Enhancing radioprotection: A chitosan-based chelating polymer is a versatile radioprotective agent for prophylactic and therapeutic interventions against radionuclide contamination.

To mitigate the risk of radioactive isotope dissemination, the development of preventative and curative measures is of particular interest. For mass treatment, the developed solution must be easily administered, preferably orally, with effective, nontoxic decorporating properties against a wide range of radioactive isotopes. Currently, most orally administered chelation therapy products are quickly absorbed into the blood circulation, where chelation of the radioactive isotope is a race against time due to the short circulation half-life of the therapeutic. This report presents an alternative therapeutic approach by using a functionalized chitosan (chitosan@DOTAGA) with chelating properties that remains within the gastrointestinal tract and is eliminated in feces, that can protect against ingested radioactive isotopes. The polymer shows important in vitro chelation properties towards different metallic cations of importance, including (Cs(I), Ir(III), Th(IV), Tl(I), Sr(II), U(VI) and Co(II)), at different pH (from 1 to 7) representing the different environments in the gastrointestinal tract. An in vivo proof of concept is presented on a rodent model of uranium contamination following an oral administration of Chitosan@DOTAGA. The polymer partially prevents the accumulation of uranium within the kidneys (providing a protective effect) and completely prevents its uptake by the spleen.

Subcutaneous Administration of a Zwitterionic Chitosan-Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies.

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA-/EMA-approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150 kDa) after SC delivery in clinical settings. Here, a novel two-component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation.

RESPIRATION-RELATED VARIATIONS IN CENTRAL VENOUS PRESSURE AS PREDICTORS OF FLUID RESPONSIVENESS IN SPONTANEOUSLY BREATHING PATIENTS.

ABSTRACT: Objective : The hemodynamic parameters used to accurately predict fluid responsiveness (FR) in spontaneously breathing patients (SB) require specific material and expertise. Measurements of the central venous pressure (CVP) are relatively simple and, importantly, are feasible in many critically ill patients. We analyzed the accuracy of respiration-related variations in CVP (vCVP) to predict FR in SB patients and examined the optimization of its measurement using a standardized, deep inspiratory maneuver. Patients and Methods : We performed a monocentric, prospective, diagnostic evaluation. Spontaneously breathing patients in intensive care units with a central venous catheter were prospectively included. The vCVP was measured while the patient was spontaneously breathing, both with (vCVP-st) and without (vCVP-ns) a standardized inspiratory maneuver, and calculated as: Minimum inspiratory v-wave peak pressure - Maximum expiratory v-wave peak pressure. A passive leg raising-induced increase in the left ventricular outflow tract velocity-time integral ≥10% defined FR. Results : Among 63 patients, 38 (60.3%) presented FR. The vCVP-ns was not significantly different between responders and nonresponders (-4.9 mm Hg [-7.5 to -3.1] vs. -4.1 mm Hg [-5.4 to 2.8], respectively; P = 0.15). The vCVP-st was lower in responders than nonresponders (-9.7 mm Hg [-13.9 to -6.2] vs. -3.6 mm Hg [-10.6 to -1.6], respectively; P = 0.004). A vCVP-st < -4.7 mm Hg predicted FR with 89.5% sensitivity, a specificity of 56.0%, and an area under the receiver operating characteristic curve of 0.72 (95% CI, 0.58 to 0.86) ( P = 0.004). Conclusion : When a central venous catheter is present, elevated values for vCVP-st may be useful to identify spontaneously breathing patients unresponsive to volume expansion. Nevertheless, the necessity of performing a standardized, deep-inspiration maneuver may limit its clinical application.

Sepsis-like Energy Deficit Is Not Sufficient to Induce Early Muscle Fiber Atrophy and Mitochondrial Dysfunction in a Murine Sepsis Model.

Sepsis-induced myopathy is characterized by muscle fiber atrophy, mitochondrial dysfunction, and worsened outcomes. Whether whole-body energy deficit participates in the early alteration of skeletal muscle metabolism has never been investigated. Three groups were studied: "Sepsis" mice, fed ad libitum with a spontaneous decrease in caloric intake (n = 17), and "Sham" mice fed ad libitum (Sham fed (SF), n = 13) or subjected to pair-feeding (Sham pair fed (SPF), n = 12). Sepsis was induced by the intraperitoneal injection of cecal slurry in resuscitated C57BL6/J mice. The feeding of the SPF mice was restricted according to the food intake of the Sepsis mice. Energy balance was evaluated by indirect calorimetry over 24 h. The tibialis anterior cross-sectional area (TA CSA), mitochondrial function (high-resolution respirometry), and mitochondrial quality control pathways (RTqPCR and Western blot) were assessed 24 h after sepsis induction. The energy balance was positive in the SF group and negative in both the SPF and Sepsis groups. The TA CSA did not differ between the SF and SPF groups, but was reduced by 17% in the Sepsis group compared with the SPF group (p < 0.05). The complex-I-linked respiration in permeabilized soleus fibers was higher in the SPF group than the SF group (p < 0.05) and lower in the Sepsis group than the SPF group (p < 0.01). Pgc1α protein expression increased 3.9-fold in the SPF mice compared with the SF mice (p < 0.05) and remained unchanged in the Sepsis mice compared with the SPF mice; the Pgc1α mRNA expression decreased in the Sepsis compared with the SPF mice (p < 0.05). Thus, the sepsis-like energy deficit did not explain the early sepsis-induced muscle fiber atrophy and mitochondrial dysfunction, but led to specific metabolic adaptations not observed in sepsis.

Assessment of Metabolic Dysfunction in Sepsis in a Retrospective Single-Centre Cohort.

OBJECTIVE: Our primary aim was to assess selected metabolic dysfunction parameters, both independently and as a complement to the SOFA score, as predictors of short-term mortality in patients with infection admitted to the intensive care unit (ICU). METHODS: We retrospectively enrolled all consecutive adult patients admitted to the eight ICUs of Lille University Hospital, between January 2015 and September 2016, with suspected or confirmed infection. We selected seven routinely measured biological and clinical parameters of metabolic dysfunction (maximal arterial lactatemia, minimal and maximal temperature, minimal and maximal glycaemia, cholesterolemia, and triglyceridemia), in addition to age and the Charlson's comorbidity score. All parameters and SOFA scores were recorded within 24 h of admission. RESULTS: We included 956 patients with infection, among which 295 (30.9%) died within 90 days. Among the seven metabolic parameters investigated, only maximal lactatemia was associated with higher risk of 90-day hospital mortality in SOFA-adjusted analyses (SOFA-adjusted OR, 1.17; 95%CI, 1.10 to 1.25; p < 0.001). Age and the Charlson's comorbidity score were also statistically associated with a poor prognosis in SOFA-adjusted analyses. We were thus able to develop a metabolic failure, age, and comorbidity assessment (MACA) score based on scales of lactatemia, age, and the Charlson's score, intended for use in combination with the SOFA score. CONCLUSIONS: The maximal lactatemia level within 24 h of ICU admission is the best predictor of short-term mortality among seven measures of metabolic dysfunction. Our combined "SOFA + MACA" score could facilitate early detection of patients likely to develop severe infections. Its accuracy requires further evaluation.

SARS-CoV-2 Versus Influenza-associated Acute Respiratory Distress Syndrome Requiring Veno-venous Extracorporeal Membrane Oxygenation Support.

No study has compared patients with COVID-19-related refractory ARDS requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO) to a relevant and homogenous control population. We aimed to compare the outcomes, the clinical characteristics, and the adverse effects of COVID-19 patients to a retrospective cohort of influenza patients. This retrospective case-control study was conducted in the ICUs of Lille and Rouen University Hospitals between January 2014 and May 2020. Two independent cohorts of patients with ARDS requiring V-V ECMO infected with either COVID-19 (n = 30) or influenza (n = 22) were compared. A 3-month follow-up was completed for all patients. Median age of COVID-19 and influenza patients was similar (57 vs. 55 years; p = 0.62). The 28-day mortality rate did not significantly differ between COVID-19 (43.3%) and influenza patients (50%, p = 0.63). There was no significant difference considering the cumulative incidence of ECMO weaning, hospital discharge, and 3-month survival. COVID-19 patients had a lower SAPS II score (58 [37-64] vs. 68 [52-83]; p = 0.039), a higher body mass index (33 [29-38] vs. 30 [26-34] kg/m2; p = 0.05), and were cannulated later (median delay between mechanical support and V-V ECMO 6 vs. 3 days, p = 0.004) compared with influenza patients. No difference in overall adverse events was observed between COVID-19 and influenza patients (70% vs. 95.5% respectively; p = 0.23). Despite differences in clinical presentation before V-V ECMO implantation, 28-day and 3-month mortality rate did not differ between COVID-19 and influenza patients. Considering the lack of specific treatment for COVID-19, V-V ECMO should be considered as a relevant rescue organ support.

Measurement site of inferior vena cava diameter affects the accuracy with which fluid responsiveness can be predicted in spontaneously breathing patients: a post hoc analysis of two prospective cohorts.

BACKGROUND: The collapsibility index of the inferior vena cava (cIVC) has potential for predicting fluid responsiveness in spontaneously breathing patients, but a standardized approach for measuring the inferior vena cava diameter has yet to be established. The aim was to test the accuracy of different measurement sites of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing patients with sepsis-related circulatory failure and examine the influence of a standardized breathing manoeuvre. RESULTS: Among the 81 patients included in the study, the median Simplified Acute Physiologic Score II was 34 (24; 42). Sepsis was of pulmonary origin in 49 patients (60%). Median volume expansion during the 24 h prior to study inclusion was 1000 mL (0; 2000). Patients were not severely ill: none were intubated, only 20% were on vasopressors, and all were apparently able to perform a standardized breathing exercise. Forty-one (51%) patients were responders to volume expansion (i.e. a ≥ 10% stroke volume index increase). The cIVC was calculated during non-standardized (cIVC-ns) and standardized breathing (cIVC-st) conditions. The accuracy with which both cIVC-ns and cIVC-st predicted fluid responsiveness differed significantly by measurement site (interaction p < 0.001 and < 0.0001, respectively). Measuring inferior vena cava diameters 4 cm caudal to the right atrium predicted fluid responsiveness with the best accuracy. At this site, a standardized breathing manoeuvre also significantly improved predictive power: areas under ROC curves [mean and (95% CI)] for cIVC-ns = 0.85 [0.78-0.94] versus cIVC-st = 0.98 [0.97-1.0], p < 0.001. When cIVC-ns is superior or equal to 33%, fluid responsiveness is predicted with a sensitivity of 66% and a specificity of 92%. When cIVC-st is superior or equal to 44%, fluid responsiveness is predicted with a sensitivity of 93% and a specificity of 98%. CONCLUSION: The accuracy with which cIVC measurements predict fluid responsiveness in spontaneously breathing patients depends on both the measurement site of inferior vena cava diameters and the breathing regime. Measuring inferior vena cava diameters during a standardized inhalation manoeuvre at 4 cm caudal to the right atrium seems to be the method by which to obtain cIVC measurements best-able to predict patients' response to volume expansion.

Central venous-to-arterial PCO2 difference, arteriovenous oxygen content and outcome after adult cardiac surgery with cardiopulmonary bypass: A prospective observational study.

BACKGROUND: Rapid identification and treatment of tissue hypoxia reaching anaerobiosis (dysoxia) may reduce organ failure and the occurrence of major postoperative complications (MPC) after cardiac surgery. The predictive ability of PCO2-based dysoxia biomarkers, central venous-to-arterial PCO2 difference (ΔPCO2) and ΔPCO2 to arteriovenous oxygen content difference ratio, is poorly studied in this setting. OBJECTIVES: We evaluated the ability of PCO2-based tissue dysoxia biomarkers, blood lactate concentration and central venous oxygen saturation measured 2 h after admission to the ICU as predictors of MPC. DESIGN: A prospective, observational cohort study. SETTING: Single-centre, academic hospital cardiovascular ICU. PATIENTS: We included adult patients undergoing cardiac surgery with cardiopulmonary bypass and measured dysoxia biomarkers at ICU admission, and after 2, 6 and 24 h. MAIN OUTCOME MEASURES: The primary endpoint was MPC, a composite of cardiac and noncardiac MPC evaluated in the 48 h following surgery. After univariate analysis of MPC covariates including dysoxia biomarkers measured at 2 h, multivariate logistic regression analyses were performed to identify the association of these biomarkers with MPC for confounders. Areas under the receiver operating characteristic curves were determined for biomarkers which remained independently associated with MPC. RESULTS: MPC occurred in 56.5% of the 308 patients analysed. ΔPCO2, blood lactate concentration and central venous oxygen saturation measured at 2 h, but not ΔPCO2 to arteriovenous oxygen content difference ratio, were significantly associated with MPC. However, only ΔPCO2 was independently associated with MPC after multivariate analysis. The areas under the receiver operating characteristic curves of ΔPCO2 measured at 2 h for MPC prediction was 0.64 (95% CI 0.57 to 0.70, P < 0.001). CONCLUSION: After cardiac surgery with cardiopulmonary bypass, ΔPCO2 measured 2 h after ICU admission was the only dysoxia biomarker independently associated with MPC, but with limited performance. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03107572.

Single Low Dose of Human Recombinant Antithrombin (ATryn) has no Impact on Endotoxin-Induced Disseminated Intravascular Coagulation: An Experimental Randomized Open Label Controlled Study.

BACKGROUND: Antithrombin (AT) III physiological levels are decreased during septic shock and supplementation therapy could therefore be beneficial. OBJECTIVE: We hypothesized that the use of recombinant human AT could reduce disseminated intravascular coagulation (DIC) occurrence. METHODS: We conducted a randomized open label controlled experimental study. Ten female "Large White" pigs were challenged with i.v. infusion of Escherichia coli endotoxin. Two groups of 5 pigs were randomly assigned to receive either recombinant human AT 100 U/kg over 30 min (ATryn group) or 0.9% saline (control group). AT III levels, coagulation, hemostasis, inflammation parameters, hemodynamics, and microcirculatory parameters were measured over a 5-h period. Immediately after euthanasia, kidneys were withdrawn for histology evaluation. Statistical analysis was performed with nonparametric tests and Dunn's test for multiple comparisons. RESULTS: AT III activity was significantly higher in the ATryn group than in the control group from 60% (213% [203-223] vs. 104% [98-115], P = 0.008, respectively) to 300 min (115% [95-124] vs. 79% [67-93], P = 0.03). Recombinant human AT supplementation had no impact on hemodynamics, microcirculatory parameters, and sequential changes of coagulation parameters (platelet count, fibrinogen level, thrombin-AT complexes, and von Willebrand factor). Interleukin 6 and tumor necrosis factor α values were statistically the same for both groups throughout the study. Percentage of thrombosed glomeruli and percentage of thrombosed capillary in glomerulus were not significantly different between both groups. CONCLUSIONS: In our model of endotoxic shock, a single low dose of recombinant human AT did not prevent DIC occurrence, severity, inflammatory profile, or hemodynamic alterations.

Sodium lactate improves renal microvascular thrombosis compared to sodium bicarbonate and 0.9% NaCl in a porcine model of endotoxic shock: an experimental randomized open label controlled study.

BACKGROUND: Sodium lactate seemed to improve fluid balance and avoid fluid overload. The objective of this study was to determine if these beneficial effects can be at least partly explained by an improvement in disseminated intravascular coagulation (DIC)-associated renal microvascular thrombosis. METHODS: Ancillary work of an interventional randomized open label controlled experimental study. Fifteen female "Large White" pigs (2 months old) were challenged with intravenous infusion of E. coli endotoxin. Three groups of five animals were randomly assigned to receive different fluids: a treatment group received sodium lactate 11.2% (SL group); an isotonic control group received 0.9% NaCl (NC group); a hypertonic control group, with the same amount of osmoles and sodium than SL group, received sodium bicarbonate 8.4% (SB group). Glomerular filtration rate (GFR) markers, coagulation and inflammation parameters were measured over a 5-h period. Immediately after euthanasia, kidneys were withdrawn for histological study. Statistical analysis was performed with nonparametric tests and the Dunn correction for multiple comparisons. A p < 0.05 was considered significant. RESULTS: The direct immunofluorescence study revealed that the percentage of capillary sections thrombosed in glomerulus were significantly lesser in SL group [5 (0-28) %] compared to NC [64 (43-79) %, p = 0.01] and SB [64 (43-79), p = 0.03] groups. Alterations in platelet count and fibrinogen level occurred earlier and were significantly more pronounced in both control groups compared to SL group (p < 0.05 at 210 and 300 min). The increase in thrombin-antithrombin complexes was significantly higher in NC [754 (367-945) µg/mL; p = 0.03] and SB [463 (249-592) µg/mL; p = 0.03] groups than in SL group [176 (37-265) µg/mL]. At the end of the experiment, creatinine clearance was significantly higher in SL group [55.46 (30.07-67.85) mL/min] compared to NC group [1.52 (0.17-27.67) mL/min, p = 0.03]. CONCLUSIONS: In this study, we report that sodium lactate improves DIC-associated renal microvascular thrombosis and preserves GFR. These findings could at least partly explain the better fluid balance observed with sodium lactate infusion.

Involvement of Mitochondrial Disorders in Septic Cardiomyopathy.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains a leading cause of death worldwide, despite the development of various therapeutic strategies. Cardiac dysfunction, also referred to as septic cardiomyopathy, is a frequent and well-described complication of sepsis and associated with worse clinical outcomes. Recent research has increased our understanding of the role of mitochondrial dysfunction in the pathophysiology of septic cardiomyopathy. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions.

Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway.

Oxidative stress and mitochondrial dysfunction are recognized as major contributors of cardiovascular damage in diabetes and high fat diet (HFD) fed mice. Blockade of receptor for advanced glycation end products (RAGE) attenuates vascular oxidative stress and development of atherosclerosis. We tested whether HFD-induced myocardial dysfunction would be reversed in RAGE deficiency mice, in association with changes in oxidative stress damage, mitochondrial respiration, mitochondrial fission and autophagy-lysosomal pathway. Cardiac antioxidant capacity was upregulated in RAGE-/- mice under normal diet as evidenced by increased superoxide dismutase and sirtuin mRNA expressions. Mitochondrial fragmentation and mitochondrial fission protein Drp1 and Fis1 expressions were increased in RAGE-/- mice. Autophagy-related protein expressions and cathepsin-L activity were increased in RAGE-/- mice suggesting sustained autophagy-lysosomal flux. HFD induced mitochondrial respiration defects, cardiac contractile dysfunction, disrupted mitochondrial dynamics and autophagy inhibition, which were partially prevented in RAGE-/- mice. Our results suggest that cardioprotection against HFD in RAGE-/- mice include reactivation of autophagy, as inhibition of autophagic flux by chloroquine fully abrogated beneficial myocardial effects and its stimulation by rapamycin improved myocardial function in HFD wild type mice. As mitochondrial fission is necessary to mitophagy, increased fragmentation of mitochondrial network in HFD RAGE-/- mice may have facilitated removal of damaged mitochondria leading to better mitochondrial quality control. In conclusion, modulation of RAGE pathway may improve mitochondrial damage and myocardial dysfunction in HFD mice. Attenuation of cardiac oxidative stress and maintenance of healthy mitochondria population ensuring adequate energy supply may be involved in myocardial protection against HFD.

Comparison of fluid balance and hemodynamic and metabolic effects of sodium lactate versus sodium bicarbonate versus 0.9% NaCl in porcine endotoxic shock: a randomized, open-label, controlled study.

BACKGROUND: Sodium lactate has been shown to improve hemodynamics and avoid fluid overload. The objective of this study was to confirm a beneficial effect on fluid balance with sodium lactate infusion and to specify whether the advantage of lactate is related to a negative chloride balance, its particular metabolism, or simply its energy load. METHODS: This was an interventional, randomized, open-label, controlled experimental study. Fifteen female "large white" pigs (2 months old) were challenged with intravenous infusion of Escherichia coli endotoxin. Three groups of five animals were randomly assigned to receive different fluids: a treatment group received sodium lactate 11.2% (SL group); an isotonic control group received 0.9% NaCl (NC group); and a hypertonic control group, with the same amount of osmoles and sodium as the SL group, received sodium bicarbonate 8.4% (SB group). In order to provide the same energy load in the three groups, control groups were perfused with an equivalent energy supply. Statistical analysis was performed with non-parametric tests and the Dunn correction for multiple comparisons at p < 0.05. RESULTS: Fluid and chloride balance, hemodynamics, oxygenation markers, and microcirculatory parameters were measured over a 5-h period. Cumulative fluid balance was significantly lower in the SL group (550 (415-800) mL; median (interquartile range)) compared to the NC group (1100 (920-1640) mL, p = 0.01) and the SB group (935 (790-1220) mL, p = 0.03). Hemodynamics, cardiac efficiency, and microcirculation were significantly enhanced in the SL group, resulting in a significant improvement in oxygen delivery (SL group 417 (305-565) mL/min/m2 at 300 min versus the NC (207 (119-272) mL/min/m2, p = 0.01) and the SB (278, (211-315) mL/min/m2, p = 0.03) groups). Oxygenation markers (arterial oxygen partial pressure (PaO2)/inspired oxygen fraction (FiO2), mixed venous oxygen saturation (SvO2), and venoarterial carbon dioxide tension difference (Pv-aCO2) were enhanced with sodium lactate infusion. Chloride balance was equivalent in both hypertonic groups and significantly reduced compared to the NC group. CONCLUSION: Sodium lactate infusion improves fluid balance and hemodynamics. The advantage of lactate does not seem to be explained by its energy load or by the induced negative chloride balance with subsequent water movements.

Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction.

Adrenergic receptors couple to Gs-proteins leading to transmembrane adenylyl cyclase activation and cytosolic cyclic adenosine monophosphate (cAMP) production. Cyclic AMP is also produced in the mitochondrial matrix, where it regulates respiration through protein kinase A (PKA)-dependent phosphorylation of respiratory chain complexes. We hypothesized that a blunted mitochondrial cAMP-PKA pathway would participate in sepsis-induced heart dysfunction. Adult male mice were subjected to intra-abdominal sepsis. Mitochondrial respiration of cardiac fibers and myocardial contractile performance were evaluated in response to 8Br-cAMP, PKA inhibition (H89), soluble adenylyl cyclase inhibition (KH7), and phosphodiesterase inhibition (IBMX; BAY60-7550). Adenosine diphosphate (ADP)-stimulated respiratory rates of cardiac fibers were reduced in septic mice. Compared with controls, stimulatory effects of 8Br-cAMP on respiration rates were enhanced in septic fibers, whereas inhibitory effects of H89 were reduced. Ser-58 phosphorylation of cytochrome c oxidase subunit IV-1 was reduced in septic hearts. In vitro, incubation of septic cardiac fibers with BAY60-7550 increased respiratory control ratio and improved cardiac MVO2 efficiency in isolated septic heart. In vivo, BAY60-7550 pre-treatment of septic mice have limited impact on myocardial function. Mitochondrial cAMP-PKA signaling is impaired in the septic myocardium. PDE2 phosphodiesterase inhibition by BAY60-7550 improves mitochondrial respiration and cardiac MVO2 efficiency in septic mice.

Failure of statins in ARDS: the quest for the Holy Grail continues.

Experimental and clinical observational studies have shown potential benefits of statin administration in the acute respiratory distress syndrome (ARDS) by modulating inflammation and preventing worsening respiratory function. More recently, two randomized clinical trials failed to demonstrate an improved survival of ARDS patients treated with statins. In the first study, conducted by the ARDS Network, 745 patients with sepsis­associated ARDS were randomized within 48-hours of onset to receive either rosuvastatin or placebo. There was no significant difference between the rosuvastatin and placebo groups for hospital mortality (primary outcome, 29% vs. 25%, P=0.21) or ventilator­free days (15±11 vs. 15±11, respectively; P=0.96). In rosuvastatin­treated patients, renal and hepatic failure free­days were significantly lower than in the placebo group, raising serious safety concerns. In the second study (HARP-2 trial), 540 patients with ARDS were randomized within 48-hours of onset to receive either simvastatin (80 mg/day) or placebo. There was no significant difference between the study groups for number of ventilator­free days (primary outcome, 13±10 in the simvastatin vs. 12±10 in the placebo group, P=0.21) or 28-day mortality (22% vs. 27%, respectively; P=0.23). No significant difference in serious adverse events was reported between groups. Herein, we discuss the main reasons for these negative findings and consider where there could be a role for statins in ARDS patients.

Monitoring the microcirculation in critically ill patients.

Alterations in microvascular perfusion have been identified in critically ill patients, especially in sepsis but also in cardiogenic shock, after cardiac arrest, and in high-risk surgery patients. These alterations seem to be implicated in the development of organ dysfunction and are associated with outcome. Even though microvascular perfusion can sometimes be homogenously decreased as in acute hemorrhage or in non-resuscitated cardiogenic shock, heterogeneity of perfusion is observed in sepsis and in resuscitated hemorrhagic/cardiogenic shock. Heterogeneity of perfusion has major implications for monitoring, as many techniques cannot detect microcirculatory alterations when heterogeneity of flow is present in significant amount. Indeed, devices such as laser Doppler or O2 electrodes and near-infrared spectroscopy have a relatively large sampling volume and measurements are affected by the highest values in the field. Using these techniques during a vascular occlusion test may help to characterize microvascular reactivity; however, microvascular reactivity sometimes fails to represent actual microvascular perfusion. Videomicroscopic techniques can nowadays be applied at bedside but are still restricted to some selected patients (quiet or sedated patients). Tissue PCO2 is an elegant alternative but is not yet broadly used. In this manuscript, we discuss the main advantages and limitations of the techniques available for bedside evaluation of the microcirculation in critically ill patients.