SHOCK, Vol. 41, No. 2, pp. 89Y90, 2014
Commentary WHAT’S NEW IN SHOCK? FEBRUARY 2014 Mark G. Clemens Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina
The February issue of Shock provides another excellent collection of articles on the clinical and basic aspects of shock. These include reports on sepsis, hemorrhage, cardiopulmonary resuscitation, myocardial ischemia, and a potentially very important report regarding a methodological issue. Leading off the sepsis studies is a report from Craciun et al. (1) who compared liver, pancreas, and kidney injury to determine which was a better predictor of death in a cecal ligation and puncture (CLP) model in a mouse model. Their results showed that blood urea nitrogen and cystatin C as indicators of kidney injury were good predictors whereas aspartate aminotransferase and amylase levels (markers of liver and kidney injury) were not. They conclude that limited hepatic and pancreatic injuries occur in CLP when kidney injury is present. A limitation of this study is that aspartate aminotransferase and amylase are markers of cellular injury whereas blood urea nitrogen and cystatin C are more sensitive indicators of decreased glomerular filtration. Nevertheless, the importance of kidney injury is supported. Luo et al. (2) may have a solution for this injury. They treated mice with mesenchymal stem cells after CLP. Stem cell treatment ameliorated decreased glomerular filtration rate and tubular injury as well as markers of inflammation. Interestingly, administered stem cells were found in multiple organs but not the kidneys, suggesting that the protective effect is on the inflammatory response and not the renal response to inflammation. An important component of the management of sepsis is appropriate nutrition. Two articles this month address issues of nutrition. De Haan et al. (3) present a very interesting study in which they examined the effect of a lipid-rich enteral nutrition on susceptibility to a secondary Pseudomonas aeruginosa infection 4 days after CLP. The lipid-rich diet attenuated the early inflammatory response after CLP and the expression of anti-inflammatory cytokines with secondary infection in late sepsis. The result was a decreased pulmonary bacterial load after P. aeruginosa secondary infection. This suggests that a lipid-rich diet may be a useful adjunct in controlling the balance between proinflammatory and anti-inflammatory responses in the various stages of sepsis. Glutamine has long been considered to be an important nutrient in sepsis. Hu et al. (4) examined its role in another aspect of the effect of immune response on lung injury. They administered glutamine intravenously 1 h after CLP in mice and examined the effect on +% T cells, the inflammatory response, and neutrophil-mediated lung injury. Glutamine treatment increased the number and decreased the rate of apoptosis of +% T cells in the lungs after CLP, along with decreased numbers of neutrophils and proinflammatory cytokines. Although the mechanisms by
which glutamine affects the inflammatory response remain unclear, this report adds to our understanding of what pathways may be affected. Sepsis often occurs in conjunction with other injuries such as burn or hemorrhage. This month, we have two articles addressing these Btwo-hit[ scenarios. Diao et al. (5) studied the effect of a burn/lipopolysaccharide model on endoplasmic reticulum stress in the liver in a rat model. In contrast to the findings of Craciun et al. (1) in a CLP model, these investigators found significant, albeit modest, increases in serum transaminases; however, this was accompanied by substantial increases in hepatocyte apoptosis, endoplasmic reticulum stress, inflammasome activation, and metabolic derangements. Although the difference in models must be considered, a comparison of these two studies suggests that findings of organ dysfunction are highly dependent on the end points measured. In addition to burn/sepsis, hemorrhage/sepsis is an important clinical scenario. Liu et al. (6) used hemorrhage/CLP to study the effect of an inhibitor of histone deacetylase (HDAC) on the immunological profile with sequential stresses. Histone deacetylase alters the function of proteins by decreasing the level of acetylation of lysine residues and has been shown to modulate the immune response. The HDAC inhibitor decreased neutrophil activation and levels of tumor necrosis factor-! and interleukin-6", decreased lung injury, and improved survival. These results suggest that protein acetylation is protective with sequential stresses, and that inhibition of deacetylation by HDAC favors a survival phenotype with respect to inflammatory response. In addition to its association with sepsis, hemorrhage is often a sequela of trauma. In this vein, Prunet et al. (7) used a swine model of lung contusion and hemorrhage to study fluid resuscitation strategies. They compared resuscitation with normal saline, low-volume normal saline with norepinephrine, and hypertonic saline with hydroxyethyl starch. All three protocols were associated with pulmonary edema and decreased compliance. Although some were better at preserving lung function, they were associated with other issues such as circulatory problems. They conclude that resuscitation has only modest effects on contused lungs, and that further research is needed to determine optimal protocols. In addition to its role in sequential stresses, hemorrhage can be a problem in itself. Thus, two articles this month specifically focus on hemorrhage. Clearly, treatment of hemorrhage requires the knowledge that hemorrhage has occurred. Tavakolian et al. (8) report the use of a seismocardiogram (SCG) device to detect early hemorrhage in a human subject study. They used lower body negative pressure to simulate hemorrhage in normal volunteers and correlated the SGC signal with other measures of 89
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
90
SHOCK VOL. 41, NO. 2
decreased effective volume. Their results showed SCG to be highly sensitive to decreased effective volume and able to detect functional hemorrhage earlier than measures such a blood pressure or pulse pressure. Because they describe the SCG as a simple and easily used device, it may have application for the early detection of functional hemorrhage in trauma patients. A major cause of mortality in hemorrhage is ischemia to vital organs as blood pressure falls. Morrison et al. (9) report the use of a Bresuscitative endovascular balloon occlusion of the aorta[ (REBOA) device to stabilize victims of noncompressible torso hemorrhage. Using an 80% liver resection model in pigs to simulate torso hemorrhage, both intermittent and complete REBOA improved aortic blood pressure and improved survival, with the complete REBOA being more effective, suggesting that it may be useful to stabilize these patients until bleeding can be controlled. Two articles this month address issues of cardiac resuscitation and ischemia. Kohlhauer et al. (10) addressed the effects of hypothermia and adrenaline during cardiopulmonary resuscitation in a rabbit model. Both of these are used in cardiopulmonary resuscitation, and they wanted to test whether the effects of hypothermia were independent of adrenaline use. They found that although adrenaline was effective in restoring spontaneous contraction, hypothermia without adrenaline was ineffective. Thus, although hypothermia may preserve peripheral tissue viability during cardiac arrest, alone it is not effective in restoring cardiac or vascular function. In the area of myocardial ischemia, Macchi et al. (11) used an isolated perfused rat heart model to examine the mechanisms of protection against reperfusion injury of the synthetic pentasaccharide fondaparinux. Fondaparinux is a heparin-like anticoagulant that, like heparin, has effects independent of its anticoagulant properties. The use of an isolated crystalloid-perfused heart in addition to an in vivo model allows the elimination of any effects on coagulation. They found that fondaparinux was effective in decreasing infarct size in vivo but not in the isolated perfused heart, suggesting the dependence on components of whole blood such as clotting factors. Moreover, the protective effect was abrogated by treatment with AG490, an inhibitor of epidermal growth factor tyrosine kinases, suggesting the involvement of this pathway in the protective effects. It is now well recognized that gender plays an important role in determining the response to shock and inflammation. In studying these effects, investigators commonly use vaginal
CLEMENS
smears in female mice to determine the stage of the estrus cycle and thus estimate circulating estrogen levels. Weixelbaumer et al. (12) provide a potentially very important report testing the validity of this assumption. They examined mice of different ages and compared vaginal cytology, impedance, and fecal estrogen. Their results demonstrated that common assumptions regarding the effect of age on hormone levels and estrus cycle may not be valid. These results need to be very carefully considered when interpreting studies on the hormonal basis for gender differences in response to shock and inflammation. REFERENCES 1. Craciun FL, Iskander KN, Chiswick EL, Stepien DM, Henderson JM, Remick DG: Early murine polymicrobial sepsis predominantly causes renal injury. Shock 41:97Y103, 2014. 2. Luo C-j, Zhang F-j, Zhang L, Geng Y-q, Li Q-g, Hong Q, Fu B, Zhu F, Cui S-y, Feng Z, et al.: Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice. Shock 41:123Y129, 2014. 3. De Haan JJ, Pastille E, Wirsdo¨rfer F, Lubbers T, Greve J-WM, Zhang Y, Buurman WA, Flohe´ SB: Lipid-rich enteral nutrition improves the defense against an opportunistic infection during polymicrobial sepsis. Shock 41:109Y114, 2014. 4. Hu Y-M, Yeh C-L, Pai M-H, Lee W-Y, Yeh S-L: Glutamine administration modulates lung +% T-lymphocyte expression in mice with polymicrobial sepsis. Shock 41:115Y122, 2014. 5. Diao L, Marshall AH, Dai X, Bogdanovic E, Abdullahi A, Amini-Nik S, Jeschke MG: Burn plus lipopolysaccharide augments endoplasmic reticulum stress and NLRP3 inflammasome activation and reduces PGC-1! in liver. Shock 41:138Y144, 2014. 6. Liu Z, Li Y, Chong W, Deperalta DK, Duan X, Liu B, Halaweish I, Zhou P, Alam HB: Creating a prosurvival phenotype through a histone deacetylase inhibitor in a lethal two-hit model. Shock 41:104Y108, 2014. 7. Prunet B, Prat N, Couret D, Cordier P-Y, De Bourmont S, Lambert D, Asencio Y, Meaudre E, Michelet P: Midterm effects of fluid resuscitation strategies in an experimental model of lung contusion and hemorrhagic shock. Shock 41:159Y165, 2014. 8. Tavakolian K, Dumont GA, Houlton G, Blaber AP: Precordial vibrations provide noninvasive detection of early-stage hemorrhage. Shock 41:91Y96, 2014. 9. Morrison JJ, Ross JD, Houston IV R, Watson JDB, Sokol KK, Rasmussen TE: Use of resuscitative endovascular balloon occlusion of the aorta (REBOA) in a highly lethal model of noncompressible torso hemorrhage. Shock 41:130Y137, 2014. 10. Kohlhauer M, Darbera L, Lidouren F, Chenoune M, Ghaleh B, Vivien B, Carli P, Dabire H, Berdeaux A, Tissier R: Comparative effect of hypothermia and adrenaline during cardiopulmonary resuscitation in rabbits. Shock 41:154Y158, 2014. 11. Macchi L, Moussa W, Guillou S, Tamareille S, Lamon D, Mirebeau-Prunier D, Prunier F: The synthetic pentasaccharide fondaparinux attenuates myocardial ischemia-reperfusion injury in rats via STAT-3. Shock 41:166Y171, 2014. 12. Weixelbaumer KM, Drechsler S, Wehrenpfennig P, Khadem A, Bahrami S, Tichy A, Palme R, Osuchowski MF: Estrus cycle status defined by vaginal cytology does not correspond to fluctuations of circulating estrogens in female mice. Shock 41:145Y153, 2014.
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Commentary WHAT’S NEW IN SHOCK? FEBRUARY 2014 Mark G. Clemens Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina
The February issue of Shock provides another excellent collection of articles on the clinical and basic aspects of shock. These include reports on sepsis, hemorrhage, cardiopulmonary resuscitation, myocardial ischemia, and a potentially very important report regarding a methodological issue. Leading off the sepsis studies is a report from Craciun et al. (1) who compared liver, pancreas, and kidney injury to determine which was a better predictor of death in a cecal ligation and puncture (CLP) model in a mouse model. Their results showed that blood urea nitrogen and cystatin C as indicators of kidney injury were good predictors whereas aspartate aminotransferase and amylase levels (markers of liver and kidney injury) were not. They conclude that limited hepatic and pancreatic injuries occur in CLP when kidney injury is present. A limitation of this study is that aspartate aminotransferase and amylase are markers of cellular injury whereas blood urea nitrogen and cystatin C are more sensitive indicators of decreased glomerular filtration. Nevertheless, the importance of kidney injury is supported. Luo et al. (2) may have a solution for this injury. They treated mice with mesenchymal stem cells after CLP. Stem cell treatment ameliorated decreased glomerular filtration rate and tubular injury as well as markers of inflammation. Interestingly, administered stem cells were found in multiple organs but not the kidneys, suggesting that the protective effect is on the inflammatory response and not the renal response to inflammation. An important component of the management of sepsis is appropriate nutrition. Two articles this month address issues of nutrition. De Haan et al. (3) present a very interesting study in which they examined the effect of a lipid-rich enteral nutrition on susceptibility to a secondary Pseudomonas aeruginosa infection 4 days after CLP. The lipid-rich diet attenuated the early inflammatory response after CLP and the expression of anti-inflammatory cytokines with secondary infection in late sepsis. The result was a decreased pulmonary bacterial load after P. aeruginosa secondary infection. This suggests that a lipid-rich diet may be a useful adjunct in controlling the balance between proinflammatory and anti-inflammatory responses in the various stages of sepsis. Glutamine has long been considered to be an important nutrient in sepsis. Hu et al. (4) examined its role in another aspect of the effect of immune response on lung injury. They administered glutamine intravenously 1 h after CLP in mice and examined the effect on +% T cells, the inflammatory response, and neutrophil-mediated lung injury. Glutamine treatment increased the number and decreased the rate of apoptosis of +% T cells in the lungs after CLP, along with decreased numbers of neutrophils and proinflammatory cytokines. Although the mechanisms by
which glutamine affects the inflammatory response remain unclear, this report adds to our understanding of what pathways may be affected. Sepsis often occurs in conjunction with other injuries such as burn or hemorrhage. This month, we have two articles addressing these Btwo-hit[ scenarios. Diao et al. (5) studied the effect of a burn/lipopolysaccharide model on endoplasmic reticulum stress in the liver in a rat model. In contrast to the findings of Craciun et al. (1) in a CLP model, these investigators found significant, albeit modest, increases in serum transaminases; however, this was accompanied by substantial increases in hepatocyte apoptosis, endoplasmic reticulum stress, inflammasome activation, and metabolic derangements. Although the difference in models must be considered, a comparison of these two studies suggests that findings of organ dysfunction are highly dependent on the end points measured. In addition to burn/sepsis, hemorrhage/sepsis is an important clinical scenario. Liu et al. (6) used hemorrhage/CLP to study the effect of an inhibitor of histone deacetylase (HDAC) on the immunological profile with sequential stresses. Histone deacetylase alters the function of proteins by decreasing the level of acetylation of lysine residues and has been shown to modulate the immune response. The HDAC inhibitor decreased neutrophil activation and levels of tumor necrosis factor-! and interleukin-6", decreased lung injury, and improved survival. These results suggest that protein acetylation is protective with sequential stresses, and that inhibition of deacetylation by HDAC favors a survival phenotype with respect to inflammatory response. In addition to its association with sepsis, hemorrhage is often a sequela of trauma. In this vein, Prunet et al. (7) used a swine model of lung contusion and hemorrhage to study fluid resuscitation strategies. They compared resuscitation with normal saline, low-volume normal saline with norepinephrine, and hypertonic saline with hydroxyethyl starch. All three protocols were associated with pulmonary edema and decreased compliance. Although some were better at preserving lung function, they were associated with other issues such as circulatory problems. They conclude that resuscitation has only modest effects on contused lungs, and that further research is needed to determine optimal protocols. In addition to its role in sequential stresses, hemorrhage can be a problem in itself. Thus, two articles this month specifically focus on hemorrhage. Clearly, treatment of hemorrhage requires the knowledge that hemorrhage has occurred. Tavakolian et al. (8) report the use of a seismocardiogram (SCG) device to detect early hemorrhage in a human subject study. They used lower body negative pressure to simulate hemorrhage in normal volunteers and correlated the SGC signal with other measures of 89
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
90
SHOCK VOL. 41, NO. 2
decreased effective volume. Their results showed SCG to be highly sensitive to decreased effective volume and able to detect functional hemorrhage earlier than measures such a blood pressure or pulse pressure. Because they describe the SCG as a simple and easily used device, it may have application for the early detection of functional hemorrhage in trauma patients. A major cause of mortality in hemorrhage is ischemia to vital organs as blood pressure falls. Morrison et al. (9) report the use of a Bresuscitative endovascular balloon occlusion of the aorta[ (REBOA) device to stabilize victims of noncompressible torso hemorrhage. Using an 80% liver resection model in pigs to simulate torso hemorrhage, both intermittent and complete REBOA improved aortic blood pressure and improved survival, with the complete REBOA being more effective, suggesting that it may be useful to stabilize these patients until bleeding can be controlled. Two articles this month address issues of cardiac resuscitation and ischemia. Kohlhauer et al. (10) addressed the effects of hypothermia and adrenaline during cardiopulmonary resuscitation in a rabbit model. Both of these are used in cardiopulmonary resuscitation, and they wanted to test whether the effects of hypothermia were independent of adrenaline use. They found that although adrenaline was effective in restoring spontaneous contraction, hypothermia without adrenaline was ineffective. Thus, although hypothermia may preserve peripheral tissue viability during cardiac arrest, alone it is not effective in restoring cardiac or vascular function. In the area of myocardial ischemia, Macchi et al. (11) used an isolated perfused rat heart model to examine the mechanisms of protection against reperfusion injury of the synthetic pentasaccharide fondaparinux. Fondaparinux is a heparin-like anticoagulant that, like heparin, has effects independent of its anticoagulant properties. The use of an isolated crystalloid-perfused heart in addition to an in vivo model allows the elimination of any effects on coagulation. They found that fondaparinux was effective in decreasing infarct size in vivo but not in the isolated perfused heart, suggesting the dependence on components of whole blood such as clotting factors. Moreover, the protective effect was abrogated by treatment with AG490, an inhibitor of epidermal growth factor tyrosine kinases, suggesting the involvement of this pathway in the protective effects. It is now well recognized that gender plays an important role in determining the response to shock and inflammation. In studying these effects, investigators commonly use vaginal
CLEMENS
smears in female mice to determine the stage of the estrus cycle and thus estimate circulating estrogen levels. Weixelbaumer et al. (12) provide a potentially very important report testing the validity of this assumption. They examined mice of different ages and compared vaginal cytology, impedance, and fecal estrogen. Their results demonstrated that common assumptions regarding the effect of age on hormone levels and estrus cycle may not be valid. These results need to be very carefully considered when interpreting studies on the hormonal basis for gender differences in response to shock and inflammation. REFERENCES 1. Craciun FL, Iskander KN, Chiswick EL, Stepien DM, Henderson JM, Remick DG: Early murine polymicrobial sepsis predominantly causes renal injury. Shock 41:97Y103, 2014. 2. Luo C-j, Zhang F-j, Zhang L, Geng Y-q, Li Q-g, Hong Q, Fu B, Zhu F, Cui S-y, Feng Z, et al.: Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice. Shock 41:123Y129, 2014. 3. De Haan JJ, Pastille E, Wirsdo¨rfer F, Lubbers T, Greve J-WM, Zhang Y, Buurman WA, Flohe´ SB: Lipid-rich enteral nutrition improves the defense against an opportunistic infection during polymicrobial sepsis. Shock 41:109Y114, 2014. 4. Hu Y-M, Yeh C-L, Pai M-H, Lee W-Y, Yeh S-L: Glutamine administration modulates lung +% T-lymphocyte expression in mice with polymicrobial sepsis. Shock 41:115Y122, 2014. 5. Diao L, Marshall AH, Dai X, Bogdanovic E, Abdullahi A, Amini-Nik S, Jeschke MG: Burn plus lipopolysaccharide augments endoplasmic reticulum stress and NLRP3 inflammasome activation and reduces PGC-1! in liver. Shock 41:138Y144, 2014. 6. Liu Z, Li Y, Chong W, Deperalta DK, Duan X, Liu B, Halaweish I, Zhou P, Alam HB: Creating a prosurvival phenotype through a histone deacetylase inhibitor in a lethal two-hit model. Shock 41:104Y108, 2014. 7. Prunet B, Prat N, Couret D, Cordier P-Y, De Bourmont S, Lambert D, Asencio Y, Meaudre E, Michelet P: Midterm effects of fluid resuscitation strategies in an experimental model of lung contusion and hemorrhagic shock. Shock 41:159Y165, 2014. 8. Tavakolian K, Dumont GA, Houlton G, Blaber AP: Precordial vibrations provide noninvasive detection of early-stage hemorrhage. Shock 41:91Y96, 2014. 9. Morrison JJ, Ross JD, Houston IV R, Watson JDB, Sokol KK, Rasmussen TE: Use of resuscitative endovascular balloon occlusion of the aorta (REBOA) in a highly lethal model of noncompressible torso hemorrhage. Shock 41:130Y137, 2014. 10. Kohlhauer M, Darbera L, Lidouren F, Chenoune M, Ghaleh B, Vivien B, Carli P, Dabire H, Berdeaux A, Tissier R: Comparative effect of hypothermia and adrenaline during cardiopulmonary resuscitation in rabbits. Shock 41:154Y158, 2014. 11. Macchi L, Moussa W, Guillou S, Tamareille S, Lamon D, Mirebeau-Prunier D, Prunier F: The synthetic pentasaccharide fondaparinux attenuates myocardial ischemia-reperfusion injury in rats via STAT-3. Shock 41:166Y171, 2014. 12. Weixelbaumer KM, Drechsler S, Wehrenpfennig P, Khadem A, Bahrami S, Tichy A, Palme R, Osuchowski MF: Estrus cycle status defined by vaginal cytology does not correspond to fluctuations of circulating estrogens in female mice. Shock 41:145Y153, 2014.
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
