Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage.

Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls.

Dimethyl malonate slows succinate accumulation and preserves cardiac function in a swine model of hemorrhagic shock.

BACKGROUND: Succinate (SI) is a citric acid cycle metabolite that accumulates in tissues during hemorrhagic shock (HS) due to electron transport chain uncoupling. Dimethyl malonate (DMM) is a competitive inhibitor of SI dehydrogenase, which has been shown to reduce SI accumulation and protect against reperfusion injury. Whether DMM can be therapeutic after severe HS is unknown. We hypothesized that DMM would prevent SI buildup during resuscitation (RES) in a swine model of HS, leading to better physiological recovery after RES. METHODS: The carotid arteries of Yorkshire pigs were cannulated with a 5-Fr catheter. After placement of a Swan-Ganz catheter and femoral arterial line, the carotid catheters were opened and the animals were exsanguinated to a mean arterial pressure (MAP) of 45 mm. After 30 minutes in the shock state, the animals were resuscitated to a MAP of 60 mm using lactated ringers. A MAP above 60 mm was maintained throughout RES. One group received 10 mg/kg of DMM (n = 6), while the control received sham injections (n = 6). The primary end-point was SI levels. Secondary end-points included cardiac function and lactate. RESULTS: Succinate levels increased from baseline to the 20-minute RES point in control, while the DMM cohort remained unchanged. The DMM group required less intravenous fluid to maintain a MAP above 60 (450.0 vs. 229.0 mL; p = 0.01). The DMM group had higher pulmonary capillary wedge pressure at the 20-minute and 40-minute RES points. The DMM group had better recovery of cardiac output and index during RES, while the control had no improvement. While lactate levels were similar, DMM may lead to increased ionized calcium levels. DISCUSSION: Dimethyl malonate slows SI accumulation during HS and helps preserve cardiac filling pressures and function during RES. In addition, DMM may protect against depletion of ionized calcium. Dimethyl malonate may have therapeutic potential during HS.

Does consecutive influenza vaccination reduce protection against influenza: A systematic review and meta-analysis.

INTRODUCTION: Vaccination against influenza on an annual basis is widely recommended, yet recent studies suggest consecutive vaccination may reduce vaccine effectiveness (VE). PURPOSE: To assess whether when examining the entirety of existing data consecutive influenza vaccination reduces VE compared to current season influenza vaccination. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 26, 2017; citations of included studies. STUDY SELECTION: Randomized, controlled trials (RCTs) and observational studies of children, adults and/or the elderly that reported laboratory-confirmed influenza infection over 2 or more consecutive influenza seasons were eligible. DATA EXTRACTION: Data related to study characteristics, participant demographics, cases of influenza infection by vaccination group and risk of bias assessment was extracted in duplicate. DATA SYNTHESIS: Five RCTs involving 11,987 participants did not show a significant reduction in VE when participants vaccinated in two consecutive seasons (VE 71%, 95% CI 62-78%) were compared to those vaccinated in the current season (VE 58%, 95% CI 48-66%) (odds ratio [OR] 0.88, 95% CI 0.62-1.26, p = 0.49, I2 = 39%). Twenty-eight observational studies involving 28,627 participants also did not show a reduction (VE for two consecutive seasons 41%, 95% CI 30-51% compared to VE for current season 47%, 95% CI 39-54%; OR 1.14, 95% CI 0.98-1.32, p = 0.09, I2 = 63%). Results from subgroup analyses by influenza type/subtype, vaccine type, age, vaccine match and co-morbidity support these findings; however, dose-response results were inconsistent. Certainty in the evidence was assessed to be very low due to unexplained heterogeneity and imprecision. LIMITATIONS: The inclusion of studies with relatively small sample sizes and low event rates contributed to the imprecision of summary VE and OR estimates, which were based on unadjusted data. CONCLUSION: Available evidence does not support a reduction in VE with consecutive influenza vaccination, but the possibility of reduced effectiveness cannot be ruled out due to very low certainty in this evidence. FUNDING SOURCE: CIHR Foundation Grant (PROSPERO: CRD42017059893).