The Experts below are selected from a list of 201 Experts worldwide ranked by ideXlab platform

Andre F Palmer - One of the best experts on this subject based on the ideXlab platform.

  • Polymerized human Hemoglobin increases the effectiveness of cisplatin based chemotherapy in non small cell lung cancer
    Oncotarget, 2020
    Co-Authors: Alfredo Lucas, Andre F Palmer, Donald A Belcher, Carlos Munoz, Alexander T Williams, Pedro Cabrales
    Abstract:

    Cisplatin is a promising therapeutic for the treatment of non-small cell lung cancer (NSCLC). Unfortunately, a significant portion of NSCLC patients relapse due to cisplatin chemoresistance. This chemoresistance is thought to be primarily associated with hypoxia in the tumor microenvironment. Administration of Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) is a promising strategy to alleviate hypoxia in the tumor, which may make cisplatin more effective. In this study, we administered a high O2 affinity, relaxed state (R-state) Polymerized Hemoglobin (PolyHb) to three different NSCLC cell lines cultured in vitro and implanted in vivo into healthy mice. The R-state PolyHb administered in this study is unable to deliver O2 unless under severe hypoxia which significantly limits its oxygenation potential. In vitro sensitivity studies indicate that the administration of PolyHb increases the effectiveness of cisplatin under hypoxic conditions. Additional animal studies revealed that co-administration of PolyHb with cisplatin attenuated tumor growth without alleviating hypoxia. Analysis of reactive O2 species production in the presence of hypoxic culture indicates that exogenous ROS production by oxidized PolyHb may the mechanism of chemosensitization. This ROS mechanism, coupled with oxygenation, may be a potential chemosensitizing strategy for use in NSCLC treatment.

  • apoHemoglobin haptoglobin complexes attenuate the hypertensive response to low molecular weight Polymerized Hemoglobin
    Blood Advances, 2020
    Co-Authors: Donald A Belcher, Carlos Munoz, Ivan S Pires, Alexander T Williams, Pedro Cabrales, Andre F Palmer
    Abstract:

    Abstract Polymerized Hemoglobin (PolyHb) is a promising Hemoglobin (Hb)-based oxygen carrier currently undergoing development as a red blood cell substitute. Unfortunately, commercially developed products are composed of low-molecular-weight (LMW) PolyHb molecules, which extravasate, scavenge nitric oxide, and result in vasoconstriction and hypertension. The naturally occurring Hb-scavenging species haptoglobin (Hp), combined with the purified heme-scavenging species apoHemoglobin (apoHb), is a potential candidate to alleviate the pressor effect of PolyHb. This study evaluated the protective activity of administering the apoHb-Hp complex to mitigate the vasoactive response induced by the transfusion of LMW PolyHb. Hp binding to PolyHb was characterized in vitro. The effectiveness of apoHb–Hp administration on reducing the vasoconstriction and pressor effects of PolyHb was assessed by measuring systemic and microcirculatory hemodynamics. Transfusion of LMW PolyHb to vehicle control pretreated animals increased mean arterial pressure while decreasing arteriole diameter and functional capillary density. However, transfusion of LMW PolyHb to apoHb–Hp pretreated animals prevented changes in mean arterial pressure, heart rate, arteriole diameter, blood flow, and functional capillary density relative to before transfusion. These results indicate that the increased size of PolyHb after binding to the apoHb-Hp complex may help compartmentalize PolyHb in the vascular space and thus reduce extravasation, nitric oxide scavenging, and toxicity responsible for vasoconstriction and systemic hypertension.

  • Polymerized Hemoglobin with increased molecular size reduces toxicity in healthy guinea pigs
    ACS Applied Bio Materials, 2020
    Co-Authors: Alexander T Williams, Andre F Palmer, Donald A Belcher, Cynthia R Muller, Crystal Boldenrush, Allyn M Eaker, Pedro Cabrales
    Abstract:

    Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) have been developed as an alternative to red blood cells (RBCs) for use in transfusion medicine. HBOCs have many benefits over RBCs; however, prev...

  • resuscitation from hemorrhagic shock with fresh and stored blood and Polymerized Hemoglobin
    Shock, 2020
    Co-Authors: Alexander T Williams, Andre F Palmer, Carlos Munoz, Alfredo Lucas, Cynthia R Muller, Crystal Boldenrush, Pedro Cabrales
    Abstract:

    BACKGROUND Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been proposed as alternatives to blood for decades. Previous studies demonstrated that large molecular diameter HBOCs based on Polymerized bovine Hb (PolybHb) attenuate Hb side-effects and toxicity. The objective of this study was to test the safety and efficacy of tense state PolybHb after long-term storage. METHODS AND RESULTS PolybHb was subjected to diafiltration to remove low molecular weight (< 500 kDa) species and stored for 2 years. PolybHb was studied in parallel with blood, collected from rats and stored leukodepleted under blood bank conditions for 3 weeks. Rats were hemorrhaged and resuscitated to 90% of the blood pressure before the hemorrhage with fresh blood, stored blood, fresh PolybHb, or 2-year-stored PolybHb. Hemorrhagic shock impaired oxygen delivery and cardiac function. Resuscitation restored blood pressure and cardiac function, but stored blood required a significantly larger transfusion volume to recover from shock compared with fresh blood and PolybHb (fresh and stored). Stored blood transfusion elevated markers of organ damage compared with all other groups. CONCLUSIONS These studies indicate that large molecular diameter PolybHb is as efficacious as fresh blood in restoring cardiac function and confirm the lack of degradation of PolybHb's safety or efficacy during long-term storage.

  • controlled polymerization and ultrafiltration increase the consistency of Polymerized Hemoglobin for use as an oxygen carrier
    Bioconjugate Chemistry, 2020
    Co-Authors: Donald A Belcher, Ivan S Pires, Clayton Cuddington, Evan L Martindale, Andre F Palmer
    Abstract:

    Polymerized human Hemoglobins (PolyhHbs) are a promising class of red blood cell substitute for use in transfusion medicine. Unfortunately, the application of the commonly used glutaraldehyde cross...

Pedro Cabrales - One of the best experts on this subject based on the ideXlab platform.

  • Polymerized human Hemoglobin increases the effectiveness of cisplatin based chemotherapy in non small cell lung cancer
    Oncotarget, 2020
    Co-Authors: Alfredo Lucas, Andre F Palmer, Donald A Belcher, Carlos Munoz, Alexander T Williams, Pedro Cabrales
    Abstract:

    Cisplatin is a promising therapeutic for the treatment of non-small cell lung cancer (NSCLC). Unfortunately, a significant portion of NSCLC patients relapse due to cisplatin chemoresistance. This chemoresistance is thought to be primarily associated with hypoxia in the tumor microenvironment. Administration of Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) is a promising strategy to alleviate hypoxia in the tumor, which may make cisplatin more effective. In this study, we administered a high O2 affinity, relaxed state (R-state) Polymerized Hemoglobin (PolyHb) to three different NSCLC cell lines cultured in vitro and implanted in vivo into healthy mice. The R-state PolyHb administered in this study is unable to deliver O2 unless under severe hypoxia which significantly limits its oxygenation potential. In vitro sensitivity studies indicate that the administration of PolyHb increases the effectiveness of cisplatin under hypoxic conditions. Additional animal studies revealed that co-administration of PolyHb with cisplatin attenuated tumor growth without alleviating hypoxia. Analysis of reactive O2 species production in the presence of hypoxic culture indicates that exogenous ROS production by oxidized PolyHb may the mechanism of chemosensitization. This ROS mechanism, coupled with oxygenation, may be a potential chemosensitizing strategy for use in NSCLC treatment.

  • apoHemoglobin haptoglobin complexes attenuate the hypertensive response to low molecular weight Polymerized Hemoglobin
    Blood Advances, 2020
    Co-Authors: Donald A Belcher, Carlos Munoz, Ivan S Pires, Alexander T Williams, Pedro Cabrales, Andre F Palmer
    Abstract:

    Abstract Polymerized Hemoglobin (PolyHb) is a promising Hemoglobin (Hb)-based oxygen carrier currently undergoing development as a red blood cell substitute. Unfortunately, commercially developed products are composed of low-molecular-weight (LMW) PolyHb molecules, which extravasate, scavenge nitric oxide, and result in vasoconstriction and hypertension. The naturally occurring Hb-scavenging species haptoglobin (Hp), combined with the purified heme-scavenging species apoHemoglobin (apoHb), is a potential candidate to alleviate the pressor effect of PolyHb. This study evaluated the protective activity of administering the apoHb-Hp complex to mitigate the vasoactive response induced by the transfusion of LMW PolyHb. Hp binding to PolyHb was characterized in vitro. The effectiveness of apoHb–Hp administration on reducing the vasoconstriction and pressor effects of PolyHb was assessed by measuring systemic and microcirculatory hemodynamics. Transfusion of LMW PolyHb to vehicle control pretreated animals increased mean arterial pressure while decreasing arteriole diameter and functional capillary density. However, transfusion of LMW PolyHb to apoHb–Hp pretreated animals prevented changes in mean arterial pressure, heart rate, arteriole diameter, blood flow, and functional capillary density relative to before transfusion. These results indicate that the increased size of PolyHb after binding to the apoHb-Hp complex may help compartmentalize PolyHb in the vascular space and thus reduce extravasation, nitric oxide scavenging, and toxicity responsible for vasoconstriction and systemic hypertension.

  • Polymerized Hemoglobin with increased molecular size reduces toxicity in healthy guinea pigs
    ACS Applied Bio Materials, 2020
    Co-Authors: Alexander T Williams, Andre F Palmer, Donald A Belcher, Cynthia R Muller, Crystal Boldenrush, Allyn M Eaker, Pedro Cabrales
    Abstract:

    Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) have been developed as an alternative to red blood cells (RBCs) for use in transfusion medicine. HBOCs have many benefits over RBCs; however, prev...

  • resuscitation from hemorrhagic shock with fresh and stored blood and Polymerized Hemoglobin
    Shock, 2020
    Co-Authors: Alexander T Williams, Andre F Palmer, Carlos Munoz, Alfredo Lucas, Cynthia R Muller, Crystal Boldenrush, Pedro Cabrales
    Abstract:

    BACKGROUND Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been proposed as alternatives to blood for decades. Previous studies demonstrated that large molecular diameter HBOCs based on Polymerized bovine Hb (PolybHb) attenuate Hb side-effects and toxicity. The objective of this study was to test the safety and efficacy of tense state PolybHb after long-term storage. METHODS AND RESULTS PolybHb was subjected to diafiltration to remove low molecular weight (< 500 kDa) species and stored for 2 years. PolybHb was studied in parallel with blood, collected from rats and stored leukodepleted under blood bank conditions for 3 weeks. Rats were hemorrhaged and resuscitated to 90% of the blood pressure before the hemorrhage with fresh blood, stored blood, fresh PolybHb, or 2-year-stored PolybHb. Hemorrhagic shock impaired oxygen delivery and cardiac function. Resuscitation restored blood pressure and cardiac function, but stored blood required a significantly larger transfusion volume to recover from shock compared with fresh blood and PolybHb (fresh and stored). Stored blood transfusion elevated markers of organ damage compared with all other groups. CONCLUSIONS These studies indicate that large molecular diameter PolybHb is as efficacious as fresh blood in restoring cardiac function and confirm the lack of degradation of PolybHb's safety or efficacy during long-term storage.

  • hemorrhagic shock resuscitation using a Polymerized Hemoglobin oxygen carrier versus whole blood 707 5
    The FASEB Journal, 2014
    Co-Authors: Daniel Ortiz, Pedro Cabrales
    Abstract:

    The development of an efficient alternative to blood transfusion to treat severe hemorrhage is of great public health importance, especially in far forward scenarios where blood is not available. Hemoglobin (Hb) based oxygen (O2) carriers (HBOCs) have been developed to address this need. Hemopure® (HBOC-201, bovine Hb glutamer-250, OPK Biotech,Cambridge, MA, USA), a Polymerized Hb based HBOC, has been approved for clinical use in South Africa and Russia. At the time of its approval, however, few studies aimed to understand Hemopure’s function, administration, and adverse effects compared to blood. We have used intravital microscopy to study the microcirculation hemodynamics (arteriolar and venular diameters and blood flow and functional capillary density (FCD)) and oxygenation outcomes of Hemopure® administration at different Hb concentrations _4, 8, and 12 gHb/dL_ compared to fresh blood transfusion for resuscitation from hemorrhagic shock. Experiments are performed in unanesthetized hamsters instrumente...

Anirban Banerjee - One of the best experts on this subject based on the ideXlab platform.

  • Polymerized Hemoglobin induces heme oxygenase 1 protein expression and inhibits intercellular adhesion molecule 1 protein expression in human lung microvascular endothelial cells
    Journal of The American College of Surgeons, 2005
    Co-Authors: Aaron M Cheng, Jeffrey L Johnson, Ernest E Moore, Mark D Walsh, Peter K Moore, Anirban Banerjee
    Abstract:

    Background Our clinical trials using a Polymerized Hemoglobin solution (PolyHb) as a red cell substitute in severely injured patients suggested that this Hemoglobin-based oxygen carrier has a systemic antiinflammatory effect. Heme oxygenase-1 (HO-1) has recently been shown to be cytoprotective, and is known to be induced by heme moieties. We investigated the effects of this Hemoglobin-based oxygen carrier on HO-1 induction and proinflammatory activation of pulmonary endothelium. Study design Human lung microvascular endothelial cells were grown to confluence and preincubated with either cell media (control) or with an equal volume mixture of Polymerized Hemoglobin/cell media (experimental). The cell cultures were subsequently stimulated with lipopolysaccharide. HO-1 expression was detected by protein immunoblot and further quantified by ELISA; intercellular adhesion molecule-1 protein expression was measured by flow cytometry. Results Polymerized Hemoglobin induced synthesis of HO-1 protein in human lung microvascular endothelial cells and, concurrently, inhibited lipopolysaccharide-induced intercellular adhesion molecule-1 protein cell surface expression. Conclusions Polymerized Hemoglobin attenuates lipopolysaccharide-stimulated expression of intercellular adhesion molecule-1 protein, which is associated with upregulation of the cytoprotective protein HO-1 in human pulmonary endothelial cells. This antiinflammatory effect offers a novel mechanism by which Hemoglobin-based oxygen carrier solutions may be exploited therapeutically as resuscitative fluids.

  • insights from studies of blood substitutes in trauma
    Shock, 2005
    Co-Authors: Ernest E Moore, Aaron M Cheng, Takayuki Masuno, Jeffrey L Johnson, Anirban Banerjee
    Abstract:

    Most authorities believe that the greatest need for blood substitutes is in patients with unanticipated acute blood loss, and trauma is the most likely scenario. The blood substitutes reaching advanced clinical trials today are red blood cell (RBC) substitutes, derived from Hemoglobin. The Hemoglobin-based oxygen carriers (HBOCs) tested currently in FDA Phase III clinical trials are Polymerized Hemoglobin solutions. The standard approach to restoring oxygen delivery in hemorrhagic shock has been crystalloid administration to expand intravascular volume, followed by stored RBCs for critical anemia. However, allogenic RBCs may have adverse immunoinflammatory effects that increase the risk of postinjury multiple organ failure (MOF). Phase II clinical trials, as well as in vitro and in vivo work, suggest that resuscitation with a HBOC-in lieu of stored RBCs-attenuates the systemic inflammatory response invoked in the pathogenesis of MOF. Specifically, an HBOC has been shown to obviate stored RBC provoked neutrophil priming, endothelial activation, and systemic release of interleukins 6, 8, and 10. Based on this background and work by others, we have initiated a multicenter prehospital trial in which severely injured patients with major blood loss (systemic blood pressure <90 mmHg) are randomized to initial field resuscitation with crystalloid versus HBOC. During the hospital phase, the control group is further resuscitated with stored RBCs, whereas the study group receives HBOC (up to 6 units) in the first 12 h. The primary study endpoint is 30-day mortality, and secondary endpoints include reduction in allogenic RBCs, Hemoglobin levels <5 g/dL, uncrossmatched RBCs, and MOF. The potential efficacy of HBOCs extends beyond the temporary replacement for stored RBCs. Hemoglobin solutions might ultimately prove superior in delivering oxygen to ischemic or injured tissue. The current generation of HBOCs can be lifesaving for acute blood loss today, but the next generation might be biochemically tailored for specific clinical indications.

  • anti oxidant heme oxygenase 1 is induced by a Polymerized Hemoglobin solution in human pulmonary endothelial cells
    Journal of The American College of Surgeons, 2004
    Co-Authors: Aaron M Cheng, Jeffrey L Johnson, Ernest E Moore, Eric L Sarin, Christopher C Silliman, Anirban Banerjee
    Abstract:

    Abstract Introduction: In previous clinical trials with severely injured patients, we observed that resuscitation with a Polymerized Hemoglobin solution (PolyHb) compared to stored pRBCs reduced circulating plasma levels of pro-inflammatory cytokines IL-6 and IL-8 at 6–12 hours after injury. HO-1, the inducible isoform of the anti-oxidant protein heme-oxygenase, is present in most tissues and can be induced by heme products. HO-1 has been shown to protect against ischemic tissue injury. We hypothesize that PolyHb can induce HO-1 in human lung microvascular endothelial cells (HMVEC). Methods: HMVEC cultures were grown to > 80% confluence on 12-well plates and incubated for 2hrs, 5hrs, 8hrs, or 10hrs with a 50% (v/v) mixture of a Polymerized Hemoglobin solution with cell culture media. Endothelial cell lysates were collected at each timepoint and HO-1 protein expression was detected by Western blot. HO-1 protein was quantified in cell lysates by ELISA. Results: HO-1 protein was detected by Western blot in HMVEC cultures after incubation periods of 5hrs, 8hrs, and 10hrs with PolyHb. By ELISA, cells incubated with PolyHb for 2hrs, 5hrs, 8hrs, and 10hrs showed a 1.1-fold, 4-fold, 7-fold, and 10-fold increase, respectively, in HO-1 protein as compared to control cells not exposed to PolyHb. Conclusions: Polymerized Hemoglobin can induce heme-oxygenase 1 in human lung microvascular endothelial cells. Heme-oxygenase 1 activity may explain the anti-inflammatory effects we observed in clinical trials and could be exploited for tissue protection following trauma or ischemia.

Ernest E Moore - One of the best experts on this subject based on the ideXlab platform.

  • postinjury resuscitation with human Polymerized Hemoglobin prolongs early survival a post hoc analysis
    Journal of Trauma-injury Infection and Critical Care, 2011
    Co-Authors: Andrew C Bernard, Ernest E Moore, Frederick A. Moore, George A Hides, Brian J Guthrie, Laurel Omert, Steven A. Gould
    Abstract:

    Hemoglobin-based oxygen carriers (HBOCs) may be useful in the early treatment of hemorrhagic shock when stored blood is not available. In the recent Phase III USA multicenter trial using human Polymerized Hemoglobin (PolyHeme), patients with hemorrhagic shock were randomized to treatment with PolyHeme or crystalloid starting in the field. Subsequent therapy in the hospital included additional PolyHeme in the treatment group (up to six units or 300 gm Hemoglobin) and red blood cells (RBCs) in both groups. Day 30 mortality was higher in the PolyHeme group but not significantly different (PolyHeme 13% [47 of 349]; Control 10% [35 of 365]; p 0.13).1 There were some baseline preinfusion differences between the treatment groups. The PolyHeme group had more pretreatment coagulopathy and more severely injured patients in the cohort with blunt mechanism. Despite the complexity of the population, failure to reach a predetermined 30-day mortality end point for noninferiority was the primary basis for the refusal of the US Food and Drug Administration to approve the biological license application for PolyHeme. There was also concern about a higher incidence of adverse events (AEs) and serious adverse events (SAEs) in the PolyHeme recipients. Since the publication of these results, a number of questions have been raised about the appropriateness of day 30 mortality as the primary end point and the confounding influence of RBC transfusions given to both groups of patients on the analysis of safety and efficacy. This report describes several post hoc subgroup analyses. The purpose of these subgroup analyses is to examine time to death and determine whether early survival is an important end point of resuscitation with PolyHeme and to scrutinize safety data in groups of patients treated similarly. Specifically, we address the following questions: Y Which patients may have benefited from early administration of PolyHeme, and how might that benefit be extrapolated to the intended population?

  • human Polymerized Hemoglobin for the treatment of hemorrhagic shock when blood is unavailable the usa multicenter trial
    Journal of The American College of Surgeons, 2009
    Co-Authors: Ernest E Moore, Frederick A. Moore, Andrew C Bernard, David B Hoyt, Timothy C Fabian, Gerard J Fulda, Therese M Duane, Leonard J Weireter, Gerardo Gomez, Mark D Cipolle
    Abstract:

    Background Human Polymerized Hemoglobin (PolyHeme, Northfield Laboratories) is a universally compatible oxygen carrier developed to treat life-threatening anemia. This multicenter phase III trial was the first US study to assess survival of patients resuscitated with a Hemoglobin-based oxygen carrier starting at the scene of injury. Study Design Injured patients with a systolic blood pressure≤90 mmHg were randomized to receive field resuscitation with PolyHeme or crystalloid. Study patients continued to receive up to 6 U of PolyHeme during the first 12 hours postinjury before receiving blood. Control patients received blood on arrival in the trauma center. This trial was conducted as a dual superiority/noninferiority primary end point. Results Seven hundred fourteen patients were enrolled at 29 urban Level I trauma centers (79% men; mean age 37.1 years). Injury mechanism was blunt trauma in 48%, and median transport time was 26 minutes. There was no significant difference between day 30 mortality in the as-randomized (13.4% PolyHeme versus 9.6% control) or per-protocol (11.1% PolyHeme versus 9.3% control) cohorts. Allogeneic blood use was lower in the PolyHeme group (68% versus 50% in the first 12 hours). The incidence of multiple organ failure was similar (7.4% PolyHeme versus 5.5% control). Adverse events (93% versus 88%; p=0.04) and serious adverse events (40% versus 35%; p=0.12), as anticipated, were frequent in the PolyHeme and control groups, respectively. Although myocardial infarction was reported by the investigators more frequently in the PolyHeme group (3% PolyHeme versus 1% control), a blinded committee of experts reviewed records of all enrolled patients and found no discernable difference between groups. Conclusions Patients resuscitated with PolyHeme, without stored blood for up to 6 U in 12 hours postinjury, had outcomes comparable with those for the standard of care. Although there were more adverse events in the PolyHeme group, the benefit-to-risk ratio of PolyHeme is favorable when blood is needed but not available.

  • Polymerized Hemoglobin induces heme oxygenase 1 protein expression and inhibits intercellular adhesion molecule 1 protein expression in human lung microvascular endothelial cells
    Journal of The American College of Surgeons, 2005
    Co-Authors: Aaron M Cheng, Jeffrey L Johnson, Ernest E Moore, Mark D Walsh, Peter K Moore, Anirban Banerjee
    Abstract:

    Background Our clinical trials using a Polymerized Hemoglobin solution (PolyHb) as a red cell substitute in severely injured patients suggested that this Hemoglobin-based oxygen carrier has a systemic antiinflammatory effect. Heme oxygenase-1 (HO-1) has recently been shown to be cytoprotective, and is known to be induced by heme moieties. We investigated the effects of this Hemoglobin-based oxygen carrier on HO-1 induction and proinflammatory activation of pulmonary endothelium. Study design Human lung microvascular endothelial cells were grown to confluence and preincubated with either cell media (control) or with an equal volume mixture of Polymerized Hemoglobin/cell media (experimental). The cell cultures were subsequently stimulated with lipopolysaccharide. HO-1 expression was detected by protein immunoblot and further quantified by ELISA; intercellular adhesion molecule-1 protein expression was measured by flow cytometry. Results Polymerized Hemoglobin induced synthesis of HO-1 protein in human lung microvascular endothelial cells and, concurrently, inhibited lipopolysaccharide-induced intercellular adhesion molecule-1 protein cell surface expression. Conclusions Polymerized Hemoglobin attenuates lipopolysaccharide-stimulated expression of intercellular adhesion molecule-1 protein, which is associated with upregulation of the cytoprotective protein HO-1 in human pulmonary endothelial cells. This antiinflammatory effect offers a novel mechanism by which Hemoglobin-based oxygen carrier solutions may be exploited therapeutically as resuscitative fluids.

  • insights from studies of blood substitutes in trauma
    Shock, 2005
    Co-Authors: Ernest E Moore, Aaron M Cheng, Takayuki Masuno, Jeffrey L Johnson, Anirban Banerjee
    Abstract:

    Most authorities believe that the greatest need for blood substitutes is in patients with unanticipated acute blood loss, and trauma is the most likely scenario. The blood substitutes reaching advanced clinical trials today are red blood cell (RBC) substitutes, derived from Hemoglobin. The Hemoglobin-based oxygen carriers (HBOCs) tested currently in FDA Phase III clinical trials are Polymerized Hemoglobin solutions. The standard approach to restoring oxygen delivery in hemorrhagic shock has been crystalloid administration to expand intravascular volume, followed by stored RBCs for critical anemia. However, allogenic RBCs may have adverse immunoinflammatory effects that increase the risk of postinjury multiple organ failure (MOF). Phase II clinical trials, as well as in vitro and in vivo work, suggest that resuscitation with a HBOC-in lieu of stored RBCs-attenuates the systemic inflammatory response invoked in the pathogenesis of MOF. Specifically, an HBOC has been shown to obviate stored RBC provoked neutrophil priming, endothelial activation, and systemic release of interleukins 6, 8, and 10. Based on this background and work by others, we have initiated a multicenter prehospital trial in which severely injured patients with major blood loss (systemic blood pressure <90 mmHg) are randomized to initial field resuscitation with crystalloid versus HBOC. During the hospital phase, the control group is further resuscitated with stored RBCs, whereas the study group receives HBOC (up to 6 units) in the first 12 h. The primary study endpoint is 30-day mortality, and secondary endpoints include reduction in allogenic RBCs, Hemoglobin levels <5 g/dL, uncrossmatched RBCs, and MOF. The potential efficacy of HBOCs extends beyond the temporary replacement for stored RBCs. Hemoglobin solutions might ultimately prove superior in delivering oxygen to ischemic or injured tissue. The current generation of HBOCs can be lifesaving for acute blood loss today, but the next generation might be biochemically tailored for specific clinical indications.

  • transfusion induced leukocyte il 8 gene expression is avoided by the use of human Polymerized Hemoglobin
    Journal of Trauma-injury Infection and Critical Care, 2004
    Co-Authors: Forest R Sheppard, Aaron M Cheng, Jeffrey L Johnson, Ernest E Moore, Nathan J D Mclaughlin, Christopher C Silliman
    Abstract:

    Background: Red blood cell (pRBC) transfusion is an independent risk factor for multiple organ failure (MOF); a mal-adaptive immuno-inflammatory response is implicated. Interleukin-8 (IL-8) is one putative mediator of this response. We previously observed that injured patients resuscitated with pRBCs have increased plasma IL-8 compared with those given human Polymerized Hemoglobin (PolyHb). To further elucidate the mechanisms responsible for this difference in IL-8, we devised an ex-vivo transfusion model. We hypothesize that pRBC transfusion induces increased IL-8 gene expression that is avoided by the use of PolyHb. Methods: Human volunteer blood was incubated alone (RB) or with a major transfusion (50% exchange) of either post-storage leukoreduced O-pRBCs (RB + pRBC) or PolyHb (RB + PolyHb) for 30 minutes at 37°C. Total leukocyte (TL) or polymorphonuclear leukocyte (PMN) total RNA was isolated and IL-8 mRNA quantified. Results are reported as amol IL-8 mRNA/μg total RNA ± SEM. Stats: ANOVA with Bonferroni/Dunn post hoc analysis. Results: Simulated transfusion of pRBCs increased TL IL-8 mRNA (RB = 0.28 ± 0.10 amol/μg total RNA, RB + pRBC = 2.24 ± 0.25 amol/μg total RNA, p < 0.01), whereas PolyHb did not (B + PolyHb = 0.82 ± 0.30 amol/μg total RNA). PolyHb IL-8 mRNA was less than pRBC transfused (p < 0.01). In PMNs, simulated transfusion of pRBCs increase IL-8 mRNA (RB = 3.17 ± 1.05 amol/μg total RNA, RB + pRBC = 7.60 ± 1.79 amol/μg total RNA, p < 0.01), whereas PolyHb did not (RB + PolyHb = 4.53 ± 1.64 amol/μg total RNA). Conclusions: Stored pRBCs induces increased TL and PMN IL-8 gene expression, whereas human Polymerized Hemoglobin, in lieu or pRBCs, avoids this increase. These experimental results corroborate our previous clinical studies and further encourage the study of PolyHb as a resuscitation strategy to decrease postinjury MOF.

Nora Philbin - One of the best experts on this subject based on the ideXlab platform.

  • Bovine Polymerized Hemoglobin (HBOC-201) for the Prehospital Resuscitation of Combat Casualties with Hemorrhagic Shock (HS)
    2016
    Co-Authors: Nora Philbin, Jennifer Rice, Francoise Arnaud, Jennifer Gurney, Benjamin Esperat, Noemy Carballo, Felicia Wilson, Frank Dong, Richard Mccarron, Daniel Freilich
    Abstract:

    OBJECTIVES: To compare the physiologic effects of BPH vs. hetastarch (HEX), the current resuscitative fluid used by U.S. Special Forces, in delayed resuscitation HS models simulating battlefield injuries. METHODS: After induction of HS in controlled (catheter withdrawal) and uncontrolled (liver injury) hemorrhage swine models, the effects of BPH, HEX, and no resuscitation (NON), followed by hospital-like care after a 4 hour “evacuation delay”, were compared. Standard physiologic parameters were followed for 72 hours. Hemostasis was evaluated by routine coagulation assays, thromboelastography, collagen/ADP-coated membrane aperture closing time, and platelet aggregation ADP-release. Leukocyte adhesion an

  • Bovine Polymerized Hemoglobin (HBOC-201) for the Prehospital Resuscitation of Combat Casualties with Hemorrhagic Shock (HS)
    2012
    Co-Authors: Nora Philbin, Jennifer Rice, Francoise Arnaud, Jennifer Gurney, Benjamin Esperat, Noemy Carballo, Felicia Wilson, Frank Dong, Richard Mccarron, Daniel Freilich
    Abstract:

    OBJECTIVES: To compare the physiologic effects of BPH vs. hetastarch (HEX), the current resuscitative fluid used by U.S. Special Forces, in delayed resuscitation HS models simulating battlefield injuries. METHODS: After induction of HS in controlled (catheter withdrawal) and uncontrolled (liver injury) hemorrhage swine models, the effects of BPH, HEX, and no resuscitation (NON), followed by hospital-like care after a 4 hour “evacuation delay”, were compared. Standard physiologic parameters were followed for 72 hours. Hemostasis was evaluated by routine coagulation assays, thromboelastography, collagen/ADPcoated membrane aperture closing time, and platelet aggregation ADP-release. Leukocyte adhesion and immunophenotype were compared using FACS. Plasma cytokines were assayed by ELISA and Western Blot

  • vasoactivity of bovine Polymerized Hemoglobin hboc 201 in swine with traumatic hemorrhagic shock with and without brain injury
    Journal of Trauma-injury Infection and Critical Care, 2006
    Co-Authors: Jennifer Rice, Nora Philbin, Richard M Mccarron, Gerald Mcgwin, Francoise Arnaud, Michael Handrigan, Carrie H Hall, Stephen T Ahlers, L B Pearce, Daniel Freilich
    Abstract:

    BACKGROUND We previously reported that bovine Polymerized Hemoglobin (HBOC- 201) improved outcome in swine with hemorrhagic shock (HS) with and without traumatic brain injury (TBI). Herein, we add analyses of blood pressure (BP) responses, associated physiologic data, and HS fluid infusion guidelines. METHODS HBOC-201 versus standard fluid resuscitation was compared in four anesthetized invasively monitored swine models: moderate controlled HS, severe controlled HS, severe uncontrolled HS (liver injury), and severe uncontrolled HS/TBI (liver/parietal brain injuries). Pigs received fluid for hypotension and tachycardia, and were followed up to 6 (HS alone) or 72 hours (HS/TBI). The change in mean arterial pressure (DeltaMAP) response severity was stratified and analyzed based on infusion number and HS severity, using Student's t and Fisher's exact tests. RESULTS HBOC-201 vasoactivity resulted in higher MAP in all studies. Among HBOC-201 pigs, DeltaMAP responses were significant for the first two infusions and inversely related to HS severity. Among controls, DeltaMAP responses remained significant through the fourth infusion in controlled HS models, and through the first in severe uncontrolled HS/TBI; none were significant in severe uncontrolled HS. DeltaMAP was higher with HBOC-201 through the first infusion in moderate controlled HS, the fifth in severe uncontrolled HS, and the second in severe uncontrolled HS/TBI; there were no group differences in severe controlled HS. No severe MAP responses occurred. Higher DeltaMAP severity did not impact outcome. Hypotension satisfied fluid reinfusion criteria less consistently than tachycardia. Overall, HBOC-201 improved physiologic parameters and survival without causing hypoperfusion; in severe HS, perfusion improved. CONCLUSIONS In swine with HS +/- TBI, HBOC-201 had mild to moderate vasoactivity, resulting in significant DeltaMAP responses mainly after initial infusions, no severe/adverse responses, and improved outcome. Our data suggest that use of physiologic parameters (e.g., tachycardia), in addition to hypotension to guide fluid reinfusion during HS resuscitation with HBOC-201, will minimize hypoperfusion risk and maximize potential benefit.

  • bovine Polymerized Hemoglobin versus hextend resuscitation in a swine model of severe controlled hemorrhagic shock with delay to definitive care
    Shock, 2006
    Co-Authors: Jennifer Rice, Nora Philbin, Bruce L Pearce, Richard M Mccarron, Gerald Mcgwin, Francoise Arnaud, Todd Johnson, Shannon W Flournoy, Lew Kaplan, Michael Handrigan
    Abstract:

    To compare the efficacy of low-volume resuscitation with bovine Polymerized Hemoglobin (HBOC-201) versus hetastarch (HEX) in an intermediate severity combat-relevant hemorrhagic shock swine model with a simulated delay to hospital care. Twenty-four anesthetized pigs were hemorrhaged 55% estimated blood volume in conjunction with a 5-min rectus abdominus crush. At 20 min, pigs were resuscitated with 10 mL/kg of HBOC-201 or HEX or nothing (NON); resuscitated pigs received additional infusions (5 mL/kg) at 30, 60, 120, or 180 min if hypotension or tachycardia persisted. Pigs were monitored for a 4-h "prehospital" period. At 4-h, hospital arrival was simulated: surgical sites were repaired, blood, or saline provided, and pigs were recovered from anesthesia. Pigs were monitored for 72 h and then killed for histological evaluation. One hundred percent (8/8) of HBOC-201-, 75% (6/8) of HEX-, and 25% (2/8) of NON-resuscitated pigs survived to 72 h (P = 0.007 overall, HBOC vs. HEX P > 0.05). Mean arterial pressure and mean pulmonary arterial pressure were highest in the HBOC-201 group (P < 0.001), and HR was lowest (P < 0.001). HBOC-201- and HEX-resuscitated pigs had comparable cardiac index and prehospital fluid requirements. HBOC-201 pigs had higher transcutaneous tissue oxygen tension, P < 0.001) and lower urine output (P < 0.001). At simulated hospital arrival, no HBOC-201 pigs required additional fluids or blood transfusion. In contrast, 100% of HEX pigs required blood transfusions (P < 0.01). In this swine model of controlled hemorrhage with low-volume resuscitation and delayed definitive care, HBOC-201 pigs had improved hemodynamics, transcutaneous tissue oxygen tension, and transfusion avoidance compared with HEX.

  • bovine Polymerized Hemoglobin Hemoglobin based oxygen carrier 201 resuscitation in three swine models of hemorrhagic shock with militarily relevant delayed evacuation effects on histopathology and organ function
    Critical Care Medicine, 2006
    Co-Authors: Todd Johnson, Ludmila Asher, Nora Philbin, Jennifer Rice, Feng Dong, Francoise Arnaud, Jennifer M Gurney, Martin Arrisueno, Matthew Warndorf, Gerald Mcgwin
    Abstract:

    Objective: To test our hypothesis that Hemoglobin-based oxygen carrier (HBOC)-201 resuscitation in hemorrhagic shock (HS) will not lead to increased organ injury and dysfunction. Design: Three swine HS models simulating military-relevant delayed evacuation: a) moderate controlled HS, b) severe controlled HS, and c) severe uncontrolled HS. Setting: Military research laboratory. Subjects: Swine. Interventions: Swine were anesthetized/intubated and instrumented. To induce HS, in two controlled hemorrhage experiments, 40% (moderate controlled HS) or 55% (severe controlled HS) of blood volume was withdrawn; in an uncontrolled HS experiment, the liver was crushed/lacerated. During a 4-hr "prehospital phase," pigs were resuscitated with HBOC-201 (HBOC) or Hextend (HEX) or were non-resuscitated (NON). Upon "hospital arrival," liver injury was repaired (severe uncontrolled HS), blood or saline was infused, hemodynamics were monitored, and blood was collected. Upon animal death and/or 72 hrs, necropsy was followed by histopathologic evaluation of organ injury (hematoxylin and eosin, electron microscopy) and immunohistochemistry of oxidative potential (3-nitrotyrosine). Significance (p <.05) was assessed by Kruskal-Wallis, analysis of variance/Bonferroni, and mixed procedure tests. Measurements and Main Results: Survival was significantly higher with HBOC than HEX only with severe uncontrolled HS (p =.002). Myocardial necrosis/fibroplasia, fluid requirements, cardiac output, and cardiac enzymes were generally similar or lower in HBOC than HEX pigs, but creatine kinase-MB (but not creatine kinase-MB/creatine kinase ratio) was higher with HBOC in moderate controlled HS. Alveolar/interstitial pulmonary edema was similar with HBOC and HEX, but Po 2 was higher with HBOC in severe uncontrolled HS. Jejunal villar epithelial and hepatocellular necrosis were similarly minimal to moderate in all groups. Minimal biliary changes occurred exclusively with HBOC. Aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase were generally higher with HBOC than HEX. Mild renal papillary injury occurred more frequently with HBOC, but consistent patterns for urine output, blood urea nitrogen, and creatinine, were not seen. The 3-nitrotyrosine staining intensity was not different Conclusions: In comparison with hetastarch, HBOC-201 resuscitation of swine with HS increased survival (with severe HS), did not increase evidence of oxidative potential, and had histopathologic and/or functional effects on organs that were clinically equivocal (myocardium, lungs, hepatic parenchyma, jejunum, and renal cortex/ medulla) and potentially adverse (hepatobiliary and renal papilla). The effects of HBOC-201-resuscitation in HS should be corroborated in controlled clinical trials.