Histopathological findings were correlated to severity and duration of ARDS. Using clinical criteria the revised Berlin definition for ARDS allowed the identification of severe ARDS of more than 72 hours as a homogeneous group of patients characterized by a high proportion of DAD.

Severe coronavirus disease is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophagemediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.

• Washing older blood before transfusion reduces plasma iron, improving outcomes from established infection in canines.• In contrast, washing fresh blood before transfusion increases in vivo plasma CFH release, worsening outcomes.In a randomized controlled blinded trial, 2-year-old purpose-bred beagles (n 5 24), with Staphylococcus aureus pneumonia, were exchanged-transfused with either 7-or 42-dayold washed or unwashed canine universal donor blood (80 mL/kg in 4 divided doses). Washing red cells (RBC) before transfusion had a significantly different effect on canine survival, multiple organ injury, plasma iron, and cell-free hemoglobin (CFH) levels depending on the age of stored blood (all, P < .05 for interactions). Washing older units of blood improved survival rates, shock score, lung injury, cardiac performance and liver function, and reduced levels of non-transferrin bound iron and plasma labile iron. In contrast, washing fresh blood worsened all these same clinical parameters and increased CFH levels. Our data indicate that transfusion of fresh blood, which results in less hemolysis, CFH, and iron release, is less toxic than transfusion of older blood in critically ill infected subjects. However, washing older blood prevented elevations in plasma circulating iron and improved survival and multiple organ injury in animals with an established pulmonary infection. Our data suggest that fresh blood should not be washed routinely because, in a setting of established infection, washed RBC are prone to release CFH and result in worsened clinical outcomes. (Blood. 2014;123(9):1403-1411 IntroductionTransfusion of older stored canine universal donor blood in a canine model of experimental Staphylococcus aureus pneumonia results in markedly increased lung injury and mortality rates.1 Transfusion with older blood is also associated with increased levels of cell-free hemoglobin (CFH), transferrin bound iron (TBI), non-TBI (NTBI) and plasma labile iron (PLI). NTBI represents iron excess bound to proteins that do not normally handle circulating iron, and PLI is the toxic iron moiety in plasma. Whereas increased nitric oxide scavenging by CFH causing vasoconstriction and vascular injury and increased available iron promoting bacterial growth represent 2 candidate mechanisms of injury, multiple other biological changes have been documented with increasing blood storage interval.2,3 Some of these changes involve the release into the plasma of biologically active proteins, microvesicles, potassium, acid, and plasticizer, all of which can be reduced by means of standard red cell (RBC) washing procedures. [4][5][6][7][8][9][10] The clinical effect(s) of washing on the RBC storage lesion has not been studied.RBC washing has long been performed to reduce potassium levels in stored blood transfused to neonates, debris from RBCs recovered during surgery, cryoprotectant glycerol from cryopreserved RBCs, and plasma proteins from blood intended for patients who have been sensitized to those proteins.11-13 Automated cell washers cap...

Current research is focusing on preventing extubation failure, especially in the most challenging cases. The use of weaning protocols - written or computerized - attempts to early identify patients who are able to breathe spontaneously and to hasten extubation, resulting in better outcomes. Nevertheless, individualized care is needed in the most vulnerable patients, trying to prompt weaning without exposing patients to unnecessary risks.

BACKGROUND In experimental pneumonia we found transfused older blood increased mortality and lung injury that was associated with increased in vivo hemolysis and elevated plasma cell-free Hb (CFH), non-transferrin bound (NTBI), and plasma labile (PLI) iron levels. In the present study, we additionally analyze identically treated animals that received lower or higher bacterial doses. STUDY DESIGN AND METHODS Two-year-old purpose-bred beagles (n=48) challenged intrabronchially with Staphylococcus aureus [0 (n=8), 1.0 (n=8), 1.25 (n=24) and ≥1.5 (n=8) × 109 CFU/kg) were exchange transfused with either 7- or 42-day-old canine universal donor blood (80 ml/kg in 4 divided doses). RESULTS The greater increases in cell-free Hb (CFH) with older blood over days following exchange proved relatively independent of bacterial dose. The lesser increases in CFH observed with fresher blood were bacterial dose-dependent potentially related to bacterial hemolysins. Without bacterial challenge, levels of CFH, NTBI, and PLI were significantly higher with older vs. fresher blood transfusion but there was no significant measurable injury. With higher dose bacterial challenge, the elevated NTBI and PLI levels declined more rapidly and to a greater extent after transfusion with older vs. fresher blood, and older blood was associated with significantly worse shock, lung injury, and mortality. CONCLUSION The augmented in vivo hemolysis of transfused older red cells appears to result in excess plasma cell-free Hb and iron release, which requires the presence of established infection to worsen outcome. These data suggest that transfused older red cells increase the risks from infection in septic subjects.

Background and Objectives Preclinical studies generated the hypothesis that older stored red blood cells (RBCs) can increase transfusion risks. To examine the most updated and complete clinical evidence and compare results between two trial designs, we assessed both observational studies and randomized controlled trials (RCTs) studying the effect of RBC storage age on mortality. Materials and Methods Five databases were searched through December 2014 for studies comparing mortality using transfused RBCs having longer and shorter storage times. Results Analysis of six RCTs found no significant differences in survival comparing current practice (average storage age of 2 to 3 weeks) to transfusion of 1- to 10-day-old RBCs (OR 0·91, 95% CI 0·77–1·07). RBC storage age was lower in RCTs vs. observational studies (P = 0·01). The 31 observational studies found an increased risk of death (OR 1·13, 95% CI 1·03–1·24) (P = 0·01) with increasing age of RBCs, a different mortality effect than RCTs (P = 0·02). Conclusion RCTs established that transfusion of 1- to 10-day-old stored RBCs is not superior to current practice. The apparent discrepancy in mortality between analyses of RCTs and observational studies may in part relate to differences in hypotheses tested and ages of stored RBCs studied. Further trials investigating 1-to 10-day-old stored RBC benefits would seem of lower priority than studies to determine whether 4- to 6-week stored units have safety and efficacy equivalent to the 2- to 3-week-old stored RBCs commonly transfused today.

BACKGROUND In canine models, transfused older stored red blood cells (RBCs) hemolyze in vivo resulting in significantly increased intravascular cell free hemoglobin (CFH) and non-transferrin bound iron (NTBI). During canine bacterial pneumonia with septic shock, but not in controls, older stored RBCs were associated with significantly increased lung injury and mortality. It is unknown if in shock without infection transfusion of older RBCs will result in similar adverse effects. STUDY DESIGN AND METHODS Two-year-old purpose-bred beagles (n=12) were transfused similar quantities of either older (42-day) or fresher (7-day) stored universal donor canine RBCs 2.5 hours after undergoing controlled hemorrhage (55ml/kg). RESULTS With older transfused RBCs, CFH (p<0.0001) and NTBI (p=0.004) levels increased, but lung injury (p=0.01) and C-reactive protein levels (p=0.002) declined and there was a trend toward lower mortality (18% versus 50%). All 3 deaths after transfused fresher red cells resulted from hepatic fractures. Lowered exogenous norepinephrine requirements (p<0.05) and cardiac outputs (p<0.05) after older transfused RBCs were associated with increased CFH levels that have known vasoconstrictive nitric oxide scavenging capability. CONCLUSIONS In hemorrhagic shock, older RBCs altered resuscitation physiology but did not worsen clinical outcomes. Elevated CFH may lower norepinephrine requirements and cardiac outputs ameliorating reperfusion injuries. With hemorrhagic shock, NTBI levels persist in contrast to the increased clearance, lung injury, and mortality in the previously reported infection model. These preclinical data suggest that whereas iron derived from older RBCs promotes bacterial growth, worsening septic shock mortality during infection, release of CFH and NTBI during hemorrhagic shock is not necessarily harmful.

This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids (EpFA), which are natural mediators that reduce pain, resolve inflammation, and maintain normal blood pressure. EC5026 is a slow-tight binding transitionstate mimic that inhibits the soluble epoxide hydrolase (sEH) at picomolar concentrations. The sEH rapidly degrades EpFA; thus, inhibiting sEH increases EpFA in vivo and confers beneficial effects. This mechanism addresses disease states by shifting endoplasmic reticulum stress from promoting cellular senescence and inflammation toward cell survival and homeostasis. We describe the synthesis and optimization of EC5026 and its development through human Phase 1a trials with no drug-related adverse events. Additionally, we outline fundamental work leading to discovery of the analgesic and inflammationresolving CYP450 branch of the arachidonate cascade.