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Transfusion of red cell concentrates (RCCs) is associated with increased risk of adverse outcomes that may be affected by different blood manufacturing methods and the presence of extracellular vesicles (EVs). We investigated the effect of different manufacturing methods on hemolysis, residual cells, cell-derived EVs, and immunomodulatory effects on monocyte activity. Thirty-two RCC units produced using whole blood filtration (WBF), red cell filtration (RCF), apheresis-derived (AD), and whole blood–derived (WBD) methods were examined (n = 8 per method). Residual platelet and white blood cells (WBCs) and the concentration, cell of origin, and characterization of EVs in RCC supernatants were assessed in fresh and stored supernatants. Immunomodulatory activity of RCC supernatants was assessed by quantifying monocyte cytokine production capacity in an in vitro transfusion model. RCF units yielded the lowest number of platelet and WBC-derived EVs, whereas the highest number of platelet EVs was in AD (day 5) and in WBD (day 42). The number of small EVs (

International audience; External validation of population pharmacokinetic (PK) models is warranted before they can be clinically applied to aid in antibiotic dose selection. The primary objective of this study was to assess the predictive performance of a gentamicin population PK model in intensive care unit (ICU) patients in two independent western populations of critically ill patients. METHODS: Data were collected from the ICU where the model was developed (Academic Medical Centre, Amsterdam [AMC]) and from the Centre Hospitalier Universitaire de N\ⁱmes (CHU N\ⁱmes). Primary endpoints were bias and accuracy. The model was regarded as valid if bias was not significantly different from 0 and accuracy was equal to or less than 2.5 mg/L. Non-linear mixed-effects modelling (NONMEM) was used for data analysis. RESULTS: The AMC validation dataset consisted of 192 samples from 66 ICU patients and the CHU N\ⁱmes dataset of 230 gentamicin samples from 50 ICU patients. The structural model predicted the gentamicin plasma concentrations in the AMC population with a non-significant bias (0.35, 95%CI: -0.11-0.81) and a sufficient accuracy of 2.5 mg/L (95%CI: 2.3-2.8). The gentamicin plasma concentrations were overpredicted in the CHU N\ⁱmes population with a significant bias of 4.8 mg/L (95%CI: 4.00-5.62) and an accuracy of 5.5 mg/L (95%CI: 4.7-6.2). CONCLUSION: The model is valid for use in the AMC ICU population but not in the CHU N\ⁱmes ICU population. This illustrates that caution is needed when using a population PK model in an external population.

Secondary bacterial pneumonia is a frequent complication of influenza, associated with high morbidity and mortality. We hypothesized that treatment with neutralizing influenza A antibody AT10_002 protects against severe secondary pneumococcal infection in a mouse model of influenza A infection. Influenza A (H3N2) virus-infected male C57Bl6 mice were treated intravenously with either AT10_002 or a control 2 days postinfection. Seven days later, both groups were infected with Streptococcus pneumoniae and killed 18 hours later. Mice receiving AT10_002 showed less loss of bodyweight compared with controls (+1% vs -12%, P < .001), lower viral loads in bronchoalveolar lavage fluids (BALFs) (7 vs 194 RNA copies per µL; P < .001), and reduced bacterial outgrowth in lung homogenates (3.3 × 101 vs 2.5 × 105 colony-forming units per mg; P < .001). The treatment group showed lower pulmonary wet weights, lower cell counts, and lower protein levels in BALF compared with controls. Treatment with AT10_002 was associated with lower levels of tumor necrosis factor-α, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (KC), and interferon-γ in BALF and lower IL-6 and KC in lung homogenates. Treatment with anti-influenza antibody AT10_002 is associated with reduced weight loss, viral load, bacterial outgrowth, and lung injury in a murine model of secondary pneumococcal pneumonia following influenza infection.

Systemic inflammatory response syndrome (SIRS) is characterized by the activation of the innate immune system resulting in stimulation of inflammatory responses, coagulation, and platelet activation that may contribute to complication such as the development of acute kidney injury (AKI). AKI importantly worsens the outcome of SIRS, implying the existence of a detrimental cross talk via systemic messages. Mitochondria are a source of damage-associated molecular patterns (DAMPs) and are thought to form a molecular link between tissue injury and stimulation of innate immunity. The role of mitochondrial DNA (mtDNA) in the cross talk between the onset of SIRS and subsequent development of AKI is unknown. Hence, we performed a case control study in critically ill patients with SIRS diagnosed with or without AKI, in which we determined mtDNA levels in plasma and urine, and correlated these to markers of renal impairment, inflammation, coagulation, and platelet activation. In addition, we exposed mice, primary renal tubular epithelial cells (TECs), and platelets to mtDNA or purified mitochondrial ligands, and measured their response to elucidate underlying pathophysiological mechanisms. Our data reveal that increased systemic mtDNA levels in SIRS patients do not correlate with systemic inflammation and renal disease activity. Moreover, AKI does not have an additional effect on circulating mtDNA levels. In contrast, we found that urinary mtDNA levels correlate with an elevated albumin creatinine ratio (ACR) as well as with increased urinary markers of inflammation, coagulation, and platelet activation. Both renal TECs and platelets respond to mtDNA and mtDNA ligands, leading to increased expression of, respectively, inflammatory cytokines and P-selectin. Moreover, activation of platelets results in mtDNA release. Together, these data suggest that circulating mtDNA is probably not important in the detrimental cross talk between SIRS and AKI, whereas renal mtDNA accumulation may be related to intrarenal inflammation, coagulation processes, and renal dysfunction in the pathophysiology of SIRS.

Transfusion clinique et biologique - In Press.Proof corrected by the author Available online since mardi 18 juin 2019

Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC products contain a multitude of immunomodulatory mediators that interact with and alter immune cell function. These interactions can lead to both proinflammatory and immunosuppressive effects. Defining clinical outcomes related to immunomodulatory effects of RBCs in transfused patients remains a challenge, likely due to complex interactions between individual blood product characteristics and patient-specific risk factors. Unpacking these complexities requires an in-depth understanding of the mechanisms of immunomodulatory effects of RBC products. In this review, we outline and classify potential mediators of RBC transfusion-related immunomodulation and provide suggestions for future research directions.

Background Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis. Methods We did a retrospective multicentre cohort study. Data were collected from adult patients with severe influenza admitted to seven ICUs across Belgium and The Netherlands during seven influenza seasons. Patients were older than 18 years, were admitted to the ICU for more than 24 h with acute respiratory failure, had pulmonary infiltrates on imaging, and a confirmed influenza infection based on a positive airway PCR test (influenza cohort). We used logistic regression analyses to determine if influenza was independently associated with invasive pulmonary aspergillosis in non-immunocompromised (ie, no European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] host factor) influenza-positive patients (influenza case group) compared with nonimmunocompromised patients with severe community-acquired pneumonia who had a negative airway influenza PCR test (control group). Findings Data were collected from patients admitted to the ICU between Jan 1, 2009, and June 30, 2016. Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU. The incidence was similar for influenza A and B. For patients with influenza who were immunocompromised, incidence of invasive pulmonary aspergillosis was as high as 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis. The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0.0001). In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5.19; 95% CI 2.63-10.26; p

Molecular tests may enable early adjustment of antimicrobial therapy and be complementary to blood culture (BC) which has imperfect sensitivity in critically ill patients. We evaluated a novel multiplex real-time PCR assay to diagnose bloodstream pathogens directly in whole blood samples (BSI-PCR). BSI-PCR included 11 species- and four genus-specific PCRs, a molecular Gram-stain PCR, and two antibiotic resistance markers. We collected 5 mL blood from critically ill patients simultaneously with clinically indicated BC. Microbial DNA was isolated using the Polaris method followed by automated DNA extraction. Sensitivity and specificity were calculated using BC as reference. BSI-PCR was evaluated in 347 BC-positive samples (representing up to 50 instances of each pathogen covered by the test) and 200 BC-negative samples. Bacterial species-specific PCR sensitivities ranged from 65 to 100%. Sensitivity was 26% for the Gram-positive PCR, 32% for the Gram-negative PCR, and ranged 0 to 7% for yeast PCRs. Yeast detection was improved to 40% in a smaller set-up. There was no overall association between BSI-PCR sensitivity and time-to-positivity of BC (which was highly variable), yet Ct-values were lower for true-positive versus false-positive PCR results. False-positive results were observed in 84 (4%) of the 2200 species-specific PCRs in 200 culture-negative samples, and ranged from 0 to 6% for generic PCRs. Sensitivity of BSI-PCR was promising for individual bacterial pathogens, but still insufficient for yeasts and generic PCRs. Further development of BSI-PCR will focus on improving sensitivity by increasing input volumes and on subsequent implementation as a bedside test. Electronic supplementary material The online version of this article (10.1007/s10096-018-3255-1) contains supplementary material, which is available to authorized users.

It remains uncertain whether nebulization of mucolytics with bronchodilators should be applied for clinical indication or preventively in intensive care unit (ICU) patients receiving invasive ventilation. To determine if a strategy that uses nebulization for clinical indication (on-demand) is noninferior to one that uses preventive (routine) nebulization. Randomized clinical trial enrolling adult patients expected to need invasive ventilation for more than 24 hours at 7 ICUs in the Netherlands. On-demand nebulization of acetylcysteine or salbutamol (based on strict clinical indications, n = 471) or routine nebulization of acetylcysteine with salbutamol (every 6 hours until end of invasive ventilation, n = 473). The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for a difference between groups of -0.5 days. Secondary outcomes included length of stay, mortality rates, occurrence of pulmonary complications, and adverse events. Nine hundred twenty-two patients (34% women; median age, 66 (interquartile range [IQR], 54-75 years) were enrolled and completed follow-up. At 28 days, patients in the on-demand group had a median 21 (IQR, 0-26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0-26) ventilator-free days (1-sided 95% CI, -0.00003 to ∞). There was no significant difference in length of stay or mortality, or in the proportion of patients developing pulmonary complications, between the 2 groups. Adverse events (13.8% vs 29.3%; difference, -15.5% [95% CI, -20.7% to -10.3%]; P

Background Red blood cell (RBC) transfusion is associated with organ failure, in particular in the critically ill. We hypothesized that endotoxemia contributes to increased trapping of RBCs in organs. Furthermore, we hypothesized that this effect is more pronounced following transfusion of stored RBCs compared with fresh RBCs. Methods Adult male Sprague-Dawley rats were randomized to receive injection with lipopolysaccharide from E coli or vehicle and transfusion with fresh or stored biotinylated RBCs. After 24 h, the amount of biotinylated RBCs in organs was measured by flow cytometry, as well as the 24-h post-transfusion recovery. Markers of organ injury and histopathology of organs were assessed. Results Endotoxemia resulted in systemic inflammation and organ injury. Following RBC transfusion, donor RBCs were recovered from the lung and kidney of endotoxemic recipients (1.2 [0.8-1.6]% and 2.2 [0.4-4.4]% of donor RBCs respectively), but not from organs of healthy recipients. Trapping of donor RBCs in the lung was associated with increased lung injury, but not with kidney injury. Stored RBCs induced organ injury in the spleen and yielded a lower 24-h post-transfusion recovery, but other effects of storage time were limited. Conclusion Endotoxemia results in an increased percentage of donor RBCs recovered from the lung and kidney, which is associated with lung injury following transfusion.

Induced hypothermia may protect from ischemia reperfusion injury. The mechanism of protection is not fully understood and may include an effect on mitochondria. Here we describe the effect of hypothermia on circulating mitochondrial (mt) DNA in a substudy of a multicenter randomized trial (the Target Temperature Management trial). Circulating levels of mtDNA were elevated in patients with cardiac arrest at all-time points compared to healthy controls. After 24 h of temperature management, patients kept at 33 °C had significantly lower levels of COX3, NADH1 and NADH2 compared to baseline, in contrast to those kept at 36 °C. After regain of temperature, cytochrome – B was significantly reduced in patients kept at 33 °C with cardiac arrest. Cardiac arrest results in circulating mtDNA levels, which reduced during a temperature management protocol in patients with a target temperature of 33 °C.

BACKGROUND: Red blood cell (RBC) transfusion is associated with adverse effects, which may involve activation of the host immune response. The effect of RBC transfusion on neutrophil Reactive Oxygen Species (ROS) production and adhesion ex vivo was investigated in endotoxemic volunteers and in critically ill patients that received a RBC transfusion. We hypothesized that RBC transfusion would cause neutrophil activation, the extent of which depends on the storage time and the inflammatory status of the recipient. STUDY DESIGN AND METHODS: Volunteers were injected with lipopolysaccharide (LPS) and transfused with either saline, fresh, or stored autologous RBCs. In addition, 47 critically ill patients with and without sepsis receiving either fresh (

Current treatment of acute respiratory distress syndrome (ARDS) in critically ill patients is limited to supportive measures including mechanical ventilation. It is our view that effective therapies for ARDS can only be found through experimental and translational science that seeks to better understand the mechanisms of injury and identify therapeutic approaches, using pre-clinical models of acute lung injury that closely mimic the clinical syndrome of ARDS. This editorial gives examples of ways in which translational science contributes to the development of more specific measures against ARDS in the critically ill. In order to improve focus on this essential research as well as to enhance collaborative research efforts, a Translational Biology Group was founded within the European Society of Intensive Care Medicine. INSPIRES is an international symposium on translational research in lung injury as well as in other areas of critical illness, intended to serve as a platform for the translational biology working group. This issue of ICMx is dedicated to the proceedings of INSPIRES III. Sin financiación No data 2019 UEM

Background Anemia of inflammation (AI) is common in critically ill patients. Although this syndrome negatively impacts the outcome of critical illness, understanding of its pathophysiology is limited. Also, new therapies that increase iron availability for erythropoiesis during AI are upcoming. A model of AI induced by bacterial infections that are relevant for the critically ill is currently not available. This paper describes the development of an animal model for AI that is relevant for critical care research. Results In experiments with rats, the rats were inoculated either repeatedly or with a slow release of Streptococcus pneumoniae or Pseudomonas aeruginosa. Rats became ill, but their hemoglobin levels remained stable. The use of a higher dose of bacteria resulted in a lethal model. Then, we turned to a model with longer disease duration, using pigs that were supported by mechanical ventilation after inoculation with P. aeruginosa. The pigs became septic 12 to 24 h after inoculation, with a statistically significant decrease in mean arterial pressure and base excess, while heart rate tended to increase. Pigs needed resuscitation and vasopressor therapy to maintain a mean arterial pressure > 60 mmHg. After 72 h, the pigs developed anemia (baseline 9.9 g/dl vs. 72 h, 7.6 g/dl, p = 0.01), characterized by statistically significant decreased iron levels, decreased transferrin saturation, and increased ferritin. Hepcidin levels tended to increase and transferrin levels tended to decrease. Conclusions Using pathogens commonly involved in pulmonary sepsis, AI could not be induced in rats. Conversely, in pigs, P. aeruginosa induced pulmonary sepsis with concomitant AI. This AI model can be applied to study the pathophysiology of AI in the critically ill and to investigate the effectivity and toxicity of new therapies that aim to increase iron availability. Electronic supplementary material The online version of this article (10.1186/s40635-019-0261-2) contains supplementary material, which is available to authorized users.

Author(s): Vlaar, Alexander PJ; Toy, Pearl; Fung, Mark; Looney, Mark R; Juffermans, Nicole P; Bux, Juergen; Bolton-Maggs, Paula; Peters, Anna L; Silliman, Christopher C; Kor, Daryl J; Kleinman, Steve | Abstract: BackgroundTransfusion-related acute lung injury (TRALI) is a serious complication of blood transfusion and is among the leading causes of transfusion-related morbidity and mortality in most developed countries. In the past decade, the pathophysiology of this potentially life-threatening syndrome has been increasingly elucidated, large cohort studies have identified associated patient conditions and transfusion risk factors, and preventive strategies have been successfully implemented. These new insights provide a rationale for updating the 2004 consensus definition of TRALI.Study design and methodsAn international expert panel used the Delphi methodology to develop a redefinition of TRALI by modifying and updating the 2004 definition. Additionally, the panel reviewed issues related to TRALI nomenclature, patient conditions associated with acute respiratory distress syndrome (ARDS) and TRALI, TRALI pathophysiology, and standardization of reporting of TRALI cases.ResultsIn the redefinition, the term "possible TRALI" has been dropped. The terminology of TRALI Type I (without an ARDS risk factor) and TRALI Type II (with an ARDS risk factor or with mild existing ARDS) is proposed. Cases with an ARDS risk factor that meet ARDS diagnostic criteria and where respiratory deterioration over the 12 hours before transfusion implicates the risk factor as causative should be classified as ARDS. TRALI remains a clinical diagnosis and does not require detection of cognate white blood cell antibodies.ConclusionsClinicians should report all cases of posttransfusion pulmonary edema to the transfusion service so that further investigation can allow for classification of such cases as TRALI (Type I or Type II), ARDS, transfusion-associated circulatory overload (TACO), or TRALI or TACO cannot distinguish or an alternate diagnosis.

Background In acute respiratory distress syndrome (ARDS), uncontrolled production of activators of coagulation and proinflammatory mediators results in a shift from an adequate local innate immune response to hypercoagulability and inflammation. This study aimed to investigate whether the protease inhibitors antithrombin (AT) and alpha-1 protease inhibitor (A1PI) may attenuate an exaggerated pulmonary immune response. Methods Lung injury was induced either by single intranasal administration of lipopolysaccharide (LPS) (5 mg/kg) in BALB/c mice or by combination of an intravenous injection of LPS (10 mg/kg) with subsequent injurious ventilation using high tidal volumes (12–15 ml/kg) for 4 h in RccHan Wistar rats. Animals received either a single bolus of AT (250 IU/kg) or A1PI (60 mg/kg) alone or in combination, with or without intravenous low-dose heparin (100 U/kg). Control animals received saline. Additional controls received neither LPS, nor ventilation, nor treatment. Endpoints were local and systemic markers of coagulation, e.g., thrombin–antithrombin complexes (TATc), and inflammation, e.g., interleukin-6. Results Both lung injury models resulted in a pronounced immune response within the pulmonary compartment shown by elevated levels of markers of coagulation and inflammation. The two-hit lung injury model also induced profound systemic coagulopathy and inflammation. Monotherapy with AT or A1PI did not reduce pulmonary coagulopathy or inflammation in any lung injury model. Nor did combination therapy with AT and A1PI result in a decrease of coagulation or inflammatory parameters. AT markedly reduced systemic levels of TATc in the two-hit lung injury model. Systemic inflammation was not affected by the different interventions. Additional administration of heparin did not lead to macroscopic bleeding incidences. Conclusions In two different murine models of acute lung injury, neither single therapy with AT or A1PI nor combination of both agents attenuates the pronounced pulmonary coagulation or inflammatory response.

Sepsis can be associated with different degrees of coagulopathy, ranging from a mild activation of the coagulation system to disseminated intravascular coagulation (DIC). The evaluation of haemostasis in the context of sepsis is important since it has been shown that anticoagulant therapies were beneficial mainly in patients with sepsis-induced DIC, but not in the general population of septic patients. Sepsis-induced haemostatic disturbances are not adequately reflected by standard coagulation tests (SCTs) which only consider the plasmatic components of the haemostatic system and not the cellular components. In addition, SCTs only assess the initiation phase of coagulation and reflect the activity of pro-coagulant factors, but lack sensitivity for the anticoagulant drive and the fibrinolytic activity. Viscoelastic tests (VET) are whole-blood tests which can assess clot formation and dissociation, and the contribution of both plasmatic and cellular components with a shorter turnaround time compared to SCTs. The use of VET in septic patients has proved useful for the assessment of the fibrinolytic activity, detecting hypercoagulable status and for the diagnosis of DIC and mortality risk prediction. While having relevant advantages over SCTs, the VET also present some blind spots or limitations leaving space for future improvement by the development of new reagents or new viscoelastic parameters.

BACKGROUND Transfusion‐associated circulatory overload (TACO) is the predominant complication of transfusion resulting in death. The pathophysiology is poorly understood, but inability to manage volume is associated with TACO, and observational data suggest it is different from simple cardiac overload due to fluids. We developed a two‐hit TACO animal model to assess the role of volume incompliance (“first‐hit”) and studied whether volume overload (“second‐hit”) by red blood cell (RBC) transfusion is different compared to fluids (Ringer's lactate [RL]). MATERIALS AND METHODS Male adult Lewis rats were stratified into a control group (no intervention) or a first hit: either myocardial infarction (MI) or acute kidney injury (AKI). Animals were randomized to a second hit of either RBC transfusion or an equal volume of RL. A clinically relevant difference was defined as an increase in left ventricular end‐diastolic pressure (ΔLVEDP) of +4.0 mm Hg between the RBC and RL groups. RESULTS In control animals (without first hit) LVEDP was not different between infusion groups (Δ + 1.6 mm Hg). LVEDP increased significantly more after RBCs compared to RL in animals with MI (Δ7.4 mm Hg) and AKI (Δ + 5.4 mm Hg), respectively. Volume‐incompliant rats matched clinical TACO criteria in 92% of transfused versus 25% of RL‐infused animals, with a greater increase in heart rate and significantly higher blood pressure. CONCLUSION To our knowledge, this is the first animal model for TACO, showing that a combination of volume incompliance and transfusion is essential for development of circulatory overload. This model allows for further testing of mechanistic factors as well as therapeutic approaches.

Background In the critically ill, extracellular vesicles (EV) from red blood cells (RBC) have been related to adverse effects of blood transfusion. Stored RBC units contain high concentrations of RBC- EVs, thereby increasing the concentration of EVs in the circulation after transfusion. The mechanisms underlying the clearance of donor RBC-EVs after transfusion are unknown. This study investigates whether membrane markers that are associated with clearance of RBCs are also implicated in clearance of RBC-EVs in human endotoxemic recipients of a transfusion. Methods Six volunteers were injected with Escherichia coli lipopolysaccharide, and after two hours transfused with an autologous RBC unit donated 35 days earlier. Samples were collected from the RBC unit and the volunteers before and after transfusion. RBC-EVs were labeled with (anti) glycophorin A, combined with (anti) CD44, CD47, CD55, CD59, CD147, or lactadherin to detect phosphatidylserine (PS) and analyzed on a A50 Micro flow cytometer. Results In the RBC unit, RBC-EVs solely exposed PS (7.8%). Before transfusion, circulating RBC-EVs mainly exposed PS (22%) and CD59 (9.1%), the expression of the other membrane markers was much lower. After transfusion, the concentration of RBC- EVs increased 2.4-fold in two hours. Thereafter, the EV concentration decreased towards baseline levels. The fraction of EVs positive for all tested membrane markers decreased after transfusion. Conclusion Besides a minor fraction of PS-exposing EVs, RBC-EVs produced during storage do not expose detectable levels of RBC membrane markers that are associated with clearance, which is in contrast to the EVs produced by the circulating RBCs.

When treating critically ill patients with gentamicin for severe infection, peak concentrations (C-max) determine clinical efficacy and trough concentrations (C-min) determine toxicity. Despite administration of body weight-standardised starting doses, a wide range of Cmax is generally observed. Furthermore, in therapeutic drug monitoring, several measures of renal function are used to predict appropriate Cmin and gentamicin dosing intervals, but the most accurate predictor is not known. This study aimed to quantify the impact of several patient parameters on gentamicin Cmax values and to determine which measure of renal function best predicts gentamicin clearance (CL). Clinical data and serum gentamicin levels were retrospectively collected from all critically ill patients treated with gentamicin at our intensive care unit between 1 January and 30 June 2011. Data were analysed using non-linear mixed-effects modelling (NONMEM v.7.1.2). A two-compartmental model was developed based on 303 gentamicin concentration-time data from 44 critically ill patients. Serum albumin levels explained 25% of interindividual variability in the volume of distribution (V-d). Creatinine clearance calculated from the creatinine concentration in a 6-h urine portion (CalcCL(Cr)) resulted in acceptable estimation of gentamicin CL, whilst serum creatinine (SCr) and creatinine clearance estimated by the Cockcroft-Gault formula (CGCL(Cr)) overestimated gentamicin CL and therefore underestimated C-min. In conclusion, low albumin concentrations resulted in a larger Vd and lower Cmax of gentamicin. These results suggest that use of a higher gentamicin starting dose in critically ill patients with hypoalbuminaemia may prevent underdosing. Urinary CalcCLCr is a better predictor of C-min than SCr or CGCL(Cr). (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved

Abnormal laboratory coagulation test results are frequently documented in critically ill patients, and these patients often also need to undergo invasive procedures. Clinicians have an understandable desire to minimize any perceived heightened risk of bleeding complications in those patients who require invasive procedures. In this setting, prophylactic administration of platelets or plasma is commonplace. This review explores the nature of these sequential statements and the degree to which these statements are supported by evidence. We discuss the complexity of managing the low risk of procedure-related bleeding in a setting where coagulation tests fail to reliably predict this risk. The role of prophylactic transfusion of platelets and plasma and correction of medication-induced coagulopathy is also reviewed. New strategies are required to improve the evidence base, including novel methodological approaches or the use of a clinical scoring system. (C) 2017 Elsevier Inc. All rights reserved

BACKGROUND Red blood cell (RBC) transfusion is associated with organ failure. The mechanism remains unknown, but may include adherence of blood cells to the microvasculature. We hypothesized that RBC-derived extracellular vesicles (EVs) interact with monocytes to activate endothelial cells. STUDY DESIGN AND METHODS Human umbilical vein endothelial cells were incubated with supernatant from fresh and stored RBC units either containing EVs or depleted from EVs, with or without the addition of immune cells. We measured expression of adhesion markers by flow cytometry and markers of coagulation and inflammation in the culture medium. We studied phagocytosis of EVs by monocytes by using confocal microscopy and flow cytometry. RESULTS Incubation of endothelial cells with monocytes alone did not induce up regulation of adhesion markers. The addition of both monocytes and supernatant from RBCs containing EVs resulted in up regulation of endothelial expression of intercellular adhesion molecule 1 and E-selectin when compared to baseline. Up regulation was absent when stimulated with RBC supernatant depleted from EVs. EVs are phagocytosed by monocytes, which was partly abrogated after coincubation with two different complement receptor 3 (CR3)-blocking antibodies. Addition of RBC-derived EVs also increased levels of von Willebrand factor (VWF). There were no differences between groups related to storage time. CONCLUSION EVs from RBC transfusion bags activate monocytes with subsequent up regulation of endothelial cell adhesion markers. EVs are phagocytosed by monocytes through CR3. Furthermore, these EVs proved to be a source of VWF. These effects are unrelated to storage time. Thereby, EVs from RBC transfusion bags induce a proinflammatory and procoagulant endothelial cell response.

BACKGROUND Transfusion of a single unit of stored red blood cells (RBCs) has been hypothesized to induce supra-physiological levels of non-transferrin bound iron (NTBI), which may enhance inflammation and act as a nutrient for bacteria. We investigated the relation between RBC storage time and iron levels in a clinically relevant “two-hit” human transfusion model. STUDY DESIGN AND METHODS Eighteen healthy male volunteers (ages 18-35 years) were infused with 2 ng lipopolysaccharide (LPS)/kg to induce systemic inflammatory response syndrome. Two hours later, each participant received either 1 unit of 2-day stored (2D) autologous RBCs, 35-day stored (35D) autologous RBCs, or an equal volume of saline. Every 2 hours up to 8 hours after LPS infusion, hemoglobin, hemolysis parameters, and iron parameters, including NTBI, were measured. RESULTS Transfusion of both 2D and 35D RBCs caused increases in hemoglobin, plasma iron, and transferrin saturation; whereas levels remained stable in the saline group. Transfusion of 35D RBCs did not result in hemolysis nor did it lead to increased levels of NTBI compared with 2D RBCs or saline. LPS induced increases in ferritin, haptoglobin, bilirubin, and lactate dehydrogenase that were similar in all three groups. CONCLUSION We conclude that 35D autologous RBCs do not cause hemolysis or increased levels of NTBI during human endotoxemia.

We present a female patient with severe acute respiratory distress syndrome (ARDS) necessitating intubation and mechanical ventilation on the intensive care unit (ICU). High ventilatory pressures were needed because of hypoxia and severe hypercapnia with respiratory acidosis, resulting in right ventricular dysfunction with impaired haemodynamic stability. A veno-venous extracorporeal CO2 removal (ECCO2R) circuit was initiated, effectively eliminating carbon dioxide while improving oxygenation and enabling a reduction in applied ventilatory pressures. We noted a marked improvement of right ventricular function with restoration of haemodynamic stability. Within one week, the patient was weaned from both ECCO2R and mechanical ventilation. Besides providing adequate gas exchange, extracorporeal assist devices may be helpful in ameliorating right ventricular dysfunction during ARDS.

BACKGROUND It is thought that the clearance of transfused red blood cells (RBCs) is related both to the storage time of the transfusion product and to the inflammatory status of the recipient. We investigated these effects in a randomized, “two-hit,” healthy volunteer transfusion model, comparing autologous RBCs that were stored for 35 days with those that were stored for 2 days. STUDY DESIGN AND METHODS Healthy male volunteers donated 1 unit of autologous RBCs either 2 days (2D) or 35 days (35D) before the study date. The experiment was started by infusion of 2 ng/kg lipopolysaccharide (“first hit”). Two hours later, the stored RBCs (“second hit”) were reinfused, followed by the labeling of RBCs with biotin. Clearance of biotin-labeled RBCs (BioRBCs) was measured during the 5-hour posttransfusion endotoxemia period along with measurements of phosphatidylserine (PS) exposure, lactadherin binding, and expression of CD47 (cluster of differentiation 47; a transmembrane protein encoded by the CD47 gene). RESULTS In the 2D stored RBCs group, 1.5% ± 3.4% of infused BioRBCs were cleared from the circulation 5 hours posttransfusion versus 4.8% ± 4.0% in the 35D stored RBCs group (p = 0.1). There were no differences in PS exposure, lactadherin binding, or CD47 expression between fresh and stored RBCs or between pretransfusion and posttransfusion measurements. CONCLUSION Our study shows a low clearance of RBCs even during endotoxemia. Furthermore, short-term clearance of BioRBCs during endotoxemia was not related to storage duration. Consistent with these observations, PS exposure, lactadherin binding, and CD47 expression did not differ between 2D and 35D stored cells before or after transfusion. We conclude that, in the presence of endotoxemia, clearance of 35D stored autologous RBCs is not increased compared with 2D stored fresh RBCs.

After the consensus definition of transfusion-related acute lung injury (TRALI), studies have shown that the incidence of TRALI is high in critically ill and injured patients. When another risk factor for lung injury is present in these patients, the term "possible TRALI" is used. In the past years, both animal and clinical studies have taught us that a predisposing inflammatory risk factor is frequently present in TRALI, if not mandatory. The decline in the incidence of TRALI after implementation of the use of male-only plasma as observed in general hospital patients is also seen in the critically ill and injured, suggesting that antibodies play a role in possible TRALI. Thereby, introduction of the term "possible TRALI" has helped us in estimating incidence rates as well as to understand risk factors for TRALI in patient populations with a high exposure to transfusion.

Previously termed ‘anemia of chronic diseases’, anemia developing as a consequence of inflammation is now called anemia of inflammation. In this chapter, we describe the prevalence and etiology of anemia of inflammation. Therapeutic strategies for anemia of inflammation that are currently under development are discussed, with a special emphasis on the rationale of transferrin as a novel therapy for anemia of inflammation.

OBJECTIVE: To determine the characteristics of trauma patients with low levels of fibrinolysis as detected by viscoelastic hemostatic assay (VHA) and explore the underlying mechanisms of this subtype. BACKGROUND: Hyperfibrinolysis is a central component of acute traumatic coagulopathy but a group of patients present with low levels of VHA-detected fibrinolysis. There is concern that these patients may be at risk of thrombosis if empirically administered an antifibrinolytic agent. METHODS: A prospective multicenter observational cohort study was conducted at 5 European major trauma centers. Blood was drawn on arrival, within 2 hours of injury, for VHA (rotation thromboelastometry [ROTEM]) and fibrinolysis plasma protein analysis including the fibrinolytic mediator S100A10. An outcomes-based threshold for ROTEM hypofibrinolysis was determined and patients grouped by this and by D-dimer (DD) levels. RESULTS: Nine hundred fourteen patients were included in the study. The VHA maximum lysis (ML) lower threshold was determined to be

Background Perioperative bleeding and transfusion are important causes of morbidity and mortality in patients undergoing liver transplantation. The aim of this study is to assess whether viscoelastic tests-guided therapy with the use of synthetic factor concentrates impact transfusion rates of hemocomponents in adult patients undergoing liver transplantation. Methods This is an interventional before-after comparative study. Patients undergoing liver transplantation before the implementation of a protocol using thromboelastometry and synthetic factor concentrates were compared to patients after the implementation. Primary outcome was transfusion of any hemocomponents. Secondary outcomes included: transfusion of red blood cells (RBC), fresh frozen plasma (FFP), cryoprecipitate or platelets, clinical complications, length of stay and in-hospital mortality. Results A total of 183 patients were included in the control and 54 in the intervention phase. After propensity score matching, the proportion of patients receiving any transfusion of hemocomponents was lower in the intervention phase (37.0 vs 58.4%; OR, 0.42; 95% CI, 0.20–0.87; p = 0.019). Patients in the intervention phase received less RBC (30.2 vs 52.5%; OR, 0.21; 95% CI, 0.08–0.56; p = 0.002) and FFP (5.7 vs 27.3%; OR, 0.11; 95% CI, 0.03–0.43; p = 0.002). There was no difference regarding transfusion of cryoprecipitate and platelets, complications related to the procedure, hospital length of stay and mortality. Conclusions Use of a viscoelastic test-guided transfusion algorithm with the use of synthetic factor concentrates reduces the transfusion rates of allogenic blood in patients submitted to liver transplantation. Trial registration This trial was registered retrospectively on November 15th, 2018 – clinicaltrials.gov – Identifier: NCT03756948. Electronic supplementary material The online version of this article (10.1186/s12871-018-0664-8) contains supplementary material, which is available to authorized users.

Background Selective decontamination of the digestive tract (SDD) and selective oropharyngeal decontamination (SOD) reduce colonization with antibiotic-resistant Gram-negative bacteria (ARGNB), incidence of nosocomial infections and improve survival in ICU patients. The effect on bacterial gut colonization might be caused by growth suppression by antibiotics during SDD/SOD. We investigated intestinal colonization with ARGNB after discharge from ICU and discontinuation of SDD or SOD. Methods We performed a prospective, observational follow-up study in regular hospital wards of three teaching hospitals in the Netherlands in patients discharged from the ICU, who were participating in a cluster randomized trial comparing SDD with SOD. We determined rectal carriage with ARGNB at ICU discharge (time (T) = 0) and 3, 6 and 10 days after discharge. The primary endpoint was time to first colonization with ARGNB that was not present at T = 0. Bacteria that are intrinsically resistant to antibiotics were not included in the primary analysis, but were included in post-hoc analysis. Results Of 1370 patients screened for inclusion, 996 patients had samples at T = 0 (507 after SDD and 489 after SOD). At ICU discharge, the prevalence of intestinal carriage with any ARGNB was 22/507 (4.3%) after SDD and 87/489 (17.8%) after SOD (p

Background: The main risk factors for intensive care unit-acquired weakness (ICU-AW) are sepsis, the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction. These risk factors are associated with systemic complement activation. We hypothesized that critically ill patients who develop ICU-AW have increased systemic complement activation compared to critically ill patients who do not develop ICU-AW. Methods: Complement activation products C3b/c, C4b/c and C5a were measured in plasma of ICU patients with mechanical ventilation for ≥48 hours. Samples were collected at admission to the ICU and for 6 consecutive days. ICU-AW was defined by a mean Medical Research Council (MRC) score

BACKGROUND: Transfusion is associated with organ failure and nosocomial infection in trauma patients, which may be mediated by soluble bioactive substances in blood products, including extracellular vesicles (EVs). We hypothesize that removing EVs, by washing or filtering of blood products, reduces organ failure and improves host immune response. MATERIALS AND METHODS: Blood products were prepared from syngeneic rat blood. EVs were removed from RBCs and platelets by washing. Plasma was filtered through a 0.22-μm filter. Rats were traumatized by crush injury to the intestines and liver, and a femur was fractured. Rats were hemorrhaged until a mean arterial pressure of 40 mm Hg and randomized to receive resuscitation with standard or washed/filtered blood products, in a 1:1:1 ratio. Sham controls were not resuscitated. Ex vivo whole blood stimulation tests were performed and histopathology was done. RESULTS: Washing of blood products improved quality metrics compared to standard products. Also, EV levels reduced by 12% to 77%. The coagulation status, as assessed by thromboelastometry, was deranged in both groups and normalized during transfusion, without significant differences. Use of washed/filtered products did not reduce organ failure, as assessed by histopathologic score and biochemical measurements. Immune response ex vivo was decreased following transfusion compared to sham but did not differ between transfusion groups. CONCLUSION: Filtering or washing of blood products improved biochemical properties and reduced EV counts, while maintaining coagulation abilities. However, in this trauma and transfusion model, the use of optimized blood components did not attenuate organ injury or immune suppression.

OBJECTIVE: Developing pragmatic data-driven algorithms for management of trauma induced coagulopathy (TIC) during trauma hemorrhage for viscoelastic hemostatic assays (VHAs). BACKGROUND: Admission data from conventional coagulation tests (CCT), rotational thrombelastometry (ROTEM) and thrombelastography (TEG) were collected prospectively at 6 European trauma centers during 2008 to 2013. METHODS: To identify significant VHA parameters capable of detecting TIC (defined as INR > 1.2), hypofibrinogenemia (< 2.0 g/L), and thrombocytopenia (< 100 x10/L), univariate regression models were constructed. Area under the curve (AUC) was calculated, and threshold values for TEG and ROTEM parameters with 70% sensitivity were included in the algorithms. RESULTS: A total of, 2287 adult trauma patients (ROTEM: 2019 and TEG: 968) were enrolled. FIBTEM clot amplitude at 5 minutes (CA5) had the largest AUC and 10 mm detected hypofibrinogenemia with 70% sensitivity. The corresponding value for functional fibrinogen (FF) TEG maximum amplitude (MA) was 19 mm. Thrombocytopenia was similarly detected using the calculated threshold EXTEM-FIBTEM CA5 30 mm. The corresponding rTEG-FF TEG MA was 46 mm. TIC was identified by EXTEM CA5 41 mm, rTEG MA 64 mm (80% sensitivity). For hyperfibrinolysis, we examined the relationship between viscoelastic lysis parameters and clinical outcomes, with resulting threshold values of 85% for EXTEM Li30 and 10% for rTEG Ly30.Based on these analyses, we constructed algorithms for ROTEM, TEG, and CCTs to be used in addition to ratio driven transfusion and tranexamic acid. CONCLUSIONS: We describe a systematic approach to define threshold parameters for ROTEM and TEG. These parameters were incorporated into algorithms to support data-driven adjustments of resuscitation with therapeutics, to optimize damage control resuscitation practice in trauma.

BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock.METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116.FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]).INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock.FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

BACKGROUND AB plasma is used as the universal donor plasma product in patients requiring massive transfusion. However, currently it is a recommended policy to transfuse plasma derived from male donors only as transfusion of plasma from HLA antibody–positive female donors is associated with an increased risk for transfusion-related acute lung injury. As a result, due to high demands, supplies of blood banks may run out of AB plasma, calling for alternatives. Therefore, the aim of this review was to investigate alternatives for emergency release of AB plasma as the universal donor. STUDY DESIGN AND METHODS A systematic search was conducted in Embase and PubMed. Studies on adult patients, who were transfused with at least 1 unit of plasma, investigating the incidence of transfusion-related complications or mortality in patients transfused with ABO-identical, ABO-compatible, or ABO-incompatible plasma were eligible for inclusion. The primary outcomes were the incidence of transfusion-related complications and mortality. RESULTS In total six studies were included. Transfusion of ABO-compatible plasma was associated with an increased incidence of lung injury and mortality (odds ratio, 1.10; 95% confidence interval, 1.04-1.15; p = 0.0003) compared to transfusion of ABO-identical plasma. No significant differences were observed regarding transfusion-related complications and mortality between patients transfused with ABO-compatible or ABO-incompatible plasma. DISCUSSION Studies are insufficient to formulate advice about alternatives for transfusion of AB plasma as universal donor plasma in the emergency setting due to the small number of studies. The results of this review underline the need for further research.

BACKGROUND Plasma transfusion is often used prophylactically in patients with coagulopathy. However, the doses transfused may not be adequate to normalize hemostatic tests, which are commonly used as surrogate markers in practice. Currently, there is no reliable way to predict the posttransfusion international normalized ratio (INR) after plasma transfusion. Therefore, our aim was to develop and validate a formula that can reliably estimate post–plasma transfusion INR. STUDY DESIGN AND METHODS A compartmental model was developed using demographic (sex, height, weight) and laboratory variables (hematocrit [Hct], INRinitial, and plasma volume transfused). The formula was validated using a data set from a multicenter trial conducted between May 2010 and June 2013 in critically ill, nonbleeding patients with coagulopathy, receiving prophylactic plasma transfusions. INR was measured just before and immediately after plasma transfusion. RESULTS Initial plasma volume is calculated using the patient's Hct and blood volume (derived from Nadler's formula). The estimated immediate posttransfusion INR is then calculated as INRpredicted = INRinitial−0.91961+β + β0.80391+β−1.0874,where β = Plasma volumetransfused Plasma volumeinitial. There was a significant agreement between the model predictions and the actual INR measurements after transfusion. A total of 83% of the predictions were within the acceptable range of variation. Furthermore, there was no proportional difference or systemic bias between the predictions and the actual INR measurements. CONCLUSION This mathematical formula estimates posttransfusion INR after a certain volume of plasma transfusion with a good predictive ability. This formula, which only requires basic demographic and laboratory variables, may help the physicians to determine the volume of plasma required for a specific target INR in stable, nonbleeding patients.

Background: Transfusion of red blood cells (RBCs) is associated with adverse outcome, but the causative factor is unknown. Extracellular vesicles (EVs) have pro-inflammatory properties. We hypothesized that EVs released from both fresh and stored RBC products can induce a host inflammatory response in a dose-dependent manner. Methods: Whole blood was incubated with supernatant from RBC units stored for different time periods, either containing (different numbers of) EVs or depleted from EVs. Results: Incubation with both fresh and stored supernatant containing EVs induced a strong host response with production of TNF, IL-6 and IL-8. In supernatant depleted from EVs, this host response was completely abrogated. IL-10 levels were not affected. EV-induced host response was both dependent on the number of EVs as well as on storage time. Conclusions: EVs from both fresh and stored RBC units illicit a strong inflammatory host response in recipients and may therefore contribute to adverse outcome of RBC transfusion.

Background: Advanced age is associated with an increased susceptibility and mortality of the acute respiratory distress syndrome. This may be due to the progressive changes in innate immune responses and intrinsic properties of the lung that occur during the process of aging. Therefore, this study assesses the association between maturation and aging and pulmonary responses to injury in animal models of lung injury. Methods: A systematic search was conducted in PubMed, EMBASE (up to June 2014) and in the references of relevant articles to identify the studies using in vivo models of lung injury caused by an acute pulmonary insult, in which at least two age groups were compared. Because methodological diversity precluded combining these studies in a quantitative meta-analysis, data are presented based on the qualitative comparison with the adult group. Results: Of the 2,840 identified studies, 51 were included in this review. Most studies showed that, in response to a pulmonary insult, increasing age is associated with more pulmonary inflammation, edema, alveolar damage, and higher mortality. In addition, results indicate the existence of age-dependent changes in key components of the intracellular signaling pathways involved in the inflammatory response. Conclusions: Increasing age seems to be correlated with exaggerated pulmonary responses to injury, ultimately leading to more severe lung injury. Pulmonary inflammation seems relatively suppressed in infants/juveniles, whereas in the middle aged/elderly, the inflammatory response seems delayed but aggravated. This implies that investigators and clinicians need to use caution about extrapolating results from adolescent or youngadult animals to pediatric or elderly patients in clinical practice.

BACKGROUND Red blood cell (RBC) transfusion has been related to thromboembolic events. Microvesicles in the RBC product may support coagulation because they have procoagulant effects in vitro. We investigated whether transfusion of RBCs containing extracellular vesicles promotes coagulation in human recipients. As transfusion is mostly administered to ill patients, we used a model of endotoxemia. STUDY DESIGN AND METHODS Eighteen healthy volunteers were randomized to receive either saline or fresh (2 days stored) or stored autologous (35 days stored) RBC transfusion (Dutch Trial Register: NTR4455). Two hours after infusion of lipopolysaccharide (LPS, from Escherichia coli, 2 ng/kg body weight), subjects received either saline or fresh or stored RBCs. Blood was sampled every 2 hours up to 8 hours after LPS infusion. Vesicles were measured with a flow cytometer (A50-Micro, Apogee Flow Systems). RESULTS LPS resulted in increased thrombin generation compared to baseline. During storage, the total number of extracellular vesicles increased from 1.4 × 108 /mL (interquartile range [IQR], 8.3 × 107 -1.9 × 108 /mL) in the fresh product to 1.7 × 1010 /mL (IQR, 7.9 × 109 -2.3 × 1010 /mL; p

Objectives: The presence of respiratory viruses and the association with outcomes were assessed in invasively ventilated ICU patients, stratified by admission diagnosis. Design: Prospective observational study. Setting: Five ICUs in the Netherlands. Patients: Between September 1, 2013, and April 30, 2014, 1,407 acutely admitted and invasively ventilated patients were included. Interventions: None. Measurements and Main Results: Nasopharyngeal swabs and tracheobronchial aspirates were collected upon intubation and tested for 14 respiratory viruses. Out of 1,407 patients, 156 were admitted because of a severe acute respiratory infection and 1,251 for other reasons (non-severe acute respiratory infection). Respiratory viruses were detected in 28.8% of severe acute respiratory infection patients and 17.0% in non-severe acute respiratory infection (p < 0.001). In one third, viruses were exclusively detected in tracheobronchial aspirates. Rhinovirus and human metapneumovirus were more prevalent in severe acute respiratory infection patients (9.6% and 2.6% vs 4.5 and 0.2%; p = 0.006 and p < 0.001). In both groups, there were no associations between the presence of viruses and the number of ICU-free days at day 28, crude mortality, and mortality in multivariate regression analyses. Conclusions: Respiratory viruses are frequently detected in acutely admitted and invasively ventilated patients. Rhinovirus and human metapneumovirus are more frequently found in severe acute respiratory infection patients. Detection of respiratory viruses is not associated with worse clinically relevant outcomes in the studied cohort of patients.

In efforts investigating mechanisms of the association between blood transfusion and adverse outcome, the research field has increasing attention for the contribution of specific donor characteristics. In particular, there have been reports highlighting the association between increased risks of mortality in (male) recipients of red blood cells derived from female donors (1-3), although this association was not confirmed in a recent large cohort (4).

Sin financiación 6.959 JCR (2018) Q1, 6/33 Critical Care Medicine 2.540 SJR (2018) Q1, 6/91 Critical Care and Intensive Care Medicine No data IDR 2018 UEM

Aims: Mechanical ventilation practices in patients with cardiac arrest are not well described. Also, the effect of temperature on mechanical ventilation settings is not known. The aims of this study were 1) to describe practice of mechanical ventilation and its relation with outcome 2) to determine effects of different target temperatures strategies (33 °C versus 36 °C) on mechanical ventilation settings. Methods: This is a substudy of the TTM-trial in which unconscious survivors of a cardiac arrest due to a cardiac cause were randomized to two TTM strategies, 33 °C (TTM33) and 36 °C (TTM36). Mechanical ventilation data were obtained at three time points: 1) before TTM; 2) at the end of TTM (before rewarming) and 3) after rewarming. Logistic regression was used to determine an association between mechanical ventilation variables and outcome. Repeated-measures mixed modelling was performed to determine the effect of TTM on ventilation settings. Results: Mechanical ventilation data was available for 567 of the 950 TTM patients. Of these, 81% was male with a mean (SD) age of 64 (12) years. At the end of TTM median tidal volume was 7.7 ml/kg predicted body weight (PBW)(6.4–8.7) and 60% of patients were ventilated with a tidal volume ≤ 8 ml/kg PBW. Median PEEP was 7.7cmH2O (6.4–8.7) and mean driving pressure was 14.6 cmH2O (±4.3). The median FiO2 fraction was 0.35 (0.30–0.45). Multivariate analysis showed an independent relationship between increased respiratory rate and 28-day mortality. TTM33 resulted in lower end-tidal CO2 (Pgroup = 0.0003) and higher alveolar dead space fraction (Pgroup = 0.003) compared to TTM36, while PCO2 levels and respiratory minute volume were similar between groups. Conclusions: In the majority of the cardiac arrest patients, protective ventilation settings are applied, including low tidal volumes and driving pressures. High respiratory rate was associated with mortality. TTM33 results in lower end-tidal CO2 levels and a higher alveolar dead space fraction compared to TTTM36.

Background Evidence for benefit of high positive end-expiratory pressure (PEEP) is largely lacking for invasively ventilated, critically ill patients with uninjured lungs. We hypothesize that ventilation with low PEEP is noninferior to ventilation with high PEEP with regard to the number of ventilator-free days and being alive at day 28 in this population. Methods/Design The “REstricted versus Liberal positive end-expiratory pressure in patients without ARDS” trial (RELAx) is a national, multicenter, randomized controlled, noninferiority trial in adult intensive care unit (ICU) patients with uninjured lungs who are expected not to be extubated within 24 h. RELAx will run in 13 ICUs in the Netherlands to enroll 980 patients under invasive ventilation. In all patients, low tidal volumes are used. Patients assigned to ventilation with low PEEP will receive the lowest possible PEEP between 0 and 5 cm H2O, while patients assigned to ventilation with high PEEP will receive PEEP of 8 cm H2O. The primary endpoint is the number of ventilator-free days and being alive at day 28, a composite endpoint for liberation from the ventilator and mortality until day 28, with a noninferiority margin for a difference between groups of 0.5 days. Secondary endpoints are length of stay (LOS), mortality, and occurrence of pulmonary complications, including severe hypoxemia, major atelectasis, need for rescue therapies, pneumonia, pneumothorax, and development of acute respiratory distress syndrome (ARDS). Hemodynamic support and sedation needs will be collected and compared. Discussion RELAx will be the first sufficiently sized randomized controlled trial in invasively ventilated, critically ill patients with uninjured lungs using a clinically relevant and objective endpoint to determine whether invasive, low-tidal-volume ventilation with low PEEP is noninferior to ventilation with high PEEP. Trial registration ClinicalTrials.gov, ID:NCT03167580. Registered on 23 May 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-2640-5) contains supplementary material, which is available to authorized users.

Background Dyscarbia is common in out-of-hospital cardiac arrest (OHCA) patients and its association to neurological outcome is undetermined. Methods This is an exploratory post-hoc substudy of the Target Temperature Management (TTM) trial, including resuscitated OHCA patients, investigating the association between serial measurements of arterial partial carbon dioxide pressure (PaCO2) and neurological outcome at 6 months, defined by the Cerebral Performance Category (CPC) scale, dichotomized to good outcome (CPC 1 and 2) and poor outcome (CPC 3–5). The effects of hypercapnia and hypocapnia, and the time-weighted mean PaCO2 and absolute PaCO2 difference were analyzed. Additionally, the association between mild hypercapnia (6.0–7.30 kPa) and neurological outcome, its interaction with target temperature (33 °C and 36 °C), and the association between PaCO2 and peak serum-Tau were evaluated. Results Of the 939 patients in the TTM trial, 869 were eligible for analysis. Ninety-six percent of patients were exposed to hypocapnia or hypercapnia. None of the analyses indicated a statistical significant association between PaCO2 and neurological outcome (P = 0.13–0.96). Mild hypercapnia was not associated with neurological outcome (P = 0.78) and there was no statistically significant interaction with target temperature (Pinteraction = 0.95). There was no association between PaCO2 and peak serum-Tau levels 48 or 72 h after return of spontaneous circulation (ROSC). Conclusions Dyscarbia is common after ROSC. No statistically significant association between PaCO2 in the post-cardiac arrest phase and neurological outcome at 6 months after cardiac arrest was detected. There was no significant interaction between mild hypercapnia and temperature in relation to neurological outcome. Electronic supplementary material The online version of this article (10.1186/s13054-018-2119-5) contains supplementary material, which is available to authorized users.

Background: Transfusion of blood products and mechanical ventilation with injurious settings are considered risk factors for postoperative lung injury in surgical Patients. Methods: A systematic review and individual patient data meta-analysis was done to determine the independent effects of peri-operative transfusion of blood products, intra-operative tidal volume and airway pressure in adult patients undergoing mechanical ventilation for general surgery, as well as their interactions on the occurrence of postoperative acute respiratory distress syndrome (ARDS). Observational studies and randomized trials were identified by a systematic search of MEDLINE, CINAHL, Web of Science, and CENTRAL and screened for inclusion into a meta-analysis. Individual patient data were obtained from the corresponding authors. Patients were stratified according to whether they received transfusion in the peri-operative period [red blood cell concentrates (RBC) and/or fresh frozen plasma (FFP)], tidal volume size [≤7 mL/kg predicted body weight (PBW), 7–10 and >10 mL/kg PBW] and airway pressure level used during surgery (≤15, 15–20 and >20 cmH 2 O). The primary outcome was development of postoperative ARDS. Results: Seventeen investigations were included (3,659 patients). Postoperative ARDS occurred in 40 (7.2%) patients who received at least one blood product compared to 40 patients (2.5%) who did not [adjusted hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.25–4.33; P=0.008]. Incidence of postoperative ARDS was highest in patients ventilated with tidal volumes of >10 mL/kg PBW and having airway pressures of >20 cmH 2 O receiving both RBC and FFP, and lowest in patients ventilated with tidal volume of ≤7 mL/kg PBW and having airway pressures of ≤15 cmH 2 O with no transfusion. There was a significant interaction between transfusion and airway pressure level (P=0.002) on the risk of postoperative ARDS. Conclusions: Peri-operative transfusion of blood products is associated with an increased risk of postoperative ARDS, which seems more dependent on airway pressure than tidal volume size.