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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.

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: 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.

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.

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.

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.

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.

Background Mechanical ventilation with low tidal volumes has the potential to mitigate ventilation-induced lung injury, yet the clinical effect of tidal volume size on myocardial function has not been clarified. This cross-sectional study investigated whether low tidal volume ventilation has beneficial effects on myocardial systolic and diastolic function compared to intermediate tidal volume ventilation. Methods Forty-two mechanically ventilated patients without acute respiratory distress syndrome (ARDS) underwent transthoracic echocardiography after more than 24 h of mechanical ventilation according to the Protective Ventilation in Patients without ARDS (PReVENT) trial comparing a low versus intermediate tidal volume strategy. The primary outcome was left ventricular and right ventricular myocardial performance index as measure for combined systolic and diastolic function, with lower values indicating better myocardial function and a right ventricular myocardial performance index greater than 0.54 regarded as the abnormality threshold. Secondary outcomes included specific systolic and diastolic parameters. Results One patient was excluded due to insufficient acoustic windows, leaving 21 patients receiving low tidal volumes with a tidal volume size (mean ± SD) of 6.5 ± 1.8 ml/kg predicted body weight, while 20 patients were subjected to intermediate tidal volumes receiving a tidal volume size of 9.5 ± 1.6 ml/kg predicted body weight (mean difference, −3.0 ml/kg; 95% CI, −4.1 to −2.0; P < 0.001). Right ventricular dysfunction was reduced in the low tidal volume group compared to the intermediate tidal volume group (myocardial performance index, 0.41 ± 0.13 vs. 0.64 ± 0.15; mean difference, −0.23; 95% CI, −0.32 to −0.14; P < 0.001) as was left ventricular dysfunction (myocardial performance index, 0.50 ± 0.17 vs. 0.63 ± 0.19; mean difference, −0.13; 95% CI, −0.24 to −0.01; P = 0.030). Similarly, most systolic parameters were superior in the low tidal volume group compared to the intermediate tidal volume group, yet diastolic parameters did not differ between both groups. Conclusions In patients without ARDS, intermediate tidal volume ventilation decreased left ventricular and right ventricular systolic function compared to low tidal volume ventilation, although without an effect on diastolic function. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Trauma-induced coagulopathy (TIC) is a life-threatening condition associated with high morbidity and mortality. TIC can present with different coagulation defects. In this study, the aim was to determine the effect of shock duration on TIC characteristics. We hypothesized that longer duration of shock leads to a more hypocoagulable rotational thromboelastometry (ROTEM) profile compared to a shorter duration of shock. Methods Male B57BL/6J(c) mice (n = 5–10 per group) were sedated and mechanically ventilated. Trauma was induced by bilateral lower limb fractures and crush injuries to the liver and small intestine. Shock was induced by blood withdrawals until a mean arterial pressure of 25–30 mmHg was achieved. Groups reflected trauma and shock for 30 min (TS30) and trauma and shock for 90 min (TS90). Control groups included ventilation only (V90) and trauma only (T90). Results Mice in the TS90 group had significantly increased base deficit compared to the V90 group. Mortality was 10% in the TS30 group and 30% in the TS90 group. ROTEM profile was more hypocoagulable, as shown by significantly lower maximum clot firmness (MCF) in the TS30 group (43.5 [37.5–46.8] mm) compared to the TS90 group (52.0 [47.0–53.0] mm, p = 0.04). ROTEM clotting time and parameters of clot build-up did not significantly differ between groups. Conclusions TIC characteristics change with shock duration. Contrary to the hypothesis, a shorter duration of shock was associated with decreased maximum clotting amplitudes compared to a longer duration of shock. The effect of shock duration on TIC should be further assessed in trauma patients.

Introduction Red blood cell (RBC) transfusion is associated with an increased risk of pro-thrombotic events, but the underlying mechanism is poorly understood. We hypothesized that RBC transfusion modulates platelet activity in critically ill patients with and without sepsis. Methods In a prospective cohort study, 37 critically ill patients receiving a single RBC unit to correct for anemia were sampled prior to and 1 h after transfusion. Platelet exposure of P-selectin, CD63 and binding of PAC-1 as well as formation of platelet-leukocyte complexes were measured by flow cytometry. The ability of plasma from critically ill patients to induce ex vivo platelet aggregation was assessed by flow cytometry after incubation with platelets from a healthy donor. Results RBC transfusion neither triggered the expression of platelet activation markers nor the formation of platelet-leukocyte complexes. Plasma from critically ill patients induced more spontaneous platelet aggregation prior to RBC transfusion compared to healthy controls, which was further augmented following RBC transfusion. Also collagen-induced platelet aggregation was already increased prior to RBC transfusion compared to healthy controls, and this response was unaffected by RBC transfusion. In contrast, ristocetin-induced platelet agglutination was decreased when compared to controls, suggesting impaired vWF-dependent platelet agglutination, even in the presence of high vWF levels. Following RBC transfusion, ristocetin-induced platelet agglutination further decreased. There were no differences between septic and non-septic recipients in all assays. Conclusion Ex vivo platelet aggregation is disturbed in the critically ill. Transfusion of a RBC unit may further increase the spontaneous platelet aggregatory response.

Coagulopathy has a high incidence in critically ill patients and is often caused by disseminated intravascular coagulation (DIC). Although the clinical picture of DIC ranges from a prothrombotic state to severe consumption coagulopathy with an increased bleeding tendency, there are no clinical tests that reflect of in-vivo hemostatic profile. Rotational thromboelastometry (ROTEM) may be able to indicate whether a patient has a hypocoagulable or hypercoagulable profile and possibly be able to discriminate patients with and without DIC. The aim of this article was to study the diagnostic ability of thromboelastometry to detect DIC. A predefined subgroup analysis of a clinical trial in critically ill patients with a coagulopathy was done. ROTEM and markers of coagulation and levels of natural anticoagulants were measured in patients with and without DIC. Twenty-three patients were included, 13 fulfilled criteria for overt DIC. Patients with DIC had lower platelet count, lower levels of fibrinogen, factors II, VII and VIII compared with those without DIC. Antithrombin, protein C and S were also reduced in DIC patients. Receiver operator characteristic analyses showed that EXTEM CFT, alpha angle and MCF were capable of discriminating patients with and without DIC. Combination of ROTEM values with protein C or antithrombin further improved discriminatory ability. In patients with DIC, thromboelastometry profiles were more hypocoagulable compared with those without DIC. ROTEM correlates well with ISTH DIC score, diagnostic strength improves when ROTEM values are combined with antithrombin or protein C levels. Thereby, ROTEM may be a useful tool in diagnosing DIC in the critically ill.

Background: Critically ill COVID-19 patients are in a hypercoagulable state with increased risk of thrombotic complications. Rotational thromboelastometry (ROTEM) is a viscoelastic test with the potential to reflect COVID-19-associated hypercoagulability and may therefore be useful to predict thrombotic complications. Objective: To investigate the potential of ROTEM profiles to predict thrombotic complications in critically ill COVID-19 patients. Patients/Methods: Retrospective multicenter cohort study in 113 adult patients with confirmed COVID-19 infection admitted to the intensive care unit (ICU) of two large teaching hospitals in the United States and in the Netherlands. ROTEM profiles of the EXTEM, INTEM, and FIBTEM tracings were measured within 72 h of ICU admission. Thrombotic complications encompass both arterial and venous thromboembolic complications, diagnosed with electrocardiogram, ultrasound, or computed tomography. ROTEM profiles were compared between patients with and without thrombosis. Univariable logistic regression followed by receiver operating characteristic (ROC) curves analysis was performed to identify ROTEM parameters associated with thrombosis. Results and Conclusions: Of 113 patients, 27 (23.9%) developed a thrombotic event. In the univariable analysis, EXTEM clot amplitude at 10 min (CA10) and EXTEM maximum clot formation (MCF) were associated with thrombosis with a p < 0.2 (p = 0.07 and p = 0.05, respectively). In ROC curve analysis, EXTEM CA10 had an area under the curve (AUC) of 0.58 (95% CI 0.47–0.70) and EXTEM MCF had an AUC of 0.60 (95% CI 0.49–0.71). Thereby, ROTEM profiles at ICU admission did not have the potential to differentiate between patients with a high and low risk for thrombotic complications.

Background In traumatic bleeding, transfusion practice has shifted toward higher doses of platelets and plasma transfusion. The aim of this systematic review was to investigate whether a higher platelet‐to‐red blood cell (RBC) transfusion ratio improves mortality without worsening organ failure when compared with a lower ratio of platelet‐to‐RBC. Methods Pubmed, Medline, and Embase were screened for randomized controlled trials (RCTs) in bleeding trauma patients (age ≥16 years) receiving platelet transfusion between 1946 until October 2020. High platelet:RBC ratio was defined as being the highest ratio within an included study. Primary outcome was 24 hour mortality. Secondary outcomes were 30‐day mortality, thromboembolic events, organ failure, and correction of coagulopathy. Results In total five RCTs (n = 1757 patients) were included. A high platelet:RBC compared with a low platelet:RBC ratio significantly improved 24 hour mortality (odds ratio [OR] 0.69 [0.53–0.89]) and 30‐ day mortality (OR 0.78 [0.63–0.98]). There was no difference between platelet:RBC ratio groups in thromboembolic events and organ failure. Correction of coagulopathy was reported in five studies, in which platelet dose had no impact on trauma‐induced coagulopathy. Conclusions In traumatic bleeding, a high platelet:RBC improves mortality as compared to low platelet:RBC ratio. The high platelet:RBC ratio does not influence thromboembolic or organ failure event rates.

Introduction In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. Methods We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. Results In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8–15%), 16% (13–19%) and 21% (17–25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41–0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65–1.2). Conclusions Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted., Highlights • Half overall mortality in the second wave compared to first wave COVID-19 patients. • Still high incidence of thrombotic complications in second wave. • More subsegmental PE in second wave than in first wave.

Background Alkaline phosphatase (AP), a dephosphorylating enzyme, is involved in various physiological processes and has been shown to have anti-inflammatory effects. Aim To determine the correlation between pulmonary AP activity and markers of inflammation in invasively ventilated critically ill patients with or without acute respiratory distress syndrome (ARDS), and to investigate the effect of administration of recombinant AP on pulmonary inflammation in a well-established lung injury model in rats Methods AP activity was determined and compared with levels of various inflammatory mediators in bronchoalveolar lavage fluid (BALF) samples obtained from critically ill patients within 2 days of start of invasive ventilation. The endpoints of this part of the study were the correlations between AP activity and markers of inflammation, i.e., interleukin (IL)-6 levels in BALF. In RccHan Wistar rats, lung injury was induced by intravenous administration of 10 mg/kg lipopolysaccharide, followed by ventilation with a high tidal volume for 4 h. Rats received either an intravenous bolus of 1500 IU/kg recombinant AP or normal saline 2 h after intravenous LPS administration, right before start of ventilation. Endpoints of this part of the study were pulmonary levels of markers of inflammation, including IL-6, and markers of endothelial and epithelial dysfunction. Results BALF was collected from 83 patients; 10 patients had mild ARDS, and 15 had moderate to severe ARDS. AP activity correlated well with levels of IL-6 (r = 0.70), as well as with levels of other inflammatory mediators. Pulmonary AP activity between patients with and without ARDS was comparable (0.33 [0.14–1.20] vs 0.55 [0.21–1.42] U/L; p = 0.37). Animals with acute lung injury had markedly elevated pulmonary AP activity compared to healthy controls (2.58 [2.18–3.59] vs 1.01 [0.80–1.46] U/L; p < 0.01). Intravenous administration of recombinant AP did neither affect pulmonary inflammation nor endothelial and epithelial dysfunction. Conclusions In ventilated critically ill patients, pulmonary AP activity correlates well with markers of pulmonary inflammation, such as IL-6 and IL-8. In animals with lung injury, pulmonary AP activity is elevated. Administration of recombinant AP does not alter pulmonary inflammation and endothelial or epithelial dysfunction in the acute phase of a murine lung injury model.

Background: Trauma-induced shock is associated with endothelial dysfunction. We examined whether the tyrosine kinase inhibitor bosutinib as an adjunct therapy to a balanced blood component resuscitation strategy reduces trauma-induced endothelial permeability, thereby improving shock reversal and limiting transfusion requirements and organ failure in a rat polytrauma transfusion model. Methods: Male Sprague–Dawley rats (n=13 per group) were traumatised and exsanguinated until a MAP of 40 mm Hg was reached, then randomised to two groups: red blood cells, plasma and platelets in a 1:1:1 ratio with either bosutinib or vehicle. Controls were randomised to sham (median laparotomy, no trauma) with bosutinib or vehicle. Organs were harvested for histology and wet/dry (W/D) weight ratio. Results: Traumatic injury resulted in shock, with higher lactate levels compared with controls. In trauma-induced shock, the resuscitation volume needed to obtain a MAP of 60 mm Hg was lower in bosutinib-treated animals (2.8 [2.7–3.2] ml kg−1) compared with vehicle (6.1 [5.1–7.2] ml kg−1, P

Background: Outcome prediction in invasively ventilated ICU patients remains challenging. Driving pressure (ΔP) and mechanical power of ventilation (MP) are associated with outcomes like mortality. The objective of this study was to assess the predictive validity for mortality of ΔP and MP at 24h after start of invasive ventilation. Methods: Posthoc analysis of MARS, a large observational study in two Dutch ICUs. Patients having received invasive ventilation >24h were selected. The primary outcome was 90–day mortality. The predictive validity of ΔP and MP was measured as incremental 90–day mortality beyond that predicted by the Acute Physiology, Age and Chronic Health Evaluation (APACHE) IV score or the Simplified Acute Physiology Score (SAPS) II. Results: A total of 839 patients were included; 90–day mortality was 42%. ΔP (OR for 1 cm H2O increase in ΔP, 1.05 [CI 1.03–1.08] p Conclusions: In this cohort of invasively ventilated ICU patients, ΔP and MP at 24h were associated with 90–day mortality. However, they have no predictive validity beyond that of the APACHE IV score and the SAPS II.

Background and objectives Red-blood-cell (RBC) transfusion is associated with lung injury, which is further exacerbated by mechanical ventilation. Manufacturing methods of blood products differ globally and may play a role in the induction of pulmonary cell activation through alteration of the immunomodulatory property of the products. Here, the effect of different manufacturing methods on pulmonary cell activation was investigated in an in vitro model of mechanical ventilation. Materials and methods Pulmonary type II cells were incubated with supernatant from fresh and old RBC products obtained via whole blood filtration (WBF), red cell filtration (RCF), apheresis-derived (AD) or whole blood-derived (WBD) methods. Lung cells were subjected to 25% stretch for 24 h. Controls were non-stretched or non-incubated cells. Results Fresh but not old AD products and WBF products induce lung cell production of pro-inflammatory cytokines and chemokines, which was not observed with WBD or RCF products. Effects were associated with an increased amount of platelet-derived vesicles and an increased thrombin-generating capacity. Mechanical stretching of lung cells induced more severe cell injury compared to un-stretched controls, including alterations in the cytoskeleton, which was further augmented by incubation with AD products. In all read-out parameters, RCF products seemed to induce less injury compared to the other products. Conclusions Our findings show that manufacturing methods of RBC products impact pulmonary cell activation, which may be mediated by the generation of vesicles in the product. We suggest RBC manufacturing method may be an important factor in understanding the association between RBC transfusion and lung injury.

Background: Cryopreserved platelet products can be stored for years and are mainly used in military settings. Following thawing, cryopreserved platelets are activated, resulting in faster clot formation but reduced aggregation in vitro, rendering their efficacy in bleeding unknown. Also, concerns remain on the safety of these products. The aim was to investigate the efficacy and safety of cryopreserved platelets in a rat model of traumatic hemorrhage. Study Design and Methods: After 1 hour of shock, rats (n = 13/group) were randomized to receive a balanced transfusion pack (1:1:1 red blood cell:plasma: platelet) made from syngeneic rat blood, containing either liquid stored platelets or cryopreserved platelets. Primary outcome was the transfusion volume required to obtain a mean arterial pressure (MAP) of 60 mmHg. Secondary outcomes were coagulation as assessed by thromboelastometry (ROTEM®) and organ failure as assessed by biochemistry and histopathology. Results: The transfusion volume to obtain a MAP of 60 mmHg was lower in animals receiving cryopreserved platelets (5.4 [4.1-7.1] mL/kg) compared to those receiving liquid stored platelets (7.5 [6.4-8.5] mL/kg, p < 0.05). ROTEM® clotting times were shorter (45 [41-48] vs. 49 [45-53]sec, p < 0.05), while maximum clot firmness was slightly lower (68 [67-68] vs. 69 [69-71]mm, p < 0.01). Organ failure was similar in both groups. Conclusions: Use of cryopreserved platelets required less transfusion volume to reach a targeted MAP compared to liquid stored platelets, while organ injury was similar. These results provide a rationale for clinical trials with cryopreserved platelets in (traumatic) bleeding.

Objective To investigate the relation between donor characteristics and TRALI incidence. Background Transfusion-related acute lung injury (TRALI) is a potentially fatal complication of transfusion. In pre-clinical studies and several clinical studies, TRALI has been related to loss of product quality during red blood cell (RBC) storage, called the “storage lesion”. Donor characteristics, as for example age, genetics and life style choices influence this “storage lesion”. We hypothesized that donor sex, age and blood type is related to TRALI incidence. Methods/materials We performed a secondary analysis of two cohort studies, designed to identify TRALI risk factors by matching TRALI patients to transfused controls. We obtained donor sex, age and blood type from the Dutch Blood Bank Sanquin and investigated TRALI incidence in patients who were exposed to a certain donor characteristic. We used Kruskal-Wallis testing to compare the number of transfused products and Chi2 testing to compare proportions of TRALI patients and transfused control. Results After implementation of the male-donor only plasma strategy, patients received more transfusion products from male donors. However, we did not detect a relation between TRALI incidence and donor sex. Both TRALI patients and transfused controls received mainly products from donors over 41 years old, but donor age did not influence TRALI risk. Donor blood type, the transfusion of blood type-compatible and blood type-matched products also had no influence on TRALI incidence. Conclusion We conclude that in two cohorts of TRALI patients, donor age, donor sex and donor blood type are unrelated to TRALI.

Background Septic patients are often anemic, requiring red blood cell (RBC) transfusions. However, RBC transfusions are associated with organ injury. The mechanisms of RBC-induced organ injury are unknown, but increased clearance of donor RBCs from the circulation with trapping in the organs could play a role. We hypothesized that washing of RBCs prior to transfusion may reduce clearance and trapping of donor cells and thereby reduce organ injury. Methods Sprague-Dawley rats were inoculated intratracheally with 10 colony-forming units (CFU) of Streptococcus pneumoniae or vehicle as a control and transfused with either a washed or standard (non-washed) biotinylated RBC transfusion from syngeneic rats. Controls received saline. Blood samples were taken directly after transfusion and at 24 h to calculate the 24 h post transfusion recovery (PTR). After sacrifice, flow cytometry was used to detect donor RBCs in organs and blood. The organs were histologically scored by a pathologist and CFUs in the lung and blood were counted. Results The 24h-PTR was similar between healthy and pneumoseptic rats after a standard transfusion. In healthy rats, a washed transfusion resulted in a higher PTR and less accumulation of donor RBCs in the organs compared with a standard transfusion. However, during pneumonia, this effect of washing was not seen. Transfusion did not further augment lung injury induced by pneumonia, but washing decreased bacterial outgrowth in the lungs associated with reduced lung injury. Conclusion In healthy recipients, washing increased 24h-PTR of donor RBCs and decreased trapping in organs. In pneumoseptic rats, washing reduced bacterial outgrowth and lung injury, but did not improve PTR.

BACKGROUND: Anemia of inflammation (AI) has a high prevalence in critically ill patients. In AI, iron metabolism is altered, as high levels of inflammation-induced hepcidin reduce the amount of iron available for erythropoiesis. AI is treated with red blood cell (RBC) transfusions. The effect of RBC transfusion on iron metabolism during inflammatory processes in adults is unknown. We investigated the effect of RBC transfusion on iron metabolism in critically ill patients. METHODS: In a prospective cohort study in 61 critically ill patients who received 1 RBC unit, levels of iron variables were determined before, directly after, and 24 hours after transfusion in septic and nonseptic patients. RESULTS: Serum iron levels were low and increased after transfusion (p = 0.02). However, RBC transfusion had no effect on transferrin saturation (p = 0.14) and ferritin levels (p = 0.74). Hepcidin levels increased after RBC transfusion (p = 0.01), while interleukin-6 levels decreased (p = 0.03). In septic patients, RBC transfusion induced a decrease in haptoglobin levels compared to baseline, which did not occur in nonseptic patients (p = 0.01). The effect of RBC transfusion on other iron variables did not differ between septic and nonseptic patients. CONCLUSION: Transfusion of a RBC unit transiently increases serum iron levels in intensive care unit patients. The increase in hepcidin levels after transfusion can further decrease iron release from intracellular storage making it available for erythropoiesis. RBC transfusion is associated with a decrease in haptoglobin levels in septic compared to nonseptic patients, but did not affect other markers of hemolysis.

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.

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.

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.

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