SHOCK, Vol. 43, No. 5, pp. 427Y428, 2015
Commentary WHAT’S NEW IN SHOCK? MAY 2015 Saman Arbabi University of Washington, Seattle, Washington
I have always considered the Shock journal as the premier publication to learn about new and exciting translational, molecular, and basic science research ideas related to various aspects of responses to injury, inflammation, ischemia, or infection. However, the Shock journal was not my go-to resource for clinical therapies that may be important in the immediate care of patients with sepsis. I do admit that as a member of the Shock Society and the editorial board of the Shock journal, I should have known better; no matter, reading this month’s issue clearly changed that point of view. The May 2015 issue has a great combination of clinical, translational, and basic science papers that are relevant to the care of critically ill patients. Physiological parameters such as heart rate and systolic blood pressure are not constant values; rather, there is a natural variability and constant change over time. However, this variability is not a random walk; there is a pattern. Whereas it is impossible to predict the exact value at a precise time (biological uncertainty principal), the equations that describe the variability in physiological parameters may give us a useful probabilistic pattern. In this issue of the Journal, Scully et al. (1) are using the loss or change of the natural variability in heart rate and blood pressure to predict various stages of shock, as an early warning sign. With increasing reliance on large data sets, clinical medicine may be ready to move from simple analyses of vital signs to analyzing their variability to gain more information using computer-based platforms. Staying with the computational algorithm theme, Liu et al. (2) examine an automated platform using real-time analysis of vital signs for the identification of patients with trauma with substantial bleeding before trauma center arrival. Practitioners already use several automated in-hospital systems to alert or activate processes of care for patients. Such is the case for sepsis team activation, where escalation of care is based on the results from a computer program that scans patient data in real time and alerts the medical team of potential patterns suggestive of sepsis. Extending these algorithms to prehospital data may be the next step, which may improve early activation of trauma systems and massive transfusion protocols. The article by Sarkar et al. (3) deals with an important issue that clinicians face during the treatment of septic shock. Whereas septic shock may cause a significant decrease in the systemic vascular resistance, in part inducing hypotension, it causes an increase in pulmonary vascular resistance (PVR). The higher PVR is a major pathological response, increasing strain on the right heart and potentially increasing the shunt and hypoxia. The dilemma is that the most common pressor used in the treatment of septic shock, norepinephrine, increases PVR as well as systemic vascular resistance, potentially worsening the
pulmonary status and the right heart strain. In an animal model of sepsis, the investigators demonstrate a significant increase in PVR in response to norepinephrine therapy by activating alphaadrenergic receptors in the pulmonary system. In their model, however, vasopressin has minimal effect on PVR (potentially due to lack of V1 receptors). Should we use vasopressin instead of norepinephrine as the first agent? As always, the answer is not simple. The authors review the current clinical studies and offer their opinion. Sticking with catecholamines in sepsis, Piton et al. (4) examine enterocyte damage in critically ill patients and report an association between higher epinephrine and/or norepinephrine use and enterocyte damage based on plasma intestinal fatty acidYbinding protein. Since this is not a randomized trial, it is hard to distinguish the catecholamine effect from the sequela of sepsis; nevertheless, it is a reminder that further activation of alpha- and beta-adrenergic receptors in critically ill patients may be associated with significant adverse effects. As we have already established, the use of pressors in septic shock may be associated with several undesired adverse effects. However, therapeutic guidelines advocating largevolume load and fluid resuscitation are also associated with complications such as severe pulmonary dysfunction and various compartment syndromes. Most intensivists agree that goal-directed therapy with appropriate early volume resuscitation is important; and there is the rubVhow do you know what is Bappropriate[? How do we avoid under- or overresuscitation? In this issue of the Journal, See et al. (5) investigate the effect of adherence to a protocol-based fluid management in the treatment of critically ill patients with circulatory shock, noting a trend toward improved intensive care unit survival in the group with better compliance. However, as the authors note, this is a complicated issue, and we shall see if the addition of new monitoring technology, resuscitation protocols, and computerbased platforms will improve outcomes. Whereas pressors and fluid resuscitation may support a patient in circulatory shock, these interventions do not treat the underlying pathophysiological response. Investigators have found the innate immune system and inflammatory response to be a double-edged sword. Whereas a local controlled response is necessary for appropriate host defense and wound healing, a hyperactive systemic activation may indiscriminately attack various tissues and induce end-organ failure. To date, administrations of several immunomodulatory agents have failed to attenuate the systemic inflammatory response syndrome or the risk of fatal outcome. As evident in this issue of the Shock journal, the shock scientific community is continuing the effort. Howe et al. (6) demonstrate that transforming growth 427
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
428
SHOCK VOL. 43, NO. 5
factor beta1 treatment, an anti-inflammatory cytokine with beneficial effects on intestinal epithelial barrier function, preserves loss of epithelial barrier integrity caused by the stress of hypoxia-reoxygenation in an in vitro model. In another publication, Gao et al. (7) investigate the protective effect of hydrocortisone treatment in an animal model of severe acute pancreatitis. Reading the aforementioned articles reminded me that the ultimate response to an immunomodulator depends not only on the agent but also on the specificity of drug-tissue interaction. In this complex network, systemic inhibition of one pathway may have unpredictable or undesired results. The study by Liu et al. (8) deals with one of these undesired results seen with granulocyte colony-stimulating factor treatment in sepsis: the up-regulation of lipopolysaccharide-binding protein. The authors suggest that the effect of augmentation of the host’s response via granulocyte colony-stimulating factor pretreatment is further enhanced by inhibition of lipopolysaccharide-binding protein up-regulation. Using a similar approach of blocking or reducing the undesired effects of therapy, another group of investigators from China hypothesize that the reactive nitrogen species, generated as an adverse effect of treatment with inhaled nitric oxide, can be eliminated by hydrogen gas combined therapy (9). In a mouse model of acute lung injury, these investigators show that combined nitric oxide and hydrogen gas treatments provides an enhanced therapeutic effect. I was aware of the functional importance of glycocalyx endothelial surface layer (the glycocalyx regulates vascular barrier function and protein extravasation, as well as nutritional blood flow). However, I thought assessment of this layer required complicated imaging technology or cell surface biomarker analyses. However, Jung et al. (10) examine the circulating levels of the glycocalyx components in patients with infarctrelated cardiogenic shock. The authors measure circulating levels of glycosaminoglycan heparan sulfate, a major component of the glycocalyx of endothelial cells, and syndecan-1, the most prevalent proteoglycan. The increased levels of syndecan1 are an independent predictor of short-term mortality in patients with acute myocardial infarction and cardiogenic shock. The article by Matsumoto et al. (11) is another reminder that inflammatory and coagulations systems may be governed by closely associated pathways, similar to electricity and magnetism. Endothelial microparticles are small shed membranous vesicles that are released from cells upon activation, which can express various endothelial-specific antigens such as tissue factor, thrombomoduline, and endothelial protein C receptor. Matsumoto et al. demonstrate a significant increase in the number of 3 antigen-positive endothelial microparticles in patients with sepsis as compared to healthy control subjects, which was associated with higher disseminated intravascular coagulation scores. Elucidation of pathways that induce disseminated intravascular coagulopathy and the association of these pathways with antigen-positive endothelial microparticles will be an exciting field of research. While having high levels of Ghrelin, a gastrointestinal hormone that is known to induce a positive energy balance by stimulating food intake, may not be good for your girth and
ARBABI
waist size, it may improve your neurological function after central nervous system ischemia. Xie et al. (12) demonstrate that treatment with ghrelin after recovery from cardiac arrest improves neurological recovery and decreases apoptosis in brain cells. That is one way for overweight people to remain jolly. The final article that I will discuss is related to sex: specifically, sex hormones. There have been several papers that have demonstrated improved outcomes by blocking testosterone receptors in hemorrhagic shock models. Androgen receptor antagonist can reduce cytokine production and decrease endorgan injury. Liu et al. (13) investigate whether Akt pathway plays any role in the casodex (an androgen receptor antagonist)mediated attenuation of hepatic injury after trauma-hemorrhagic shock. They show that casodex increases hepatic phospho-Akt expression and coadministration of wortmannin (PI3K inhibitor) abolishes the casodex-induced advantageous effects on cytokine expression and hepatic injury, therefore, demonstrating the involvement of the Akt pathway. I thank the publication Committee and Dr. Chaudry for the opportunity to preview this issue of Shock. This issue represents the Shock Society very well with the entire spectrum of research from bench to bedside. REFERENCES 1. Scully CG, Kramer GC, Strauss DG: Evaluation of heart rate and blood pressure variability as indicators of physiological compensation to hemorrhage prior to shock. Shock 43:463Y469, 2015. 2. Liu J, Khitrov MY, Gates JD, Odom SR, Havens JM, de Moya MA, Wilkins K, Wedel SK, Kittell EO, Reifman J, et al. Automated analysis of vital signs to identify patients with substantial bleeding prior to hospital arrival: a feasibility study. Shock 43:429Y436, 2015. 3. Sarkar J, Golden PJ, Kajiura LN, Murata L-AM, Uyehara CFT: Vasopressin decreases pulmonary-to-systemic vascular resistance ratio in a porcine model of severe hemorrhagic shock. Shock 43:475Y482, 2015. 4. Piton G, Cypriani B, Regnard J, Patry C, Puyraveau M, Capellier G: Catecholamine use is associated with enterocyte damage in critically ill patients. Shock 43:437Y442, 2015. 5. See KC, Mukhpadhyay A, Lau SC-X, Tan SM-Y, Lim TK, Phua J: Shock in the first 24 h of intensive care unit stay: observational study of protocol-based fluid management. Shock 43:456Y462, 2015. 6. Howe KL, Lorentz R, Assa A, Pinnell L, Johnson-Henry K, Sherman PM: Transforming growth factor beta-1 protects against intestinal epithelial barrier dysfunction caused by hypoxia-reoxygenation. Shock 43:483Y489, 2015. 7. Gao S-L, Zhang Y, Zhang S-Y, Liang Z-Y, Yu W-Q, Liang T-B: The hydrocortisone protection of glycocalyx on the intestinal capillary endothelium during severe acute pancreatitis. Shock 43:512Y517, 2015. 8. Liu A, Weiss S, Fang H, Claus RA, Ro¨del J, Dirsch O, Dahman U: LBP blockade augments the protective effect of G-CSF in a rat sepsis model. Shock 43:497Y503, 2015. 9. Liu H, Liang X, Wang D, Zhang H, Liu L, Chen H, Li Y, Duan Q, Xie K: Combination therapy with nitric oxide and molecular hydrogen in a murine model of acute lung injury. Shock 43:504Y511, 2015. 10. Jung C, Fuernau G, Muench P, Desch S, Eitel I, Schuler G, Adams V, Figulla HR, Thiele H: Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance. Shock 43:450Y455, 2015. 11. Matsumoto H, Yamakawa K, Ogura H, Koh T, Matsumoto N, Shimazu T: Enhanced expression of cell-specific surface antigens on endothelial microparticles in sepsis-induced disseminated intravascular coagulation. Shock 43:443Y449, 2015. 12. Xie X, Zhang J, Chen D, Pan H, Wu Z, Ge D, Yang G: Effects of ghrelin on post-resuscitation brain injury in a rat model of cardiac arrest. Shock 43:490Y496, 2015. 13. Liu F-C, Pang S-T, Tsai Y-F, Chaudry IH, Yu H-P: Hepatoprotective effect of casodex following trauma-hemorrhage in a rodent model. Shock 43:470Y474, 2015.
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Commentary WHAT’S NEW IN SHOCK? MAY 2015 Saman Arbabi University of Washington, Seattle, Washington
I have always considered the Shock journal as the premier publication to learn about new and exciting translational, molecular, and basic science research ideas related to various aspects of responses to injury, inflammation, ischemia, or infection. However, the Shock journal was not my go-to resource for clinical therapies that may be important in the immediate care of patients with sepsis. I do admit that as a member of the Shock Society and the editorial board of the Shock journal, I should have known better; no matter, reading this month’s issue clearly changed that point of view. The May 2015 issue has a great combination of clinical, translational, and basic science papers that are relevant to the care of critically ill patients. Physiological parameters such as heart rate and systolic blood pressure are not constant values; rather, there is a natural variability and constant change over time. However, this variability is not a random walk; there is a pattern. Whereas it is impossible to predict the exact value at a precise time (biological uncertainty principal), the equations that describe the variability in physiological parameters may give us a useful probabilistic pattern. In this issue of the Journal, Scully et al. (1) are using the loss or change of the natural variability in heart rate and blood pressure to predict various stages of shock, as an early warning sign. With increasing reliance on large data sets, clinical medicine may be ready to move from simple analyses of vital signs to analyzing their variability to gain more information using computer-based platforms. Staying with the computational algorithm theme, Liu et al. (2) examine an automated platform using real-time analysis of vital signs for the identification of patients with trauma with substantial bleeding before trauma center arrival. Practitioners already use several automated in-hospital systems to alert or activate processes of care for patients. Such is the case for sepsis team activation, where escalation of care is based on the results from a computer program that scans patient data in real time and alerts the medical team of potential patterns suggestive of sepsis. Extending these algorithms to prehospital data may be the next step, which may improve early activation of trauma systems and massive transfusion protocols. The article by Sarkar et al. (3) deals with an important issue that clinicians face during the treatment of septic shock. Whereas septic shock may cause a significant decrease in the systemic vascular resistance, in part inducing hypotension, it causes an increase in pulmonary vascular resistance (PVR). The higher PVR is a major pathological response, increasing strain on the right heart and potentially increasing the shunt and hypoxia. The dilemma is that the most common pressor used in the treatment of septic shock, norepinephrine, increases PVR as well as systemic vascular resistance, potentially worsening the
pulmonary status and the right heart strain. In an animal model of sepsis, the investigators demonstrate a significant increase in PVR in response to norepinephrine therapy by activating alphaadrenergic receptors in the pulmonary system. In their model, however, vasopressin has minimal effect on PVR (potentially due to lack of V1 receptors). Should we use vasopressin instead of norepinephrine as the first agent? As always, the answer is not simple. The authors review the current clinical studies and offer their opinion. Sticking with catecholamines in sepsis, Piton et al. (4) examine enterocyte damage in critically ill patients and report an association between higher epinephrine and/or norepinephrine use and enterocyte damage based on plasma intestinal fatty acidYbinding protein. Since this is not a randomized trial, it is hard to distinguish the catecholamine effect from the sequela of sepsis; nevertheless, it is a reminder that further activation of alpha- and beta-adrenergic receptors in critically ill patients may be associated with significant adverse effects. As we have already established, the use of pressors in septic shock may be associated with several undesired adverse effects. However, therapeutic guidelines advocating largevolume load and fluid resuscitation are also associated with complications such as severe pulmonary dysfunction and various compartment syndromes. Most intensivists agree that goal-directed therapy with appropriate early volume resuscitation is important; and there is the rubVhow do you know what is Bappropriate[? How do we avoid under- or overresuscitation? In this issue of the Journal, See et al. (5) investigate the effect of adherence to a protocol-based fluid management in the treatment of critically ill patients with circulatory shock, noting a trend toward improved intensive care unit survival in the group with better compliance. However, as the authors note, this is a complicated issue, and we shall see if the addition of new monitoring technology, resuscitation protocols, and computerbased platforms will improve outcomes. Whereas pressors and fluid resuscitation may support a patient in circulatory shock, these interventions do not treat the underlying pathophysiological response. Investigators have found the innate immune system and inflammatory response to be a double-edged sword. Whereas a local controlled response is necessary for appropriate host defense and wound healing, a hyperactive systemic activation may indiscriminately attack various tissues and induce end-organ failure. To date, administrations of several immunomodulatory agents have failed to attenuate the systemic inflammatory response syndrome or the risk of fatal outcome. As evident in this issue of the Shock journal, the shock scientific community is continuing the effort. Howe et al. (6) demonstrate that transforming growth 427
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
428
SHOCK VOL. 43, NO. 5
factor beta1 treatment, an anti-inflammatory cytokine with beneficial effects on intestinal epithelial barrier function, preserves loss of epithelial barrier integrity caused by the stress of hypoxia-reoxygenation in an in vitro model. In another publication, Gao et al. (7) investigate the protective effect of hydrocortisone treatment in an animal model of severe acute pancreatitis. Reading the aforementioned articles reminded me that the ultimate response to an immunomodulator depends not only on the agent but also on the specificity of drug-tissue interaction. In this complex network, systemic inhibition of one pathway may have unpredictable or undesired results. The study by Liu et al. (8) deals with one of these undesired results seen with granulocyte colony-stimulating factor treatment in sepsis: the up-regulation of lipopolysaccharide-binding protein. The authors suggest that the effect of augmentation of the host’s response via granulocyte colony-stimulating factor pretreatment is further enhanced by inhibition of lipopolysaccharide-binding protein up-regulation. Using a similar approach of blocking or reducing the undesired effects of therapy, another group of investigators from China hypothesize that the reactive nitrogen species, generated as an adverse effect of treatment with inhaled nitric oxide, can be eliminated by hydrogen gas combined therapy (9). In a mouse model of acute lung injury, these investigators show that combined nitric oxide and hydrogen gas treatments provides an enhanced therapeutic effect. I was aware of the functional importance of glycocalyx endothelial surface layer (the glycocalyx regulates vascular barrier function and protein extravasation, as well as nutritional blood flow). However, I thought assessment of this layer required complicated imaging technology or cell surface biomarker analyses. However, Jung et al. (10) examine the circulating levels of the glycocalyx components in patients with infarctrelated cardiogenic shock. The authors measure circulating levels of glycosaminoglycan heparan sulfate, a major component of the glycocalyx of endothelial cells, and syndecan-1, the most prevalent proteoglycan. The increased levels of syndecan1 are an independent predictor of short-term mortality in patients with acute myocardial infarction and cardiogenic shock. The article by Matsumoto et al. (11) is another reminder that inflammatory and coagulations systems may be governed by closely associated pathways, similar to electricity and magnetism. Endothelial microparticles are small shed membranous vesicles that are released from cells upon activation, which can express various endothelial-specific antigens such as tissue factor, thrombomoduline, and endothelial protein C receptor. Matsumoto et al. demonstrate a significant increase in the number of 3 antigen-positive endothelial microparticles in patients with sepsis as compared to healthy control subjects, which was associated with higher disseminated intravascular coagulation scores. Elucidation of pathways that induce disseminated intravascular coagulopathy and the association of these pathways with antigen-positive endothelial microparticles will be an exciting field of research. While having high levels of Ghrelin, a gastrointestinal hormone that is known to induce a positive energy balance by stimulating food intake, may not be good for your girth and
ARBABI
waist size, it may improve your neurological function after central nervous system ischemia. Xie et al. (12) demonstrate that treatment with ghrelin after recovery from cardiac arrest improves neurological recovery and decreases apoptosis in brain cells. That is one way for overweight people to remain jolly. The final article that I will discuss is related to sex: specifically, sex hormones. There have been several papers that have demonstrated improved outcomes by blocking testosterone receptors in hemorrhagic shock models. Androgen receptor antagonist can reduce cytokine production and decrease endorgan injury. Liu et al. (13) investigate whether Akt pathway plays any role in the casodex (an androgen receptor antagonist)mediated attenuation of hepatic injury after trauma-hemorrhagic shock. They show that casodex increases hepatic phospho-Akt expression and coadministration of wortmannin (PI3K inhibitor) abolishes the casodex-induced advantageous effects on cytokine expression and hepatic injury, therefore, demonstrating the involvement of the Akt pathway. I thank the publication Committee and Dr. Chaudry for the opportunity to preview this issue of Shock. This issue represents the Shock Society very well with the entire spectrum of research from bench to bedside. REFERENCES 1. Scully CG, Kramer GC, Strauss DG: Evaluation of heart rate and blood pressure variability as indicators of physiological compensation to hemorrhage prior to shock. Shock 43:463Y469, 2015. 2. Liu J, Khitrov MY, Gates JD, Odom SR, Havens JM, de Moya MA, Wilkins K, Wedel SK, Kittell EO, Reifman J, et al. Automated analysis of vital signs to identify patients with substantial bleeding prior to hospital arrival: a feasibility study. Shock 43:429Y436, 2015. 3. Sarkar J, Golden PJ, Kajiura LN, Murata L-AM, Uyehara CFT: Vasopressin decreases pulmonary-to-systemic vascular resistance ratio in a porcine model of severe hemorrhagic shock. Shock 43:475Y482, 2015. 4. Piton G, Cypriani B, Regnard J, Patry C, Puyraveau M, Capellier G: Catecholamine use is associated with enterocyte damage in critically ill patients. Shock 43:437Y442, 2015. 5. See KC, Mukhpadhyay A, Lau SC-X, Tan SM-Y, Lim TK, Phua J: Shock in the first 24 h of intensive care unit stay: observational study of protocol-based fluid management. Shock 43:456Y462, 2015. 6. Howe KL, Lorentz R, Assa A, Pinnell L, Johnson-Henry K, Sherman PM: Transforming growth factor beta-1 protects against intestinal epithelial barrier dysfunction caused by hypoxia-reoxygenation. Shock 43:483Y489, 2015. 7. Gao S-L, Zhang Y, Zhang S-Y, Liang Z-Y, Yu W-Q, Liang T-B: The hydrocortisone protection of glycocalyx on the intestinal capillary endothelium during severe acute pancreatitis. Shock 43:512Y517, 2015. 8. Liu A, Weiss S, Fang H, Claus RA, Ro¨del J, Dirsch O, Dahman U: LBP blockade augments the protective effect of G-CSF in a rat sepsis model. Shock 43:497Y503, 2015. 9. Liu H, Liang X, Wang D, Zhang H, Liu L, Chen H, Li Y, Duan Q, Xie K: Combination therapy with nitric oxide and molecular hydrogen in a murine model of acute lung injury. Shock 43:504Y511, 2015. 10. Jung C, Fuernau G, Muench P, Desch S, Eitel I, Schuler G, Adams V, Figulla HR, Thiele H: Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance. Shock 43:450Y455, 2015. 11. Matsumoto H, Yamakawa K, Ogura H, Koh T, Matsumoto N, Shimazu T: Enhanced expression of cell-specific surface antigens on endothelial microparticles in sepsis-induced disseminated intravascular coagulation. Shock 43:443Y449, 2015. 12. Xie X, Zhang J, Chen D, Pan H, Wu Z, Ge D, Yang G: Effects of ghrelin on post-resuscitation brain injury in a rat model of cardiac arrest. Shock 43:490Y496, 2015. 13. Liu F-C, Pang S-T, Tsai Y-F, Chaudry IH, Yu H-P: Hepatoprotective effect of casodex following trauma-hemorrhage in a rodent model. Shock 43:470Y474, 2015.
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
