg intravenously once daily on day 6–10. Patients in the control group will receive dexamethasone 6 mg day 1–10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. Main outcomes Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. Secondary endpoints a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. Randomisation Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. Blinding (masking) This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. Numbers to be randomised (sample size) The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. Trial Status This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. Trial registration The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. Full protocol The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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