Browsing by Subject "Hemorrhage"
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Item Hemodynamic Oscillations: Physiological Consequences and Therapeutic Potential(2022-05) Anderson, Garen K.; Rickards, Caroline A.; Goulopoulou, Styliani; Romero, Steven A.; Cunningham, J. ThomasHemorrhage, or massive blood loss, continues to be a leading cause of preventable death. Therapeutic approaches that protect vital organ function are needed to improve outcomes from hemorrhage. In this dissertation, I explored the use of hemodynamic oscillations below the respiratory frequency (i.e., oscillations in arterial pressure and cerebral blood flow) as a novel technique for protecting tissue oxygenation during hemorrhage. In the first study of this dissertation, I hypothesized that hemodynamic oscillations would contribute to improved tolerance to central hypovolemia simulating hemorrhage. In further assessing the role of arterial blood gases on the physiological responses to forcing hemodynamic oscillations during a simulated hemorrhage, I hypothesized that forcing hemodynamic oscillations during simulated hemorrhage would protect tissue oxygenation during conditions of hypoxia and isocapnia, and improve cerebral blood flow. I also hypothesized that this protection would occur equally for both females and males. To address these hypotheses, I conducted five independent studies using lower body negative pressure as a method of simulating hemorrhage in healthy, conscious humans: in one study I utilized a maximal step-wise LBNP protocol to assess endogenous hemodynamic oscillations and tolerance to simulated hemorrhage, and in the remaining 4 studies, I utilized oscillatory and non-oscillatory LBNP to assess the potential therapeutic utility of forcing hemodynamic oscillations during simulated hemorrhage. The major findings from these investigations were: 1) greater amplitude of low frequency oscillations in arterial pressure are associated with greater LBNP tolerance, but the relative time to peak oscillatory power was not dependent on tolerance; 2) forced hemodynamic oscillations protect cerebral tissue oxygenation without protecting cerebral blood flow during the combined stress of simulated hemorrhage and hypobaric hypoxia; 3) isocapnia with simulated hemorrhage prevents the reduction in cerebral blood flow and tissue oxygenation, and forced hemodynamic oscillations during this stress protects stroke volume and arterial pressure; 4) females exhibit protected muscle tissue oxygenation to simulated hemorrhage, and the reduction in muscle tissue oxygenation in males can be attenuated with forced hemodynamic oscillations; and 5) forced hemodynamic oscillations at high altitude are greater in amplitude and result in similar protection of cerebral tissue oxygenation as low altitude conditions. These findings contribute to the growing body of literature highlighting the potential utility of oscillatory hemodynamics for therapeutic application.Item Oxidative Stress and Inflammation during Simulated Hemorrhage(2018-05) Park, Flora S.; Rickards, Caroline A.; Mallet, Robert T.; Goulopoulou, Styliani; Warren, Joseph E.Background: Hemorrhage is a leading cause of potentially preventable death in both civilian and military trauma settings. Lower body negative pressure (LBNP) is a validated, non-invasive, and reproducible approach to simulate hemorrhage by inducing central hypovolemia in healthy conscious humans. The oxidative stress and inflammatory response to simulated hemorrhage via LBNP has not been quantified. We hypothesized that systemic markers of oxidative stress and inflammation will increase with application of maximal LBNP. Methods: 15 human subjects (11M/4F) were recruited for a LBNP exposure to presyncope (chamber pressure was progressively reduced every 5-min in a stepwise manner). Arterial pressure and stroke volume (SV) were measured continuously via finger photoplethysmography, muscle oxygen saturation (SmO2) was measured via near-infrared spectroscopy, and venous blood samples were collected. Plasma samples were analyzed for a global marker of oxidative stress [F2-isoprostanes (F2-IsoP)] and inflammatory markers (IL-1beta, IL-2, IL-4, IL-6, IL-10, TNF-alpha, and CRP). Results: The magnitude of central hypovolemia, indexed by % change SV, ranged from -27-74%. Maximal LBNP induced a -12.6?2.6% decrease in mean arterial pressure (MAP, P[less than]0.001). F2-IsoP increased by 28.5?11.6% (P=0.05) from baseline (24?2 pg/ml) to presyncope (29?3 pg/ml). The increase in F2-IsoP was not associated with % change SV (r=0.21, p=0.46), % change MAP (r=0.05, p=0.86), the maximum level of LBNP attained (r=0.35, p=0.20), or % change SmO2 (r=0.05, p=0.90). TNF-alpha and CRP increased by 3.7% (p=0.02, n=4) and 26.9% (p=0.07, n=6). TNF-alpha and CRP responses were not associated with % change SV (r=0.50, p=0.50 and r=0.36, p=0.49), % change MAP (r=0.91, p=0.09 and r=0.006, p = 0.99), the maximum level of LBNP attained (r=0.39, p=0.61 and r=0.23, p=0.66), or % change SmO2 (r=0.75, p=0.46 and r=0.90, p=0.11). Conclusion: Simulated hemorrhage induced by LBNP to presyncope elicited an increase in oxidative stress and inflammation. These findings have important implications for the study of hemorrhage using LBNP, and future investigations of targeted interventions.Item Pyruvate-Enhanced Fluid Resuscitation for Hemorrhagic Shock and Hindlimb Ischemia(2009-05-01) Flaherty, Devin C.; Mallet, Robert T.Traumatic blood loss often necessitates the use of resuscitative fluids to replenish blood volume and stabilize blood pressure. The use of tourniquets to achieve hemostasis imposes ischemia-reperfusion on wounded limbs after release. Resuscitation with the physiological antioxidant and natural intermediary metabolite pyruvate may abrogate reperfusion injury of muscle by scavenging oxyradicals and stabilizing cytoprotective proteins. This study was designed to determine the effects of pyruvate in the setting of hemorrhagic shock with resuscitation and hindlimb ischemia-reperfusion. All experiments were conducted on isoflurane-anesthetized male goats. A controlled hemorrhage was performed to lower mean arterial pressure (MAP) to c. 50 mmHg, then the right femoral artery and vein were occluded for 90 min. Lactate Ringer’s (LR) or pyruvate Ringer’s (PR) was infused intravenously (10 ml/min) for 90 min, from 30 min occlusion until 30 min after reperfusion. At 4 h reperfusion, the right gastrocnemius muscle and left ventricular myocardium were biopsied and flash-frozen for analyses of metabolites, enzymes, pro- and anti-apoptotic proteins and markers of oxidative and inflammatory stress. During the first phase of experimentation we hypothesized that controlled resuscitation with PR vs. LR more effectively stabilizes MAP and attenuates myocardial inflammation post-resuscitation. MAP (mmHg) was increased in PR (59 ± 4) vs. LR (47 ± 3) resuscitated goats (p During the second phase of experimentation, we hypothesized that PR resuscitation would protect ischemic hindlimb muscle in the setting of hemorrhagic shock and limb reperfusion. Lactate dehydrogenase and creatine kinase activities fell by 36 and 20%, respectively in LR-resuscitated vs. sham muscle (p We conclude that 1) Systemic hypotension and hindlimb ischemia-reperfusion with conventional LR treatment imposed pro-oxidative and pro-inflammatory stress both systemically and locally, thus preventing stabilization of MAP during recovery and initiating apoptotic mechanisms in the hindlimb musculature; 2) Pyruvate-fortified Ringer’s effectively stabilized hemodynamics and dampened systemic inflammation after hemorrhagic shock with resuscitation and hindlimb ischemia-reperfusion; 3) PR-fortified resuscitation blunted oxidative and inflammatory stress within the ischemic hindlimb and suppressed pro-apoptotic signaling. These investigations demonstrate the anti-oxidative and anti-inflammatory effects of pyruvate in a system exposed to hemorrhagic shock with fluid resuscitation, as well as identify the cytoprotection pyruvate affords tissue experiencing ischemia-reperfusion.Item Sex Differences in Oxidative Stress and Inflammation Responses During and After Simulated Hemorrhage(2020-05) Barnes, Haley J.; Rickards, Caroline A.; Hodge, Lisa M.; Mallet, Robert T.; Goulopoulou, StylianiHemorrhage (i.e., massive blood loss) induces an oxidative stress and inflammatory response that can persist even following hemostasis and resuscitation. Premenopausal females exhibit a survival advantage following hemorrhage compared to young males. In this study, we hypothesized that young males would elicit a greater oxidative stress and inflammatory response compared to young females, both during and after a simulated hemorrhage via lower body negative pressure (LBNP). Young, healthy human subjects (10F; 10M) participated in a stepwise-LBNP protocol to presyncope. Venous blood samples were collected at baseline, presyncope, and 1-h into recovery (i.e., following "resuscitation"). The oxidative stress response was assessed via circulating F2-isoprostanes (F2-IsoP) using gas chromatography-negative ion chemical ionization-mass spectrometry. The inflammatory response was assessed via circulating tissue necrosis factor-α (TNF-α), C-Reactive Protein (CRP), thymus and activation-regulated chemokine (TARC), and interleukin (IL)-5, IL-6, IL-7, and IL-10, using a MSD® Multiplex assay. LBNP tolerance time was similar between male and female subjects (Males, 1592±124 s vs. Females, 1437 ± 113 s; P = 0.37). There was no effect of time or sex on the absolute or relative change in F2-IsoP during or after LBNP (P ≥ 0.12). However, male subjects exhibited a greater pro-and anti-inflammatory response during and after LBNP compared to female subjects (Notable markers at 1-h recovery compared to baseline, IL-6: Males, 101.4 ± 138.9% vs. Females, 12.3 ± 34.0%, P = 0.06; IL-10: Males, 71.1 ± 133.3% vs. Females, -2.2 ± 11.8%; P = 0.06). These data suggest that there may be a potential sex difference in the inflammatory response to simulated hemorrhage.