SHOCK, Vol. 41, No. 1, pp. 1Y2, 2014
Commentary WHAT’S NEW IN SHOCK? JANUARY 2014 John G. Younger, MD, MS Department of Emergency Medicine, Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, Michigan
The final review this month comes from Hall et al. (5) and reconsiders an idea that first came to my attention by way of Cindy Otto several years ago; namely, might clinical veterinary care of acutely injured dogs be a reality-check milestone in the development of new therapies for critical injury? As the authors point out, traumatic injury represents an important part of clinical practice for many veterinarians. Animals injured by automobiles solve issues that are frequently cited as bottlenecks between small animal models and clinical practice, including high variability in specific injuries, extremes of age and size, and a broad genetic background. Incorporating an entirely different field into the translational development of new diagnostics and therapeutics would certainly be a big job, but the more modest regulatory hurdles and lower cost of clinical care in veterinary medicine might pleasantly surprise us. How much experience are we leaving on the table by not moving this idea forward? The new clinical and basic science research this month also raises great questions. Martini et al. (6) show, in a series of porcine hemorrhagic shock experiments using radiolabeled amino acid precursors, that while severe hemorrhage is associated with dramatic acute losses of circulating fibrinogen, the synthesis of this key clotting protein is spared from the broad reprioritizing of protein synthesis in the acutely injured liver, at least in the opening hours of shock. These results dovetail well with the clinical observations from the University of Colorado group (7), showing that within a couple of days of severe traumatic injury, fibrinogen levels accumulate in patients to the point that administered heparin loses its effectiveness, threatening the utility of DVT prophylaxis. In a closely related article, Lusczek and colleagues (8) at the University of Minnesota provide a detailed snap shot of the serum nuclear magnetic resonance metabolome of pigs undergoing therapeutic hypothermia during resuscitation from hemorrhagic shock. Data of these kinds and their associated analyses are increasingly available as the search for both mechanism and clinical tools intensifies. Her results suggest that acute hypothermia alters the serum concentrations of several skeletal muscleYassociated metabolites, but work remains in trying to understand how enforced cooling alters the dynamic equilibrium between synthesis and uptake of these intermediates. There is also new work related to the gut and liver and their roles following both acute injury and prolonged critical illness. In a very interesting set of experiments, DeLano and SchmidSchonbein (9) demonstrate the ability of intraluminal proteases to cross the gut mucosa following hemorrhage in rats and degrade the extracellular domain of insulin receptors; blocking luminal activity with tranexamic acid not only preserves the extracellular portion of these proteins, but also restores insulin
For those of you who don’t include planetary geoscience in your monthly journal watch, a noteworthy discovery was reported in September 2013; namely, what appears to be the second largest volcano in the solar systemVbehind only Olympus Mons on Mars and completely dwarfing smaller terrestrial hills such as Mt Everest and Mauna LoaVwas found in the western Pacific between Japan and Hawaii (1). In an age where Google Maps allows one to investigate via satellite the course of every year’s Shock Society 5K run, that a volcano as large as New Mexico had evaded detection on earth for so long is reason for every scientist to pause and contemplate what might be hiding in plain sight in their own fields. As we begin 2014, this month’s issue of Shock reminds us of the importance of keeping our eyes open and knowing the limits of our measurements and theoretical constructs of even the most common conditions. The three reviews this month are great examples. In their discussion of the basis of sepsis-related acute kidney injury, Gomez and his colleagues (2) focus on a very interesting point, arguing that to interpret renal insufficiency in sepsis as being just ischemic injury is to overlook what may be a very valuable survival strategy in the kidney. Rather than continue to function as best as possible in the setting of overwhelming systemic disease, the renal tubules may use a survival program that includes short-term autophagic and mitophagic mothballing of renal function in order to save cells. This is a much more complex picture than the more traditional view of acute tubular necrosis wherein renal tubular cells are passive victims of hypoxic and inflammatory insults. I would also strongly encourage you to read the thoughtful review of sepsis-induced cardiac dysfunction, where Zaky and colleagues (3) in Seattle and Switzerland make a strong argument that a key reason why myocardial suppression during sepsis is so poorly understood and modeled is that the even the most Bstraightforward[ clinical observations such as decreased ejection fraction are deeply conceptually flawed. The mechanical performance of the heart, they correctly argue, cannot be considered independently of the coupled mechanical behavior of the arterial vascular bed. We define at our peril cardiac dysfunction on the basis of echocardiographically determined changes in ejection fraction or other bedside techniques. Doing so both ignores a large body of recent work in cardiac organogenesis and physiology and risks establishing models that aim to reproduce a misinterpreted clinical phenotype. Another great read in this area can be found, that by Nichols and colleagues (4), a text with which I believe every investigator in cardiovascular medicine needs to be familiar. 1
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
2
SHOCK VOL. 41, NO. 1
sensitivity following severe blood loss. Vanwijngaerden and colleagues (10) provide evidence of differential alterations in bile transports on the apical versus basolateral aspect of canalicular epithelial cells. However, the injury phenotype they describe (particularly in terms of limited jaundice, complex and not always congruent changes in mRNA content and protein content of important bile transporters) suggests this story is ongoing. Stay tuned. In the other new basic science of the month, Hobson and colleagues (11) continue to dissect the beneficial role of peroxisome proliferator-activated receptor + in myocardial ischemia, showing here in an outstanding model using a cardiomyocardiocyte-specific knockout mouse, that loss of peroxisome proliferator-activated receptor + activity at the time of myocardial injury significantly worsens functional outcome, increases circulating markers of injury, and promotes an exaggerated reperfusion inflammatory response. Bauza et al (12) further their ongoing story of plasma-enhanced bacterial killing by showing an important inhibitory effect of adenosine in macrophage-mediated killing of plasma-treated microorganisms relevant to cecal ligation and puncture. Lastly, Ristagno et al. (13) show here promising early results of argon/oxygen ventilation in the early postYcardiac arrest period. Using a porcine model of cardiac arrest following occlusion of the left anterior descending coronary artery, the authors were able to demonstrate a substantial improvement in neurological recovery when argon, rather than nitrogen, was used as the carrier gas for oxygen. This extends the building excitement for a role of noble gases in neuroprotection and cardioprotection. To every reader of this month’s journal, happy new year and best of luck with your efforts to better understand and treat shock. The immensity not only of your challenges, but also of your accomplishments, has not gone unappreciated.
YOUNGER
REFERENCES 1. Sager WW, Zhang J, Korenaga J, Sano T, Koppers AAP, Widdowson, M, Mahoney JJ. An immense shield volcano within the Shatsky Rise oceanic plateau, northwest Pacific Ocean. Nature Geoscience Online 5 September 2013, DOI: 10.1038/NGEO1934. 2. Gomez H, Ince C, de Backer D, Pickkers P, Payen D, Hotchkiss J, Kellum JA: A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock 41:3Y11, 2014. 3. Zaky A, Deem S, Bendjelid J, Treggiari MM: Characterization of cardiac dysfunction in sepsis: an ongoing challenge. Shock 41:12Y24, 2014. 4. Nichols W, O’Rourke M, Vlachopoulos C: McDonald’s Blood Flow in Arteries. Theoretical, Experimental, and Clinical Perspectives. 6th ed. London: Hodder Arnold, 2011. 5. Hall KE, Sharp CR, Adams CR, Beilman G: A novel trauma model: naturally occurring canine trauma. Shock 41:25Y32, 2014. 6. Martini WZ, Chung KK, Dubick MA: Differential changes in hepatic synthesis of albumin and fibrinogen after severe hemorrhagic shock in pigs. Shock 41:68Y72, 2014. 7. Harr JN, Moore EE, Chin TL, Ghasabyan A, Gonzalez E, Wohlauer MV, Sauaia A, Banerjee A, Silliman CC: Post-injury hyperfibrinogenemia compromises efficacy of heparin-based VTE prophylaxis. Shock 41:33Y39, 2014. 8. Lusczek ER, Lexcen DR, Witowski NE, Determan C Jr, Mulier KE, Beilman G: Prolonged induced hypothermia in hemorrhagic shock is associated with decreased muscle metabolism: a nuclear magnetic resonance-based metabolomics study. Shock 41:80Y85, 2014. 9. DeLano FA, Schmid-Schonbein GW: Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock. Shock 41:56Y62, 2014. 10. Vanwijngaerden Y-M, Langouche L, Derde S, Liddle C, Coulter S, van den Berghe G, Mesotten D: Impact of parenteral nutrition versus fasting on hepatic bile acid production and transport in a rabbit model of prolonged critical illness. Shock 41:49Y55, 2014. 11. Hobson MJ, Hake PW, O’Connor M, Schulte C, Moore V, James JM, Piraino G, Zingarelli B: Conditional deletion of cardiomyocyte peroxisome proliferatoractivated receptor + enhances myocardial ischemia-reperfusion injury in mice. Shock 41:41Y48, 2014. 12. Bauza´ G, Moitra R, Remick D: Adenosine receptor antagonists effect on plasma-enhanced killing. Shock 41:63Y67, 2014. 13. Ristagno G, Fumagalli F, Russo I, Tantillo S, Zani DD, Locatelli V, de Maglie M, Novelli D, Staszewsky L, Vago T, et al.: Postresuscitation treatment with argon improves early neurological recovery in a porcine model of cardiac arrest. Shock 41:73Y79, 2014.
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Commentary WHAT’S NEW IN SHOCK? JANUARY 2014 John G. Younger, MD, MS Department of Emergency Medicine, Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, Michigan
The final review this month comes from Hall et al. (5) and reconsiders an idea that first came to my attention by way of Cindy Otto several years ago; namely, might clinical veterinary care of acutely injured dogs be a reality-check milestone in the development of new therapies for critical injury? As the authors point out, traumatic injury represents an important part of clinical practice for many veterinarians. Animals injured by automobiles solve issues that are frequently cited as bottlenecks between small animal models and clinical practice, including high variability in specific injuries, extremes of age and size, and a broad genetic background. Incorporating an entirely different field into the translational development of new diagnostics and therapeutics would certainly be a big job, but the more modest regulatory hurdles and lower cost of clinical care in veterinary medicine might pleasantly surprise us. How much experience are we leaving on the table by not moving this idea forward? The new clinical and basic science research this month also raises great questions. Martini et al. (6) show, in a series of porcine hemorrhagic shock experiments using radiolabeled amino acid precursors, that while severe hemorrhage is associated with dramatic acute losses of circulating fibrinogen, the synthesis of this key clotting protein is spared from the broad reprioritizing of protein synthesis in the acutely injured liver, at least in the opening hours of shock. These results dovetail well with the clinical observations from the University of Colorado group (7), showing that within a couple of days of severe traumatic injury, fibrinogen levels accumulate in patients to the point that administered heparin loses its effectiveness, threatening the utility of DVT prophylaxis. In a closely related article, Lusczek and colleagues (8) at the University of Minnesota provide a detailed snap shot of the serum nuclear magnetic resonance metabolome of pigs undergoing therapeutic hypothermia during resuscitation from hemorrhagic shock. Data of these kinds and their associated analyses are increasingly available as the search for both mechanism and clinical tools intensifies. Her results suggest that acute hypothermia alters the serum concentrations of several skeletal muscleYassociated metabolites, but work remains in trying to understand how enforced cooling alters the dynamic equilibrium between synthesis and uptake of these intermediates. There is also new work related to the gut and liver and their roles following both acute injury and prolonged critical illness. In a very interesting set of experiments, DeLano and SchmidSchonbein (9) demonstrate the ability of intraluminal proteases to cross the gut mucosa following hemorrhage in rats and degrade the extracellular domain of insulin receptors; blocking luminal activity with tranexamic acid not only preserves the extracellular portion of these proteins, but also restores insulin
For those of you who don’t include planetary geoscience in your monthly journal watch, a noteworthy discovery was reported in September 2013; namely, what appears to be the second largest volcano in the solar systemVbehind only Olympus Mons on Mars and completely dwarfing smaller terrestrial hills such as Mt Everest and Mauna LoaVwas found in the western Pacific between Japan and Hawaii (1). In an age where Google Maps allows one to investigate via satellite the course of every year’s Shock Society 5K run, that a volcano as large as New Mexico had evaded detection on earth for so long is reason for every scientist to pause and contemplate what might be hiding in plain sight in their own fields. As we begin 2014, this month’s issue of Shock reminds us of the importance of keeping our eyes open and knowing the limits of our measurements and theoretical constructs of even the most common conditions. The three reviews this month are great examples. In their discussion of the basis of sepsis-related acute kidney injury, Gomez and his colleagues (2) focus on a very interesting point, arguing that to interpret renal insufficiency in sepsis as being just ischemic injury is to overlook what may be a very valuable survival strategy in the kidney. Rather than continue to function as best as possible in the setting of overwhelming systemic disease, the renal tubules may use a survival program that includes short-term autophagic and mitophagic mothballing of renal function in order to save cells. This is a much more complex picture than the more traditional view of acute tubular necrosis wherein renal tubular cells are passive victims of hypoxic and inflammatory insults. I would also strongly encourage you to read the thoughtful review of sepsis-induced cardiac dysfunction, where Zaky and colleagues (3) in Seattle and Switzerland make a strong argument that a key reason why myocardial suppression during sepsis is so poorly understood and modeled is that the even the most Bstraightforward[ clinical observations such as decreased ejection fraction are deeply conceptually flawed. The mechanical performance of the heart, they correctly argue, cannot be considered independently of the coupled mechanical behavior of the arterial vascular bed. We define at our peril cardiac dysfunction on the basis of echocardiographically determined changes in ejection fraction or other bedside techniques. Doing so both ignores a large body of recent work in cardiac organogenesis and physiology and risks establishing models that aim to reproduce a misinterpreted clinical phenotype. Another great read in this area can be found, that by Nichols and colleagues (4), a text with which I believe every investigator in cardiovascular medicine needs to be familiar. 1
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
2
SHOCK VOL. 41, NO. 1
sensitivity following severe blood loss. Vanwijngaerden and colleagues (10) provide evidence of differential alterations in bile transports on the apical versus basolateral aspect of canalicular epithelial cells. However, the injury phenotype they describe (particularly in terms of limited jaundice, complex and not always congruent changes in mRNA content and protein content of important bile transporters) suggests this story is ongoing. Stay tuned. In the other new basic science of the month, Hobson and colleagues (11) continue to dissect the beneficial role of peroxisome proliferator-activated receptor + in myocardial ischemia, showing here in an outstanding model using a cardiomyocardiocyte-specific knockout mouse, that loss of peroxisome proliferator-activated receptor + activity at the time of myocardial injury significantly worsens functional outcome, increases circulating markers of injury, and promotes an exaggerated reperfusion inflammatory response. Bauza et al (12) further their ongoing story of plasma-enhanced bacterial killing by showing an important inhibitory effect of adenosine in macrophage-mediated killing of plasma-treated microorganisms relevant to cecal ligation and puncture. Lastly, Ristagno et al. (13) show here promising early results of argon/oxygen ventilation in the early postYcardiac arrest period. Using a porcine model of cardiac arrest following occlusion of the left anterior descending coronary artery, the authors were able to demonstrate a substantial improvement in neurological recovery when argon, rather than nitrogen, was used as the carrier gas for oxygen. This extends the building excitement for a role of noble gases in neuroprotection and cardioprotection. To every reader of this month’s journal, happy new year and best of luck with your efforts to better understand and treat shock. The immensity not only of your challenges, but also of your accomplishments, has not gone unappreciated.
YOUNGER
REFERENCES 1. Sager WW, Zhang J, Korenaga J, Sano T, Koppers AAP, Widdowson, M, Mahoney JJ. An immense shield volcano within the Shatsky Rise oceanic plateau, northwest Pacific Ocean. Nature Geoscience Online 5 September 2013, DOI: 10.1038/NGEO1934. 2. Gomez H, Ince C, de Backer D, Pickkers P, Payen D, Hotchkiss J, Kellum JA: A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock 41:3Y11, 2014. 3. Zaky A, Deem S, Bendjelid J, Treggiari MM: Characterization of cardiac dysfunction in sepsis: an ongoing challenge. Shock 41:12Y24, 2014. 4. Nichols W, O’Rourke M, Vlachopoulos C: McDonald’s Blood Flow in Arteries. Theoretical, Experimental, and Clinical Perspectives. 6th ed. London: Hodder Arnold, 2011. 5. Hall KE, Sharp CR, Adams CR, Beilman G: A novel trauma model: naturally occurring canine trauma. Shock 41:25Y32, 2014. 6. Martini WZ, Chung KK, Dubick MA: Differential changes in hepatic synthesis of albumin and fibrinogen after severe hemorrhagic shock in pigs. Shock 41:68Y72, 2014. 7. Harr JN, Moore EE, Chin TL, Ghasabyan A, Gonzalez E, Wohlauer MV, Sauaia A, Banerjee A, Silliman CC: Post-injury hyperfibrinogenemia compromises efficacy of heparin-based VTE prophylaxis. Shock 41:33Y39, 2014. 8. Lusczek ER, Lexcen DR, Witowski NE, Determan C Jr, Mulier KE, Beilman G: Prolonged induced hypothermia in hemorrhagic shock is associated with decreased muscle metabolism: a nuclear magnetic resonance-based metabolomics study. Shock 41:80Y85, 2014. 9. DeLano FA, Schmid-Schonbein GW: Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock. Shock 41:56Y62, 2014. 10. Vanwijngaerden Y-M, Langouche L, Derde S, Liddle C, Coulter S, van den Berghe G, Mesotten D: Impact of parenteral nutrition versus fasting on hepatic bile acid production and transport in a rabbit model of prolonged critical illness. Shock 41:49Y55, 2014. 11. Hobson MJ, Hake PW, O’Connor M, Schulte C, Moore V, James JM, Piraino G, Zingarelli B: Conditional deletion of cardiomyocyte peroxisome proliferatoractivated receptor + enhances myocardial ischemia-reperfusion injury in mice. Shock 41:41Y48, 2014. 12. Bauza´ G, Moitra R, Remick D: Adenosine receptor antagonists effect on plasma-enhanced killing. Shock 41:63Y67, 2014. 13. Ristagno G, Fumagalli F, Russo I, Tantillo S, Zani DD, Locatelli V, de Maglie M, Novelli D, Staszewsky L, Vago T, et al.: Postresuscitation treatment with argon improves early neurological recovery in a porcine model of cardiac arrest. Shock 41:73Y79, 2014.
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
