SHOCK, Vol. 44, Supplement 1, pp. 1Y2, 2015
Commentary WHAT’S NEW IN SHOCK, MILITARY SUPPLEMENT 2015? Michael A. Dubick* and Anthony E. Pusateri† *US Army Institute of Surgical Research, JBSA, Fort Sam Houston, Texas; and † Combat Casualty Care Research Program, US Army Medical Research Materiel Command, Fort Detrick, Maryland
This Military Supplement to Shock, the first of what we hope will be a yearly publication related to Combat Casualty Care, includes some of the most recent work by the US Department of Defense (DoD)Yfunded researchers, both intramural and extramural, as well as important work sponsored by the United Kingdom_s Ministry of Defence. This initial compilation of articles includes an introductory summary of the DoD Hemorrhage and Resuscitation Research and Development program (1), two review articles (2, 3), seven studies associated with clinical aspects (4Y10), and 10 animal studies (11Y20). Over the past decade, fluid resuscitation research related to combat casualty care has seen interest in the investigation and development of drugs that can be infused in low volumes, either alone or as adjuncts to standard crystalloid resuscitation fluids, to improve the therapeutic window for severely injured war fighters and address the logistic constraints of providing large volumes of fluids far forward in combat areas. Such pharmacologic approaches to resuscitation are discussed in a review of the experimental evidence that histone deacetylase inhibitors can create a Bprosurvival phenotype[ (2). Another approach to a Bprosurvival phenotype[ was investigated using preinjury carbohydrate loading in a swine hemorrhage model (15). These investigators gave a carbohydrate load 1 h before injury and evaluated hemodynamic and metabolic responses, as well as markers of organ injury and survival. Another pharmacologic approach to resuscitation was addressed experimentally in further studies with the combination of "-hydroxybutyrate and melatonin, based on observations from hibernation research, in a polytrauma swine model (12). In a related study, based on the assumption of no intravenous resuscitation fluids being available, Patel et al. (9) investigated the use of intrathoracic pressure regulation to improve stroke volume and ventricular function in ventilated normal human subjects bled 10 mL/kg. Traumatic brain injury (TBI) resulting from the detonation of explosive devices has been recognized as a signature injury in the wars in Iraq and Afghanistan. The second review in this Shock Military Supplement addresses the challenges to emergency medicine in patients with exsanguinating polytrauma complicated by TBI. In particular, the review focuses on key questions related to resuscitation approaches for combined hemorrhagic shock and TBI (3). Resuscitation of brain injury is also addressed experimentally in a swine model that further investigates the use of intrathoracic pressure regulation to
improve cerebral perfusion and cerebral blood flow (14). This technology, shown effective in cardiac arrest models, is a noninvasive approach to improve cerebral perfusion. In addition, a more basic science study of effects of blast overpressure on susceptibility of the amygdala to injury is presented (11). The focus is on oxidative stress and development of anxiety and neuropathologic changes in the amygdala, as potential targets for therapy in response to blast overpressure injuries. With the US military medical community implementing a damage control resuscitation strategy over the past several years, there has been renewed interest in the use of blood products, and in particular, plasma, as initial prehospital resuscitation in both military and civilian trauma patients. In this supplement, the challenges and design of a randomized, placebo-controlled, semiblinded prospective phase 2B trauma trial is described by civilian investigators (10). Much of this effort is focused on therapies to mitigate the acute coagulopathy of trauma recognized in severely injured trauma patients. To that end, White et al. (6) evaluated thromboelastography from 95 patients to determine the sources of heterogeneity in clot formation associated with trauma and link the results to blood product use. This subject was also addressed in a swine traumatic hemorrhage model that investigated packed red blood cells alone or with fresh frozen plasma at a 1:1 ratio compared with normal saline on coagulopathy by assessment of thromboelastography parameters (19). With the US military_s use of whole-blood transfusion in certain cases of combat trauma, there is significant interest in developing methods for whole-blood pathogen reduction. Additional work in this area is presented by OwusuOfori et al. (5), who show that their riboflavin-UV light technology can inactivate malaria parasites while maintaining blood quality during their 21-day study period. Several research efforts have been funded by the DoD to develop noninvasive technologies that can determine the physiologic state of injured war fighters and their need for resuscitation. Using an algorithm based on analysis of arterial wave forms, a compensatory reserve index was created and evaluated in 20 healthy subjects before, during, and after a voluntary hemorrhage of about 1.2 L and found that compensatory reserve index detected blood loss with greater specificity than traditional measures (4). Noninvasive blood hemoglobin via co-oximetry was compared with arterial blood hemoglobin in 12 healthy human subjects bled 10 mL/kg and 1
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
2
SHOCK VOL. 44, SUPPLEMENT 1
resuscitated with lactated Ringer_s solution to assess trend and concordance analysis (7). In addition, an experimental study in hemorrhaged swine investigated lactate, lactate clearance, noninvasive muscle pH, and noninvasive H+ clearance as predictors of mortality (13). We anticipate more activity in this area to develop noninvasive technology for assisting medics in the triage of injured war fighters. Two studies are presented that describe development of uncontrolled hemorrhage models in nonhuman primates (16, 17). As mentioned previously, the military has a high interest in providing biologics and other products far-forward of hospital facilities for resuscitation of injured war fighters. These studies characterized the effects of various degrees of laparoscopic hepatectomy, hemorrhage, and inflammatory insult on hemodynamic, coagulation, clinical chemistry, and histopathologic responses in macaques. These models have been primarily developed for the purpose of investigating humanderived blood components and other therapeutics for treating the injured, when xenogeneic or other factors make other species unsuitable. For the military, medical treatment of injured war fighters during air transport is an area of significant research investment. Although restrictions existed on transporting casualties with hemoglobin of 10 g/dL or less, further studies were warranted to verify that cutoff. In the report by Hamilton et al. (8), they performed a retrospective evaluation of 140 critically ill burn patients transported by US military critical care air transport teams comparing demographics, injury description, physiologic variables, and clinical outcomes compared with patients with hemoglobin of greater than 10 g/dL. Lastly, two studies investigated the inflammatory responses to traumatic injury in experimental animals (18, 20). The DoD has a research investment into modulation of the immune response in survivors of severe traumatic injury to reduce morbidity and late mortality. In their coagulopathic multiple trauma model, Darlington et al. (18) characterized the early proinflammatory and antiinflammatory cytokine, chemokine, and growth factor responses and observed correlations to coagulation markers associated with coagulopathy. They concluded that these relationships could be exploited in development of improved resuscitation strategies. With much interest in recent years on mitochondrial function in response to traumatic injury, Luciano et al. (20) investigated the responses of pretreatment with the sirtuin 1 agonist, Srt1720, on mitochondrial function, indices of hepatic injury, and overall immune function. Their study identified the PGC1! signaling pathway as an important regulator of mitochondrial function and biogenesis that may lead to new treatments to reduce immunosuppression following traumatic injury. REFERENCES 1. Pusateri AE, Dubick MA: The DoD hemorrhage and resuscitation research and development program. Shock 44(Suppl 1):1Y2, 2015.
DUBICK
AND
PUSATERI
2. Halaweish I, Nikolian V, Georgoff P, Li Y, Alam HB: Creating a Bprosurvival phenotype[ through histone deacetylase inhibition: past, present, and future. Shock 44(Suppl 1):6Y16, 2015. 3. Tortella FC, Leung LY: TBI and polytrauma in theatres of combat: the case for neurotrauma resuscitation? Shock 44(Suppl 1):17Y26, 2015. 4. Convertino VA, Howard JT, Hinojosa-Laborde C, Cardin S, Batchelder P, Mulligan J, Grudic GZ, Moulton SL, MacLeod DB: Individual-specific, beatto-beat trending of significant human blood loss: the compensatory reserve. Shock 44(Suppl 1):27Y32, 2015. 5. Owusu-Ofori S, Kusi J, Owusu-Ofori A, Freimanis G, Olver C, Martinez CR, Wilkinson S, Mundt JM, Keil SD, Goodrich RP, et al.: Treatment of whole blood (WB) with riboflavin and UV light: impact on malaria parasite viability and WB storage. Shock 44(Suppl 1):33Y38, 2015. 6. White NJ, Newton JC, Martin EJ, Mohammed BM, Contaifer D Jr, Bostic JL, Brophy GM, Spiess BD, Pusateri AE, Ward KR, et al.: Clot formation is associated with fibrinogen and platelet forces in a cohort of severely-injured emergency department trauma patients. Shock 44(Suppl 1):39Y44, 2015. 7. Marques NR, Kramer GC, Voigt RB, Salter MG, Kinsky MP: Trending, accuracy, and precision of noninvasive hemoglobin monitoring during human hemorrhage and fixed crystalloid bolus. Shock 44(Suppl 1):45Y49, 2015. 8. Hamilton JA, Mora AG, Chung KK, Bebarta VS: Impact of anemia in critically ill burned casualties evacuated from combat theater via US military critical care air transport teams. Shock 44(Suppl 1):50Y54, 2015. 9. Patel N, Branson R, Salter M, Henkel S, Seeton R, Khan M, Solanki D, Koutrouvelis A, Li H, Indrikovs A, et al.: Intrathoracic pressure regulation augments stroke volume and ventricular function in human hemorrhage. Shock 44(Suppl 1):55Y62, 2015. 10. Chapman MP, Moore EE, Chin TL, Ghasabyan A, Chandler J, Stringham J, Gonzalez E, Moore HB, Banerjee A, Silliman CC, et al.: COMBAT: initial experience with a randomized clinical trial of plasma-based resuscitation in the field for traumatic hemorrhagic shock. Shock 44(Suppl 1): 63Y70, 2015. 11. Sajja VS, Hubbard WB, VandeVord PJ: Subacute oxidative stress and glial reactivity in the amygdala are associated with increased anxiety following blast neurotrauma. Shock 44(Suppl 1):71Y78, 2015. 12. Wolf A, Mulier KE, Iyegha UP, Asghar JI, Beilman GJ: Safety of D-Qhydroxybutyrate and melatonin for the treatment of hemorrhagic shock with polytrauma. Shock 44(Suppl 1):79Y89, 2015. 13. Soller B, Zou F, Prince DM, Dubick MA, Sondeen JL: Comparison of noninvasive pH and blood lactate as predictors of mortality in a swine hemorrhagic shock with restricted volume resuscitation model. Shock 44(Suppl 1): 90Y95, 2015. 14. Metzger A, Rees J, Kwon Y, Matsuura T, McKnite S, Lurie KG: Intrathoracic pressure regulation improves cerebral perfusion and cerebral blood flow in a porcine model of brain injury. Shock 44(Suppl 1):96Y102, 2015. 15. Colling KP, Iyegha UP, Asghar JI, Lexcen DR, Lusczek ER, Determan CE Jr, Witowski NE, Mulier KE, Beilman GJ: Preinjury fed state alters the physiologic response in a porcine model of hemorrhagic shock and polytrauma. Shock 44(Suppl 1):103Y113, 2015. 16. Sheppard FR, Macko A, Fryer DM, Ozuna KM, Brown AK, Crossland RF, Tadaki DK: Development of a nonhuman primate (rhesus macaque) model of uncontrolled traumatic liver hemorrhage. Shock 44(Suppl 1): 114Y122, 2015. 17. Bograd BA, Radowsky JS, Vicente DA, Lee EH, Davis TA, Elster EA: An evolving uncontrolled hemorrhage model using cynomolgus macaques. Shock 44(Suppl 1): 123Y128, 2015. 18. Darlington DN, Gonzales MD, Craig T, Dubick MA, Cap AP, Schwacha MG: Trauma induced coagulopathy is associated with a complex inflammatory response in the rat. Shock 44(Suppl 1):129Y137, 2015. 19. Watts S, Nordmann G, Brohi K, Midwinter M, Woolley T, Gwyther R, Wilson C, Poon H, Kirkman E: Evaluation of pre-hospital blood products to attenuate acute coagulopathy of trauma in a model of severe injury and shock in anaesthetized pigs. Shock 44(Suppl 1):138Y148, 2015. 20. Luciano JA, Kautza B, Darwiche S, Martinez S, Stratimirovic S, Waltz P, Sperry J, Rosengart M, Shiva S, Zuckerbraun BS: Sirtuin 1 agonist minimizes injury and improves the immune response following traumatic shock. Shock 44(Suppl 1): 149Y155, 2015.
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Commentary WHAT’S NEW IN SHOCK, MILITARY SUPPLEMENT 2015? Michael A. Dubick* and Anthony E. Pusateri† *US Army Institute of Surgical Research, JBSA, Fort Sam Houston, Texas; and † Combat Casualty Care Research Program, US Army Medical Research Materiel Command, Fort Detrick, Maryland
This Military Supplement to Shock, the first of what we hope will be a yearly publication related to Combat Casualty Care, includes some of the most recent work by the US Department of Defense (DoD)Yfunded researchers, both intramural and extramural, as well as important work sponsored by the United Kingdom_s Ministry of Defence. This initial compilation of articles includes an introductory summary of the DoD Hemorrhage and Resuscitation Research and Development program (1), two review articles (2, 3), seven studies associated with clinical aspects (4Y10), and 10 animal studies (11Y20). Over the past decade, fluid resuscitation research related to combat casualty care has seen interest in the investigation and development of drugs that can be infused in low volumes, either alone or as adjuncts to standard crystalloid resuscitation fluids, to improve the therapeutic window for severely injured war fighters and address the logistic constraints of providing large volumes of fluids far forward in combat areas. Such pharmacologic approaches to resuscitation are discussed in a review of the experimental evidence that histone deacetylase inhibitors can create a Bprosurvival phenotype[ (2). Another approach to a Bprosurvival phenotype[ was investigated using preinjury carbohydrate loading in a swine hemorrhage model (15). These investigators gave a carbohydrate load 1 h before injury and evaluated hemodynamic and metabolic responses, as well as markers of organ injury and survival. Another pharmacologic approach to resuscitation was addressed experimentally in further studies with the combination of "-hydroxybutyrate and melatonin, based on observations from hibernation research, in a polytrauma swine model (12). In a related study, based on the assumption of no intravenous resuscitation fluids being available, Patel et al. (9) investigated the use of intrathoracic pressure regulation to improve stroke volume and ventricular function in ventilated normal human subjects bled 10 mL/kg. Traumatic brain injury (TBI) resulting from the detonation of explosive devices has been recognized as a signature injury in the wars in Iraq and Afghanistan. The second review in this Shock Military Supplement addresses the challenges to emergency medicine in patients with exsanguinating polytrauma complicated by TBI. In particular, the review focuses on key questions related to resuscitation approaches for combined hemorrhagic shock and TBI (3). Resuscitation of brain injury is also addressed experimentally in a swine model that further investigates the use of intrathoracic pressure regulation to
improve cerebral perfusion and cerebral blood flow (14). This technology, shown effective in cardiac arrest models, is a noninvasive approach to improve cerebral perfusion. In addition, a more basic science study of effects of blast overpressure on susceptibility of the amygdala to injury is presented (11). The focus is on oxidative stress and development of anxiety and neuropathologic changes in the amygdala, as potential targets for therapy in response to blast overpressure injuries. With the US military medical community implementing a damage control resuscitation strategy over the past several years, there has been renewed interest in the use of blood products, and in particular, plasma, as initial prehospital resuscitation in both military and civilian trauma patients. In this supplement, the challenges and design of a randomized, placebo-controlled, semiblinded prospective phase 2B trauma trial is described by civilian investigators (10). Much of this effort is focused on therapies to mitigate the acute coagulopathy of trauma recognized in severely injured trauma patients. To that end, White et al. (6) evaluated thromboelastography from 95 patients to determine the sources of heterogeneity in clot formation associated with trauma and link the results to blood product use. This subject was also addressed in a swine traumatic hemorrhage model that investigated packed red blood cells alone or with fresh frozen plasma at a 1:1 ratio compared with normal saline on coagulopathy by assessment of thromboelastography parameters (19). With the US military_s use of whole-blood transfusion in certain cases of combat trauma, there is significant interest in developing methods for whole-blood pathogen reduction. Additional work in this area is presented by OwusuOfori et al. (5), who show that their riboflavin-UV light technology can inactivate malaria parasites while maintaining blood quality during their 21-day study period. Several research efforts have been funded by the DoD to develop noninvasive technologies that can determine the physiologic state of injured war fighters and their need for resuscitation. Using an algorithm based on analysis of arterial wave forms, a compensatory reserve index was created and evaluated in 20 healthy subjects before, during, and after a voluntary hemorrhage of about 1.2 L and found that compensatory reserve index detected blood loss with greater specificity than traditional measures (4). Noninvasive blood hemoglobin via co-oximetry was compared with arterial blood hemoglobin in 12 healthy human subjects bled 10 mL/kg and 1
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
2
SHOCK VOL. 44, SUPPLEMENT 1
resuscitated with lactated Ringer_s solution to assess trend and concordance analysis (7). In addition, an experimental study in hemorrhaged swine investigated lactate, lactate clearance, noninvasive muscle pH, and noninvasive H+ clearance as predictors of mortality (13). We anticipate more activity in this area to develop noninvasive technology for assisting medics in the triage of injured war fighters. Two studies are presented that describe development of uncontrolled hemorrhage models in nonhuman primates (16, 17). As mentioned previously, the military has a high interest in providing biologics and other products far-forward of hospital facilities for resuscitation of injured war fighters. These studies characterized the effects of various degrees of laparoscopic hepatectomy, hemorrhage, and inflammatory insult on hemodynamic, coagulation, clinical chemistry, and histopathologic responses in macaques. These models have been primarily developed for the purpose of investigating humanderived blood components and other therapeutics for treating the injured, when xenogeneic or other factors make other species unsuitable. For the military, medical treatment of injured war fighters during air transport is an area of significant research investment. Although restrictions existed on transporting casualties with hemoglobin of 10 g/dL or less, further studies were warranted to verify that cutoff. In the report by Hamilton et al. (8), they performed a retrospective evaluation of 140 critically ill burn patients transported by US military critical care air transport teams comparing demographics, injury description, physiologic variables, and clinical outcomes compared with patients with hemoglobin of greater than 10 g/dL. Lastly, two studies investigated the inflammatory responses to traumatic injury in experimental animals (18, 20). The DoD has a research investment into modulation of the immune response in survivors of severe traumatic injury to reduce morbidity and late mortality. In their coagulopathic multiple trauma model, Darlington et al. (18) characterized the early proinflammatory and antiinflammatory cytokine, chemokine, and growth factor responses and observed correlations to coagulation markers associated with coagulopathy. They concluded that these relationships could be exploited in development of improved resuscitation strategies. With much interest in recent years on mitochondrial function in response to traumatic injury, Luciano et al. (20) investigated the responses of pretreatment with the sirtuin 1 agonist, Srt1720, on mitochondrial function, indices of hepatic injury, and overall immune function. Their study identified the PGC1! signaling pathway as an important regulator of mitochondrial function and biogenesis that may lead to new treatments to reduce immunosuppression following traumatic injury. REFERENCES 1. Pusateri AE, Dubick MA: The DoD hemorrhage and resuscitation research and development program. Shock 44(Suppl 1):1Y2, 2015.
DUBICK
AND
PUSATERI
2. Halaweish I, Nikolian V, Georgoff P, Li Y, Alam HB: Creating a Bprosurvival phenotype[ through histone deacetylase inhibition: past, present, and future. Shock 44(Suppl 1):6Y16, 2015. 3. Tortella FC, Leung LY: TBI and polytrauma in theatres of combat: the case for neurotrauma resuscitation? Shock 44(Suppl 1):17Y26, 2015. 4. Convertino VA, Howard JT, Hinojosa-Laborde C, Cardin S, Batchelder P, Mulligan J, Grudic GZ, Moulton SL, MacLeod DB: Individual-specific, beatto-beat trending of significant human blood loss: the compensatory reserve. Shock 44(Suppl 1):27Y32, 2015. 5. Owusu-Ofori S, Kusi J, Owusu-Ofori A, Freimanis G, Olver C, Martinez CR, Wilkinson S, Mundt JM, Keil SD, Goodrich RP, et al.: Treatment of whole blood (WB) with riboflavin and UV light: impact on malaria parasite viability and WB storage. Shock 44(Suppl 1):33Y38, 2015. 6. White NJ, Newton JC, Martin EJ, Mohammed BM, Contaifer D Jr, Bostic JL, Brophy GM, Spiess BD, Pusateri AE, Ward KR, et al.: Clot formation is associated with fibrinogen and platelet forces in a cohort of severely-injured emergency department trauma patients. Shock 44(Suppl 1):39Y44, 2015. 7. Marques NR, Kramer GC, Voigt RB, Salter MG, Kinsky MP: Trending, accuracy, and precision of noninvasive hemoglobin monitoring during human hemorrhage and fixed crystalloid bolus. Shock 44(Suppl 1):45Y49, 2015. 8. Hamilton JA, Mora AG, Chung KK, Bebarta VS: Impact of anemia in critically ill burned casualties evacuated from combat theater via US military critical care air transport teams. Shock 44(Suppl 1):50Y54, 2015. 9. Patel N, Branson R, Salter M, Henkel S, Seeton R, Khan M, Solanki D, Koutrouvelis A, Li H, Indrikovs A, et al.: Intrathoracic pressure regulation augments stroke volume and ventricular function in human hemorrhage. Shock 44(Suppl 1):55Y62, 2015. 10. Chapman MP, Moore EE, Chin TL, Ghasabyan A, Chandler J, Stringham J, Gonzalez E, Moore HB, Banerjee A, Silliman CC, et al.: COMBAT: initial experience with a randomized clinical trial of plasma-based resuscitation in the field for traumatic hemorrhagic shock. Shock 44(Suppl 1): 63Y70, 2015. 11. Sajja VS, Hubbard WB, VandeVord PJ: Subacute oxidative stress and glial reactivity in the amygdala are associated with increased anxiety following blast neurotrauma. Shock 44(Suppl 1):71Y78, 2015. 12. Wolf A, Mulier KE, Iyegha UP, Asghar JI, Beilman GJ: Safety of D-Qhydroxybutyrate and melatonin for the treatment of hemorrhagic shock with polytrauma. Shock 44(Suppl 1):79Y89, 2015. 13. Soller B, Zou F, Prince DM, Dubick MA, Sondeen JL: Comparison of noninvasive pH and blood lactate as predictors of mortality in a swine hemorrhagic shock with restricted volume resuscitation model. Shock 44(Suppl 1): 90Y95, 2015. 14. Metzger A, Rees J, Kwon Y, Matsuura T, McKnite S, Lurie KG: Intrathoracic pressure regulation improves cerebral perfusion and cerebral blood flow in a porcine model of brain injury. Shock 44(Suppl 1):96Y102, 2015. 15. Colling KP, Iyegha UP, Asghar JI, Lexcen DR, Lusczek ER, Determan CE Jr, Witowski NE, Mulier KE, Beilman GJ: Preinjury fed state alters the physiologic response in a porcine model of hemorrhagic shock and polytrauma. Shock 44(Suppl 1):103Y113, 2015. 16. Sheppard FR, Macko A, Fryer DM, Ozuna KM, Brown AK, Crossland RF, Tadaki DK: Development of a nonhuman primate (rhesus macaque) model of uncontrolled traumatic liver hemorrhage. Shock 44(Suppl 1): 114Y122, 2015. 17. Bograd BA, Radowsky JS, Vicente DA, Lee EH, Davis TA, Elster EA: An evolving uncontrolled hemorrhage model using cynomolgus macaques. Shock 44(Suppl 1): 123Y128, 2015. 18. Darlington DN, Gonzales MD, Craig T, Dubick MA, Cap AP, Schwacha MG: Trauma induced coagulopathy is associated with a complex inflammatory response in the rat. Shock 44(Suppl 1):129Y137, 2015. 19. Watts S, Nordmann G, Brohi K, Midwinter M, Woolley T, Gwyther R, Wilson C, Poon H, Kirkman E: Evaluation of pre-hospital blood products to attenuate acute coagulopathy of trauma in a model of severe injury and shock in anaesthetized pigs. Shock 44(Suppl 1):138Y148, 2015. 20. Luciano JA, Kautza B, Darwiche S, Martinez S, Stratimirovic S, Waltz P, Sperry J, Rosengart M, Shiva S, Zuckerbraun BS: Sirtuin 1 agonist minimizes injury and improves the immune response following traumatic shock. Shock 44(Suppl 1): 149Y155, 2015.
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
