A protocol based on hypotension probability indicator vs. standard care to prevent intraoperative hypotension during supratentorial brain surgery: a prospective randomized pilot trial.

BACKGROUND: To test the hypothesis that Hypotension probability indicator (HPI) driven hemodynamic protocol use may decrease the exposition to hypotension (mean arterial pressure below 65 mmHg) during supratentorial intracranial procedures. METHODS: Patients undergoing supratentorial tumor resection under general anesthesia (ASA 1-3) were included into this randomized single center-controlled pilot trial. Patients in the control group (COV, N.=20) were managed based on the institutional standard to avoid hypotension. Patients in the intervention (INT, N.=20) group were managed using a protocol triggered by the HPI above 85 based on the stroke volume variation, dynamic elastance, and cardiac index parameters. The number of patients experiencing hypotension (mean arterial pressure below 65 mmHg) during the whole procedure and anesthesia maintenance phase was the primary outcome variable. The number of hypotensive periods, time spent in hypotension, and hypotension dose served as secondary outcome variables. Other clinically relevant parameters and postsurgical outcomes were screened. RESULTS: The number of patients who never experienced hypotension was significantly lower in the INT group during the anesthesia maintenance phase (10 (50%) vs. 16 (80%); P=0.049). In several other hemodynamic outcomes, a distinct numerical, but statistically non-significant trend towards lower hypotension exposition was observed. There were no significant differences in clinically relevant parameters. CONCLUSIONS: In this pilot trial, the HPI-based protocol decreased the incidence of hypotension during the anesthesia maintenance but non-significant trends among secondary outcomes were also documented. Larger trials are needed to confirm our findings.

Individualizing Fluid Management in Patients with Acute Respiratory Distress Syndrome and with Reduced Lung Tissue Due to Surgery-A Narrative Review.

Fluids are the cornerstone of therapy in all critically ill patients. During the last decades, we have made many steps to get fluid therapy personalized and based on individual needs. In patients with lung involvement-acute respiratory distress syndrome-finding the right amount of fluids after lung surgery may be extremely important because lung tissue is one of the most vulnerable to fluid accumulation. In the current narrative review, we focus on the actual perspectives of fluid therapy with the aim of showing the possibilities to tailor the treatment to a patient's individual needs using fluid responsiveness parameters and other therapeutic modalities.

Intraoperative Measurement of Endotracheal Tube Cuff Pressure and Its Change During Surgery in Correlation With Recurrent Laryngeal Nerve Palsies, Hoarseness, and Dysphagia After Anterior Cervical Discectomy and Fusion: A Prospective Randomized Controlled Trial.

STUDY DESIGN: Prospective randomized controlled trial. OBJECTIVES: Adjustment of endotracheal tube cuff pressure (ETCP) in anterior cervical discectomy and fusion (ACDF) may influence the incidence of complications such as recurrent laryngeal nerve palsy (RLNP), hoarseness, and dysphagia. METHODS: The prospective randomized controlled trial was designed to investigate the influence of ETCP on the incidence of postoperative complications. All eligible patients underwent vocal cord examination before and after ACDF and were randomized into a control group (CG) and intervention group (IG). Endotracheal tube cuff pressure was passively monitored in CG, and in IG, it was maintained at 20 mmHg. Outcomes were evaluated during hospitalization and during follow-up. RESULTS: A total of 98 patients were randomized, each group consisted of 49 patients. Statistical analysis showed that gender and age did not influence the incidence of complications. In CG, duration of retractor placement and extent of approach significantly impacted the occurrence of complications. The incidence of postoperative RLNP was 8.2% in IG and 12.2% in CG, hoarseness and dysphonia were present in 18.4% in IG and in 37.5% in CG, and dysphagia in 20.8% in IG and in 22.5% in CG. Hoarseness was significantly present more in CG (P = .018). Only one patient from CG presented with RLNP after 1 year, the remaining nine patients spontaneously recovered. CONCLUSIONS: Unregulated ETCP can lead to a significantly higher incidence of hoarseness; however, its improvement rate is 100%. The early postoperative complication rate was higher in CG, and after one year, 1 patient had RLNP and 1 patient had dysphagia.

Air gun injury to the pericardium in a 9-year-old boy.

The authors present the case of a 9-year-old boy who sustained a gunshot injury to the pericardium by an air gun. The penetrative wound to the pericardium was, according to the performed pre-operative diagnostic methods, initially believed to be a penetrative wound into the cardiophrenic angle of the left pleural cavity. The stabilized patient was indicated for an extraction of the projectile through a left anterior minithoracotomy, during which the projectile was found and successfully removed from the pericardium. The limits of pre-operative assessment, optimal treatment procedures, and surgical approaches in pediatric patients with gunshot injuries to the chest and heart are discussed.

Atypical hemolytic uremic syndrome triggered by mRNA vaccination against SARS-CoV-2: Case report.

Atypical hemolytic uremic syndrome (aHUS), also called complement-mediated hemolytic uremic syndrome (CM-HUS), is a rare disease caused by dysregulation in the alternative complement activation pathway. It is a life-threatening condition causing ischemia of a number of organs, and it typically causes acute kidney injury. This disorder may be triggered by various factors including viral or bacterial infections, pregnancy, surgery, and injuries. In about 60% of cases, the genetic origin of the disease can be identified-commonly mutations affecting complementary factor H and MCP protein. Eculizumab, a monoclonal antibody to the C5 component of the complement, represents the current effective treatment.We describe a case of a young woman with a previous history of polyvalent allergies, who developed atypical hemolytic uremic syndrome after vaccination with mRNA vaccine against SARS-CoV-2. The disease manifested by scleral bleeding, acute renal insufficiency, anemia, and thrombocytopenia. The patient was treated with plasma exchanges without sufficient effect; remission occurred only after starting treatment with eculizumab. Genetic examination showed that the patient is a carrier of multiple inherited risk factors (a rare pathogenic variant in CFH, MCPggaac haplotype of the CD46 gene, and the risk haplotype CFH H3). The patient is currently in hematological remission with persistent mild renal insufficiency, continuing treatment with eculizumab/ravulizumab. By this case report, we meant to point out the need for careful monitoring of people after vaccination, as it may trigger immune-mediated diseases, especially in those with predisposing factors.

Metformin treatment is associated with improved outcome in patients with diabetes and advanced heart failure (HFrEF).

The role of metformin (MET) in the treatment of patients with advanced HFrEF and type 2 diabetes mellitus (DM) is not firmly established. We studied the impact of MET on metabolic profile, quality of life (QoL) and survival in these patients. A total of 847 stable patients with advanced HFrEF (57.4 ± 11.3 years, 67.7% NYHA III/IV, LVEF 23.6 ± 5.8%) underwent clinical and laboratory evaluation and were prospectively followed for a median of 1126 (IQRs 410; 1781) days for occurrence of death, urgent heart transplantation or mechanical circulatory support implantation. A subgroup of 380 patients (44.9%) had DM, 87 of DM patients (22.9%) were treated with MET. Despite worse insulin sensitivity and more severe DM (higher BMI, HbA1c, worse insulin resistance), MET-treated patients exhibited more stable HF marked by lower BNP level (400 vs. 642 ng/l), better LV and RV function, lower mitral and tricuspid regurgitation severity, were using smaller doses of diuretics (all p < 0.05). Further, they had higher eGFR (69.23 vs. 63.34 ml/min/1.73 m2) and better QoL (MLHFQ: 36 vs. 48 points, p = 0.002). Compared to diabetics treated with other glucose-lowering agents, MET-treated patients had better event-free survival even after adjustment for BNP, BMI and eGFR (p = 0.035). Propensity score-matched analysis with 17 covariates yielded 81 pairs of patients and showed a significantly better survival for MET-treated subgroup (p = 0.01). MET treatment in patients with advanced HFrEF and DM is associated with improved outcome by mechanisms beyond the improvement of blood glucose control.

Global longitudinal strain and outcome after endoscopic mitral valve repair.

AIMS: Identification of heart failure (HF) patients with secondary mitral regurgitation (SMR) that benefit from mitral valve (MV) repair remains challenging. We have focused on the role of left ventricular global longitudinal strain (LV-GLS) and reservoir left atrial longitudinal strain (LASr) for the prediction of long-term survival and reverse remodelling in patients with SMR undergoing endoscopic MV repair. METHODS AND RESULTS: The study population consisted of 110 patients (age 67 ± 11 years, 66% men) with symptomatic SMR undergoing isolated MV repair using a minimally invasive surgical approach. Speckle tracking-derived LV-GLS and LASr were assessed in apical views using vendor-independent software. Over a median of 7.7 years (IQRs 2.9-11.2), 64 patients (58%) died. Significant reverse LV (↓ LVESVI >10 mL/m2 ), LA (↓ LAVI >10 mL/m2 ) remodelling or both were observed in 43 (39%), 37 (34%) and 19 (17%) patients, respectively. LV-GLS (HR 0.68, 95% CI 0.58-0.79, P < 0.001) and LASr (HR 0.93, 95% CI 0.88-0.97, P < 0.01) but not LV ejection fraction (LVEF) and LA volume index (LAVi) emerged as independent predictors of all-cause mortality in Cox regression analysis. LV-GLS was the only independent predictor of LV reverse remodelling (OR 1.24, 95% CI 1.05-1.43, P < 0.001) whereas LAVi and LASr were both independent predictors of LA reverse remodelling (both P < 0.05). In patients with atrial fibrillation at baseline, only LASr was an independent predictor (P < 0.05) of LA reverse remodelling. CONCLUSIONS: In patients with SMR undergoing endoscopic MV repair, LV-GLS and LASr are independently associated with long-term survival and reverse remodelling and may be helpful in selecting SMR patients who may benefit from this procedure.

Fixed-dose enoxaparin provides efficient DVT prophylaxis in mixed ICU patients despite low anti-Xa levels: A prospective observational cohort study.

BACKGROUND: Deep vein thrombosis (DVT) is a serious but preventable complication of critical illness with a reported incidence from 4 to 17%. Anti-Xa activity in critically ill patients achieved with standard dosing of low-molecular-weight heparins (LMWH) is often below the target of 0.2-0.5 IU/mL. However, the clinical significance of this finding is unclear. The quality of thromboprophylaxis also strongly impacts the incidence of DVT. We performed a prospective observational study to evaluate the incidence of DVT in a mixed medical-surgical-trauma intensive care unit (ICU) using a thromboprophylaxis protocol with a fixed dose of enoxaparin. We also explored the relation between DVT incidence and anti-Xa activity. METHOD: All consecutive patients with expected ICU stay ≥72 hours and without evidence of DVT upon admission were included. They underwent ultrasound screening for DVT twice a week until ICU discharge, death, DVT or pulmonary embolism. Peak anti-Xa activity was measured twice a week. Patients received 40 mg of enoxaparin subcutaneously (60 mg in obese, 20 mg in case of renal failure). Graduated compression stockings were used in case of LMWH or another anticoagulant contraindication. RESULTS: A total of 219 patients were enrolled. We observed six cases of DVT (incidence of 2.7%). The agreement between expected and delivered DVT prophylaxis was 94%. Mean peak anti-Xa activity level was 0.24 (SD, 0.13) IU/mL. There was no significant difference in anti-Xa activity in DVT and non-DVT group. CONCLUSION: A low incidence of DVT was achieved with meticulous adherence to the standard prophylactic protocol. The low incidence of DVT was observed despite low levels of anti-Xa activity. Our findings suggest that enoxaparin dose adjustment based on regular monitoring of anti-Xa activity is unlikely to result in further reduction of DVT incidence in a mixed ICU population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03286985.

Mesenchymal Stromal Cell Therapy in Novel Porcine Model of Diffuse Liver Damage Induced by Repeated Biliary Obstruction.

In liver surgery, biliary obstruction can lead to secondary biliary cirrhosis, a life-threatening disease with liver transplantation as the only curative treatment option. Mesenchymal stromal cells (MSC) have been shown to improve liver function in both acute and chronic liver disease models. This study evaluated the effect of allogenic MSC transplantation in a large animal model of repeated biliary obstruction followed by partial hepatectomy. MSC transplantation supported the growth of regenerated liver tissue after 14 days (MSC group, n = 10: from 1087 ± 108 (0 h) to 1243 ± 92 mL (14 days); control group, n = 11: from 1080 ± 95 (0 h) to 1100 ± 105 mL (14 days), p = 0.016), with a lower volume fraction of hepatocytes in regenerated liver tissue compared to resected liver tissue (59.5 ± 10.2% vs. 70.2 ± 5.6%, p < 0.05). Volume fraction of connective tissue, blood vessels and bile vessels in regenerated liver tissue, serum levels of liver enzymes (AST, ALT, ALP and GGT) and liver metabolites (albumin, bilirubin, urea and creatinine), as well as plasma levels of IL-6, IL-8, TNF-α and TGF-ß, were not affected by MSC transplantation. In our novel, large animal (pig) model of repeated biliary obstruction followed by partial hepatectomy, MSC transplantation promoted growth of liver tissue without any effect on liver function. This study underscores the importance of translating results between small and large animal models as well as the careful translation of results from animal model into human medicine.

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study.

Background: Treatment with mesenchymal stem cells (MSCs) has elicited considerable interest as an adjunctive therapy in sepsis. However, the encouraging effects of experiments with MSC in rodents have not been adequately studied in large-animal models with better relevance to human sepsis. Objectives: Here, we aimed to assess safety and efficacy of bone marrow-derived MSCs in a clinically relevant porcine model of progressive peritonitis-induced sepsis. Methods: Thirty-two anesthetized, mechanically ventilated, and instrumented pigs were randomly assigned into four groups (n = 8 per group): (1) sham-operated group (CONTROL); (2) sham-operated group treated with MSCs (MSC-CONTROL); (3) sepsis group with standard supportive care (SEPSIS); and (4) sepsis group treated with MSCs (MSC-SEPSIS). Peritoneal sepsis was induced by inoculating cultivated autologous feces. MSCs (1 × 106/kg) were administered intravenously at 6 h after sepsis induction. Results: Before, 12, 18, and 24 h after the induction of peritonitis, we measured systemic, regional, and microvascular hemodynamics, multiple-organ functions, mitochondrial energy metabolism, systemic immune-inflammatory response, and oxidative stress. Administration of MSCs in the MSC-CONTROL group did not elicit any measurable acute effects. Treatment of septic animals with MSCs failed to mitigate sepsis-induced hemodynamic alterations or the gradual rise in Sepsis-related organ failure assessment scores. MSCs did not confer any protection against sepsis-mediated cellular myocardial depression and mitochondrial dysfunction. MSCs also failed to modulate the deregulated immune-inflammatory response. Conclusion: Intravenous administration of bone marrow-derived MSCs to healthy animals was well-tolerated. However, in this large-animal, clinically relevant peritonitis-induced sepsis model, MSCs were not capable of reversing any of the sepsis-induced disturbances in multiple biological, organ, and cellular systems.

Endothelial glycocalyx in acute care surgery - what anaesthesiologists need to know for clinical practice.

The endothelial glycocalyx (EG) is the thin sugar-based lining on the apical surface of endothelial cells. It has been linked to the physiological functioning of the microcirculation and has been found to be damaged in critical illness and after acute care surgery. This review aims to describe the role of EG in severely injured patients undergoing surgery, discuss specific situations (e.G. major trauma, hemorrhagic shock, trauma induced coagulopathy) as well as specific interventions commonly applied in these patients (e.g. fluid therapy, transfusion) and specific drugs related to perioperative medicine with regard to their impact on EG.EG in acute care surgery is exposed to damage due to tissue trauma, inflammation, oxidative stress and inadequate fluid therapy. Even though some interventions (transfusion of plasma, human serum albumin, hydrocortisone, sevoflurane) are described as potentially EG protective there is still no specific treatment for EG protection and recovery in clinical medicine.The most important principle to be adopted in routine clinical practice at present is to acknowledge the fragile structure of the EG and avoid further damage which is potentially related to worsened clinical outcome.

Multi-parametric functional hemodynamic optimization improves postsurgical outcome after intermediate risk open gastrointestinal surgery: a randomized controlled trial.

BACKGROUND: Perioperative goal directed therapy (pGDT) using flow monitoring has been associated with improved outcomes. However, its protocols are often based on stroke volume only: as a target for fluid loading, inotropic support and vasopressors (via mathematical coupling of systemic vascular resistance). In this trial, we have tested the multi-parametric pGDT protocol based on esophageal Doppler variables (corrected flow time, peak velocity) in intermediate-to-high risk patients undergoing gastrointestinal surgery. METHODS: Intermediate-to-high risk patients undergoing gastrointestinal surgery were randomized to standard care (control) or multi-parametric pGDT (intervention). Postoperative complications and death rate as well as hospital length of stay were assessed as primary and secondary outcomes. RESULTS: Overall, 140 patients (intervention, N.=71, and control, N.=69) were included and randomized out of 197 eligible. Higher vasoactive/inotropic drug use and lower fluid balance were observed in the intervention group leading to favorable hemodynamic profile. The pGDT intervention was associated with improved primary outcome (28 days mortality and morbidity defined as occurrence of any defined complication) - 20 patients (28.2%) versus 32 (46.4%) in the control group (P=0.036); RR 0.61 (95% CI: 0.39-0.95), P=0.03. No differences in mortality and hospital length of stay were observed between groups. CONCLUSIONS: In this monocentric trial the multi-parametric pGDT protocol based on domain specific functional hemodynamic parameters was associated with lower rate of postoperative complications in intermediate-to-high risk patients undergoing scheduled gastrointestinal procedures.

Propofol versus sevoflurane anaesthesia: effect on cognitive decline and event-related potentials.

Postoperative cognitive dysfunction (POCD) is diagnosed in up to 30% patients after anaesthesia. The causative role of anaesthetic toxicity remains unclear. Using clinical tests, no clear-cut differences have been observed between anaesthetics so far. The aim of this trial was to compare the incidence of POCD diagnosed by a battery of neuropsychologic tests after propofol and sevoflurane anaesthesia. Secondary goal was to examine possible relationship between POCD positivity and changes in auditory event-related potentials (ERPs). Sixty patients undergoing lumbar discectomy were prospectively randomized to receive depth-controlled sevoflurane (SEVO) or propofol (PROP) based anaesthesia. The neuropsychological examination and auditory event-related potentials (N1, P3a and P3b components) recording was performed preoperatively and on days 1, 6 and 42 after surgery. POCD was defined as a decline of more than one standard deviation in three or more tests. In 43 patients (20 in PROP and 23 in SEVO group) all selected tests were performed and used for the evaluation. POCD was present in 48%/60%, 18%/20% and 17%/11% (SEVO/PROP) of patients on days 1, 6 and 42 after surgery, with no significant intergroup difference. Among neuropsychologic tests, the most significant decline was observed in Semantic Verbal Fluency and Letter-Number Sequencing Test scores, congruently in both groups on days 1 and 6, with full recovery on the last control. Transient deteriorations in other tests were observed as well. No association of POCD positivity and ERPs changes was found, although long-term modifications of P3a and P3b components were observed, mainly in SEVO group. In our study, sevoflurane and propofol anaesthesia was associated with the similar incidence of POCD. Cognitive decline, mainly affecting executive functions, was temporary in most of the patients. Prolonged ERPs alterations after the anaesthesia seem not to have any relationship with the impairment registered by the neuropsychological examination and may represent subclinical changes.

Neuraxial anesthesia is less harmful to the endothelial glycocalyx during elective joint surgery compared to general anesthesia.

BACKGROUND: Damage of the endothelial glycocalyx (EG) has been described during surgery, but the effect of different anesthesia techniques remains unknown. Perfused boundary region (PBR) evaluated by side-stream dark field (SDF) imaging of the sublingual microcirculation enables in vivo EG assessment. PBR values are inversely related to the EG thickness. OBJECTIVE: The aim of the observational study was to evaluate the changes of PBR in patients undergoing elective joint surgery under general (GA) vs. neuraxial anesthesia (NA). Our hypothesis was that PBR will be lower in patients in NA. METHODS: Sixty consecutive patients (ASA 1-3) undergoing elective total knee or hip replacement under GA or NA were included in this prospective observational cohort study. PBR in the sublingual microcirculation was recorded in each patient using SDF at two time points - before surgery and 2 hours after surgery. RESULTS: Before surgery, there was no significant difference in baseline PBR between groups (NA: 1.95 µm (±0.24); GA: 2.02 µm (±0.26); p = 0.098). Postoperatively (2 hours after surgery) PBR was significantly increased in both groups with respect to baseline values (NA: 2.09 µm (±0.19), GA: 2.20 µm (±0.25); p < 0.001). In the GA group, postoperative PBR values were significantly higher than in the NA group (p = 0.006). CONCLUSION: Joint surgery led to significant increases of PBR. Patients in the GA group had significantly higher PBR values 2 hours after surgery compared to NA group. This might implicate that NA is associated with less EG damage then GA in elective hip/knee surgery.

Impact of Intravenous Fluid Challenge Infusion Time on Macrocirculation and Endothelial Glycocalyx in Surgical and Critically Ill Patients.

(i) Purpose. The fluid challenge (FC) is a well-established test of preload reserve. Only limited data exist in regard to the FC efficacy based on infusion time. Slow administration may be associated with lack of effect based on fluid redistribution and external conditions changes. On the contrary, fast administration may lead to brisk fluid overload and damage to the endothelium and endothelial glycocalyx (EG). The aim of this trial was to compare the FC infusion time on its hemodynamic effects and EG. (ii) Methods. Prospective randomized single-center trial of fast (5-10 minutes) versus slow (20-30 minutes) administration of 500ml balanced crystalloid FC in spinal surgery (cohort OR) and septic shock (cohort SEP) patients. Hemodynamic response was assessed using standard monitoring and blood flow measurements; damage to EG was assessed using the perfused boundary region (PBR) via intravital microscopy monitoring in the sublingual region within relevant time points ranging up to 120 minutes. (iii) Results. Overall, 66 FCs in 50 surgical and 16 septic patients were assessed. Fluid administration was associated with increase of PBR in general (1.9 (1.8-2.1) vs. 2.0 (1.8-2.2); p= 0.008). These changes were transient in OR cohort whereas they were long-lasting in septic fluid responders. The rate of fluid responsiveness after fast versus slow administration was comparable in global population (15 (47%) vs. 17 (50%); p=0.801) as well as in both cohorts. (iv) Conclusions. Fluid challenge administration was associated with increased PBR (and presumable EG volume changes) which normalized within the next 60 minutes in surgical patients but remained impeded in septic fluid responders. The fluid responsiveness rate after fast and slow FC was comparable, but fast administration tended to induce higher, though transient, response in blood pressure.

Continuous Non-Invasive Arterial Pressure Assessment during Surgery to Improve Outcome.

Blood pressure (BP) is one of the most important variables evaluated during almost every medical examination. Most national anesthesiology societies recommend BP monitoring at least once every 5 min in anesthetized subjects undergoing surgical procedures. In most cases, BP is monitored non-invasively using oscillometric cuffs. Although the risk of arterial cannulation is not very high, the invasive BP monitoring is usually indicated only in the case of high-risk patients or in complex surgical procedures. However, recent evidence points out that when using intermittent BP monitoring short periods of hypotension may be overlooked. In addition, large datasets have demonstrated that even short periods of low BP (or their cumulative duration) may have a detrimental impact on the development of postoperative outcome including increased risk of acute kidney or myocardial injury development. Recently marketed continuous non-invasive blood pressure monitoring tools may help us to recognize the BP fluctuation without the associated burden of arterial cannulation filling the gap between intermittent non-invasive cuff and continuous invasive arterial pressure. Among others, several novel devices based either on volume clamp/vascular unloading method or on applanation tonometry are nowadays available. Moreover, several near-future smart technologies may lead to better hypotension recognition or even prediction potentially improving our ability to maintain BP stability throughout the anesthesia or surgical procedure. In this review, novel or emerging technologies of non-invasive continuous blood pressure assessment and their potential to improve postoperative outcome are discussed.

Targeting the endothelial glycocalyx in acute critical illness as a challenge for clinical and laboratory medicine.

The purpose of this manuscript is to review the role of endothelial glycocalyx (EG) in the field of critical and perioperative medicine and to discuss possible future directions for investigations in this area. Under physiological conditions, EG has several well-defined functions aimed to prevent the disruption of vessel wall integrity. Under pathological conditions, the EG represent one of the earliest sites of injury during inflammation. EG structure and function distortion contribute to organ dysfunction related to sepsis, trauma, or global ischemia of any origin. Discovering new therapeutic approaches (either pharmacological or non-pharmacological) aimed to protect the EG against injury represents a promising direction in clinical medicine. Further, the currently-used common interventions in the acutely ill - fluids, blood products, nutritional support, organ-supporting techniques (e.g. continuous renal replacement therapy, extracorporeal circulation), temperature modulation and many others - should be re-evaluated during acute illness in terms of their EG "friendliness". To assess new therapies that protect the EG, or to evaluate the effect of currently-used interventions on EG integrity, a relevant marker or method to determine EG damage is needed. Such marker or method should be available to clinicians within hours, preferably in the form of a point-of-care test at the bedside. Collaborative research between clinical disciplines and laboratory medicine is warranted, and targeting the EG represents major challenges for both.

Glucose Homeostasis, Pancreatic Endocrine Function, and Outcomes in Advanced Heart Failure.

BACKGROUND: The mechanisms and relevance of impaired glucose homeostasis in advanced heart failure (HF) are poorly understood. The study goals were to examine glucose regulation, pancreatic endocrine function, and metabolic factors related to prognosis in patients with nondiabetic advanced HF. METHODS AND RESULTS: In total, 140 advanced HF patients without known diabetes mellitus and 21 sex-, age-, and body mass index-matched controls underwent body composition assessment, oral glucose tolerance testing, and measurement of glucose-regulating hormones to model pancreatic ß-cell secretory response. Compared with controls, HF patients had similar fasting glucose and insulin levels but higher levels after oral glucose tolerance testing. Insulin secretion was not impaired, but with increasing HF severity, there was a reduction in glucose, insulin, and insulin/glucagon ratio-a signature of starvation. The insulin/C-peptide ratio was decreased in HF, indicating enhanced insulin clearance, and this was correlated with lower cardiac output, hepatic insufficiency, right ventricular dysfunction, and body wasting. After a median of 449 days, 41% of patients experienced an adverse event (death, urgent transplant, or assist device). Increased glucagon and, paradoxically, low fasting plasma glucose displayed the strongest relations to outcome (P=0.01). Patients in the lowest quartile of fasting plasma glucose (3.8-5.1 mmol·L-1, 68-101 mg·dL-1) had 3-times higher event risk than in the top quartile (6.0-7.9 mmol·L-1, 108-142 mg·dL-1; relative risk: 3.05 [95% confidence interval, 1.46-6.77]; P=0.002). CONCLUSIONS: Low fasting plasma glucose and increased glucagon are robust metabolic predictors of adverse events in advanced HF. Pancreatic insulin secretion is preserved in advanced HF, but levels decrease with increasing HF severity due to enhanced insulin clearance that is coupled with right heart failure and cardiac cachexia.

Molecular differences in susceptibility of the kidney to sepsis-induced kidney injury.

BACKGROUND: Septic acute kidney injury affects 40-50% of all septic patients. Molecular differences between septic patients with and without acute kidney injury (AKI) are only poorly understood. Here, we investigated gene expression changes that differentiated the subjects who developed septic AKI from those who did not and coupled this approach with traditional parameters of renal physiology. METHODS: In 15 anesthetized, mechanically ventilated and instrumented pigs, progressive sepsis was induced either by peritonitis or by continuous intravenous infusion of Pseudomonas aeruginosa. Animals received standard intensive care including goal-directed hemodynamic management. Analyses were performed on kidneys from sham operated animals, septic pigs without AKI, and pigs with septic AKI. Before, and at 12, 18 and 22 h of progressive sepsis, systemic and renal hemodynamics, cortex microcirculation and plasma IL-6 and TNF-α were measured. At 22 h whole kidney expression of pre-selected genes was analyzed by quantitative Real Time PCR. RESULTS: Animals with septic AKI had systemic hemodynamic phenotype (normo- or hyperdynamic) comparable with non-AKI subjects, but demonstrated higher plasma levels of cytokines, an increase in renal vascular resistance and early fall in cortical microcirculatory blood flow. The genes whose expression discriminated septic AKI from non-AKI included Toll like receptor 4 (up-regulated 2.7-fold, P = 0.04); Cyclooxygenase-2 (up-regulated 14.6-fold, P = 0.01), Angiotensin II Receptor (up-regulated 8.1-fold, P = 0.01), Caspase 3 (up-regulated 5.1-fold, P = 0.02), Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha (down-regulated 2-fold, P = 0.02). CONCLUSIONS: In this preliminary experimental study, kidney gene expression was profoundly different in animals that developed septic AKI as opposed to septic animals that did not. The biological functions of the genes differentially expressed support a role of inflammatory overstimulation coupled with metabolic and apoptotic molecular responses in early septic AKI. Cyclooxygenase-2 and angiotensin type 2 receptor-dependent downstream mechanisms appear fruitful targets for future mechanistic research.