SHOCK, Vol. 41, No. 3, pp. 173Y174, 2014
Commentary WHAT’S NEW IN SHOCK? MARCH 2014 Mark G. Clemens, PhD University of North Carolina at Charlotte, Charlotte, North Carolina
The March 2014 issue of Shock provides another combination of clinical and laboratory studies with a particular abundance of clinical reports. Leading off the issue is a review by Ortiz-Diaz and Lan (1) on the topic of intra-abdominal hypertension. The importance of intra-abdominal hypertension is fairly well recognized in surgical intensive care units, but they make a case that it is also an important but infrequently recognized cause of morbidity in medical units. This report should serve to draw attention to this potentially important issue. In the realm of clinical studies this month, we have two reports on effectors/markers of injury and two related to treatment. The first report by Rahbar et al. (2) examines changes in plasma colloid oncotic pressure as a marker of hemorrhagic shock. They collected plasma from 104 trauma cases in the emergency room and divided them into low and high oncotic pressure groups. Patients with low oncotic pressure (an indicator of increased vascular permeability) had worse injury scores and required more blood products, although superficial signs at admission were not different, suggesting that plasma oncotic pressure may be a sensitive indicator of hemorrhagic shock. Although they did not see any difference in coagulation, they looked primarily for decreased coagulation. Branco et al. (3) looked at the other side of coagulation-hypercoagulability. They examined 118 patients, of whom 31 were hypercoagulable on admission as determined by thromboelastography. These patients had decreased need for blood products when compared with normal or hypocoagulable patients. They also decreased 24-h and 7-day mortality. It would be interesting to specifically compare plasma oncotic pressure and hypercoagulability in the same group of patients to see how these indicators compare. Two articles this month address issues of treatment. Bauman et al. (4) examined the difference in need for vasopressor support in African American (AA) versus white patients in septic shock. This retrospective study examined records of 159 patients (60.4% AA) looking for vasopressor support requirements. African American patients required significantly more norepinephrine to maintain a mean arterial pressure greater than 65 mmHg. A complicating factor is that AA patients had a much higher incidence of hypertension and greater incidence of end-stage renal disease. It is not clear whether race is a significant factor when these comorbidities are eliminated. The second treatment clinical study by Lomivorotov et al. (5) was performed in the context of volume support during coronary artery bypass surgery. Hypertonic saline and hydroxyethyl starch (HSH) have been shown to have beneficial immunomodulatory effects during cardiac surgery, but there is concern that the chloride load may have
nephrotoxic effects. Thus, they randomized 20 patients into each of two groups: control (0.9% saline infusion) or HSH. They found no difference in either glomerular filtration rate or tubular injury in the groups indicating that HSH is safe, at least with respect to kidney injury in these patients. This month’s issue of Shock also presents laboratory reports addressing potential treatments and mediators of shock. Breithaupt-Faloppa et al. (6) examined a new application for the use of estradiol for treatment of shock. They examined lung injury following an intestinal ischemia-reperfusion injury in a rat model. An important component of their design is that they had two groups of estradiol treated rats: one during ischemia and the other after reperfusion. The latter group is particularly important for clinical relevance. Estradiol treatment decreased neutrophil infiltration into the lungs and decreased vascular permeability. This was associated with decrease in cytokine production and decreased adhesion molecules. The fact that treatment during reperfusion was at least as effective as during ischemia suggests potential clinical relevance. It is well known that sepsis is associated with metabolic dysfunction. Glutamine supplementation has been shown to be beneficial in many contexts but has not been examined in previously malnourished animals. The report by de Oliveira et al. (7) fills this gap. They made rats septic after 4 weeks on a calorically deficient diet. The malnourished group showed an increase in mortality and organ injury, especially in the lung. Supplementation with glutamine 1 h after cecal ligation and puncture significantly improved survival as well as markers of injury in lung, kidney, intestine, and liver and appeared to be related to improved balance of M1 and M2 macrophages. These results suggest an additional role for glutamine supplementation in previously malnourished patients. Natural products and traditional medicines are a potentially abundant source of new therapeutic molecules, but require rigorous investigation to ensure both safety and efficacy. Zheng et al. (8) examined the effect of a polysaccharide purified from a Chinese herb Codonopsis pilosula on circulating regulatory T cells in a mouse cecal ligation and puncture (CLP) model. It is not clear exactly when the mice were treated, but C. pilosula suppressed excessive regulatory T cells after CLP, and this effect was abrogated by use of a Toll-like receptor 4 neutralizing antibody, suggesting that its effect is mediated by Toll-like receptor 4. It is now recognized that autophagocytosis of damaged cell organelles is an important defense mechanism following cell injury. Lin et al. (9) tested whether activation of autophagy might be protective against liver injury in septic mice. Mice were treated with carbamazine (CBZ) to activate autophagy at 0.5 and 24 h after CLP. Sepsis alone 173
Copyright © 2014 by the Shock Society. Unauthorized reproduction of this article is prohibited.
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SHOCK VOL. 41, NO. 3
activated autophagy but with incomplete clearance of autophagosomes. Carbamazine enhanced autophagosome clearance and decreased liver injury and inflammation. Inhibition of autophagosome clearance abrogated the beneficial effect of CBZ. The effectiveness of CBZ with posttreatment suggests potential clinical application. Two articles this month address novel mediators of injury in sepsis. Hviid et al. (10) provide a comprehensive assessment of the role of the matricellular protein Cyr61/CCN-1 protein (CCN) that has been shown to have immune-modulatory effects. They showed that CCN levels in plasma are markedly elevated following CLP, but mRNA expression in potential source organs was depressed. However, platelets were found to contain CCN, and it was released following platelet activation, and this release was inhibited by inhibition of platelet activation. Thus, CCN may be a significant regulator of inflammation during sepsis following its release from activated platelets. Another cell protein that may modulate the response to sepsis is lysozyme. It is released from activated leukocytes and has been shown to be involved in cardiovascular dysfunction in sepsis. Gotes et al. (11) now extend these findings by testing the effect of lysozyme on vascular smooth muscle function and its organ distribution during sepsis in a canine model. Lysozyme rapidly deposited in the smooth muscle layer of isolated carotid artery preparations and led to contractile failure of isolated human smooth muscle cells. In an in vivo sepsis model, it deposited in the superior mesenteric artery, renal tubules, and the liver. These results suggest that lysozyme, working through the production of H2O2, may be an important mediator of vascular dysfunction in sepsis. The final article in this month’s issue is a very interesting report from Oyama et al. (12). It is now well recognized that organisms and even cultured cells have well-defined circadian rhythms. These authors examined the effect of uncoupling peripheral (feeding-based) and central master clock gene rhythms on the response to CLP. Uncoupling was accomplished by providing food during the light cycle and withholding during the dark cycle (normal feeding period) for a week before CLP. Daytime-fed mice had decreased weight gain and food intake and disruption of peripheral rhythm gene expression. Following
CLEMENS
CLP, daytime-fed mice had an enhanced inflammatory response and increased mortality. These results emphasize the need for careful control of circadian rhythms in sepsis studies and suggest that more attention should be paid to these rhythms in managing patients in intensive care units. REFERENCES 1. Ortiz-Diaz E, Lan CK: Intra-abdominal hypertension in medical critically ill patients. A narrative review. Shock 41(3):175Y180, 2014. 2. Rahbar E, Baer LA, Cotton BA, Holcomb JB, Wade CE: Plasma colloid osmotic pressure is an early indicator of injury and hemorrhagic shock. Shock 41(3):181Y187, 2014. 3. Branco BC, Inaba K, Ives C, Okoye O, Shulman I, David J-S, Schochl H, Rhee P, Demetriades D: Thromboelastogram evaluation of the impact of hypercoagulability in trauma patients. Shock 41(3):200Y207, 2014. 4. Bauman ZM, Killu KF, Rech MA, Bernabei-Combs, JL, Gassner MY, Coba VE, Tovbin A, Kunkel PL, Mlynarek ME. Racial differences in vasopressor requirements for septic shock. Shock 41(3):188Y192, 2014. 5. Lomivorotov VV, Fominskiy EV, Efremov SM, Nepomniashchikh VA, Lomivorotov VN, Chernyavskiy AM, Shilova AN, Karaskov AM: Infusion of 7.2% NACL/6% hydroxyethyl starch 200/0.5 in on-pump coronary artery bypass surgery patients: a randomized, single-blind pilot study. Shock 41(3):193Y199, 2014. 6. Breithaupt-Faloppa AC, Fantozzi ET, Romero DC, da Silva Rodrigues A, Rocha de Sousa PT, Lino dos Santos Franco A, Oliveira-Filho RM, Vargaftig BB, de Lima WT: Acute effects of estradiol on lung inflammation due to intestinal ischemic insult in male rats. Shock 41(3):208Y213, 2014. 7. de Oliveira GP, Silva JD, de Araujo CC, Proto LFM, Abreu SC, Madeira C, Morales MM, Takiya CM, Diaz BL, Capelozzi VL, et al.: Intravenous glutamine administration reduces lung and distal organ injury in malnourished rats with sepsis. Shock 41(3):222Y232, 2014. 8. Zheng Y-S, Wu Z-S, Ni H-B, Ke L, Tong Z-H, Li W-Q, Li N, Li J-S: Codonopsis pilosula polysaccharide attenuates cecal ligation and puncture sepsis via circuiting regulatory cells in mice. Shock 41(3):250Y255, 2014. 9. Lin C-W, Lo S, Perng D-S, Wu DB-C, Lee P-H, Chang Y-F, Kuo P-L, Yu M-L, Yuan S-SF, Hsieh Y-A: Complete activation of autophagic process attenuates liver injury and improves survival in septic mice. Shock 41(3):241Y249, 2014. 10. Hviid CVB, Samulin-Erdem J, Drechsler S, Weixelbaumer K, Ahmed MS, Attramadal H, Redl H, Bahrami S, Osuchowski MF, Aasen AO: The matricellular Bcysteine-rich protein 61[ is released from activated platelets and increased in the circulation during experimentally-induces sepsis. Shock 41(3):233Y240, 2014. 11. Gotes J, Kasian K, Jacobs H, Cheng Z-Q, Mink SN: Lysozyme, mediator of sepsis that deposits in the systemic vasculature and kidney as a possible mechanism of acute organ dysfunction. Shock 41(3):256Y265, 2014. 12. Oyama Y, Iwasaka H, Koga H, Shingu C, Matsumoto S, Noguchi T: Uncoupling of peripheral and master clock gene rhythms by reversed feeding leads to an exacerbated inflammatory response after polymicrobial sepsis in mice. Shock 41(3):214Y221, 2014.
Copyright © 2014 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Commentary WHAT’S NEW IN SHOCK? MARCH 2014 Mark G. Clemens, PhD University of North Carolina at Charlotte, Charlotte, North Carolina
The March 2014 issue of Shock provides another combination of clinical and laboratory studies with a particular abundance of clinical reports. Leading off the issue is a review by Ortiz-Diaz and Lan (1) on the topic of intra-abdominal hypertension. The importance of intra-abdominal hypertension is fairly well recognized in surgical intensive care units, but they make a case that it is also an important but infrequently recognized cause of morbidity in medical units. This report should serve to draw attention to this potentially important issue. In the realm of clinical studies this month, we have two reports on effectors/markers of injury and two related to treatment. The first report by Rahbar et al. (2) examines changes in plasma colloid oncotic pressure as a marker of hemorrhagic shock. They collected plasma from 104 trauma cases in the emergency room and divided them into low and high oncotic pressure groups. Patients with low oncotic pressure (an indicator of increased vascular permeability) had worse injury scores and required more blood products, although superficial signs at admission were not different, suggesting that plasma oncotic pressure may be a sensitive indicator of hemorrhagic shock. Although they did not see any difference in coagulation, they looked primarily for decreased coagulation. Branco et al. (3) looked at the other side of coagulation-hypercoagulability. They examined 118 patients, of whom 31 were hypercoagulable on admission as determined by thromboelastography. These patients had decreased need for blood products when compared with normal or hypocoagulable patients. They also decreased 24-h and 7-day mortality. It would be interesting to specifically compare plasma oncotic pressure and hypercoagulability in the same group of patients to see how these indicators compare. Two articles this month address issues of treatment. Bauman et al. (4) examined the difference in need for vasopressor support in African American (AA) versus white patients in septic shock. This retrospective study examined records of 159 patients (60.4% AA) looking for vasopressor support requirements. African American patients required significantly more norepinephrine to maintain a mean arterial pressure greater than 65 mmHg. A complicating factor is that AA patients had a much higher incidence of hypertension and greater incidence of end-stage renal disease. It is not clear whether race is a significant factor when these comorbidities are eliminated. The second treatment clinical study by Lomivorotov et al. (5) was performed in the context of volume support during coronary artery bypass surgery. Hypertonic saline and hydroxyethyl starch (HSH) have been shown to have beneficial immunomodulatory effects during cardiac surgery, but there is concern that the chloride load may have
nephrotoxic effects. Thus, they randomized 20 patients into each of two groups: control (0.9% saline infusion) or HSH. They found no difference in either glomerular filtration rate or tubular injury in the groups indicating that HSH is safe, at least with respect to kidney injury in these patients. This month’s issue of Shock also presents laboratory reports addressing potential treatments and mediators of shock. Breithaupt-Faloppa et al. (6) examined a new application for the use of estradiol for treatment of shock. They examined lung injury following an intestinal ischemia-reperfusion injury in a rat model. An important component of their design is that they had two groups of estradiol treated rats: one during ischemia and the other after reperfusion. The latter group is particularly important for clinical relevance. Estradiol treatment decreased neutrophil infiltration into the lungs and decreased vascular permeability. This was associated with decrease in cytokine production and decreased adhesion molecules. The fact that treatment during reperfusion was at least as effective as during ischemia suggests potential clinical relevance. It is well known that sepsis is associated with metabolic dysfunction. Glutamine supplementation has been shown to be beneficial in many contexts but has not been examined in previously malnourished animals. The report by de Oliveira et al. (7) fills this gap. They made rats septic after 4 weeks on a calorically deficient diet. The malnourished group showed an increase in mortality and organ injury, especially in the lung. Supplementation with glutamine 1 h after cecal ligation and puncture significantly improved survival as well as markers of injury in lung, kidney, intestine, and liver and appeared to be related to improved balance of M1 and M2 macrophages. These results suggest an additional role for glutamine supplementation in previously malnourished patients. Natural products and traditional medicines are a potentially abundant source of new therapeutic molecules, but require rigorous investigation to ensure both safety and efficacy. Zheng et al. (8) examined the effect of a polysaccharide purified from a Chinese herb Codonopsis pilosula on circulating regulatory T cells in a mouse cecal ligation and puncture (CLP) model. It is not clear exactly when the mice were treated, but C. pilosula suppressed excessive regulatory T cells after CLP, and this effect was abrogated by use of a Toll-like receptor 4 neutralizing antibody, suggesting that its effect is mediated by Toll-like receptor 4. It is now recognized that autophagocytosis of damaged cell organelles is an important defense mechanism following cell injury. Lin et al. (9) tested whether activation of autophagy might be protective against liver injury in septic mice. Mice were treated with carbamazine (CBZ) to activate autophagy at 0.5 and 24 h after CLP. Sepsis alone 173
Copyright © 2014 by the Shock Society. Unauthorized reproduction of this article is prohibited.
174
SHOCK VOL. 41, NO. 3
activated autophagy but with incomplete clearance of autophagosomes. Carbamazine enhanced autophagosome clearance and decreased liver injury and inflammation. Inhibition of autophagosome clearance abrogated the beneficial effect of CBZ. The effectiveness of CBZ with posttreatment suggests potential clinical application. Two articles this month address novel mediators of injury in sepsis. Hviid et al. (10) provide a comprehensive assessment of the role of the matricellular protein Cyr61/CCN-1 protein (CCN) that has been shown to have immune-modulatory effects. They showed that CCN levels in plasma are markedly elevated following CLP, but mRNA expression in potential source organs was depressed. However, platelets were found to contain CCN, and it was released following platelet activation, and this release was inhibited by inhibition of platelet activation. Thus, CCN may be a significant regulator of inflammation during sepsis following its release from activated platelets. Another cell protein that may modulate the response to sepsis is lysozyme. It is released from activated leukocytes and has been shown to be involved in cardiovascular dysfunction in sepsis. Gotes et al. (11) now extend these findings by testing the effect of lysozyme on vascular smooth muscle function and its organ distribution during sepsis in a canine model. Lysozyme rapidly deposited in the smooth muscle layer of isolated carotid artery preparations and led to contractile failure of isolated human smooth muscle cells. In an in vivo sepsis model, it deposited in the superior mesenteric artery, renal tubules, and the liver. These results suggest that lysozyme, working through the production of H2O2, may be an important mediator of vascular dysfunction in sepsis. The final article in this month’s issue is a very interesting report from Oyama et al. (12). It is now well recognized that organisms and even cultured cells have well-defined circadian rhythms. These authors examined the effect of uncoupling peripheral (feeding-based) and central master clock gene rhythms on the response to CLP. Uncoupling was accomplished by providing food during the light cycle and withholding during the dark cycle (normal feeding period) for a week before CLP. Daytime-fed mice had decreased weight gain and food intake and disruption of peripheral rhythm gene expression. Following
CLEMENS
CLP, daytime-fed mice had an enhanced inflammatory response and increased mortality. These results emphasize the need for careful control of circadian rhythms in sepsis studies and suggest that more attention should be paid to these rhythms in managing patients in intensive care units. REFERENCES 1. Ortiz-Diaz E, Lan CK: Intra-abdominal hypertension in medical critically ill patients. A narrative review. Shock 41(3):175Y180, 2014. 2. Rahbar E, Baer LA, Cotton BA, Holcomb JB, Wade CE: Plasma colloid osmotic pressure is an early indicator of injury and hemorrhagic shock. Shock 41(3):181Y187, 2014. 3. Branco BC, Inaba K, Ives C, Okoye O, Shulman I, David J-S, Schochl H, Rhee P, Demetriades D: Thromboelastogram evaluation of the impact of hypercoagulability in trauma patients. Shock 41(3):200Y207, 2014. 4. Bauman ZM, Killu KF, Rech MA, Bernabei-Combs, JL, Gassner MY, Coba VE, Tovbin A, Kunkel PL, Mlynarek ME. Racial differences in vasopressor requirements for septic shock. Shock 41(3):188Y192, 2014. 5. Lomivorotov VV, Fominskiy EV, Efremov SM, Nepomniashchikh VA, Lomivorotov VN, Chernyavskiy AM, Shilova AN, Karaskov AM: Infusion of 7.2% NACL/6% hydroxyethyl starch 200/0.5 in on-pump coronary artery bypass surgery patients: a randomized, single-blind pilot study. Shock 41(3):193Y199, 2014. 6. Breithaupt-Faloppa AC, Fantozzi ET, Romero DC, da Silva Rodrigues A, Rocha de Sousa PT, Lino dos Santos Franco A, Oliveira-Filho RM, Vargaftig BB, de Lima WT: Acute effects of estradiol on lung inflammation due to intestinal ischemic insult in male rats. Shock 41(3):208Y213, 2014. 7. de Oliveira GP, Silva JD, de Araujo CC, Proto LFM, Abreu SC, Madeira C, Morales MM, Takiya CM, Diaz BL, Capelozzi VL, et al.: Intravenous glutamine administration reduces lung and distal organ injury in malnourished rats with sepsis. Shock 41(3):222Y232, 2014. 8. Zheng Y-S, Wu Z-S, Ni H-B, Ke L, Tong Z-H, Li W-Q, Li N, Li J-S: Codonopsis pilosula polysaccharide attenuates cecal ligation and puncture sepsis via circuiting regulatory cells in mice. Shock 41(3):250Y255, 2014. 9. Lin C-W, Lo S, Perng D-S, Wu DB-C, Lee P-H, Chang Y-F, Kuo P-L, Yu M-L, Yuan S-SF, Hsieh Y-A: Complete activation of autophagic process attenuates liver injury and improves survival in septic mice. Shock 41(3):241Y249, 2014. 10. Hviid CVB, Samulin-Erdem J, Drechsler S, Weixelbaumer K, Ahmed MS, Attramadal H, Redl H, Bahrami S, Osuchowski MF, Aasen AO: The matricellular Bcysteine-rich protein 61[ is released from activated platelets and increased in the circulation during experimentally-induces sepsis. Shock 41(3):233Y240, 2014. 11. Gotes J, Kasian K, Jacobs H, Cheng Z-Q, Mink SN: Lysozyme, mediator of sepsis that deposits in the systemic vasculature and kidney as a possible mechanism of acute organ dysfunction. Shock 41(3):256Y265, 2014. 12. Oyama Y, Iwasaka H, Koga H, Shingu C, Matsumoto S, Noguchi T: Uncoupling of peripheral and master clock gene rhythms by reversed feeding leads to an exacerbated inflammatory response after polymicrobial sepsis in mice. Shock 41(3):214Y221, 2014.
Copyright © 2014 by the Shock Society. Unauthorized reproduction of this article is prohibited.
