PEGYLATED CARBOXYHEMOGLOBIN BOVINE EXHIBITS SUPERIOR RESUSCITATIVE CAPACITY IN RODENT MODEL OF SEVERE HEMORRHAGE
(Abstract release date: 05/19/16)
EHA Library. Jubin R. 06/09/16; 133119; E1570
Disclosure(s): Ronald G Jubin is an employee of Prolong Pharmaceuticals. Song Technologies was funded for the study by Prolong Pharmaceuticals.
Dr. Ronald Jubin
Contributions
Contributions
Abstract
Abstract: E1570
Type: Eposter Presentation
Background
PEGylated Carboxyhemoglobin bovine (PEG-HbCO) is a novel biological therapy designed to release carbon monoxide and then transfer oxygen to hypoxic tissue. Prior in vitro cell culture and in vivo animal models including stroke and myocardial infarction have demonstrated the PEG-HbCO exhibits both anti-inflammatory and anti-hypoxia activities. Severe hemorrhage results in rapid hypotension and tissue hypoxia. Fluid restoration and pressors are standard of care that positively impact blood pressure and circulatory volume, but unfortunately they have minimal impact towards resolution of tissue hypoxia and systemic inflammation resulting from hemorrhagic shock.
Aims
A rat model of severe hemorrhage was developed to evaluate the effects of PEG-HbCO on cardiovascular and respiratory macro function in comparison to the colloid volume expander, Hetastarch. Additionally, microscopic measurements of microcirculation and tissue oxygenation were compared between the two resuscitative agents as well as circulating markers of inflammation and hypoxia.
Methods
Male Sprague-Dawley rats underwent a controlled 45% blood volume hemorrhage at 3.5 ml x min-1 x kg-1 through a cannulated carotid artery and were maintained in a hypovolemic, hemorrhagic shock phase for 30 minutes. Resuscitation fluids were infused at a rate of 3.5 ml x min-1 x kg-1 to a volume equal to 20% of the total estimated blood volume through a cannulated jugular vein. Systemic measurements were recorded via a cannulated femoral artery that was connected to a pressure transducer while microcirculatory parameters were collected through phosphorescence quenching and intravital microscopic examination of the exteriorized spinotrapezius muscle.
Results
Compared to baseline, the 45% hemorrhage produced a significant reduction in heart rate, blood pressure, arterial diameter and interstitial fluid oxygen partial pressure (ISF PO2). Resuscitation with either PEG-HbCO or Hetastarch improved animal heart rate and mean arterial pressure systemic parameters towards pre-conditional baseline levels, but only PEG-HbCO -treated animals showed an improvement in ISF PO2. The impact of improved systemic variables was evident in mortality with untreated animals (sham) expiring an hour after hemorrhage, while Hetastarch resuscitated animals expired after 4 hours. PEG-HbCO animals survived for the entire 8 hour observation period. In addition to extended survival times, PEG-HbCO animals showed steady systemic and microcirculatory parameters. Hetastarch resuscitated animals, however, developed rigor mortis in their limbs at approximately 3 hours post-hemorrhage, which was concurrent with a rapid decline in systemic variables. Additionally, only PEG-HbCO yielded reduction in hypoxia and inflammatory gene expression levels as compared to Hetastarch and sham control animals.
Conclusion
Systemic hypoxia is a major factor in trauma-related mortality and early intervention can improve survival rates. This study showed that PEG-HbCO has a unique capacity to restore macro and microcirculatory functions in addition to reducing inflammation and tissue hypoxia. Moreover, reestablishing blood pressure is acutely important for post-hemorrhage survival and restoring oxygen delivery to peripheral tissues is critical for improving long-term outcomes.
Session topic: E-poster
Keyword(s): Hemorrhage, Hypoxia-sensing, PEGylation, Trauma
Type: Eposter Presentation
Background
PEGylated Carboxyhemoglobin bovine (PEG-HbCO) is a novel biological therapy designed to release carbon monoxide and then transfer oxygen to hypoxic tissue. Prior in vitro cell culture and in vivo animal models including stroke and myocardial infarction have demonstrated the PEG-HbCO exhibits both anti-inflammatory and anti-hypoxia activities. Severe hemorrhage results in rapid hypotension and tissue hypoxia. Fluid restoration and pressors are standard of care that positively impact blood pressure and circulatory volume, but unfortunately they have minimal impact towards resolution of tissue hypoxia and systemic inflammation resulting from hemorrhagic shock.
Aims
A rat model of severe hemorrhage was developed to evaluate the effects of PEG-HbCO on cardiovascular and respiratory macro function in comparison to the colloid volume expander, Hetastarch. Additionally, microscopic measurements of microcirculation and tissue oxygenation were compared between the two resuscitative agents as well as circulating markers of inflammation and hypoxia.
Methods
Male Sprague-Dawley rats underwent a controlled 45% blood volume hemorrhage at 3.5 ml x min-1 x kg-1 through a cannulated carotid artery and were maintained in a hypovolemic, hemorrhagic shock phase for 30 minutes. Resuscitation fluids were infused at a rate of 3.5 ml x min-1 x kg-1 to a volume equal to 20% of the total estimated blood volume through a cannulated jugular vein. Systemic measurements were recorded via a cannulated femoral artery that was connected to a pressure transducer while microcirculatory parameters were collected through phosphorescence quenching and intravital microscopic examination of the exteriorized spinotrapezius muscle.
Results
Compared to baseline, the 45% hemorrhage produced a significant reduction in heart rate, blood pressure, arterial diameter and interstitial fluid oxygen partial pressure (ISF PO2). Resuscitation with either PEG-HbCO or Hetastarch improved animal heart rate and mean arterial pressure systemic parameters towards pre-conditional baseline levels, but only PEG-HbCO -treated animals showed an improvement in ISF PO2. The impact of improved systemic variables was evident in mortality with untreated animals (sham) expiring an hour after hemorrhage, while Hetastarch resuscitated animals expired after 4 hours. PEG-HbCO animals survived for the entire 8 hour observation period. In addition to extended survival times, PEG-HbCO animals showed steady systemic and microcirculatory parameters. Hetastarch resuscitated animals, however, developed rigor mortis in their limbs at approximately 3 hours post-hemorrhage, which was concurrent with a rapid decline in systemic variables. Additionally, only PEG-HbCO yielded reduction in hypoxia and inflammatory gene expression levels as compared to Hetastarch and sham control animals.
Conclusion
Systemic hypoxia is a major factor in trauma-related mortality and early intervention can improve survival rates. This study showed that PEG-HbCO has a unique capacity to restore macro and microcirculatory functions in addition to reducing inflammation and tissue hypoxia. Moreover, reestablishing blood pressure is acutely important for post-hemorrhage survival and restoring oxygen delivery to peripheral tissues is critical for improving long-term outcomes.
Session topic: E-poster
Keyword(s): Hemorrhage, Hypoxia-sensing, PEGylation, Trauma
Abstract: E1570
Type: Eposter Presentation
Background
PEGylated Carboxyhemoglobin bovine (PEG-HbCO) is a novel biological therapy designed to release carbon monoxide and then transfer oxygen to hypoxic tissue. Prior in vitro cell culture and in vivo animal models including stroke and myocardial infarction have demonstrated the PEG-HbCO exhibits both anti-inflammatory and anti-hypoxia activities. Severe hemorrhage results in rapid hypotension and tissue hypoxia. Fluid restoration and pressors are standard of care that positively impact blood pressure and circulatory volume, but unfortunately they have minimal impact towards resolution of tissue hypoxia and systemic inflammation resulting from hemorrhagic shock.
Aims
A rat model of severe hemorrhage was developed to evaluate the effects of PEG-HbCO on cardiovascular and respiratory macro function in comparison to the colloid volume expander, Hetastarch. Additionally, microscopic measurements of microcirculation and tissue oxygenation were compared between the two resuscitative agents as well as circulating markers of inflammation and hypoxia.
Methods
Male Sprague-Dawley rats underwent a controlled 45% blood volume hemorrhage at 3.5 ml x min-1 x kg-1 through a cannulated carotid artery and were maintained in a hypovolemic, hemorrhagic shock phase for 30 minutes. Resuscitation fluids were infused at a rate of 3.5 ml x min-1 x kg-1 to a volume equal to 20% of the total estimated blood volume through a cannulated jugular vein. Systemic measurements were recorded via a cannulated femoral artery that was connected to a pressure transducer while microcirculatory parameters were collected through phosphorescence quenching and intravital microscopic examination of the exteriorized spinotrapezius muscle.
Results
Compared to baseline, the 45% hemorrhage produced a significant reduction in heart rate, blood pressure, arterial diameter and interstitial fluid oxygen partial pressure (ISF PO2). Resuscitation with either PEG-HbCO or Hetastarch improved animal heart rate and mean arterial pressure systemic parameters towards pre-conditional baseline levels, but only PEG-HbCO -treated animals showed an improvement in ISF PO2. The impact of improved systemic variables was evident in mortality with untreated animals (sham) expiring an hour after hemorrhage, while Hetastarch resuscitated animals expired after 4 hours. PEG-HbCO animals survived for the entire 8 hour observation period. In addition to extended survival times, PEG-HbCO animals showed steady systemic and microcirculatory parameters. Hetastarch resuscitated animals, however, developed rigor mortis in their limbs at approximately 3 hours post-hemorrhage, which was concurrent with a rapid decline in systemic variables. Additionally, only PEG-HbCO yielded reduction in hypoxia and inflammatory gene expression levels as compared to Hetastarch and sham control animals.
Conclusion
Systemic hypoxia is a major factor in trauma-related mortality and early intervention can improve survival rates. This study showed that PEG-HbCO has a unique capacity to restore macro and microcirculatory functions in addition to reducing inflammation and tissue hypoxia. Moreover, reestablishing blood pressure is acutely important for post-hemorrhage survival and restoring oxygen delivery to peripheral tissues is critical for improving long-term outcomes.
Session topic: E-poster
Keyword(s): Hemorrhage, Hypoxia-sensing, PEGylation, Trauma
Type: Eposter Presentation
Background
PEGylated Carboxyhemoglobin bovine (PEG-HbCO) is a novel biological therapy designed to release carbon monoxide and then transfer oxygen to hypoxic tissue. Prior in vitro cell culture and in vivo animal models including stroke and myocardial infarction have demonstrated the PEG-HbCO exhibits both anti-inflammatory and anti-hypoxia activities. Severe hemorrhage results in rapid hypotension and tissue hypoxia. Fluid restoration and pressors are standard of care that positively impact blood pressure and circulatory volume, but unfortunately they have minimal impact towards resolution of tissue hypoxia and systemic inflammation resulting from hemorrhagic shock.
Aims
A rat model of severe hemorrhage was developed to evaluate the effects of PEG-HbCO on cardiovascular and respiratory macro function in comparison to the colloid volume expander, Hetastarch. Additionally, microscopic measurements of microcirculation and tissue oxygenation were compared between the two resuscitative agents as well as circulating markers of inflammation and hypoxia.
Methods
Male Sprague-Dawley rats underwent a controlled 45% blood volume hemorrhage at 3.5 ml x min-1 x kg-1 through a cannulated carotid artery and were maintained in a hypovolemic, hemorrhagic shock phase for 30 minutes. Resuscitation fluids were infused at a rate of 3.5 ml x min-1 x kg-1 to a volume equal to 20% of the total estimated blood volume through a cannulated jugular vein. Systemic measurements were recorded via a cannulated femoral artery that was connected to a pressure transducer while microcirculatory parameters were collected through phosphorescence quenching and intravital microscopic examination of the exteriorized spinotrapezius muscle.
Results
Compared to baseline, the 45% hemorrhage produced a significant reduction in heart rate, blood pressure, arterial diameter and interstitial fluid oxygen partial pressure (ISF PO2). Resuscitation with either PEG-HbCO or Hetastarch improved animal heart rate and mean arterial pressure systemic parameters towards pre-conditional baseline levels, but only PEG-HbCO -treated animals showed an improvement in ISF PO2. The impact of improved systemic variables was evident in mortality with untreated animals (sham) expiring an hour after hemorrhage, while Hetastarch resuscitated animals expired after 4 hours. PEG-HbCO animals survived for the entire 8 hour observation period. In addition to extended survival times, PEG-HbCO animals showed steady systemic and microcirculatory parameters. Hetastarch resuscitated animals, however, developed rigor mortis in their limbs at approximately 3 hours post-hemorrhage, which was concurrent with a rapid decline in systemic variables. Additionally, only PEG-HbCO yielded reduction in hypoxia and inflammatory gene expression levels as compared to Hetastarch and sham control animals.
Conclusion
Systemic hypoxia is a major factor in trauma-related mortality and early intervention can improve survival rates. This study showed that PEG-HbCO has a unique capacity to restore macro and microcirculatory functions in addition to reducing inflammation and tissue hypoxia. Moreover, reestablishing blood pressure is acutely important for post-hemorrhage survival and restoring oxygen delivery to peripheral tissues is critical for improving long-term outcomes.
Session topic: E-poster
Keyword(s): Hemorrhage, Hypoxia-sensing, PEGylation, Trauma
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