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This is the first paper to simulate mitochondrial oxygen tension in skin in circulatory shock. The relationships of mitoPo2 with parameters of (microcirculatory) oxygen delivery aid in the understanding of noninvasive bedside measurement of mitoPo2 values and show that mitochondrial oxygen tension is two orders of magnitude higher than classically assumed. The model can be used to enhance clinical trial design investigating mitoPo2 as a resuscitation target in circulatory shock.

BACKGROUND: Most studies describing traumatic coagulopathy have used data from patient cohorts with an average age of between 35 and 45 years. The last 10 years has seen a steep increase in the number of patients admitted with significant injury and bleeding who are older than the age of 65 years. Many coagulation protein levels alter significantly with normal aging, and it is possible that traumatic coagulopathy has a different signature with age. OBJECTIVES: The aim of this study was to report the coagulation profiles, including standard and extended laboratory, as well as viscoelastic hemostatic assays, stratified according to age to explore age-related differences in hemostatic capability. METHODS: In total, 1576 patients were analyzed from 6 European level 1 trauma centers. RESULTS: As age increased, there was evidence of higher fibrinogen, greater thrombin generation, greater clotting factor consumption, and greater activation of fibrinolysis. Despite this, shock and severe injury led to the same pattern of changes within age groups: lower procoagulant factors (including fibrinogen), increased fibrinolysis, and higher levels of activated protein C. Thromboelastography and rotational thromboelastometry tests detected traumatic coagulopathy with prolongation of R/clotting time and reductions in clot amplitudes in each age cohort. Advancing age strongly correlated with higher fibrinogen levels and greater fibrinolysis. CONCLUSION: Age-related coagulation changes are evident in injured patients. Broadly, similar patterns of coagulation abnormalities are seen across age groups following severe injury/shock, but thresholds for single clotting factors differ. Age-related differences may need to be considered when clinical treatments (eg, transfusion therapy) are indicated.

Severely injured trauma patients are often coagulopathic and early hemostatic resuscitation is essential. Previous studies have revealed linear relationships between thrombelastography (TEG®) five- and ten-min amplitudes (A5 and A10), and maximum amplitude (MA), using TEG® 5000 technology. We aimed to investigate the performance of A5 and A10 in predicting low MA in severely injured trauma patients and identify optimal cut-off values for hemostatic intervention based on early amplitudes, using the cartridge-based TEG® 6s technology. Adult trauma patients with hemorrhagic shock were included in the iTACTIC randomized controlled trial at six European Level I trauma centers between 2016 and 2018. After admission, patients were randomized to hemostatic therapy guided by conventional coagulation tests (CCT) or viscoelastic hemostatic assays (VHA). Patients with available admission-TEG® 6s data were included in the analysis, regardless of treatment allocation. Low MA was defined as

Background: A third of patients with colorectal cancer who are eligible for surgery in high-income countries have concomitant anaemia associated with adverse outcomes. We aimed to compare the efficacy of preoperative intravenous and oral iron supplementation in patients with colorectal cancer and iron deficiency anaemia. Methods: In the FIT multicentre, open-label, randomised, controlled trial, adult patients (aged 18 years or older) with M0 stage colorectal cancer scheduled for elective curative resection and iron deficiency anaemia (defined as haemoglobin level of less than 7·5 mmol/L (12 g/dL) for women and less than 8 mmol/L (13 g/dL) for men, and a transferrin saturation of less than 20%) were randomly assigned to either 1–2 g of ferric carboxymaltose intravenously or three tablets of 200 mg of oral ferrous fumarate daily. The primary endpoint was the proportion of patients with normalised haemoglobin levels before surgery (≥12 g/dL for women and ≥13 g/dL for men). An intention-to-treat analysis was done for the primary analysis. Safety was analysed in all patients who received treatment. The trial was registered at ClincalTrials.gov, NCT02243735, and has completed recruitment. Findings: Between Oct 31, 2014, and Feb 23, 2021, 202 patients were included and assigned to intravenous (n=96) or oral (n=106) iron treatment. Treatment began a median of 14 days (IQR 11–22) before surgery for intravenous iron and 19 days (IQR 13–27) for oral iron. Normalisation of haemoglobin at day of admission was reached in 14 (17%) of 84 patients treated intravenously and 15 (16%) of 97 patients treated orally (relative risk [RR] 1·08 [95% CI 0·55–2·10]; p=0·83), but the proportion of patients with normalised haemoglobin significantly increased for the intravenous treatment group at later timepoints (49 [60%] of 82 vs 18 [21%] of 88 at 30 days; RR 2·92 [95% CI 1·87–4·58]; p

Background: Lung ultrasound (LUS) is a non-invasive method to detect and quantify pulmonary edema. However, it remains uncertain how components of the LUS examination should be aggregated into a score for quantifying pulmonary edema. We examined the diagnostic accuracy of various LUS scores with the extravascular lung water index (EVLWi) assessed with PiCCO in patients with moderate-to-severe COVID-19 ARDS. Methods: In this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were included within 48h after intubation and underwent LUS and EVLWi measurement at two time points (first and fourth study day). EVLWi and ∆EVLWi were used as reference standard. Two 12-region scores (global LUS and LUS-ARDS), an 8-region anterior-lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi>15mL/kg) was calculated. Results: 26 of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 of 29 patients (83%) at time point 2. The global LUS (r=0.54), LUS-ARDS (r=0.58) and anterior-lateral score (r=0.54) were significantly correlated with EVLWi, while the B-line score was not (r=0.32). ∆global LUS (r=0.49) and ∆anterior-lateral LUS (r=0.52) were significantly correlated with ∆EVLWi, while correlation of ∆LUS-ARDS (r=0.43) and ∆B-lines (r=0.32) did not reach statistical significance. AUROCC for EVLWi>15ml/kg was 0.73 for the global LUS, 0.79 for the anterior-lateral and 0.85 for the LUS-ARDS score. Conclusions: The global LUS, LUS-ARDS and antero-lateral score can quantify PiCCO-derived pulmonary edema measurements in COVID-19 ARDS. The LUS-ARDS score showed the highest diagnostic accuracy for severe pulmonary edema. Trial registration: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020-005447-23.

Objective: Bleeding and thromboembolic complications frequently occur after subarachnoid hemorrhage (SAH) and substantially contribute to poor outcome. Viscoelastic testing could be used for detection of coagulopathies after SAH. This review summarizes literature on the usefulness of viscoelastic testing to detect coagulopathy in patients with SAH and explores whether viscoelastic parameters are associated with SAH-related complications and clinical outcome. Methods: PubMed, Embase, and Google Scholar were systematically searched on August 18, 2022. Two authors independently selected studies that reported viscoelastic testing in patients with SAH and assessed the quality of studies using the Newcastle-Ottawa Scale or a previously reported framework for quality assessment. Data were meta-analyzed if methodologically possible. Results: The search yielded 19 studies (1160 patients with SAH). Pooling of data including all relevant studies was not possible for any of the outcome measurements because of methodological differences. Thirteen of 19 studies evaluated the association of coagulation profiles and SAH, of which 11 studies showed a hypercoagulable profile. Rebleeding was associated with platelet dysfunction, deep venous thrombosis was associated with faster clot initiation, and both delayed cerebral ischemia and poor outcome were associated with increased clot strength. Conclusions: This explorative review shows that patients with SAH frequently have a hypercoagulable profile. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) parameters are associated with rebleeding, delayed cerebral ischemia, deep venous thrombosis, and poor clinical outcome after SAH; however, more research on the subject is needed. Future studies should focus on determining the optimal time frame and cutoff values for TEG or ROTEM to predict these complications.

Background: Observational studies suggest that sex-mismatched transfusion is associated with increased mortality. Mechanisms driving mortality are not known but may include endothelial activation. The aim of this study is to investigate the effects of sex-mismatched red blood cell (RBC) transfusions on endothelial cell activation markers in critically ill patients. Study Design and Methods: In patients admitted to the intensive care unit who received a single RBC unit, blood samples were drawn before (T0), 1 h after (T1), and 24 h after transfusion (T24) for analysis of soluble syndecan-1, soluble intercellular adhesion molecule-1, soluble thrombomodulin (sTM), von Willebrand factor antigen, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα). Changes in the levels of these factors were compared between sex-matched and sex-mismatched groups. Results: Of 69 included patients, 32 patients were in the sex-matched and 37 patients were in the sex-mismatched group. Compared to baseline, sex-matched transfusion was associated with significant reduction in sTM level (p value = 0.03). Between-group comparison showed that levels of syndecan-1 and sTM were significantly higher in the sex-mismatched group compared to the sex-matched group at T24 (p value = 0.04 and 0.01, respectively). Also, TNFα and IL-6 levels showed a statistically marginal significant increase compared to baseline in the sex-mismatched group at T24 (p value = 0.06 and 0.05, respectively), but not in the sex-matched group. Discussion: Transfusion of a single sex-mismatched RBC unit was associated with higher syndecan-1 and sTM levels compared to transfusion of sex-matched RBC unit. These findings may suggest that sex-mismatched RBC transfusion is associated with endothelial activation.

Coagulation abnormalities and microthrombi contribute to septic shock, but the impact of body temperature regulation on coagulation in patients with sepsis is unknown. We tested the hypothesis that mild induced hypothermia reduces coagulation and platelet aggregation in patients with septic shock. Secondary analysis of randomized controlled trial. Adult patients with septic shock who required mechanical ventilation from eight intensive care units in Denmark were randomly assigned to mild induced hypothermia for 24 h or routine thermal management. Viscoelastography and platelet aggregation were assessed at trial inclusion, after 12 h of thermal management, and 24 h after inclusion. A total of 326 patients were randomized to mild induced hypothermia (n = 163) or routine thermal management (n = 163). Mild induced hypothermia slightly prolonged activated partial thromboplastin time and thrombus initiation time (R time 8.0 min [interquartile range, IQR 6.6–11.1] vs. 7.2 min [IQR 5.8–9.2]; p =.004) and marginally inhibited thrombus propagation (angle 68° [IQR 59–73] vs. 71° [IQR 63–75]; p =.014). The effect was also present after 24 h. Clot strength remained unaffected (MA 71 mm [IQR 66–76] with mild induced hypothermia vs. 72 mm (65–77) with routine thermal management, p =.9). The proportion of patients with hyperfibrinolysis was not affected (0.7% vs. 3.3%; p =.19), but the proportion of patients with no fibrinolysis was high in the mild hypothermia group (8.8% vs. 40.4%; p

Endotheliopathy following trauma is associated with poor outcome, but the underlying mechanisms are unknown. This study hypothesized that an increased extracellular vesicle (EV) concentration is associated with endotheliopathy after trauma and that red blood cell (RBC) transfusion could further enhance endotheliopathy. In this post hoc sub study of a multicentre observational trial, 75 trauma patients were stratified into three groups based on injury severity score or shock. In patient plasma obtained at hospital admission and after transfusion of four RBC transfusions, markers for endotheliopathy were measured and EVs were labelled with anti CD41 (platelet EVs), anti CD235a (red blood cell EVs), anti CD45 (leucocyte EVs), anti CD144 (endothelial EVs) or anti CD62e (activated endothelial EVs) and EV concentrations were measured with flow cytometry. Statistical analysis was performed by a Kruskall Wallis test with Bonferroni correction or Wilcoxon rank test for paired data. In patients with shock, syndecan-1 and von Willebrand Factor (vWF) were increased compared to patients without shock. Additionally, patients with shock had increased red blood cell EV and leucocyte EV concentrations compared to patients without shock. Endotheliopathy markers correlated with leucocyte EVs (ρ = 0.263, p = 0.023), but not with EVs derived from other cells. Injury severity score had no relation with EV release. RBC transfusion increased circulating red blood cell EVs but did not impact endotheliopathy. In conclusion, shock is (weakly) associated with EVs from leucocytes, suggesting an immune driven pathway mediated (at least in part) by shock.

Background The advocated pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin, AUC/MIC ≥ 400 mg·h/L, may not be reached with a conventional fixed starting dose of 1000 mg in critically ill patients, but increasing the dose may cause nephrotoxicity. Objectives To evaluate the effect of a weight-based loading dose of 25 mg/kg vancomycin on PK/PD target attainment in the first 24 h (AUC0–24) in critically ill patients and to evaluate whether this increases the risk of acute kidney injury (AKI). Patients and methods A prospective observational before/after study was performed in ICU patients, comparing the percentage of vancomycin courses with AUC0–24 ≥ 400 mg·h/L and the incidence of AKI, defined as worsening of the risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE) score. The conventional dose group received 1000 mg of vancomycin as initial dose; the loading dose group received a weight-based loading dose of 25 mg/kg. A population PK model developed using non-linear mixed-effects modelling was used to estimate AUC0–24 in all patients. Results One hundred and four courses from 82 patients were included. With a loading dose, the percentage of courses achieving AUC0–24 ≥ 400 mg·h/L increased significantly from 53.8% to 88.0% (P = 0.0006). The percentage of patients with new-onset AKI was not significantly higher when receiving a 25 mg/kg loading dose (28.6% versus 37.8%; P = 0.48). However, the risk of AKI was significantly higher in patients achieving AUC0–24 > 400 mg·h/L compared with patients achieving AUC Conclusions A weight-based loading dose of 25 mg/kg vancomycin led to significantly more patients achieving AUC0–24 ≥ 400 mg·h/L without increased risk of AKI. However, some harm cannot be ruled out since higher exposure was associated with increased risk of AKI.

Purpose To develop evidence-based clinical practice recommendations regarding transfusion practices and transfusion in bleeding critically ill adults. Methods A taskforce involving 15 international experts and 2 methodologists used the GRADE approach to guideline development. The taskforce addressed three main topics: transfusion support in massively and non-massively bleeding critically ill patients (transfusion ratios, blood products, and point of care testing) and the use of tranexamic acid. The panel developed and answered structured guideline questions using population, intervention, comparison, and outcomes (PICO) format. Results The taskforce generated 26 clinical practice recommendations (2 strong recommendations, 13 conditional recommendations, 11 no recommendation), and identified 10 PICOs with insufficient evidence to make a recommendation. Conclusions This clinical practice guideline provides evidence-based recommendations for the management of massively and non-massively bleeding critically ill adult patients and identifies areas where further research is needed. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06531-x.

BACKGROUND Nucleosomes and neutrophil extracellular traps (NETs) are important in the pathophysiology of disseminated intravascular coagulation (DIC). Fibrinogen, as an acute phase reactant, may be protective by engaging neutrophils. We hypothesize that DIC can occur when NET formation becomes uncontrolled in relation to low fibrinogen levels. PATIENTS/METHOD The ratio of both circulating nucleosomes and human neutrophil elastase alpha-1-antitrypsine complexes (HNE-a1ATc) to fibrinogen was correlated to thrombocytopenia, DIC and organ failure in 64 critically ill coagulopathic patients. RESULTS A high nucleosome to fibrinogen ratio correlated with thrombocytopenia and organ failure (ρ - 0.391, p 0.01 and ρ 0.556, p 0.01, respectively). A high HNE-a1ATc to fibrinogen ratio correlated with thrombocytopenia, DIC and organ failure (ρ -0.418, p 0.01, ρ 0.391, p 0.01 and ρ 0.477, p 0.01 respectively). CONCLUSION These findings support the hypothesis that fibrinogen is protective against DIC by counterbalancing excessive neutrophil activation. This article is protected by copyright. All rights reserved.

Trauma-induced organ failure is characterized by endothelial dysfunction. The aim of this study was to investigate the role of von Willebrand factor (VWF) and its cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) in the occurrence of endothelial permeability and organ failure in trauma. In an observational study in a level-1 trauma center, 169 adult trauma patients with clinical signs of shock and/or severe injuries were included. Trauma was associated with low ADAMTS13 and high VWF antigen levels, thus generating an imbalance of ADAMTS13 to VWF. Patients who developed organ failure (23%) had greater ADAMTS13-to-VWF imbalances, persistently lower platelet counts, and elevated levels of high-molecular-weight VWF multimers compared with those without organ failure, suggesting microthrombi formation. To investigate the effect of replenishing low ADAMTS13 levels on endothelial permeability and organ failure using either recombinant human ADAMTS13 (rhADAMTS13) or plasma transfusion, a rat model of trauma-induced shock and transfusion was used. Rats in traumatic hemorrhagic shock were randomized to receive crystalloids, crystalloids supplemented with rhADAMTS13, or plasma transfusion. A 70-kDa fluorescein isothiocyanate-labeled dextran was injected to determine endothelial leakage. Additionally, organs were histologically assessed. Both plasma transfusion and rhADAMTS13 were associated with a reduction in pulmonary endothelial permeability and organ injury when compared with resuscitation with crystalloids, but only rhADAMTS13 resulted in significant improvement of a trauma-induced decline in ADAMTS13 levels. We conclude that rhADAMTS13 and plasma transfusion can reduce organ failure following trauma. These findings implicate the ADAMTS13-VWF axis in the pathogenesis of organ failure. ispartof: BLOOD ADVANCES vol:5 issue:17 pages:3478-3491 ispartof: location:United States status: published

Severely injured trauma patients are often coagulopathic and early hemostatic resuscitation is essential. Previous studies have revealed linear relationships between thrombelastography (TEG

Background and Objectives: Transfusion-associated circulatory overload (TACO) is the primary cause of transfusion-related mortality. Speed and volume of transfusion are major risk factors. The aim of this study was to investigate the interaction of red blood cell (RBC) transfusion speed and volume on the development of TACO. Materials and Methods: A validated model for TACO in anaemic Lewis rats with an acute myocardial infarction was used. The effect on pulmonary hydrostatic pressure of one, two or four units of packed RBCs transfused in either 30 or 60 min was evaluated (3.3–26.6 ml·kg −1·hr −1). Pulmonary capillary pressure was measured as left ventricular end-diastolic pressure (LVEDP). Cardiac stress biomarkers atrial natriuretic-peptide (ANP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured 1-h post-transfusion. Results: Thirty animals were included (n = 5 per group). Transfusion of RBCs increased LVEDP in a volume-dependent manner (ΔLVEDP [mmHg]: −0.95, +0.50, +6.26, p < 0.001). Fast transfusion increased overall ΔLVEDP by +3.5 mmHg and up to +11.8 mmHg in the four units' group (p = 0.016). Doubling transfusion speed increased ΔLVEDP more than doubling volume in the larger volume groups. No difference in ANP or NT-proBNP were seen in high transfusion volume or groups. Conclusion: Transfusion volume dose-dependently increased LVEDP, with speed of transfusion rapidly elevating LVEDP at higher transfusion volumes. ANP and NT-proBNP were not impacted by transfusion volume or speed in this model. TACO is seen as purely volume overload, however, this study emphasizes that limiting transfusion speed, as a modifiable risk factor, might aid in preventing TACO.

The clinical state of shock constitutes a relative or absolute deficiency of circulating volume for adequate oxygen delivery to meet the metabolic demands.1 Although shock states differ in epidemiology, etiology, and pathophysiologic pathways, a common denominator of shock is endothelial barrier dysfunction.2, 3 Different kinds of shock states, such as occurring after major surgery, trauma, and in sepsis, can result in strong pro‐inflammatory host responses with ensuing endothelial hyperpermeability.4, 5, 6 Loss of endothelial barrier results in leakage of fluid into surrounding tissue, contributing to edema, tissue hypoxia, and organ failure.6 This loss of fluids further aggravates the intravascular circulatory volume deficiency during shock. Obviously, septic and traumatic shock are different entities, with different etiologies and differences in initiation of host response and coagulation response. However, endothelial activation with loss of endothelial barrier integrity is a common finding in both shock states. In trauma‐induced shock, current resuscitation strategies consist of the early transfusion of whole blood or a balanced ratio of plasma, platelets, and red blood cells.7, 8 The aim of resuscitation is to ensure adequate oxygen delivery and to correct coagulopathy. Plasma transfusion may play a key role, as trials point toward improved survival with high dose or early use of plasma transfusion compared to standard care.9, 10, 11 Upon reaching surgical hemostasis, it is general practice to stop transfusion. However, as a result of ongoing inflammation and endothelial activation, patients can continue to be fluid dependent, which is often responded to with crystalloids. However, liberal use of crystalloids in traumatic hemorrhagic shock is associated with increased mortality and increased endothelial permeability, inflammation, and reduced perfusion of vital organs.12, 13, 14 In septic shock, the primary treatment of shock is volume resuscitation with crystalloid or colloids, as advocated in guidelines.15 However, comparable to traumatic hemorrhagic shock, use of a restrictive fluid balance reduces the occurrence of organ failure as well as mortality in sepsis.16, 17, 18 most likely, the association between the amount of infused volume and adverse outcome in shock states is related to increased shedding of the glycocalix, breakdown of adherent junctions, and tight junctions resulting in an increased gradient of leakage over the hyper permeable endothelium.19 Taken together, due to a relative or absolute deficiency of intravascular volume, patients with shock are likely to need volume expansion to maintain perfusion pressure. This poses a challenge to the treatment of shock, as fluid therapy is both a cornerstone of therapy as well as a foe. Different fluids may have differential effects on endothelial integrity. Low‐protein‐content fluids seem to aggravate shedding of glycocalix,20 whereas protein‐rich fluids such as plasma may be superior to normal saline in protecting the glycocalix and endothelial barrier function.21 Transfusion with plasma as a volume expander in shock may seem controversial at first, but one needs to consider that despite the fact that plasma is transfused in millions of patients annually, there currently is limited understanding of its mechanisms of action. In traumatic blood loss, transfusion of plasma may improve survival by decreasing exsanguination.7, 10 The common perception is that plasma is a pro‐coagulant blood product, by replenishing coagulation factors. However, as plasma contains coagulation factors but also anticoagulant proteins, the net effect of plasma on coagulation may be neutral. In line with this, plasma transfusion increases the amount of coagulation factors as well as levels of anti‐coagulant proteins,22 resulting in unchanged thrombin generation, at least in non‐bleeding critically ill patients with an inflammatory‐driven consumption coagulopathy. In patients with traumatic hemorrhagic shock, it is not apparent whether the mechanism of effect of plasma is directly related to the correction of coagulopathy.23 In rats with hemorrhagic shock, deranged thrombin formation was somewhat restored with resuscitation with plasma but not with crystalloids, but whether this relates to prevention of dilutional coagulopathy or to a specific pro‐coagulant effect of plasma is not clear.24, 25 Other mechanisms of the protective effect of plasma may be at hand. These may include preservation of the glycocalix, decreasing inflammation and decreasing endothelial leak. This review aims to discuss the potential of plasma as a resuscitation fluid in shock, with an emphasis on possible mechanisms of benefit on the activated endothelium. Studies comparing plasma with other fluids on (markers of) endothelial integrity have found effects both in (models of) trauma‐induced shock and in septic shock. As loss of endothelial integrity may be a common denominator of shock, we will discuss both these shock states.

Purpose Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome. Methods A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity. Results In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I2 = 88%, p

Transfusion of red blood cells (RBCs) from female donors has been associated with increased risk of mortality. This study aims to investigate the associations between donor-recipient sex and posttransfusion mortality and morbidity in critically ill patients who received RBC transfusions from either male-only donors or from female-only donors (unisex-transfusion cases). Survival analysis was used to compare 4 groups: female-to-female, female-to-male, male-to-female, and male-to-male transfusion. Multivariate logistic model was used to evaluate the association between donor sex and intensive care unit (ICU) mortality. Associations between transfusion and acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), and nosocomial infections were assessed. Of the 6992 patients included in the original cohort study, 403 patients received unisex-transfusion. Survival analysis and the logistic model showed that transfusion of female RBCs to male patients was associated with an increased ICU mortality compared with transfusion of female RBCs to female patients (odds ratio, 2.43; 95% confidence interval, 1.02-5.77; P < .05). There was a trend toward increased ARDS in patients receiving RBC from female donors compared with those receiving blood from males (P = .06), whereas AKI was higher in donor-recipient sex-matched transfusion groups compared with sex-mismatched groups (P = .05). This was an exploratory study with potential uncontrolled confounders that limits broad generalization of the findings. Results warrant further studies investigating biological mechanisms underlying the association between donor sex with adverse outcomes as well as studies on the benefit of matching of blood between donor and recipient.

The current coronavirus pandemic has impacted heavily on ICUs worldwide. Although many hospitals and healthcare systems had plans in place to manage multiple casualties as a result of major natural disasters or accidents, there was insufficient preparation for the sudden, massive influx of severely ill patients with COVID-19. As a result, systems and staff were placed under immense pressure as everyone tried to optimize patient management. As the pandemic continues, we must apply what we have learned about our response, both good and bad, to improve organization and thus patient care in the future., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: It is unknown whether lung-protective ventilation is applied in burn patients and whether they benefit from it. This study aimed to determine ventilation practices in burn intensive care units (ICUs) and investigate the association between lung-protective ventilation and the number of ventilator-free days and alive at day 28 (VFD-28). Methods: This is an international prospective observational cohort study including adult burn patients requiring mechanical ventilation. Low tidal volume (V T) was defined as V T ≤ 8 mL/kg predicted body weight (PBW). Levels of positive end-expiratory pressure (PEEP) and maximum airway pressures were collected. The association between V T and VFD-28 was analyzed using a competing risk model. Ventilation settings were presented for all patients, focusing on the first day of ventilation. We also compared ventilation settings between patients with and without inhalation trauma. Results: A total of 160 patients from 28 ICUs in 16 countries were included. Low V T was used in 74% of patients, median V T size was 7.3 [interquartile range (IQR) 6.2-8.3] mL/kg PBW and did not differ between patients with and without inhalation trauma (p = 0.58). Median VFD-28 was 17 (IQR 0-26), without a difference between ventilation with low or high V T (p = 0.98). All patients were ventilated with PEEP levels ≥5 cmH2O; 80% of patients had maximum airway pressures

Purpose of review Although there is clear evidence for benefit of protective ventilation settings [including low tidal volume and higher positive end-expiratory pressure (PEEP)] in patients with acute respiratory distress syndrome (ARDS), it is less clear what the optimal mechanical ventilation settings are for patients with healthy lungs. Recent findings Use of low tidal volume during operative ventilation decreases postoperative pulmonary complications (PPC). In the critically ill patients with healthy lungs, use of low tidal volume is as effective as intermediate tidal volume. Use of higher PEEP during operative ventilation does not decrease PPCs, whereas hypotension occurred more often compared with use of lower PEEP. In the critically ill patients with healthy lungs, there are conflicting data regarding the use of a higher PEEP, which may depend on recruitability of lung parts. There are limited data suggesting that higher driving pressures because of higher PEEP contribute to PPCs. Lastly, use of hyperoxia does not consistently decrease postoperative infections, whereas it seems to increase PPCs compared with conservative oxygen strategies. Summary In patients with healthy lungs, data indicate that low tidal volume but not higher PEEP is beneficial. Thereby, ventilation strategies differ from those in ARDS patients.

During hyperinflammatory conditions that can occur in acute critical illness, such as shock or hypoperfusion, inflammatory mediators activate the endothelium, fueling a proinflammatory host-response as well as procoagulant processes. These changes result in shedding of the glycocalyx, endothelial hyperpermeability, edema formation, and lead to disturbed microcirculatory perfusion and organ failure. Different fluid strategies that are used in shock may have differential effects on endothelial integrity. Collectively, low protein content fluids seem to have negative effects on the endothelial glycocalyx, aggravating endothelial hyperpermeability, whereas fluids containing albumin or plasma proteins may be superior to normal saline in protecting the glycocalyx and endothelial barrier function. Targeting the endothelium may be a therapeutic strategy to limit organ failure, which hitherto has not received much attention. Treatment targets aimed at restoring the endothelium should focus on maintaining glycocalyx function and/or targeting coagulation pathways or specific endothelial receptors. Potential treatments could be supplementing glycocalyx constituents or inhibiting glycocalyx breakdown. In this review, we summarize mechanisms of endothelial dysfunction during acute critical illness, such as the systemic inflammatory response, shedding of the glycocalyx, endothelial activation, and activation of coagulation. In addition, this review focuses on the effects of different fluid strategies on endothelial permeability. Also, potential mechanisms for treatment options to reduce endothelial hyperpermeability with ensuing organ failure are evaluated. Future research is needed to elucidate these pathways and to translate these data to the first human safety and feasibility trials.

Red blood cell transfusions are a frequent intervention in critically ill patients, including in those who are receiving mechanical ventilation. Both these interventions can impact negatively on lung function with risks of transfusion-related acute lung injury (TRALI) and other forms of acute respiratory distress syndrome (ARDS). The interactions between transfusion, mechanical ventilation, TRALI and ARDS are complex and other patient-related (e.g. presence of sepsis or shock, disease severity, and hypervolemia) or blood product-related (e.g. presence of antibodies or biologically active mediators) factors also play a role. We propose several strategies targeted at these factors that may help limit the risks of associated lung injury in critically ill patients being considered for transfusion., SCOPUS: re.j, info:eu-repo/semantics/published

Purpose: Contemporary trauma resuscitation prioritizes control of bleeding and uses major haemorrhage protocols (MHPs) to prevent and treat coagulopathy. We aimed to determine whether augmenting MHPs with Viscoelastic Haemostatic Assays (VHA) would improve outcomes compared to Conventional Coagulation Tests (CCTs). Methods: This was a multi-centre, randomized controlled trial comparing outcomes in trauma patients who received empiric MHPs, augmented by either VHA or CCT-guided interventions. Primary outcome was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion (10 or more red cell transfusions). Secondary outcomes included 28-day mortality. Pre-specified subgroups included patients with severe traumatic brain injury (TBI). Results: Of 396 patients in the intention to treat analysis, 201 were allocated to VHA and 195 to CCT-guided therapy. At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%, OR 1.15, 95% CI 0.76–1.73). 28-day mortality was not different overall (VHA: 25%, CCT: 28%, OR 0.84, 95% CI 0.54–1.31), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups, there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm (OR 2.12, 95% CI 0.84–5.34). Conclusion: There was no difference in overall outcomes between VHA- and CCT-augmented-major haemorrhage protocols.

Hypercoagulability is an increasingly recognized complication of SARS‐CoV‐2 infection. As such, anticoagulation has become part and parcel of comprehensive COVID‐19 management. However, several uncertainties exist in this area including the appropriate type and dose of heparin. In addition, special patient populations, including those with high body mass index and renal impairment, require special consideration. Although the current evidence is still insufficient, we provide a pragmatic approach to anticoagulation in COVID‐19, but stress the need for further trials in this area.

INTRODUCTION: Transfusion therapy in hemorrhaging trauma patients is associated with the development of thromboembolic events. It is unknown whether current resuscitation strategies, including large volumes of plasma and early administration of procoagulant therapy, increases this risk. METHODS: A systematic search was conducted in MEDLINE, PubMed, and Embase. Studies were screened by two independent reviewers and included if they reported on thromboembolic events in patients with severe trauma (injury severity score ≥16) who received transfusion of at least 1 unit of red blood cells. The ratio by which blood products were transfused, as well as use of procoagulant or antifibrinolytic medication, was recorded. RESULTS: A total of 40 studies with 11.074 bleeding trauma patients were included, in which 1.145 thromboembolic events were reported, yielding an incidence of 10% thromboembolic events. In studies performing routine screening for thromboembolic complications, the incidence ranged from 12% to 23%. The risk of thromboembolic events was increased after administration of tranexamic acid (TXA; odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-4.1; p < 0.001) and fibrinogen concentrate (OR, 2.1; 95% CI, 1.0-4.2; p = 0.04). Blood product ratio, the use of prothrombin complex concentrate or recombinant factor VIIa were not associated with thromboembolic events. CONCLUSION: This systematic review identified an incidence of thromboembolic events of 10% in severely injured bleeding trauma patients. The use of TXA and fibrinogen concentrate was associated with the development of thromboembolic complications.

Prothrombin complex concentrate (PCC) is increasingly being used as a treatment for major bleeding in patients who are not taking anticoagulants. The aim of this systematic review and meta‐analysis is to evaluate the effectiveness of PCC administration for the treatment of bleeding in patients not taking anticoagulants. Studies investigating the effectivity of PCC to treat bleeding in adult patients and providing data on either mortality or blood loss were eligible. Data were pooled using Mantel‐Haenszel random effects meta‐analysis or inverse variance random effects meta‐analysis. From 4668 identified studies, 17 observational studies were included. In all patient groups combined, PCC administration was not associated with mortality (odds ratio = 0.83; 95% confidence interval [CI], 0.66‐1.06; P = .13; I 2 = 0%). However, in trauma patients, PCC administration, in addition to fresh frozen plasma, was associated with reduced mortality (odds ratio = 0.64; CI, 0.46‐0.88; P = .007; I 2 = 0%). PCC administration was associated with a reduction in blood loss in cardiac surgery patients (mean difference: −384; CI, −640 to −128, P = .003, I 2 = 81%) and a decreased need for red blood cell transfusions when compared with standard care across a wide range of bleeding patients not taking anticoagulants (mean difference: −1.80; CI, −3.22 to −0.38; P = .01; I 2 = 92%). In conclusion, PCC administration was not associated with reduced mortality in the whole cohort but did reduce mortality in trauma patients. In bleeding patients, PCC reduced the need for red blood cell transfusions when compared with treatment strategies not involving PCC. In bleeding cardiac surgery patients, PCC administration reduced blood loss.

OBJECTIVE: Ventilation strategies aiming at prevention of ventilator-induced lung injury (VILI), including low tidal volumes (VT) and use of positive end-expiratory pressures (PEEP) are increasingly used in critically ill patients. It is uncertain whether ventilation practices changed in a similar way in burn patients. Our objective was to describe applied ventilator settings and their relation to development of VILI in burn patients. DATA SOURCES: Systematic search of the literature in PubMed and EMBASE using MeSH, EMTREE terms and keywords referring to burn or inhalation injury and mechanical ventilation. STUDY SELECTION: Studies reporting ventilator settings in adult or pediatric burn or inhalation injury patients receiving mechanical ventilation during the ICU stay. DATA EXTRACTION: Two authors independently screened abstracts of identified studies for eligibility and performed data extraction. DATA SYNTHESIS: The search identified 35 eligible studies. VT declined from 14 ml/kg in studies performed before to around 8 ml/kg predicted body weight in studies performed after 2006. Low-PEEP levels (

Hypothermia is associated with high mortality in sepsis, but it is now recognized that this association may simply reflect its higher prevalence in sicker patients. Furthermore, there is evidence to suggest that hypothermia may not represent a dysfunction in sepsis. In this study, we conducted a survey to assess how this scientific evidence relates to the perceptions of health care professionals regarding septic hypothermia, and how such perceptions drive clinical conduct concerning the use of active rewarming in this population. A survey with questions on opinions and management of spontaneous hypothermia in sepsis was developed and posted online at the European Society of Intensive Care Medicine (ESICM) website from March 24th, 2017 to the June 26th, 2017 and distributed by electronic email. Respondents were asked to fill in the survey from the perspective of their usual or average practice in their intensive care unit. In total, there were 440 survey respondents. Respondents were predominantly from Europe (66%) The majority of respondents were intensivists (78%) and worked in an academic hospital (66%). One percent of respondents were nurses. Most respondents (96%) reported that there was no protocol for the management of hypothermic sepsis. Of the respondents, 62% actively rewarmed patients with hypothermic sepsis. Hypothermia was defined as a temperature below 36°C (44%) and below 35°C (15%). Rewarming practices showed large variation in terms of the temperature, at which respondents initiate rewarming as well as the target temperature to which patients are rewarmed. The most predominant first-line rewarming method was forced-warm air followed by warm IV fluids. Rewarming decisions were mostly physician driven (58%). Most respondents thought rewarming was beneficial (43%), a small proportion thought rewarming to be harmful (9%). In conclusion, policies, procedures, and beliefs about spontaneous hypothermia and active rewarming in patients with sepsis are variable. This must be taken into consideration in designing future trials. We propose a working group to define hypothermic sepsis to improve comparability of research.