Prevention of post-operative delirium using an overnight infusion of dexmedetomidine in patients undergoing cardiac surgery: a pragmatic, randomized, double-blind, placebo-controlled trial.

BACKGROUND: After cardiac surgery, post-operative delirium (PoD) is acknowledged to have a significant negative impact on patient outcome. To date, there is no valuable and specific treatment for PoD. Critically ill patients often suffer from poor sleep condition. There is an association between delirium and sleep quality after cardiac surgery. This study aimed to establish whether promoting sleep using an overnight infusion of dexmedetomidine reduces the incidence of delirium after cardiac surgery. METHODS: Randomized, pragmatic, multicentre, double-blind, placebo controlled trial from January 2019 to July 2021. All adult patients aged 65 years or older requiring elective cardiac surgery were randomly assigned 1:1 either to the dexmedetomidine group or the placebo group on the day of surgery. Dexmedetomidine or matched placebo infusion was started the night after surgery from 8 pm to 8 am and administered every night while the patient remained in ICU, or for a maximum of 7 days. Primary outcome was the occurrence of postoperative delirium (PoD) within the 7 days after surgery. RESULTS: A total of 348 patients provided informed consent, of whom 333 were randomized: 331 patients underwent surgery and were analysed (165 assigned to dexmedetomidine and 166 assigned to placebo). The incidence of PoD was not significantly different between the two groups (12.6% vs. 12.4%, p = 0.97). Patients treated with dexmedetomidine had significantly more hypotensive events (7.3% vs 0.6%; p < 0.01). At 3 months, functional outcomes (Short-form 36, Cognitive failure questionnaire, PCL-5) were comparable between the two groups. CONCLUSION: In patients recovering from an elective cardiac surgery, an overnight infusion of dexmedetomidine did not decrease postoperative delirium. Trial registration This trial was registered on ClinicalTrials.gov (number: NCT03477344; date: 26th March 2018).

Moderate Exercise Modulates Inflammatory Responses and Improves Survival in a Murine Model of Acute Pneumonia.

OBJECTIVES: An association between physical inactivity and worse outcome during infectious disease has been reported. The effect of moderate exercise preconditioning on the immune response during an acute pneumonia in a murine model was evaluated. SETTING: Laboratory experiments. SUBJECTS: C57BL6/j male mice. INTERVENTIONS: Six-week-old C57BL/6J mice were divided in two groups: an exercise group and a control group. In the exercise group, a moderate, progressive, and standardized physical exercise was applied for 8 weeks. It consisted in a daily treadmill training lasting 60 minutes and with an intensity of 65% of the maximal theoretical oxygen uptake. Usual housing recommendation were applied in the control group during the same period. After 8 weeks, pneumonia was induced in both groups by intratracheal instillation of a fixed concentration of a Klebsiella pneumoniae (5 × 103 colony-forming unit) solution. MEASUREMENTS AND MAIN RESULTS: Mice preconditioned by physical exercise had a less sever onset of pneumonia as shown by a significant decrease of the Mouse Clinical Assessment Severity Score and had a significantly lower mortality compared with the control group (27% vs. 83%; p = 0.019). In the exercise group, we observed a significantly earlier but transient recruitment of inflammatory immune cells with a significant increase of neutrophils, CD4+ cells and interstitial macrophages counts compared with control group. Lung tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-10 were significantly decreased at 48 hours after pneumonia induction in the exercise group compared with the control group. CONCLUSIONS: In our model, preconditioning by moderate physical exercise improves outcome by reducing the severity of acute pneumonia with an increased but transient activation of the innate immune response.

Prophylactic platelet transfusion response in critically ill patients: a prospective multicentre observational study.

BACKGROUND: Response to prophylactic platelet transfusion is suspected to be inconsistent in critically ill patients questioning how to optimize transfusion practices. This study aimed to describe prophylactic platelet transfusion response, to identify factors associated with a suboptimal response, to analyse the correlation between corrected count increment and platelet count increment and to determine the association between poor platelet transfusion response and clinical outcomes. METHODS: This prospective multicentre observational study recruited patients who received at least one prophylactic platelet transfusion in one of the nine participating intensive care units for a period up to 16 months. Poor platelet transfusion response was defined as a corrected count increment (CCI) that adjusts for platelet dose and body surface area, less than 7 at 18-24 h after platelet transfusion. Factors associated with poor platelet transfusion response were assessed in a mixed-effect model. Sensitivity analyses were conducted in patients with and without haematology malignancy and chemotherapy. RESULTS: Poor platelet transfusion response occurred in 349 of the 472 (73.9%) prophylactic platelet transfusions and in 141/181 (77.9%) patients. The mixed-effect model identified haemoglobin at ICU admission (odds ratio (OR): 0.79 [95% confidence interval (CI) 0.7-0.89]) and body mass index (BMI) (OR: 0.93 [0.89-0.98]) being positively and independently associated with platelet transfusion response, while a haematological malignancy (OR 1.93 [1.09-3.43]), sepsis as primary ICU admission diagnosis (OR: 2.81 [1.57-5.03]), SOFA score (OR 1.10 [1.03; 1.17]) and maximum storage duration of platelet (OR: 1.24 [1.02-1.52]) were independently associated with a suboptimal platelet increment. Clinical outcomes did not differ between groups, nor the requirement for red blood cells. Poor platelet transfusion response was found in 93.5% of patients with haematology malignancy and chemotherapy. CONCLUSIONS: In this study of critically ill patients, of whom more than half had bone marrow failure, almost three quarters of prophylactic platelet transfusions led to suboptimal platelet increment measured 18 to 24 h following platelet transfusion. Platelet storage duration was the only factor associated with poor platelet response that may be accessible to intervention. Trial registration in October 2017: ClinicalTrials.gov: NCT03325140.

Guidelines on perioperative optimization protocol for the adult patient 2023.

OBJECTIVE: The French Society of Anesthesiology and Intensive Care Medicine [Société Française d'Anesthésie et de Réanimation (SFAR)] aimed at providing guidelines for the implementation of perioperative optimization programs. DESIGN: A consensus committee of 29 experts from the SFAR was convened. A formal conflict-of-interest policy was developed at the outset of the process and enforced throughout. The entire guidelines process was conducted independently of any industry funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence. METHODS: Four fields were defined: 1) Generalities on perioperative optimization programs; 2) Preoperative measures; 3) Intraoperative measures and; 4) Postoperative measures. For each field, the objective of the recommendations was to answer a number of questions formulated according to the PICO model (population, intervention, comparison, and outcomes). Based on these questions, an extensive bibliographic search was carried out using predefined keywords according to PRISMA guidelines and analyzed using the GRADE® methodology. The recommendations were formulated according to the GRADE® methodology and then voted on by all the experts according to the GRADE grid method. As the GRADE® methodology could have been fully applied for the vast majority of questions, the recommendations were formulated using a "formalized expert recommendations" format. RESULTS: The experts' work on synthesis and application of the GRADE® method resulted in 30 recommendations. Among the formalized recommendations, 19 were found to have a high level of evidence (GRADE 1±) and ten a low level of evidence (GRADE 2±). For one recommendation, the GRADE methodology could not be fully applied, resulting in an expert opinion. Two questions did not find any response in the literature. After two rounds of rating and several amendments, strong agreement was reached for all the recommendations. CONCLUSIONS: Strong agreement among the experts was obtained to provide 30 recommendations for the elaboration and/or implementation of perioperative optimization programs in the highest number of surgical fields.

Postoperative transfusion hemoglobin threshold and functional recovery after high-risk oncologic surgery: A randomized controlled pilot study.

BACKGROUND: Robust evidence to inform best transfusion management after major oncologic surgery, where postoperative recovery might impact treatment regimens for cancer, is lacking. We conducted a study to validate the feasibility of a larger trial comparing liberal versus restrictive red blood cells (RBC) transfusion strategies after major oncologic surgery. STUDY DESIGN AND METHODS: This was a two-center, randomized, controlled, study of patients admitted to the intensive care unit after major oncologic surgery. Patients whose hemoglobin level dropped below 9.5 g/dL, were randomly assigned to immediately receive a 1-unit RBC transfusion (liberal) or delayed until the hemoglobin level dropped below 7.5 g/dL (restrictive). The primary outcome was the median hemoglobin level between randomization to day 30 post-surgery. Disability-free survival was evaluated by the WHODAS 2.0 questionnaire. RESULTS: 30 patients were randomized (15 patients/group) in 15 months with a mean recruitment rate of 1.8 patients per month. The median hemoglobin level was significantly higher in the liberal group than in the restrictive group: 10.1 g/dL (IQR 9.6-10.5) versus 8.8 g/dL (IQR 8.3-9.4), p < .001, and RBC transfusion rates were 100% versus 66.7%, p = .04. The disability-free survival was similar between groups: 26.7% versus 20%, p = 1. DISCUSSION: Our results support the feasibility of a phase 3 randomized controlled trial comparing the impact of liberal versus restrictive transfusion strategies on the functional recovery of critically ill patients following major oncologic surgery.

Management of urgent invasive procedures in patients treated with direct oral anticoagulants: An observational registry analysis.

BACKGROUND: Patients treated with direct oral anticoagulants (DOACs) may require urgent procedures. Managing these patients is challenging due to different bleeding risks and may include laboratory testing, procedural delays, or haemostatic/reversal agent administration. OBJECTIVE: We evaluated management strategies and outcomes of urgent, non-haemostatic invasive procedures in patients treated with DOACs. METHODS AND RESULTS: In a descriptive cohort study, we prospectively evaluated 478 patients in the GIHP-NACO registry, from June 2013 to November 2015. Hospitalised patients receiving dabigatran (n = 160), rivaroxaban (n = 274), or apixaban (n = 44) requiring urgent, procedural interventions were evaluated, of which 384/478 (80 %) were surgical procedures. Orthopaedic surgery included 216/384 patients (56 %), while gastrointestinal surgery included 75/384 (20 %) patients. On admission, the median age was 79 (70-85), and creatinine clearance was <60 mL·min-1 in 316/478 (66 %) patients. DOAC concentration was determined in 277 (58 %) patients and was 85 ng·mL-1 (median; range 0-764), 61 ng·mL-1 (3-541), and 81 ng·mL-1 (26-354) for dabigatran, rivaroxaban, and apixaban, respectively. Procedures were delayed in 194/455 (43 %) of the cases. Excessive bleeding was observed in 62/478 (13 %) procedures, and haemostatic agents were administered in 76/478 (16 %) procedures. By day 30, major cerebral and cardiovascular events were observed in 38/478 (7.9 %) patients, and mortality was 28/478 (5.9 %). CONCLUSIONS: In the GIHP-NACO registry, before specific antidotes were available, DOAC treated patients undergoing urgent invasive procedures were delayed in nearly half of the cases, and showed a low rate of excessive bleeding, suggesting that most urgent procedures can be performed safely without DOAC reversal. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov. Identifier: NCT02185027.

Dexmedetomidine after Cardiac Surgery for Prevention of Delirium (EXACTUM) trial protocol: a multicentre randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Incidence of delirium after cardiac surgery remains high and delirium has a significant burden on short-term and long-term outcomes. Multiple causes can trigger delirium occurence, and it has been hypothesised that sleep disturbances can be one of them. Preserving the circadian rhythm with overnight infusion of low-dose dexmedetomidine has been shown to lower the occurrence of delirium in older patients after non-cardiac surgery. However, these results remain controversial. The aim of this study was to demonstrate the usefulness of sleep induction by overnight infusion of dexmedetomidine to prevent delirium after cardiac surgery. METHODS AND ANALYSIS: Dexmedetomidine after Cardiac Surgery for Prevention of Delirium is an investigator-initiated, randomised, placebo-controlled, parallel, multicentre, double-blinded trial. Nine centres in France will participate in the study. Patients aged 65 years or older and undergoing cardiac surgery will be enrolled in the study. The intervention starts on day 0 (the day of surgery) until intensive care unit (ICU) discharge; the treatment is administered from 20:00 to 08:00 on the next day. Infusion rate is modified by the treating nurse or the clinician with an objective of Richmond Agitation and Sedation Scale score from -1 to +1. The primary outcome is delirium occurrence evaluated with confusion assessment method for the ICU two times per day during 7 days following surgery. Secondary outcomes include incidence of agitation related events, self-evaluated quality of sleep, cognitive evaluation 3 months after surgery and quality of life 3 months after surgery. The sample size is 348. ETHICS AND DISSEMINATION: The study was approved for all participating centers by the French Central Ethics Committee (Comité de Protection des Personnes Ile de France VI, registration number 2018-000850-22). The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03477344.

The impact of iron store on red blood cell transfusion: a multicentre prospective cohort study in cardiac surgery.

BACKGROUND: Anaemia is common prior to cardiac surgery and contributes to perioperative morbidity. Iron deficiency is the main cause of anaemia but its impact remains controversial in the surgical setting. We aimed to estimate the impact of iron deficiency on in-hospital perioperative red blood cell transfusion for patients undergoing elective and urgent cardiac surgery. Secondary objectives were to identify risk factors associated with in-hospital red blood cell transfusion. METHODS: We conducted a prospective multicentre observational study in three university hospitals performing cardiac surgery. We determined iron status prior to surgery and collected all transfusion data to compare iron-deficient and iron-replete patients during hospital stay. We performed a multivariable logistic regression to compare transfusion among groups. RESULTS: Five hundred and two patients were included. A trend of low haemoglobin levels associated with iron deficiency persisted until discharge. Red blood cell transfusion was significantly higher in the group of iron deficient patients during surgery (22% vs 13%, p = 0.017), however the incidence during the whole hospital stay was 31% in the iron-deficient group, not significantly different with the non-deficient group (26%, p = 0.28). Iron deficiency was not independently associated with in-hospital red blood cell transfusion (adjusted OR = 0.85 [0.53-1.36], p = 0.49). CONCLUSIONS: In-hospital red blood cell transfusion was not significantly higher in iron-deficient patients and iron deficiency was not associated with in-hospital red blood cell transfusion in patients undergoing elective and urgent cardiac surgery. Iron deficiency was the main cause of anaemia and anaemia was a strong driver of red blood cell transfusion. Further studies should identify sub-population of iron-deficient patients which may benefit from preoperative iron deficiency management and explore the long-term impact of lower haemoglobin levels at discharge in the iron deficient population.

Detection of cerebral hypoperfusion with a dynamic hyperoxia test using brain oxygenation pressure monitoring.

INTRODUCTION: Brain multimodal monitoring including intracranial pressure (ICP) and brain tissue oxygen pressure (PbtO2) is more accurate than ICP alone in detecting cerebral hypoperfusion after traumatic brain injury (TBI). No data are available for the predictive role of a dynamic hyperoxia test in brain-injured patients from diverse etiology. AIM: To examine the accuracy of ICP, PbtO2 and the oxygen ratio (OxR) in detecting regional cerebral hypoperfusion, assessed using perfusion cerebral computed tomography (CTP) in patients with acute brain injury. METHODS: Single-center study including patients with TBI, subarachnoid hemorrhage (SAH) and intracranial hemorrhage (ICH) undergoing cerebral blood flow (CBF) measurements using CTP, concomitantly to ICP and PbtO2 monitoring. Before CTP, FiO2 was increased directly from baseline to 100% for a period of 20 min under stable conditions to test the PbtO2 catheter, as a standard of care. Cerebral monitoring data were recorded and samples were taken, allowing the measurement of arterial oxygen pressure (PaO2) and PbtO2 at FiO2 100% as well as calculation of OxR (= ΔPbtO2/ΔPaO2). Regional CBF (rCBF) was measured using CTP in the tissue area around intracranial monitoring by an independent radiologist, who was blind to the PbtO2 values. The accuracy of different monitoring tools to predict cerebral hypoperfusion (i.e., CBF < 35 mL/100 g × min) was assessed using area under the receiver-operating characteristic curves (AUCs). RESULTS: Eighty-seven CTPs were performed in 53 patients (median age 52 [41-63] years-TBI, n = 17; SAH, n = 29; ICH, n = 7). Cerebral hypoperfusion was observed in 56 (64%) CTPs: ICP, PbtO2 and OxR were significantly different between CTP with and without hypoperfusion. Also, rCBF was correlated with ICP (r = - 0.27; p = 0.01), PbtO2 (r = 0.36; p < 0.01) and OxR (r = 0.57; p < 0.01). Compared with ICP alone (AUC = 0.65 [95% CI, 0.53-0.76]), monitoring ICP + PbO2 (AUC = 0.78 [0.68-0.87]) or ICP + PbtO2 + OxR (AUC = 0.80 (0.70-0.91) was significantly more accurate in predicting cerebral hypoperfusion. The accuracy was not significantly different among different etiologies of brain injury. CONCLUSIONS: The combination of ICP and PbtO2 monitoring provides a better detection of cerebral hypoperfusion than ICP alone in patients with acute brain injury. The use of dynamic hyperoxia test could not significantly increase the diagnostic accuracy.

Perioperative hemodynamic optimization: from guidelines to implementation-an experts' opinion paper.

Despite a large body of evidence, the implementation of guidelines on hemodynamic optimization and goal-directed therapy remains limited in daily routine practice. To facilitate/accelerate this implementation, a panel of experts in the field proposes an approach based on six relevant questions/answers that are frequently mentioned by clinicians, using a critical appraisal of the literature and a modified Delphi process. The mean arterial pressure is a major determinant of organ perfusion, so that the authors unanimously recommend not to tolerate absolute values below 65 mmHg during surgery to reduce the risk of postoperative organ dysfunction. Despite well-identified limitations, the authors unanimously propose the use of dynamic indices to rationalize fluid therapy in a large number of patients undergoing non-cardiac surgery, pending the implementation of a "validity criteria checklist" before applying volume expansion. The authors recommend with a good agreement mini- or non-invasive stroke volume/cardiac output monitoring in moderate to high-risk surgical patients to optimize fluid therapy on an individual basis and avoid volume overload. The authors propose to use fluids and vasoconstrictors in combination to achieve optimal blood flow and maintain perfusion pressure above the thresholds considered at risk. Although purchase of disposable sensors and stand-alone monitors will result in additional costs, the authors unanimously acknowledge that there are data strongly suggesting this may be counterbalanced by a sustained reduction in postoperative morbidity and hospital lengths of stay. Beside existing guidelines, knowledge and explicit clinical reasoning tools followed by decision algorithms are mandatory to implement individualized hemodynamic optimization strategies and reduce postoperative morbidity and duration of hospital stay in high-risk surgical patients.

High intraluminal pressure promotes vascular inflammation via caveolin-1.

The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.

Is there an optimal trade-off between anaemia and red blood cell transfusion in surgical critically ill patients after oncologic surgery?

BACKGROUND AND OBJECTIVES: Equipoise remains on the optimal transfusion strategy in surgical oncologic patients. The primary objective of our study was to determine the impact of anaemia and red blood cells (RBCs) transfusion on severe postoperative complications in surgical oncologic critically ill patients. MATERIALS AND METHODS: Retrospective single-centre study. Adults admitted to intensive care unit after major oncologic surgery were eligible. Analyses to determine the independent risk factors, including anaemia or RBC transfusion, for postoperative complications and/or hospital mortality were performed. RESULTS: Of the 283 patients included, 246 patients (86.9%) had anaemia. Fifty-five patients (19·4%) were transfused. Patients exposed to moderate-to-severe anaemia or RBC transfusion had more often severe complications, especially acute kidney injury and infectious complications. Multivariate analysis found an independent association between moderate and severe anaemia and severe postoperative complications (moderate anaemia: OR 14·02 [2·52-264]; severe anaemia: OR 16·25 [2·62-318·5]; P < 0·05). Elderly, obese patients and patients operated from abdominal surgery appeared to be more vulnerable to anaemia than other patients. Transfusion was also an independent risk factor for postoperative complications (OR 4·19 [2·12-8·39]; P < 0·001). When considering moderate-to-severe anaemic patients, RBC transfusion was no longer associated with postoperative complications. CONCLUSIONS: Anaemia was associated with severe postoperative complications, and this association was stronger in elderly, obese patients and after abdominal surgery. RBC transfusion also negatively impacts on patients' prognosis. However, this association was not found in case of moderate-to-severe anaemia exposure (haemoglobin < 10 g/dl).

Risk factors for ventilator-associated pneumonia due to Staphylococcus aureus in patients with severe brain injury: A multicentre retrospective cohort study.

BACKGROUND: The present study aims at identifying the risk factors for ventilator-associated pneumonia (VAP) Staphylococcus aureus (S. aureus) in patients with severe brain injury (SBI). METHODS: In this multicentre, retrospective, observational study, patients ≥ 18 year old who had SBI (Glasgow coma scale GCS score < 9) who received mechanical ventilation for at least 48 h were analysed. The main objective was to identify risk factors for S. aureus VAP vs VAP due to other pathogens and to identify risk factors for S. aureus VAP vs patients who did not experience VAP. RESULTS: Eight hundred and forty-seven patients with SBI were admitted in ICU after severe traumatic brain injury (n = 489, 58%), aneurysmal SAH (n = 156, 18%), stroke (n = 27, 3%), spontaneous intracranial haemorrhage (n = 80, 9%), arteriovenous malformation rupture (n = 25, 3%), and other causes (n = 70, 8%). Three hundred fifty of 847 patients (41%) had VAP with S. aureus (n = 161) or other pathogens (n = 189). In patients with VAP, the multivariate analysis shows that age per 10 years of ageing (OR 0.80, 95% CI [0.70; 0.90]; p < 0.001) and tobacco use (OR 0.54, 95%CI [0.33;0.88]; p = 0.014) were protective factors against S. aureus. Age per 10 years of ageing remained a protective factor against S. aureus VAP vs no VAP (OR 0.80, 95%CI [0.73; 0.89], p < 0.001). CONCLUSIONS: In this retrospective study involving patients with SBI and who experienced VAP, increased age and tobacco use were protective factors against VAP due to S. aureus. Increased age remained protective against S. aureus in VAP vs no VAP analysis.

Effect of Hydroxyethyl Starch vs Saline for Volume Replacement Therapy on Death or Postoperative Complications Among High-Risk Patients Undergoing Major Abdominal Surgery: The FLASH Randomized Clinical Trial.

Importance: It is not known if use of colloid solutions containing hydroxyethyl starch (HES) to correct for intravascular deficits in high-risk surgical patients is either effective or safe. Objective: To evaluate the effect of HES 130/0.4 compared with 0.9% saline for intravascular volume expansion on mortality and postoperative complications after major abdominal surgery. Design, Setting, and Participants: Multicenter, double-blind, parallel-group, randomized clinical trial of 775 adult patients at increased risk of postoperative kidney injury undergoing major abdominal surgery at 20 university hospitals in France from February 2016 to July 2018; final follow-up was in October 2018. Interventions: Patients were randomized to receive fluid containing either 6% HES 130/0.4 diluted in 0.9% saline (n = 389) or 0.9% saline alone (n = 386) in 250-mL boluses using an individualized hemodynamic algorithm during surgery and for up to 24 hours on the first postoperative day, defined as ending at 7:59 am the following day. Main Outcomes and Measures: The primary outcome was a composite of death or major postoperative complications at 14 days after surgery. Secondary outcomes included predefined postoperative complications within 14 days after surgery, durations of intensive care unit and hospital stays, and all-cause mortality at postoperative days 28 and 90. Results: Among 826 patients enrolled (mean age, 68 [SD, 7] years; 91 women [12%]), 775 (94%) completed the trial. The primary outcome occurred in 139 of 389 patients (36%) in the HES group and 125 of 386 patients (32%) in the saline group (difference, 3.3% [95% CI, -3.3% to 10.0%]; relative risk, 1.10 [95% CI, 0.91-1.34]; P = .33). Among 12 prespecified secondary outcomes reported, 11 showed no significant difference, but a statistically significant difference was found in median volume of study fluid administered on day 1: 1250 mL (interquartile range, 750-2000 mL) in the HES group and 1500 mL (interquartile range, 750-2150 mL) in the saline group (median difference, 250 mL [95% CI, 83-417 mL]; P = .006). At 28 days after surgery, 4.1% and 2.3% of patients had died in the HES and saline groups, respectively (difference, 1.8% [95% CI, -0.7% to 4.3%]; relative risk, 1.76 [95% CI, 0.79-3.94]; P = .17). Conclusions and Relevance: Among patients at risk of postoperative kidney injury undergoing major abdominal surgery, use of HES for volume replacement therapy compared with 0.9% saline resulted in no significant difference in a composite outcome of death or major postoperative complications within 14 days after surgery. These findings do not support the use of HES for volume replacement therapy in such patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02502773.

Erythropoietin in traumatic brain injury associated acute kidney injury: A randomized controlled trial.

BACKGROUND: Acute kidney injury (AKI) in traumatic brain injury (TBI) is poorly understood and it is unknown if it can be attenuated using erythropoietin (EPO). METHODS: Pre-planned analysis of patients included in the EPO-TBI (ClinicalTrials.gov NCT00987454) trial who were randomized to weekly EPO (40 000 units) or placebo (0.9% sodium chloride) subcutaneously up to three doses or until intensive care unit (ICU) discharge. Creatinine levels and urinary output (up to 7 days) were categorized according to the Kidney Disease Improving Global Outcome (KDIGO) classification. Severity of TBI was categorized with the International Mission for Prognosis and Analysis of Clinical Trials in TBI. RESULTS: Of 3348 screened patients, 606 were randomized and 603 were analyzed. Of these, 82 (14%) patients developed AKI according to KDIGO (60 [10%] with KDIGO 1, 11 [2%] patients with KDIGO 2, and 11 [2%] patients with KDIGO 3). Male gender (hazard ratio [HR] 4.0 95% confidence interval [CI] 1.4-11.2, P = 0.008) and severity of TBI (HR 1.3 95% CI 1.1-1.4, P < 0.001 for each 10% increase in risk of poor 6 month outcome) predicted time to AKI. KDIGO stage 1 (HR 8.8 95% CI 4.5-17, P < 0.001), KDIGO stage 2 (HR 13.2 95% CI 3.9-45.2, P < 0.001) and KDIGO stage 3 (HR 11.7 95% CI 3.5-39.7, P < 0.005) predicted time to mortality. EPO did not influence time to AKI (HR 1.08 95% CI 0.7-1.67, P = 0.73) or creatinine levels during ICU stay (P = 0.09). CONCLUSIONS: Acute kidney injury is more common in male patients and those with severe compared to moderate TBI and appears associated with worse outcome. EPO does not prevent AKI after TBI.

Cause and Timing of Death and Subgroup Differential Effects of Erythropoietin in the EPO-TBI Study.

The EPO-TBI study randomized 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal, or death during maximal care) and non-cerebral (death following withdrawal or during maximal care, which had a non-cerebral cause). The study included 305 patients treated with EPO and 297 treated with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (interquartile range [IQR] 5-16) compared with 29 days (IQR 7-56) (p = 0.01) for non-cerebral COD. When assessing subgroups by admission CT scan injury findings, we found no significant differential effects of EPO compared with placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to intensive care unit (ICU) admission (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.61, p = 0.001, p for interaction = 0.003) and in this subgroup, fewer patients died of cerebral causes in the EPO than in the placebo group (5% compared with 14%, p = 0.03). In conclusion, most TBI deaths were from cerebral causes that occurred during the first 2 weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomization.

Erythropoietin in patients with traumatic brain injury and extracranial injury-A post hoc analysis of the erythropoietin traumatic brain injury trial.

BACKGROUND: Erythropoietin (EPO) may reduce mortality after traumatic brain injury (TBI). Secondary brain injury is exacerbated by multiple trauma, and possibly modifiable by EPO. We hypothesized that EPO decreases mortality more in TBI patients with multiple trauma, than in patients with TBI alone. METHODS: A post hoc analysis of the EPO-TBI randomized controlled trial conducted in 2009 to 2014. To evaluate the impact of injuries outside the brain, we calculated an extracranial Injury Severity Score (ISS) that included the same components of the ISS, excluding head and face components. We defined multiple trauma as two injured body regions with an Abbreviated Injury Scale (AIS) score of 3 or higher. Cox regression analyses, allowing for potential differential responses per the presence or absence of extracranial injury defined by these injury scores, were used to assess the effect of EPO on time to mortality. RESULTS: Of 603 included patients, the median extracranial ISS was 6 (interquartile range, 1-13) and 258 (43%) had an AIS score of 3 or higher in at least two body regions. On Cox regression, EPO was associated with decreased mortality in patients with greater extracranial ISS (interaction p = 0.048) and weakly associated with differential mortality with multiple trauma (AIS score > 3 or in two regions, interaction p = 0.17). At 6 months in patients with extracranial ISS higher than 6, 10 (6.8%) of 147 EPO-treated patients compared with 26 (17%) of 154 placebo-treated patients died (risk reduction, 10%; 95% confidence interval, 2.9-17%; p = 0.007). CONCLUSION: In this post hoc analysis, EPO administration was associated with a potential differential improvement in 6-month mortality in TBI patients with more severe extracranial injury. These findings need confirmation in future clinical and experimental studies. LEVEL OF EVIDENCE: Therapeutic study, level III.

Nitroxyl (HNO) reduces endothelial and monocyte activation and promotes M2 macrophage polarization.

Nitroxyl anion (HNO) donors are currently being assessed for their therapeutic utility in several cardiovascular disorders including heart failure. Here, we examine their effect on factors that precede atherosclerosis including endothelial cell and monocyte activation, leucocyte adhesion to the endothelium and macrophage polarization. Similar to the NO donor glyceryl trinitrate (GTN), the HNO donors Angeli's salt (AS) and isopropylamine NONOate (IPA/NO) decreased leucocyte adhesion to activated human umbilical vein endothelial cells (HUVECs) and mouse isolated aorta. This reduction in adhesion was accompanied by a reduction in intercellular adhesion molecule-1 (ICAM-1) and the cytokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6) which was inhibitor of nuclear factor κB (NFκB) α (IκBα)- and subsequently NFκB-dependent. Intriguingly, the effects of AS on leucocyte adhesion, like those on vasodilation, were found to not be susceptible to pharmacological tolerance, unlike those observed with GTN. As well, HNO reduces monocyte activation and promotes polarization of M2 macrophages. Taken together, our data demonstrate that HNO donors can reduce factors that are associated with and which precede atherosclerosis and may thus be useful therapeutically. Furthermore, since the effects of the HNO donors were not subject to tolerance, this confers an additional advantage over NO donors.

Septic shock: desperately seeking treatment.

Septic shock results from the dysregulation of the innate immune response following infection. Despite major advances in fundamental and clinical research, patients diagnosed with septic shock still have a poor prognostic outcome, with a mortality rate of up to 50%. Indeed, the reasons leading to septic shock are still poorly understood. First postulated 30 years ago, the general view of septic shock as an acute and overwhelming inflammatory response still prevails today. Recently, the fact that numerous clinical trials have failed to demonstrate any positive medical outcomes has caused us to question our fundamental understanding of this condition. New and sophisticated technologies now allow us to accurately profile the various stages and contributory components of the inflammatory response defining septic shock, and many studies now report a more complex inflammatory response, particularly during the early phase of sepsis. In addition, novel experimental approaches, using more clinically relevant animal models, to standardize and stratify research outcomes are now being argued for. In the present review, we discuss the most recent findings in relation to our understanding of the underlying mechanisms involved in septic shock, and highlight the attempts made to improve animal experimental models. We also review recent studies reporting promising results with two vastly different therapeutic approaches influencing the renin-angiotensin system and applying mesenchymal stem cells for clinical intervention.