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Sergio I Prada,1,2 Maria P Garcia-Garcia,1 Gustavo A Ospina-Tascón,3,4 Diego Rosselli5 1Fundación Valle del Lili, Centro de Investigaciones Clínicas, Cali, Colombia; 2Universidad Icesi, Centro PROESA, Cali, Colombia; 3Department of Intensive Care, Fundación Valle del Lili, Cali, Colombia; 4Translational Medicine Laboratory in Critical Care (TransLab-CCM), Universidad Icesi, Cali, Colombia; 5Clinical Epidemiology and Biostatistics Department, Pontificia Universidad Javeriana, Bogota, ColombiaCorrespondence: Sergio I Prada, Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cra. 98 18-49, Cali, Valle, Colombia, Email sergio.prada@fvl.org.coBackground: A randomized clinical trial (HiFlo-COVID-19 Trial) showed that among patients with severe COVID-19, treatment with high-flow oxygen therapy (HFOT) significantly reduced the need for invasive mechanical ventilation support and time for clinical recovery compared with conventional oxygen therapy (COT). However, the cost of this strategy is unknown.Objective: We examined total cost of HFOT treatment compared with COT in real-world setting.Methods: We conducted a post-trial-based cost analysis from the perspective of a managed competition healthcare system, using actual records of billed costs. Cost categories include general ward, intensive care unit, procedures, imaging, laboratories, medications, supplies, and others.Results: A total of 188 participants (mean age 60, 33% female) were included. Average costs (and standard deviation) in the HFOT group were USD $7992 (7394) and in the COT group USD $ 10,190 (9402). Differences, however, did not reach statistical significance (P=0.093). However, resource use was always less costly for the HNFO group, with an overall percentage decrease of 27%. Two categories make up 72% of all savings: medications (41%) and intensive care unit (31%).Conclusion: For patients in ICU with severe COVID-19 the cost of treatment with HFOT as compared to COT is likely to be cost-saving due to less use of medications and length of stay in ICU.Keywords: SARS-CoV-2, COVID-19, cost analysis, economic evaluation, high-flow nasal oxygen, conventional oxygen therapy, high-flow oxygen therapy, clinical trial, cost, Colombia

Objective: Lack of evidence that some monitoring systems can improve outcomes has raised doubts about their use in the intensive care unit (ICU). The objective of this study was to determine which monitoring techniques have been shown to improve outcomes in ICU patients.Design: Comprehensive literature review.Methods: We conducted a highly sensitive search, up to June 2006, in the Cochrane Central Register of Controlled Trials (CENTRAL) and MedLine, for prospective, randomized controlled trials (RCTs) conducted in adult patients in the ICU and the operating room (major surgical procedures) and focusing on the impact of monitoring on outcome.Measurements and Results: Of 4,175 potential articles, 67 evaluated the impact of monitoring in acutely ill adult patients. There were 40 studies related to hemodynamic monitoring, 17 to respiratory monitoring, and 10 to neurological monitoring. Seven studies were classified in two different categories. Positive non-mortality outcomes were observed in 17 of 40 hemodynamic studies, 11 of 17 respiratory, and in all 10 neurological studies. Mortality was evaluated in 31 hemodynamic studies, but a beneficial impact was demonstrated in only 10. For respiratory monitoring, 7 studies evaluated mortality, but only 3 of them showed an improved outcome. We found no neurological monitoring studies that assessed mortality.Conclusion: There is no broad evidence that any form of monitoring improves outcomes in the ICU and most commonly used devices have not been evaluated by RCT. This review puts into perspective the recent negative studies on the use of the pulmonary artery catheter in the acutely ill. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine how many multicenter, randomized controlled trials have been published that assess mortality as a primary outcome in the adult intensive care unit population, and to evaluate their methodologic quality. DATA SOURCE: A sensitive search strategy for randomized controlled trials was conducted in the Cochrane Central Register of Controlled Trials and in MedLine using the PubMed interface. STUDY SELECTION: All publications of adult, multicenter randomized controlled trials carried out in the intensive care unit, with mortality as a primary outcome, and including >50 patients were selected. DATA EXTRACTION: Seventy-two randomized controlled trials were retrieved and were classified according to their effect on mortality: beneficial, detrimental, or neutral. DATA SYNTHESIS: Ten of the studies reported a positive impact of the studied intervention on mortality, seven studies reported a detrimental effect of the intervention, and 55 studies showed no effect on mortality. CONCLUSIONS: This literature search demonstrates that relatively few of the randomized controlled trials conducted in intensive care units and using mortality as a primary outcome show a beneficial impact of the intervention on the survival of critically ill patients. Methodological limitations of some of the randomized controlled trials may have prevented positive results. Other forms of evidence and end points other than mortality need to be considered when evaluating interventions in critically ill patients. [ABSTRACT FROM AUTHOR]

Purpose: To generate consensus and provide expert clinical practice statements for the management of adult sepsis in resource-limited settings., Methods: An international multidisciplinary Steering Committee with expertise in sepsis management and including a Delphi methodologist was convened by the Asia Pacific Sepsis Alliance (APSA). The committee selected an international panel of clinicians and researchers with expertise in sepsis management. A Delphi process based on an iterative approach was used to obtain the final consensus statements., Results: A stable consensus was achieved for 30 (94%) of the statements by 41 experts after four survey rounds. These include consensus on managing patients with sepsis outside a designated critical care area, triggers for escalating clinical management and criteria for safe transfer to another facility. The experts agreed on the following: in the absence of serum lactate, clinical parameters such as altered mental status, capillary refill time and urine output may be used to guide resuscitation; special considerations regarding the volume of fluid used for resuscitation, especially in tropical infections, including the use of simple tests to assess fluid responsiveness when facilities for advanced hemodynamic monitoring are limited; use of Ringer's lactate or Hartmann's solution as balanced salt solutions; epinephrine when norepinephrine or vasopressin are unavailable; and the administration of vasopressors via a peripheral vein if central venous access is unavailable or not feasible. Similarly, where facilities for investigation are unavailable, there was consensus for empirical antimicrobial administration without delay when sepsis was strongly suspected, as was the empirical use of antiparasitic agents in patients with suspicion of parasitic infections., Conclusion: Using a Delphi method, international experts reached consensus to generate expert clinical practice statements providing guidance to clinicians worldwide on the management of sepsis in resource-limited settings. These statements complement existing guidelines where evidence is lacking and add relevant aspects of sepsis management that are not addressed by current international guidelines. Future studies are needed to assess the effects of these practice statements and address remaining uncertainties., Competing Interests: Declarations. Conflicts of interest: Massimo Antonelli: Grants from GE and Fisher & Paykel; Lecture fees from Menarini, Shionogi, Fisher & Paykel, Dimar. Jan De Waele: Consulted for Biomerieux, Menarini, MSD, Pfizer, Roche Diagnostics, ThermoFisher and Viatris (fees and honoraria paid to institution). Supported by a Sr Clinical Research Grant from the Research Foundation Flanders (FWO, Ref.1881020N). Jigeeshu Divatia: Lecture fees from Edwards India paid to my institution. Simon Finfer: Supported by an NHMRC Investigator Fellowship (Leadership Level 3 App 2017580), has received consulting fees paid to his employer from RevImmune Inc. and owns options in Sepsis Scout. Naomi E Hammond: Supported by an NHMRC Investigator Fellowship (Emerging Leader Level 1 App 1196320), has received consulting fees paid to her employer from RevImmune Inc. Arthur Kwizera: Grants from the Wellcome Trust; NIHR; Fisher & Paykel Ltd; Gradian Health Systems; Vygon Ltd; Speaker support from the ESICM; Makerere University Research and Innovation Fund. Marlies Ostermann: Institution received research funding from Baxter and Biomerieux. Ethical approval and consent: The study protocol was registered on clinicaltrials.gov [NCT05909384]. Oxford Tropical Research Ethics Committee (OxTREC) confirmed that the study was exempt from ethics review in March 2023. Consent to participate and publish: All authors and collaborators consented to participate in and publish this study., (© 2024. The Author(s).)

Background: Dynamic arterial elastance (Ea dyn ) has been investigated for its ability to predict hypotension during the weaning of vasopressors. Our study focused on assessing Ea dyn 's performance in the context of critically ill adult patients admitted to the intensive care unit, regardless of diagnosis., Main Body: Our study was conducted in accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis checklist. The protocol was registered in PROSPERO (CRD42023421462) on May 26, 2023. We included prospective observational studies from the MEDLINE and Embase databases through May 2023. Five studies involving 183 patients were included in the quantitative analysis. We extracted data related to patient clinical characteristics, and information about Ea dyn measurement methods, results, and norepinephrine dose. Most patients (76%) were diagnosed with septic shock, while the remaining patients required norepinephrine for other reasons. The average pressure responsiveness rate was 36.20%. The synthesized results yielded an area under the curve of 0.85, with a sensitivity of 0.87 (95% CI 0.74-0.93), specificity of 0.76 (95% CI 0.68-0.83), and diagnostic odds ratio of 19.07 (95% CI 8.47-42.92). Subgroup analyses indicated no variations in the Ea dyn based on norepinephrine dosage, the Ea dyn measurement device, or the Ea dyn diagnostic cutoff to predict cessation of vasopressor support., Conclusions: Ea dyn , evaluated through subgroup analyses, demonstrated good predictive ability for the discontinuation of vasopressor support in critically ill patients., (© 2024. The Author(s).)

Background: Current recommendations support guiding fluid resuscitation through the assessment of fluid responsiveness. Recently, the concept of fluid tolerance and the prevention of venous congestion (VC) have emerged as relevant aspects to be considered to avoid potentially deleterious side effects of fluid resuscitation. However, there is paucity of data on the relationship of fluid responsiveness and VC. This study aims to compare the prevalence of venous congestion in fluid responsive and fluid unresponsive critically ill patients after intensive care (ICU) admission., Methods: Multicenter, prospective cross-sectional observational study conducted in three medical-surgical ICUs in Chile. Consecutive mechanically ventilated patients that required vasopressors and admitted < 24 h to ICU were included between November 2022 and June 2023. Patients were assessed simultaneously for fluid responsiveness and VC at a single timepoint. Fluid responsiveness status, VC signals such as central venous pressure, estimation of left ventricular filling pressures, lung, and abdominal ultrasound congestion indexes and relevant clinical data were collected., Results: Ninety patients were included. Median age was 63 [45-71] years old, and median SOFA score was 9 [7-11]. Thirty-eight percent of the patients were fluid responsive (FR+), while 62% were fluid unresponsive (FR-). The most prevalent diagnosis was sepsis (41%) followed by respiratory failure (22%). The prevalence of at least one VC signal was not significantly different between FR+ and FR- groups (53% vs. 57%, p = 0.69), as well as the proportion of patients with 2 or 3 VC signals (15% vs. 21%, p = 0.4). We found no association between fluid balance, CRT status, or diagnostic group and the presence of VC signals., Conclusions: Venous congestion signals were prevalent in both fluid responsive and unresponsive critically ill patients. The presence of venous congestion was not associated with fluid balance or diagnostic group. Further studies should assess the clinical relevance of these results and their potential impact on resuscitation and monitoring practices., (© 2024. The Author(s).)

Background: In the postoperative period of cardiac surgical procedure, there is an imbalance in the ratio of oxygen supply to oxygen consumption that leads to organic dysfunction and death. There is evidence of microcirculation involvement in cardiac surgical procedure, and a dysregulated inflammatory response similar to sepsis can occur., Methods: We present a cohort of 280 consecutive adults who were monitored in the postoperative period after cardiac surgical procedure. We performed serial measurements of macrocirculatory indices, indices of global oxygenation, CO 2 -derived indices, and perfusion indices in the first 24 hours postoperatively., Results: We identified a dissociation between circulatory macrohemodynamic parameters/global oxygenation indices and the CO 2 -derived indices. The CO 2 -derived indices constitute a surrogate for microcirculatory flow and indicate the presence of anaerobic metabolism., Conclusions: A better understanding of these clinical variables will help establish optimal management protocols. It will also aid in the identification of patients in subpopulations with organic dysfunction despite conventional circulatory parameters within normal limits who can be overlooked if this exhaustive hemodynamic evaluation is not performed., (© 2023 The Authors.)

Introduction: Prediction of fluid responsiveness in acutely ill patients might be influenced by a number of clinical and technical factors. We aim to identify variables potentially modifying the operative performance of fluid responsiveness predictors commonly used in clinical practice., Methods: A sensitive strategy was conducted in the Medline and Embase databases to search for prospective studies assessing the operative performance of pulse pressure variation, stroke volume variation, passive leg raising (PLR), end-expiratory occlusion test (EEOT), mini-fluid challenge, and tidal volume challenge to predict fluid responsiveness in critically ill and acutely ill surgical patients published between January 1999 and February 2023. Adjusted diagnostic odds ratios (DORs) were calculated by subgroup analyses (inverse variance method) and meta-regression (test of moderators). Variables potentially modifying the operative performance of such predictor tests were classified as technical and clinical., Results: A total of 149 studies were included in the analysis. The volume used during fluid loading, the method used to assess variations in macrovascular flow (cardiac output, stroke volume, aortic blood flow, volume‒time integral, etc.) in response to PLR/EEOT, and the apneic time selected during the EEOT were identified as technical variables modifying the operative performance of such fluid responsiveness predictor tests (p < 0.05 for all adjusted vs. unadjusted DORs). In addition, the operative performance of fluid responsiveness predictors was also influenced by clinical variables such as the positive end-expiratory pressure (in the case of EEOT) and the dose of norepinephrine used during the fluid responsiveness assessment for PLR and EEOT (for all adjusted vs. unadjusted DORs)., Conclusion: Prediction of fluid responsiveness in critically and acutely ill patients is strongly influenced by a number of technical and clinical aspects. Such factors should be considered for individual intervention decisions., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: To investigate the effects of immediate start of norepinephrine versus initial fluid loading followed by norepinephrine on macro hemodynamics, regional splanchnic and intestinal microcirculatory flows in endotoxic shock., Design: Animal experimental study., Setting: University translational research laboratory., Subjects: Fifteen Landrace pigs., Interventions: Shock was induced by escalating dose of lipopolysaccharide. Animals were allocated to immediate start of norepinephrine (i-NE) ( n = 6) versus mandatory 1-hour fluid loading (30 mL/kg) followed by norepinephrine (i-FL) ( n = 6). Once mean arterial pressure greater than or equal to 75 mm Hg was, respectively, achieved, successive mini-fluid boluses of 4 mL/kg of Ringer Lactate were given whenever: a) arterial lactate greater than 2.0 mmol/L or decrease less than 10% per 30 min and b) fluid responsiveness was judged to be positive. Three additional animals were used as controls (Sham) ( n = 3). Time × group interactions were evaluated by repeated-measures analysis of variance., Measurements and Main Results: Hypotension was significantly shorter in i-NE group (7.5 min [5.5-22.0 min] vs 49.3 min [29.5-60.0 min]; p < 0.001). Regional mesenteric and microcirculatory flows at jejunal mucosa and serosa were significantly higher in i-NE group at 4 and 6 hours after initiation of therapy ( p = 0.011, p = 0.032, and p = 0.017, respectively). Misdistribution of intestinal microcirculatory blood flow at the onset of shock was significantly reversed in i-NE group ( p < 0.001), which agreed with dynamic changes in mesenteric-lactate levels ( p = 0.01) and venous-to-arterial carbon dioxide differences ( p = 0.001). Animals allocated to i-NE showed significantly higher global end-diastolic volumes ( p = 0.015) and required significantly less resuscitation fluids ( p < 0.001) and lower doses of norepinephrine ( p = 0.001) at the end of the experiment. Pulmonary vascular permeability and extravascular lung water indexes were significantly lower in i-NE group ( p = 0.021 and p = 0.004, respectively)., Conclusions: In endotoxemic shock, immediate start of norepinephrine significantly improved regional splanchnic and intestinal microcirculatory flows when compared with mandatory fixed-dose fluid loading preceding norepinephrine. Immediate norepinephrine strategy was related with less resuscitation fluids and lower vasopressor doses at the end of the experiment., Competing Interests: Dr. Ospina-Tascón disclosed that this study received funding from the Universidad Icesi, Cali, Colombia (COL0099642-989) and Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cali, Colombia (FVL-2020-004). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Purpose of Review: To discuss the different techniques used to assess tissue oxygenation in critically ill patients., Recent Findings: While historically the analysis of oxygen consumption (VO2)/oxygen delivery (DO2) relationships has provided important information, methodological limitations prevent its use at bedside. PO2 measurements, while attractive, are unfortunately of limited value in the presence of microvascular blood flow heterogeneity which is observed in many critically ill conditions including sepsis. Surrogates of tissue oxygenation are hence used. Elevated lactate levels may suggest inadequate tissue oxygenation, but other sources than tissue hypoxia can also contribute to hyperlactatemia so that lactate measurements should be used in combination with other measurements of tissue oxygenation. Venous O2 saturation can be used to evaluate the adequacy of DO2 in respect to VO2, but it can be misleading normal or even high in sepsis. Measurements of Pv-aCO2 and computation of Pv-aCO2/CavO2 are very promising as physiologically sound, easy to measure, rapidly respond to therapy, and are associated with outcome. An elevated Pv-aCO2 reflects an impaired tissue perfusion while an increased Pv-aCO2/CavO2 ratio reflects tissue dysoxia., Summary: Recent studies have highlighted the interest of surrogate measurements of tissue oxygenation and in particular PCO2 gradients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Reported risk of bleeding complications after central catheter access in patients with thrombocytopenia is highly variable. Current guidelines recommend routine prophylactic platelet (PLT) transfusion before central venous catheter placement in patients with severe thrombocytopenia. Nevertheless, the strength of such recommendations is weak and supported by observational studies including few patients with very low PLT counts (<20 × 10 9 /L). This study aims to assess the risk of bleeding complications related to using or not using prophylactic PLT transfusion before ultrasound-guided central venous access in patients with very low PLT counts., Methods: This was a retrospective cohort study of patients with very low PLT counts (<20 × 10 9 /L) subjected to ultrasound-guided central venous catheterization between January 2011 and November 2019 in a university hospital. Bleeding complications were graded according to the Common Terminology Criteria for Adverse Events. A multivariate logistic regression was conducted to assess the risk of major and minor bleeding complications comparing patients who did or did not receive prophylactic PLT transfusion for the procedure. Multiple imputation by chained equations was used to handle missing data. A two-tailed p < 0.05 was considered statistically significant., Results: Among 221 patients with very low PLT counts, 72 received prophylactic PLT transfusions while 149 did not. Baseline characteristics were similar between transfused and nontransfused patients. No major bleeding events were identified, while minor bleeding events were recognized in 35.7% of patients. Multivariate logistic regression analysis showed no significant differences in bleeding complications between patients who received prophylactic PLT transfusions and those who did not (odds ratio 0.83, 95% confidence interval 0.45-1.55, p = 0.567). Additional complete case and sensitivity analyses yielded results similar to those of the main analysis., Conclusions: In this single-center retrospective cohort study of ultrasound-guided central venous access in patients with very low PLT counts, no major bleeding was identified, and prophylactic PLT transfusions did not significantly decrease minor bleeding events., (© 2023 Society for Academic Emergency Medicine.)

Capillary refill time (CRT), a costless and widely available tool, has emerged as a promising target to guide septic shock resuscitation. However, it has yet to gain universal acceptance due to its potential inter-observer variability. Standardization of CRT assessment may minimize this problem, but few studies have compared this approach with techniques that directly assess skin blood flow (SBF). Our objective was to determine if an abnormal CRT is associated with impaired SBF and microvascular reactivity in early septic shock patients. Twelve septic shock patients were subjected to multimodal perfusion and hemodynamic monitoring for 24 h. Three time-points (0, 1, and 24 h) were registered for each patient. SBF was measured by laser doppler. We performed a baseline SBF measurement and two microvascular reactivity tests: one with a thermal challenge at 44 °C and other with a vascular occlusion test. Ten healthy volunteers were evaluated to obtain reference values. The patients (median age 70 years) exhibited a 28-day mortality of 50%. Baseline CRT was 3.3 [2.7-7.3] seconds. In pooled data analysis, abnormal CRT presented a significantly lower SBF when compared to normal CRT [44 (13.3-80.3) vs 193.2 (99.4-285) APU, p = 0.0001]. CRT was strongly associated with SBF (R 2 0.76, p < 0.0001). An abnormal CRT also was associated with impaired thermal challenge and vascular occlusion tests. Abnormal CRT values observed during early septic shock resuscitation are associated with impaired skin blood flow, and abnormal skin microvascular reactivity. Future studies should confirm these results., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Previous observational studies showed higher rates of abdominal wall closure with the use of hypertonic saline in trauma patients with abdominal injuries. However, no randomized controlled trials have been performed on this matter. This double-blind randomized clinical trial assessed the effect of 3% hypertonic saline (HS) solution on primary fascial closure and the timing of abdominal wall closure among patients who underwent damage control laparotomy for bleeding control., Methods: Double-blind randomized clinical trial. Patients with abdominal injuries requiring damage control laparotomy (DCL) were randomly allocated to receive a 72-h infusion (rate: 50 mL/h) of 3% HS or 0.9 N isotonic saline (NS) after the index DCL. The primary endpoint was the proportion of patients with abdominal wall closure in the first seven days after the index DCL., Results: The study was suspended in the first interim analysis because of futility. A total of 52 patients were included. Of these, 27 and 25 were randomly allocated to NS and HS, respectively. There were no significant differences in the rates of abdominal wall closure between groups (HS: 19 [79.2%] vs. NS: 17 [70.8%]; p = 0.71). In contrast, significantly higher hypernatremia rates were observed in the HS group (HS: 11 [44%] vs. NS: 1 [3.7%]; p < 0.001)., Conclusion: This double-blind randomized clinical trial showed no benefit of HS solution in primary fascial closure rates. Patients randomized to HS had higher sodium concentrations after the first day and were more likely to present hypernatremia. We do not recommend using HS in patients undergoing damage control laparotomy. Trial registration The trial protocol was registered in clinicaltrials.gov (identifier: NCT02542241)., (© 2023. The Author(s).)

Although guidelines provide excellent expert guidance for managing patients with septic shock, they leave room for personalization according to patients' condition. Hemodynamic monitoring depends on the evolution phase: salvage, optimization, stabilization, and de-escalation. Initially during the salvage phase, monitoring to identify shock etiology and severity should include arterial pressure and lactate measurements together with clinical examination, particularly skin mottling and capillary refill time. Low diastolic blood pressure may trigger vasopressor initiation. At this stage, echocardiography may be useful to identify significant cardiac dysfunction. During the optimization phase, echocardiographic monitoring should be pursued and completed by the assessment of tissue perfusion through central or mixed-venous oxygen saturation, lactate, and carbon dioxide veno-arterial gradient. Transpulmonary thermodilution and the pulmonary artery catheter should be considered in the most severe patients. Fluid therapy also depends on shock phases. While administered liberally during the resuscitation phase, fluid responsiveness should be assessed during the optimization phase. During stabilization, fluid infusion should be minimized. In the de-escalation phase, safe fluid withdrawal could be achieved by ensuring tissue perfusion is preserved. Norepinephrine is recommended as first-line vasopressor therapy, while vasopressin may be preferred in some patients. Essential questions remain regarding optimal vasopressor selection, combination therapy, and the most effective and safest escalation. Serum renin and the angiotensin I/II ratio may identify patients who benefit most from angiotensin II. The optimal therapeutic strategy for shock requiring high-dose vasopressors is scant. In all cases, vasopressor therapy should be individualized, based on clinical evaluation and blood flow measurements to avoid excessive vasoconstriction. Inotropes should be considered in patients with decreased cardiac contractility associated with impaired tissue perfusion. Based on pharmacologic properties, we suggest as the first test a limited dose of dobutamine, to add enoximone or milrinone in the second line and substitute or add levosimendan if inefficient. Regarding adjunctive therapies, while hydrocortisone is nowadays advised in patients receiving high doses of vasopressors, patients responding to corticosteroids may be identified in the future by the analysis of selected cytokines or specific transcriptomic endotypes. To conclude, although some general rules apply for shock management, a personalized approach should be considered for hemodynamic monitoring and support., (© 2022. The Author(s).)

Clinical and pathophysiological understanding of septic shock has progressed exponentially in the previous decades, translating into a steady decrease in septic shock-related morbidity and mortality. Even though large randomized, controlled trials have addressed fundamental aspects of septic shock resuscitation, many questions still exist. In this review, we will describe the current standards of septic shock resuscitation, but the emphasis will be placed on evolving concepts in different domains such as clinical resuscitation targets, adequate use of fluids and vasoactive drugs, refractory shock, and the use of extracorporeal therapies. Multiple research opportunities remain open, and collaborative endeavors should be performed to fill in these gaps., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Early reversion of sepsis-induced tissue hypoperfusion is essential for survival in septic shock. However, consensus regarding the best initial resuscitation strategy is lacking given that interventions designed for the entire population with septic shock might produce unnecessary fluid administration. This article reports the rationale, study design and analysis plan of the ANDROMEDA-2 study, which aims to determine whether a peripheral perfusion-guided strategy consisting of capillary refill time-targeted resuscitation based on clinical and hemodynamic phenotypes is associated with a decrease in a composite outcome of mortality, time to organ support cessation, and hospital length of stay compared to standard care in patients with early (< 4 hours of diagnosis) septic shock., Methods: The ANDROMEDA-2 study is a multicenter, multinational randomized controlled trial. In the intervention group, capillary refill time will be measured hourly for 6 hours. If abnormal, patients will enter an algorithm starting with pulse pressure assessment. Patients with pulse pressure less than 40mmHg will be tested for fluid responsiveness and receive fluids accordingly. In patients with pulse pressure > 40mmHg, norepinephrine will be titrated to maintain diastolic arterial pressure > 50mmHg. Patients who fail to normalize capillary refill time after the previous steps will be subjected to critical care echocardiography for cardiac dysfunction evaluation and subsequent management. Finally, vasopressor and inodilator tests will be performed to further optimize perfusion. A sample size of 1,500 patients will provide 88% power to demonstrate superiority of the capillary refill time-targeted strategy., Conclusions: If hemodynamic phenotype-based, capillary refill time-targeted resuscitation demonstrates to be a superior strategy, care processes in septic shock resuscitation can be optimized with bedside tools.

Importance: The effect of high-flow oxygen therapy vs conventional oxygen therapy has not been established in the setting of severe COVID-19., Objective: To determine the effect of high-flow oxygen therapy through a nasal cannula compared with conventional oxygen therapy on need for endotracheal intubation and clinical recovery in severe COVID-19., Design, Setting, and Participants: Randomized, open-label clinical trial conducted in emergency and intensive care units in 3 hospitals in Colombia. A total of 220 adults with respiratory distress and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 200 due to COVID-19 were randomized from August 2020 to January 2021, with last follow-up on February 10, 2021., Interventions: Patients were randomly assigned to receive high-flow oxygen through a nasal cannula (n = 109) or conventional oxygen therapy (n = 111)., Main Outcomes and Measures: The co-primary outcomes were need for intubation and time to clinical recovery until day 28 as assessed by a 7-category ordinal scale (range, 1-7, with higher scores indicating a worse condition). Effects of treatments were calculated with a Cox proportional hazards model adjusted for hypoxemia severity, age, and comorbidities., Results: Among 220 randomized patients, 199 were included in the analysis (median age, 60 years; n = 65 women [32.7%]). Intubation occurred in 34 (34.3%) randomized to high-flow oxygen therapy and in 51 (51.0%) randomized to conventional oxygen therapy (hazard ratio, 0.62; 95% CI, 0.39-0.96; P = .03). The median time to clinical recovery within 28 days was 11 (IQR, 9-14) days in patients randomized to high-flow oxygen therapy vs 14 (IQR, 11-19) days in those randomized to conventional oxygen therapy (hazard ratio, 1.39; 95% CI, 1.00-1.92; P = .047). Suspected bacterial pneumonia occurred in 13 patients (13.1%) randomized to high-flow oxygen and in 17 (17.0%) of those randomized to conventional oxygen therapy, while bacteremia was detected in 7 (7.1%) vs 11 (11.0%), respectively., Conclusions and Relevance: Among patients with severe COVID-19, use of high-flow oxygen through a nasal cannula significantly decreased need for mechanical ventilation support and time to clinical recovery compared with conventional low-flow oxygen therapy., Trial Registration: ClinicalTrials.gov Identifier: NCT04609462.

Purpose of Review: The aim of this study was to discuss the implication of microvascular dysfunction in septic shock., Recent Findings: Resuscitation of sepsis has focused on systemic haemodynamics and, more recently, on peripheral perfusion indices. However, central microvascular perfusion is altered in sepsis and these alterations often persist despite normalization of various macro haemodynamic resuscitative goals. Endothelial dysfunction is a key element in sepsis pathophysiology. It is responsible for the sepsis-induced hypotension. In addition, endothelial dysfunction is also implicated involved in the activation of inflammation and coagulation processes leading to amplification of the septic response and development of organ dysfunction. It also promotes an increase in permeability, mostly at venular side, and impairs microvascular perfusion and hence tissue oxygenation.Microvascular alterations are characterized by heterogeneity in blood flow distribution, with adequately perfused areas in close vicinity to not perfused areas, thus characterizing the distributive nature of septic shock. Such microvascular alterations have profound implications, as these are associated with organ dysfunction and unfavourable outcomes. Also, the response to therapy is highly variable and cannot be predicted by systemic hemodynamic assessment and hence cannot be detected by classical haemodynamic tools., Summary: Microcirculation is a key element in the pathophysiology of sepsis. Even if microcirculation-targeted therapy is not yet ready for the prime time, understanding the processes implicated in microvascular dysfunction is important to prevent chasing systemic hemodynamic variables when this does not contribute to improve tissue perfusion., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Dynamic predictors of fluid responsiveness have shown good performance in mechanically ventilated patients at tidal volumes (Vt) > 8 mL kg -1 . Nevertheless, most critically ill conditions demand lower Vt. We sought to evaluate the operative performance of several predictors of fluid responsiveness at Vt ≤ 8 mL kg -1 by using meta-regression and subgroup analyses., Methods: A sensitive search was conducted in the Embase and MEDLINE databases. We searched for studies prospectively assessing the operative performance of pulse pressure variation (PPV), stroke volume variation (SVV), end-expiratory occlusion test (EEOT), passive leg raising (PLR), inferior vena cava respiratory variability (Δ-IVC), mini-fluid challenge (m-FC), and tidal volume challenge (VtC), to predict fluid responsiveness in adult patients mechanically ventilated at Vt ≤ 8 ml kg -1 , without respiratory effort and arrhythmias, published between 1999 and 2020. Operative performance was assessed using hierarchical and bivariate analyses, while subgroup analysis was used to evaluate variations in their operative performance and sources of heterogeneity. A sensitivity analysis based on the methodological quality of the studies included (QUADAS-2) was also performed., Results: A total of 33 studies involving 1,352 patients were included for analysis. Areas under the curve (AUC) values for predictors of fluid responsiveness were: for PPV = 0.82, Δ-IVC = 0.86, SVV = 0.90, m-FC = 0.84, PLR = 0.84, EEOT = 0.92, and VtC = 0.92. According to subgroup analyses, variations in methods to measure cardiac output and in turn, to classify patients as responders or non-responders significantly influence the performance of PPV and SVV (p < 0.05). Operative performance of PPV was also significantly affected by the compliance of the respiratory system (p = 0.05), while type of patient (p < 0.01) and thresholds used to determine responsiveness significantly affected the predictability of SVV (p = 0.05). Similarly, volume of fluids infused to determine variation in cardiac output, significantly affected the performance of SVV (p = 0.01) and PLR (p < 0.01). Sensitivity analysis showed no variations in operative performance of PPV (p = 0.39), SVV (p = 0.23) and EEOT (p = 0.15)., Conclusion: Most predictors of fluid responsiveness reliably predict the response of cardiac output to volume expansion in adult patients mechanically ventilated at tidal volumes ≤ 8 ml kg -1 . Nevertheless, technical and clinical variables might clearly influence on their operative performance.

Red blood cell transfusion is thought to improve cell respiration during septic shock. Nevertheless, its acute impact on oxygen transport and metabolism in this condition remains highly debatable. The objective of this study was to evaluate the impact of red blood cell transfusion on microcirculation and oxygen metabolism in patients with sepsis and septic shock. We conducted a search in the MEDLINE®, Elsevier and Scopus databases. We included studies conducted in adult humans with sepsis and septic shock. A systematic review and meta-analysis were performed using the DerSimonian and Laird random-effects model. A p value < 0.05 was considered significant. Nineteen manuscripts with 428 patients were included in the analysis. Red blood cell transfusions were associated with an increase in the pooled mean venous oxygen saturation of 3.7% (p < 0.001), a decrease in oxygen extraction ratio of -6.98 (p < 0.001) and had no significant effect on the cardiac index (0.02L/minute; p = 0,96). Similar results were obtained in studies including simultaneous measurements of venous oxygen saturation, oxygen extraction ratio, and cardiac index. Red blood cell transfusions led to a significant increase in the proportion of perfused small vessels (2.85%; p = 0.553), while tissue oxygenation parameters revealed a significant increase in the tissue hemoglobin index (1.66; p = 0.018). Individual studies reported significant improvements in tissue oxygenation and sublingual microcirculatory parameters in patients with deranged microcirculation at baseline. Red blood cell transfusions seemed to improve systemic oxygen metabolism with apparent independence from cardiac index variations. Some beneficial effects have been observed for tissue oxygenation and microcirculation parameters, particularly in patients with more severe alterations at baseline. More studies are necessary to evaluate their clinical impact and to individualize transfusion decisions.

Introduction: The presence of oral or naso-enteral probes during non-invasive mechanical ventilation (NIMV) increases the risk of leakage and patient discomfort. The objective of this study was to evaluate the effectiveness of a novel tube adapter for NIMV (TA-NIMV) in relation to leakage and comfort level., Methods: A non-randomized quasi-experimental design was performed in an adult intensive care unit of a highly complex hospital, in which patients were their own controls. We included adult patients who required NIV with oronasal mask and who simultaneously had oral or naso-enteric tubes. The interventions were as follows: every participant received two therapies, one with the TA-NIMV and one conventional therapy of NIMV (CT-NIMV). Comfort could be evaluated in 99 patients with a Glasgow Coma Scale of 15. The outcomes of interest was the average percentage of air leak and patient comfort during each intervention., Results: 196 patients were included in the study during a 16-month period. The mean air leak percentage was 9.2% [standard deviation (SD), 7.7] during TA-NIMV and 32.5% (SD, 12.5) during CT-NIMV (p<0.001). 84.9% reported being comfortable or very comfortable during TA-VMNI. 66.7% Uncomfortable or Very uncomfortable during CT-NIMV (p<0.001)., Conclusion: Higher comfort levels and lower air leakage volume percentages were achieved using the TA-NIMV than those achieved by CT-NIMV., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)

Septic shock involves a complex interaction between abnormal vasodilation, relative and/or absolute hypovolemia, myocardial dysfunction, and altered blood flow distribution to the tissues. Fluid administration, vasopressor support and inotropes, represent fundamental pieces of quantitative resuscitation protocols directed to assist the restoration of impaired tissue perfusion during septic shock. Indeed, current recommendations on sepsis management include the use of inotropes in the case of myocardial dysfunction, as suggested by a low cardiac output, increased filling pressures, or persisting signals of tissue hypoperfusion despite an adequate correction of intravascular volume and mean arterial pressure by fluid administration and vasopressor support. Evidence supporting the use of inotropes in sepsis and septic shock is mainly based on physiological studies. Most of them suggest a beneficial effect of inotropes on macro hemodynamics especially when sepsis coexists with myocardial dysfunction; others, however, have demonstrated variable results on regional splanchnic circulation, while others suggest favorable effects on microvascular distribution independently of its impact on cardiac output. Conversely, impact of inodilators on clinical outcomes in this context has been more controversial. Use of dobutamine has not been consistently related with more favorable clinical results, while systematic administration of levosimendan in sepsis do not prevent the development of multiorgan dysfunction, even in patients with evidence of myocardial dysfunction. Nevertheless, a recent metanalysis of clinical studies suggests that cardiovascular support regimens based on inodilators in sepsis and septic shock could provide some beneficial effect on mortality, while other one corroborated such effect on mortality specially in patients with proved lower cardiac output. Thus, using or not inotropes during sepsis and septic shock remains as controversy matter that deserves more research efforts., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm.2020.04.43). The series “Hemodynamic Monitoring in Critically Ill Patients” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Post-extubation respiratory failure in patients with difficult airway is considered a challenge for the health team. Some intratracheal devices such as airway exchange catheters (AECs) could be used during scheduled tube removing to ensure a rapid access to airway in the case of requiring emergent reintubation. Nevertheless, using such devices could impede adequate non-invasive mechanical ventilation (NIMV) support because of the air leaks generated by interfering with mask interfaces. We describe the case of a woman with a very difficult airway in whom an AEC was placed before scheduled extubation and then developed post-extubation respiratory failure. Mask interface was adequately sealed by using a novel tube adapter for NIMV and successful non-invasive ventilation was provided while maintaining the AEC placed in the trachea until the emergency reintubation risk was overcome., (© 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: Loss of vascular tone is a key pathophysiological feature of septic shock. Combination of gradual diastolic hypotension and tachycardia could reflect more serious vasodilatory conditions. We sought to evaluate the relationships between heart rate (HR) to diastolic arterial pressure (DAP) ratios and clinical outcomes during early phases of septic shock., Methods: Diastolic shock index (DSI) was defined as the ratio between HR and DAP. DSI calculated just before starting vasopressors (Pre-VPs/DSI) in a preliminary cohort of 337 patients with septic shock (January 2015 to February 2017) and at vasopressor start (VPs/DSI) in 424 patients with septic shock included in a recent randomized controlled trial (ANDROMEDA-SHOCK; March 2017 to April 2018) was partitioned into five quantiles to estimate the relative risks (RR) of death with respect to the mean risk of each population (assumed to be 1). Matched HR and DAP subsamples were created to evaluate the effect of the individual components of the DSI on RRs. In addition, time-course of DSI and interaction between DSI and vasopressor dose (DSI*NE.dose) were compared between survivors and non-survivors from both populations, while ROC curves were used to identify variables predicting mortality. Finally, as exploratory observation, effect of early start of vasopressors was evaluated at each Pre-VPs/DSI quintile from the preliminary cohort., Results: Risk of death progressively increased at gradual increments of Pre-VPs/DSI or VPs/DSI (One-way ANOVA, p < 0.001). Progressive DAP decrease or HR increase was associated with higher mortality risks only when DSI concomitantly increased. Areas under the ROC curve for Pre-VPs/DSI, SOFA and initial lactate were similar, while mean arterial pressure and systolic shock index showed poor performances to predict mortality. Time-course of DSI and DSI*NE.dose was significantly higher in non-survivors from both populations (repeated-measures ANOVA, p < 0.001). Very early start of vasopressors exhibited an apparent benefit at higher Pre-VPs/DSI quintile., Conclusions: DSI at pre-vasopressor and vasopressor start points might represent a very early identifier of patients at high risk of death. Isolated DAP or HR values do not clearly identify such risk. Usefulness of DSI to trigger or to direct therapeutic interventions in early resuscitation of septic shock need to be addressed in future studies.

Background: Ventilation/perfusion inequalities impair gas exchange in acute respiratory distress syndrome (ARDS). Although increased dead-space ventilation (V D /V T ) has been described in ARDS, its mechanism is not clearly understood. We sought to evaluate the relationships between dynamic variations in V D /V T and extra-pulmonary microcirculatory blood flow detected at sublingual mucosa hypothesizing that an altered microcirculation, which is a generalized phenomenon during severe inflammatory conditions, could influence ventilation/perfusion mismatching manifested by increases in V D /V T fraction during early stages of ARDS., Methods: Forty-two consecutive patients with early moderate and severe ARDS were included. PEEP was set targeting the best respiratory-system compliance after a PEEP-decremental recruitment maneuver. After 60 min of stabilization, hemodynamics and respiratory mechanics were recorded and blood gases collected. V D /V T was calculated from the CO 2 production ([Formula: see text]) and CO 2 exhaled fraction ([Formula: see text]) measurements by volumetric capnography. Sublingual microcirculatory images were simultaneously acquired using a sidestream dark-field device for an ulterior blinded semi-quantitative analysis. All measurements were repeated 24 h after., Results: Percentage of small vessels perfused (PPV) and microcirculatory flow index (MFI) were inverse and significantly related to V D /V T at baseline (Spearman's rho = - 0.76 and - 0.63, p < 0.001; R 2  = 0.63, and 0.48, p < 0.001, respectively) and 24 h after (Spearman's rho = - 0.71, and - 0.65; p < 0.001; R 2  = 0.66 and 0.60, p < 0.001, respectively). Other respiratory, macro-hemodynamic and oxygenation parameters did not correlate with V D /V T . Variations in PPV between baseline and 24 h were inverse and significantly related to simultaneous changes in V D /V T (Spearman's rho = - 0.66, p < 0.001; R 2  = 0.67, p < 0.001)., Conclusion: Increased heterogeneity of microcirculatory blood flow evaluated at sublingual mucosa seems to be related to increases in V D /V T , while respiratory mechanics and oxygenation parameters do not. Whether there is a cause-effect relationship between microcirculatory dysfunction and dead-space ventilation in ARDS should be addressed in future research.

Rationale: A recent randomized controlled trial showed that a peripheral perfusion-guided resuscitation strategy was associated with lower mortality and less organ dysfunction when compared with lactate-guided resuscitation strategy in patients with septic shock, but the difference in the primary outcome, 28-day mortality, did not reach the proposed statistical significance threshold ( P  = 0.06). We tested different analytic methods to aid in the interpretation of these results. Objectives: To reassess the results of the ANDROMEDA-SHOCK trial using both Bayesian and frequentist frameworks. Methods: All patients recruited in ANDROMEDA-SHOCK were included. Both a post hoc Bayesian analysis and a mixed logistic regression analysis were performed. The Bayesian analysis included four different priors (optimistic, neutral, null, and pessimistic) for mortality endpoints. The probability of having a Sequential Organ Failure Assessment in the lowest quartile at 72 hours was assessed using Bayesian networks. Measurements and Main Results: In the Bayesian analysis, the posterior probability that a peripheral perfusion-targeted resuscitation strategy is superior to lactate-targeted resuscitation at 28 days was above 90% for all priors; the probability of benefit at 90 days was above 90% for all but the pessimistic prior. Using an optimistic prior, posterior median odds ratios were 0.61 (95% credible interval, 0.41-0.90) and 0.68 (95% credible interval, 0.47-1.01) for 28-day and 90-day mortality, respectively. The comparable frequentist odds ratios for 28-day and 90-day mortality were 0.61 (95% confidence interval [CI], 0.38-0.92) and 0.70 (95% CI, 0.45-1.08), respectively. The odds that that patients in the peripheral perfusion-targeted resuscitation arm had Sequential Organ Failure Assessment scores in the lower quartile at 72 hours was 1.55 (95% CI, 1.02-2.37). Conclusions: Peripheral perfusion-targeted resuscitation may result in lower mortality and faster resolution of organ dysfunction when compared with a lactate-targeted resuscitation strategy.

Background: Optimal timing for the start of vasopressors (VP) in septic shock has not been widely studied since it is assumed that fluids must be administered in advance. We sought to evaluate whether a very early start of VP, even without completing the initial fluid loading, might impact clinical outcomes in septic shock., Methods: A total of 337 patients with sepsis requiring VP support for at least 6 h were initially selected from a prospectively collected database in a 90-bed mixed-ICU during a 24-month period. They were classified into very-early (VE-VPs) or delayed vasopressor start (D-VPs) categories according to whether norepinephrine was initiated or not within/before the next hour of the first resuscitative fluid load. Then, VE-VPs (n = 93) patients were 1:1 propensity matched to D-VPs (n = 93) based on age; source of admission (emergency room, general wards, intensive care unit); chronic and acute comorbidities; and lactate, heart rate, systolic, and diastolic pressure at vasopressor start. A risk-adjusted Cox proportional hazard model was fitted to assess the association between VE-VPs and day 28 mortality. Finally, a sensitivity analysis was performed also including those patients requiring VP support for less than 6 h., Results: Patients subjected to VE-VPs received significantly less resuscitation fluids at vasopressor starting (0[0-510] vs. 1500[650-2300] mL, p < 0.001) and during the first 8 h of resuscitation (1100[500-1900] vs. 2600[1600-3800] mL, p < 0.001), with no significant increase in acute renal failure and/or renal replacement therapy requirements. VE-VPs was related with significant lower net fluid balances 8 and 24 h after VPs. VE-VPs was also associated with a significant reduction in the risk of death compared to D-VPs (HR 0.31, CI95% 0.17-0.57, p < 0.001) at day 28. Such association was maintained after including patients receiving vasopressors for < 6 h., Conclusion: A very early start of vasopressor support seems to be safe, might limit the amount of fluids to resuscitate septic shock, and could lead to better clinical outcomes.

Introduction: Pulse pressure variation (PPV) has been shown to be useful to predict fluid responsiveness in patients ventilated at tidal volume (Vt) >8 mL kg -1 . Nevertheless, most conditions in critical care force to use lower Vt. Thus, we sought to evaluate the operative performance of PPV when a Vt ⩽8 mL kg -1 is used during mechanical ventilation support., Methods: We searched PubMed and Embase databases for articles evaluating the operative performance of PPV as a predictor of fluid responsiveness in critical care and perioperative adult patients ventilated with tidal volume ⩽8 mL kg -1 without respiratory effort and arrhythmias, between January 1990 and January 2019. We included cohort and cross-sectional studies. Two authors performed an Independently selection using predefined terms of search. The fitted data of sensitivity, specificity, and area under the curve (AUC) were assessed by bivariate and hierarchical analyses., Results: We retrieved 19 trials with a total of 777 patients and a total of 935 fluid challenges. The fitted sensitivity of PPV to predict fluid responsiveness during mechanical ventilation at Vt ⩽8 mL kg -1 was 0.65 (95% confidence interval [CI]: 0.57-0.73), the specificity was 0.79 (95% CI: 0.73-0.84), and the AUC was 0.75. The diagnostic odds ratio was 5.5 (95% CI: 3.08-10.01, P  < .001) by the random-effects model., Conclusions: Pulse pressure variation shows a fair operative performance as a predictor of fluid responsiveness in critical care and perioperative patients ventilated with a tidal volume ⩽8 mL kg -1 without respiratory effort and arrhythmias., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Fluid boluses are administered to septic shock patients with the purpose of increasing cardiac output as a means to restore tissue perfusion. Unfortunately, fluid therapy has a narrow therapeutic index, and therefore, several approaches to increase safety have been proposed. Fluid responsiveness (FR) assessment might predict which patients will effectively increase cardiac output after a fluid bolus (FR+), thus preventing potentially harmful fluid administration in non-fluid responsive (FR-) patients. However, there are scarce data on the impact of assessing FR on major outcomes. The recent ANDROMEDA-SHOCK trial included systematic per-protocol assessment of FR. We performed a post hoc analysis of the study dataset with the aim of exploring the relationship between FR status at baseline, attainment of specific targets, and clinically relevant outcomes., Methods: ANDROMEDA-SHOCK compared the effect of peripheral perfusion- vs. lactate-targeted resuscitation on 28-day mortality. FR was assessed before each fluid bolus and periodically thereafter. FR+ and FR- subgroups, independent of the original randomization, were compared for fluid administration, achievement of resuscitation targets, vasoactive agents use, and major outcomes such as organ dysfunction and support, length of stay, and 28-day mortality., Results: FR could be determined in 348 patients at baseline. Two hundred and forty-two patients (70%) were categorized as fluid responders. Both groups achieved comparable successful resuscitation targets, although non-fluid responders received less resuscitation fluids (0 [0-500] vs. 1500 [1000-2500] mL; p 0.0001), exhibited less positive fluid balances, but received more vasopressor testing. No difference in clinically relevant outcomes between FR+ and FR- patients was found, including 24-h SOFA score (9 [5-12] vs. 8 [5-11], p = 0.4), need for MV (78% vs. 72%, p = 0.16), need for RRT (18% vs. 21%, p = 0.7), ICU-LOS (6 [3-11] vs. 6 [3-16] days, p = 0.2), and 28-day mortality (40% vs. 36%, p = 0.5). Only thirteen patients remained fluid responsive along the intervention period., Conclusions: Systematic assessment allowed determination of fluid responsiveness status in more than 80% of patients with early septic shock. Fluid boluses could be stopped in non-fluid responsive patients without any negative impact on clinical relevant outcomes. Our results suggest that fluid resuscitation might be safely guided by FR assessment in septic shock patients., Trial Registration: ClinicalTrials.gov identifier, NCT03078712. Registered retrospectively on March 13, 2017.

Oxygen-derived parameters have been traditionally used to guide resuscitation during shock states. Nevertheless, normalization of venous oxygen saturation does not exclude the persistence of tissue hypoperfusion and tissue hypoxia. Combination of O 2 and CO 2 -derived variables has consistently demonstrated to be related with clinical outcomes and its variations could anticipate changes in lactate and also predict fluid responsiveness in terms of oxygen consumption. Here we discuss the potential mechanisms leading to increase the venous-to-arterial CO 2 (Cv-aCO 2 ) to arterial-to-venous O 2 content difference (Ca-vO 2 ), i.e., the Cv-aCO 2 /Ca-vO 2 ratio, its potential clinical application, limitations and uncertainties. Finally, although biologically plausible, the potential applications of the Cv-aCO 2 /Ca-vO 2 ratio in the clinical practice require to be confirmed., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Importance: Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established., Objective: To determine if a peripheral perfusion-targeted resuscitation during early septic shock in adults is more effective than a lactate level-targeted resuscitation for reducing mortality., Design, Setting, and Participants: Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018., Interventions: Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period., Main Outcomes and Measures: The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation-, renal replacement therapy-, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay., Results: Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, -8.5% [95% CI, -18.2% to 1.2%]). Peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, -1.00 [95% CI, -1.97 to -0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed., Conclusions and Relevance: Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality., Trial Registration: ClinicalTrials.gov Identifier: NCT03078712.

Importance: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain., Objective: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy., Design, Setting, and Participants: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS., Interventions: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning., Main Outcomes and Measures: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality., Results: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality., Conclusions and Relevance: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients., Trial Registration: clinicaltrials.gov Identifier: NCT01374022.

Objective: To evaluate the microcirculatory blood flow in severe preeclampsia and compare it with healthy pregnant and non-pregnant women controls, using a portable intravital-microscopy technique., Methods: Using a side-stream dark field (SDF) device, we prospectively evaluated the sublingual microcirculatory blood flow before placental delivery in 40 women with severe preeclampsia (PE-group) complicated (n=8) or not (n=32) with HELLP syndrome, 40 healthy pregnant women (HP-group) matched by gestational and chronological age, and 20 healthy non-pregnant women (NP-group). Microvessels were classified as large or small using a cutoff value of 20μm and those with continuous flow were considered as normal while sluggish, intermittent and stopped flows were considered as abnormal. We computed the proportion of well-perfused small vessels (PPV), and total and functional capillary densities (TCD and FCD) were calculated according to the total number and quantity of well-perfused small vessels per area unit, respectively., Results: Total capillary densities were significantly higher in all pregnant women when compared to non-pregnant controls. The PE-group exhibited, however, significantly lower TCD compared with the HP-group. Meanwhile, significant decreases in PPV and FCD were observed in the PE-group, with deeper alterations in those with coexisting HELLP syndrome. These altered PPVs were significant although incompletely reversed after placental delivery in pregnancies complicated by HELLP syndrome, while capillary densities remained unaltered at least during very early post-delivery period., Conclusions: Substantial distributive microcirculatory blood flow alterations and restricted capillary densities are observed in preeclampsia, suggesting a key role for microvascular dysfunction in the pathophysiology of this condition., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Derangements of microvascular blood flow distribution might contribute to disturbing O 2 extraction by peripheral tissues. We evaluated the dynamic relationships between the mesenteric O 2 extraction ratio ([Formula: see text]) and the heterogeneity of microvascular blood flow at the gut and sublingual mucosa during the development and resuscitation of septic shock in a swine model of fecal peritonitis. Jejunal-villi and sublingual microcirculation were evaluated using a portable intravital-microscopy technique. Simultaneously, we obtained arterial, mixed-venous, and mesenteric blood gases, and jejunal-tonometric measurements. During resuscitation, pigs were randomly allocated to a fixed dose of dobutamine (5 µg·kg -1 ·min -1 ) or placebo while three sham models with identical monitoring served as controls. At the time of shock, we observed a significant decreased proportion of perfused intestinal-villi (villi-PPV) and sublingual percentage of perfused small vessels (SL-PPV), paralleling an increase in [Formula: see text] in both dobutamine and placebo groups. After starting resuscitation, villi-PPV and SL-PPV significantly increased in the dobutamine group with subsequent improvement of functional capillary density, whereas [Formula: see text] exhibited a corresponding significant decrease (repeated-measures ANOVA, P = 0.02 and P = 0.04 for time × group interactions and intergroup differences for villi-PPV and [Formula: see text], respectively). Variations in villi-PPV were paralleled by variations in [Formula: see text] ( R 2  = 0.88, P < 0.001) and these, in turn, by mesenteric lactate changes ( R 2  = 0.86, P < 0.001). There were no significant differences in cardiac output and systemic O 2 delivery throughout the experiment. In conclusion, dynamic changes in microvascular blood flow heterogeneity at jejunal mucosa are closely related to the mesenteric O 2 extraction ratio, suggesting a crucial role for microvascular blood flow distribution on O 2 uptake during development and resuscitation from septic shock. NEW & NOTEWORTHY Our observations suggest that dynamic changes in the heterogeneity of microvascular blood flow at the gut mucosa are closely related to mesenteric O 2 extraction, thus supporting the role of decreasing functional capillary density and increased intercapillary distances on alterations of O 2 uptake during development and resuscitation from septic shock. Addition of a low-fixed dose of dobutamine might reverse such flow heterogeneity, improving microcirculatory flow distribution and tissue O 2 consumption., (Copyright © 2017 the American Physiological Society.)

Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. This review covers current insight in EC-associated hemostatic responses to sepsis and the EC response to inflammation. The endothelial cell lining is highly heterogeneous between different organ systems and consequently also in its response to sepsis. In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014., Competing Interests: Declaration of interest: C.I. has received research grants the Dutch Kidney Foundation (grant C 09.2290 and grant 14OIP11), Bussum, The Netherlands. C.I. has also received honoraria and independent research grants from Fresenius-Kabi, Bad Homburg, Germany; Baxter Health Care, Deerfield, Illinois and AM-Pharma, Bunnik, The Netherlands. C.I. has developed SDF imaging and is listed as inventor on related patents commercialized by MicroVision Medical (MVM) under a license from the Academic Medical Center (AMC). C.I. has received consultant fees from MVM in the past, but has not been involved with this company for more than five years now, except that he still holds shares. Braedius Medical, a company owned by a relative of C.I., has developed and designed a hand-held microscope called Cyto-Cam-IDF imaging; however, C.I. has no financial relation with Braedius Medical of any sort. P.M., T.N., G.O., H.G., and G.H. have no declared interests. J.K. has received consulting fees from Abbott, Aethlon, Alere, Alung, AM Pharma, Astute Medical, Atox Bio, Baxter, Cytosorbents, venBio, Gambro, Grifols, Roche, Spectral Diagnostics, Sangart, and Siemens. J.K. has also received research grants from Alere, Astute Medical, Atox Bio, Bard, Baxter, Cytosorbents, Gambro, Grifols, Kaneka, and Spectral Diagnostics, and has licensed technologies through the University of Pittsburgh to Astute Medical, Cytosorbents, and Spectral Diagnostics. P.M. has received consulting fees from AM Pharma, Abbvie, FAST Diagnostics. He has also received research funding from Abbott, Alere, EKF Diagnostics. D.D.B. is a member of the Advisory Board Baxter-Gambro renal, and Nestlé Health Sciences. He received research grants and material for studies from Edwards Lifesciences, Vytech, and Imacor. P.M., T.N., G.O., H.G., and G.H. have no declared interests.

Purpose: Septic shock has been associated with microvascular alterations and these in turn with the development of organ dysfunction. Despite advances in video microscopic techniques, evaluation of microcirculation at the bedside is still limited. Venous-to-arterial carbon dioxide difference (Pv-aCO2) may be increased even when venous O2 saturation (SvO2) and cardiac output look normal, which could suggests microvascular derangements. We sought to evaluate whether Pv-aCO2 can reflect the adequacy of microvascular perfusion during the early stages of resuscitation of septic shock., Methods: Prospective observational study including 75 patients with septic shock in a 60-bed mixed ICU. Arterial and mixed-venous blood gases and hemodynamic variables were obtained at catheter insertion (T0) and 6 h after (T6). Using a sidestream dark-field device, we simultaneously acquired sublingual microcirculatory images for blinded semiquantitative analysis. Pv-aCO2 was defined as the difference between mixed-venous and arterial CO2 partial pressures., Results: Progressively lower percentages of small perfused vessels (PPV), lower functional capillary density, and higher heterogeneity of microvascular blood flow were observed at higher Pv-aCO2 values at both T0 and T6. Pv-aCO2 was significantly correlated to PPV (T0: coefficient -5.35, 95 % CI -6.41 to -4.29, p < 0.001; T6: coefficient, -3.49, 95 % CI -4.43 to -2.55, p < 0.001) and changes in Pv-aCO2 between T0 and T6 were significantly related to changes in PPV (R (2) = 0.42, p < 0.001). Absolute values and changes in Pv-aCO2 were not related to global hemodynamic variables. Good agreement between venous-to-arterial CO2 and PPV was maintained even after corrections for the Haldane effect., Conclusions: During early phases of resuscitation of septic shock, Pv-aCO2 could reflect the adequacy of microvascular blood flow.

Purpose: To evaluate the prognostic value of the Cv-aCO2/Da-vO2 ratio combined with lactate levels during the early phases of resuscitation in septic shock., Methods: Prospective observational study in a 60-bed mixed ICU. One hundred and thirty-five patients with septic shock were included. The resuscitation protocol targeted mean arterial pressure, pulse pressure variations or central venous pressure, mixed venous oxygen saturation, and lactate levels. Patients were classified into four groups according to lactate levels and Cv-aCO2/Da-vO2 ratio at 6 h of resuscitation (T6): group 1, lactate ≥2.0 mmol/L and Cv-aCO2/Da-vO2 >1.0; group 2, lactate ≥2.0 mmol/L and Cv-aCO2/Da-vO2 ≤1.0; group 3, lactate <2.0 mmol/L and Cv-aCO2/Da-vO2 >1.0; and group 4, lactate <2.0 mmol/L and Cv-aCO2/Da-vO2 ≤1.0., Results: Combination of hyperlactatemia and high Cv-aCO2/Da-vO2 ratio was associated with the worst SOFA scores and lower survival rates at day 28 [log rank (Mantel-Cox) = 31.39, p < 0.0001]. Normalization of both variables was associated with the best outcomes. Patients with a high Cv-aCO2/Da-vO2 ratio and lactate <2.0 mmol/L had similar outcomes to hyperlactatemic patients with low Cv-aCO2/Da-vO2 ratio. The multivariate analysis revealed that Cv-aCO2/Da-vO2 ratio at both T0 (RR 3.85; 95 % CI 1.60-9.27) and T6 (RR 3.97; 95 % CI 1.54-10.24) was an independent predictor for mortality at day 28, as well as lactate levels at T6 (RR 1.58; 95 % CI 1.13-2.22)., Conclusion: Complementing lactate assessment with Cv-aCO2/Da-vO2 ratio during early stages of resuscitation of septic shock can better identify patients at high risk of adverse outcomes. The Cv-aCO2/Da-vO2 ratio may become a potential resuscitation goal in patients with septic shock.