SHOCK, Vol. 44, No. 2, pp. 99Y100, 2015
Commentary WHAT’S NEW IN SHOCK? AUGUST 2015 Brian M. Fuller Emergency Medicine and AnesthesiologyYCritical Care Medicine, Washington University School of Medicine, St Louis, Missouri
in global markers of perfusion (urine output and lactate). Splanchnic and cerebral blood flow also increased, suggesting perhaps that milrinone could alleviate regional hypoperfusion, especially in neonates at high risk for certain complications, such as necrotizing enterocolitis. Next, we turn to the basic science aspects section. I_ll first draw your attention to the team of investigators in the first investigation, a pairing from emergency medicine and chemical engineering (4). It_s nice to see this unique collaboration and ask some very important research questions at that. This investigation revolves around heat. Namely, can heat help vancomycin kill Staphylococcus aureus and Staphylococcus epidermidis? The answer seems to be yes. The investigators exposed clinical and laboratory isolates of S. aureus and S. epidermidis to temperatures up to 45-C, with and without vancomycin. Figure 1 shows some interesting results: at temperatures greater than 40-C, the growth of both organisms was dramatically reduced, with an even more impressive result with vancomycin exposure. Heat also had a pretty impressive effect on stress gene expression and weakened staphylococcal biofilm. Why is this investigation needed? Because infected implantable devices are common, deadly, and expensive, and antibiotics alone are often insufficient to eradicate infection. The authors state that their results Bsupport further exploration of therapeutic hyperthermia as an adjunctive means to manage infected medical devices.[ I agree. The study by Hsu and colleagues (5) tackles a critical care syndrome with high mortality and survivor morbidity: acute respiratory distress syndrome (ARDS). Combining a murine model of lung injury and a small retrospective observational cohort study of 38 critically ill adult patients into one report, the authors aimed to look at matrix metalloproteinase 9 (MMP-9) activity and its potential role in the risk of developing ARDS. Experimental mice had lung inflammation induced by intratracheal LPS, and these mice had detectable lung and bronchoalveolar lavage MMP-9 activity (control mice did not) and greater plasma MMP-9 expression as well. In the human arm of the data, both patients with and without ARDS had detectable plasma MMP-9 activity, but in looking at changes over time, the change in MMP-9 activity on a particular day had a negative correlation to oxygenation on the following day. Taken together, these results seem to suggest that MMP-9 activity reflects early neutrophil priming and migration from the plasma to the lung, where they continue to be very active. Although small, the clinical study suggests that MMP-9 over time may be a useful predictor of subsequent ARDS. In another study looking at neutrophils, Bock and colleagues (6) looked at the role of intracellular proteins with protease
There are a lot of things happening in the world these days, both locally and abroad, which are complex, difficult to understand, and very discouraging. So the timing of this edition of Shock could not have been better for me personally. It was wonderful to sit down with the entire content that the journal had to offer and read and admire the work. We have contributions from a diverse array of investigators, and these teams typify the multidisciplinary approach needed to help patients survive and recover from critical illness. There are also teams from all over the world, showing just how impressive a reach that Shock has. So while this science can also be complex and difficult to understand, I am very encouraged by what the future holds for our critically ill patients. There are three clinical investigations this month, each asking some interesting research questions. The first is a case-control study from the University of Pittsburgh involving blunt trauma patients (1). It challenges the paradigm of posttraumatic inflammation as an Bup or down[ phenomenon and delves deeper into inflammation as a highly complex and integrated network, which is differentially expressed based on injury severity. There are some expected findings, such as an association between greater injury severity with clinical outcomes, lactate, base deficit, organ dysfunction, and magnitude of systemic inflammation. But the real novelty here is the Bayesian analysis that analyzed not only inflammatory mediators, but also their interactions and influence over one another over time (their roles within the Bnetwork[). They found that interleukin 6 is influenced by different chemokines based on injury severity. So to boil it down, the investigators have shown that the magnitude and character of inflammation change based on injury severity. I am interested to see where they take this. In the next clinical study, van Vught and colleagues (2) studied leukocyte responsiveness in 73 critically ill patients, matching them to control subjects. Whole blood was drawn on the first morning after admission and then stimulated with lipopolysaccharide (LPS) with the aim of determining if reduced leukocyte responsiveness is related to intensive care unit (ICU)Y acquired infections. Compared with control patients, leukocytes from ICU patients did indeed have less cytokine release after LPS stimulation; this did not relate to the subsequent development of ICU-acquired infections, however. The final clinical study is an interesting physiology study on 17 neonates dosed with a milrinone infusion while awaiting cardiac surgery (3). Doppler ultrasound was used to assess the effect of milrinone infusion on splanchnic and cerebral perfusion, two regional vascular beds at risk in critically ill neonates. Milrinone, not surprisingly, increased cardiac output with subsequent improvement 99
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
100
SHOCK VOL. 44, NO. 2
activity and the proinflammatory role they may have in lung injury and organ failure. Specifically, because !-enolase plays a role in other inflammatory conditions, does !-enolase have a role in critically ill patients with respect to neutrophil priming and organ failure? Blood from two trauma patients was compared with four control subjects. Injury was associated with increased !-enolase levels, as was storage of red blood cells. Furthermore, !-enolase primed neutrophils and contributed to proinflammatory activation of pulmonary vascular endothelium. This suggests that this protein may play a role in ARDS development. The next study deals with the favorite drug for many of us: caffeine (7). Citing some background data to suggest that caffeine may be proinflammatory and have deleterious immune effects via adenosine antagonism, Bauza´ and Remick (7) conducted this study to assess caffeine_s effect on immunity in sepsis. In this cecal ligation and puncture model of sepsis, caffeine had no impact on survival or inflammatory cytokines, but increased chemokine KC, and did have some physiologic effects on heart rate and blood pressure. I wonder how many other routinely ingested substances need to be studied for their effect on critical care outcomes? Geng and colleagues (8) give us our second study on heat and examined the thermoregulatory profile in exertional heat stroke versus passive heat stroke. Exertion did indeed alter the thermoregulatory profile of rats and contributed to increased mortality. Tawadros and colleagues (9) give us in vivo and in vitro data on oxidative stress. They hypothesized that ceramide has an important role in oxidant-induced TLR4 translocation, and their data support this hypothesis, providing maybe another target in the future for organ failure prevention. Often what we do while taking care of the critically ill is all about timing of interventions and assessment of physiologic response in a short-loop feedback manner. Many therapies used early should not be used later as they are, at best, not effective and potentially harmful. The study by Mai and colleagues (10) sings a similar tune. Cell-free DNA (cfDNA) has been associated with worse outcome in severe sepsis, but the effect of counter-regulating cfDNA with DNase therapy is uncertain. In a study that is reported really nicely, mice given DNase soon after cecal ligation and puncture had increased inflammation and organ failure. Mice given DNase later experienced less inflammation, organ failure, and mortality. These results suggest that the clearance of cfDNA later in sepsis can ameliorate its injurious effects. Wouldn_t it be nice if we could give our patients a therapy that improved mitochondrial dysfunction in organ failure? Wang and colleagues (11) administered resveratrol, a naturally occurring polyphenol with antioxidant and anti-inflammatory properties, to rats in hemorrhagic shock. Animals given resveratrol showed an improved acid-base profile and renal mitochondrial function and respiratory capacity. Longer-term studies are needed, but this therapy may have some promise moving forward. Methane is commonI we all know that. But we don_t know yet if it has a role treatment of illness. Ye and colleagues (12) gave methane-rich saline to rats to test the hypothesis that methane could protect against hepatic ischemia-reperfusion injury. The results seem to show some
FULLER
pleiotropic effects of methane, as it exhibited antiapoptotic, antioxidant, and anti-inflammatory actions. Our last basic science investigation is from Yi and colleagues (13) in China. They tested the hypothesis that sinomenine, a naturally occurring plant alkaloid possessing immunomodulatory and antiinflammatory properties, may act on nicotinic acetylcholine receptors to reduce inflammation. Sinomenine was found to decrease inflammatory cytokines, with the effect being blocked by antagonism at the !-7 nicotinic acetylcholine receptors. Can this drug, currently used for rheumatoid arthritis in China, have efficacy in critical illness? Too early to tell, but an interesting study nonetheless. So that_s it. I hope you all enjoy these investigations as much as I have. I would like to thank the investigators for inching us closer to improved phenotyping of our critical care syndromes and getting us a little closer to individualizing critical care to improve outcomes. I am also very thankful to Dr. Chaudry and the journal for this opportunity to tell you all what_s new in Shock! REFERENCES 1. Almahmoud K, Namas RA, Abdul-Malak O, Zaaqoq AM, Zamora R, Zuckerbraun BS, Sperry J, Peitzman AB, Billiar TR, Vodovotz Y: Impact of injury severity on dynamic inflammation networks following blunt trauma. Shock 44:101Y109, 2015. 2. van Vught LA, Wiewel MA, Hoogendijk AJ, Scicluna BP, Belkasim-Bohoudi H, Horn J, Schultz MJ, van der Poll T: Reduced responsiveness of blood leukocytes to lipopolysaccharide does not predict nosocomial infections in critically ill patients. Shock 44:110Y114, 2015. 3. Bianchi MO, Cheung PY, Phillipos E, Aranha-Netto A, Joynt C: The effect of milrinone on splanchnic and cerebral perfusion in infants with congenital heart disease prior to surgery: an observational study. Shock 44:115Y120, 2015. 4. Sturtevant RA, Sharma P, Pavlovsky L, Stewart EJ, Solomon MJ, Younger JG: Thermal augmentation of vancomycin against staphylococcal biofilms. Shock 44:121Y127, 2015. 5. Hsu AT, Barrett CD, DeBusk MG, Ellson CD, Gautam S, Talmor DS, Gallagher DC, Yaffe MB: Kinetics and role of plasma matrix metalloproteinase-9 expression in acute lung injury and the acute respiratory distress syndrome. Shock 44:128Y136, 2015. 6. Bock A, Tucker N, Kelher MR, Khan SY, Gonzalez E, Wohlauer M, Hansen K, Dzieciatkowska M, Sauaia A, Banerjee A, et al.: !-Enolase causes proinflammatory activation of pulmonary microvascular endothelial cells and primes neutrophils through plasmin activation of protease-activated receptor-2. Shock 44: 137Y142, 2015. 7. Bauza´ G, Remick D: Caffeine improves heart rate without improving sepsis survival. Shock 44:143Y148, 2015. 8. Geng Y, Peng N, Li X-G, Liu Y-N, Li B-l, Peng L-Q, Ma Q, Su L: Physical effort affects heatstroke thermoregulatory response and mortality in rats. Shock 44:149Y156, 2015. 9. Tawadros PS, Powers KA, Ailenberg M, Birch SE, Marshall JC, Szaszi K, Kapus A, Rotstein OD: Oxidative stress increases surface Toll-like receptor 4 expression in murine macrophages via ceramide generation. Shock 44: 157Y165, 2015. 10. Mai SHC, Khan M, Dwivedi DJ, Ross CA, Zhou J, Gould TJ, Gross PL, Weitz JI, Fox-Robichaud AE, Liaw PC, for the Canadian Critical Care Translational Biology Group: Delayed but not early treatment with DNase reduces organ damage and improves outcome in a murine model of sepsis. Shock 44:166Y172, 2015. 11. Wang H, Guan Y, Karamercan MA, Ye L, Bhatti T, Becker LB, Baur JA, Sims CA: Resveratrol rescues kidney mitochondrial function following hemorrhagic shock. Shock 44:173Y180, 2015. 12. Ye Z, Chen O, Zhang R, Nakao A, Fan D, Zhang T, Gu Z, Tao H, Sun X. Methane attenuates hepatic ischemia-reperfusion injury in rats through antiapoptosis, anti-inflammatory and anti-oxidative. Shock 44:181Y187, 2015. 13. Yi L, Luo JF, Xie BB, Liu JX, Wang JY, Liu L, Wang PX, Zhou H, Dong Y. !7 Nicotinic acetylcholine receptor is a novel mediator of sinomenine antiinflammation effect in macrophages stimulated by lipopolysaccharide. Shock 44:188Y195, 2015.
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Commentary WHAT’S NEW IN SHOCK? AUGUST 2015 Brian M. Fuller Emergency Medicine and AnesthesiologyYCritical Care Medicine, Washington University School of Medicine, St Louis, Missouri
in global markers of perfusion (urine output and lactate). Splanchnic and cerebral blood flow also increased, suggesting perhaps that milrinone could alleviate regional hypoperfusion, especially in neonates at high risk for certain complications, such as necrotizing enterocolitis. Next, we turn to the basic science aspects section. I_ll first draw your attention to the team of investigators in the first investigation, a pairing from emergency medicine and chemical engineering (4). It_s nice to see this unique collaboration and ask some very important research questions at that. This investigation revolves around heat. Namely, can heat help vancomycin kill Staphylococcus aureus and Staphylococcus epidermidis? The answer seems to be yes. The investigators exposed clinical and laboratory isolates of S. aureus and S. epidermidis to temperatures up to 45-C, with and without vancomycin. Figure 1 shows some interesting results: at temperatures greater than 40-C, the growth of both organisms was dramatically reduced, with an even more impressive result with vancomycin exposure. Heat also had a pretty impressive effect on stress gene expression and weakened staphylococcal biofilm. Why is this investigation needed? Because infected implantable devices are common, deadly, and expensive, and antibiotics alone are often insufficient to eradicate infection. The authors state that their results Bsupport further exploration of therapeutic hyperthermia as an adjunctive means to manage infected medical devices.[ I agree. The study by Hsu and colleagues (5) tackles a critical care syndrome with high mortality and survivor morbidity: acute respiratory distress syndrome (ARDS). Combining a murine model of lung injury and a small retrospective observational cohort study of 38 critically ill adult patients into one report, the authors aimed to look at matrix metalloproteinase 9 (MMP-9) activity and its potential role in the risk of developing ARDS. Experimental mice had lung inflammation induced by intratracheal LPS, and these mice had detectable lung and bronchoalveolar lavage MMP-9 activity (control mice did not) and greater plasma MMP-9 expression as well. In the human arm of the data, both patients with and without ARDS had detectable plasma MMP-9 activity, but in looking at changes over time, the change in MMP-9 activity on a particular day had a negative correlation to oxygenation on the following day. Taken together, these results seem to suggest that MMP-9 activity reflects early neutrophil priming and migration from the plasma to the lung, where they continue to be very active. Although small, the clinical study suggests that MMP-9 over time may be a useful predictor of subsequent ARDS. In another study looking at neutrophils, Bock and colleagues (6) looked at the role of intracellular proteins with protease
There are a lot of things happening in the world these days, both locally and abroad, which are complex, difficult to understand, and very discouraging. So the timing of this edition of Shock could not have been better for me personally. It was wonderful to sit down with the entire content that the journal had to offer and read and admire the work. We have contributions from a diverse array of investigators, and these teams typify the multidisciplinary approach needed to help patients survive and recover from critical illness. There are also teams from all over the world, showing just how impressive a reach that Shock has. So while this science can also be complex and difficult to understand, I am very encouraged by what the future holds for our critically ill patients. There are three clinical investigations this month, each asking some interesting research questions. The first is a case-control study from the University of Pittsburgh involving blunt trauma patients (1). It challenges the paradigm of posttraumatic inflammation as an Bup or down[ phenomenon and delves deeper into inflammation as a highly complex and integrated network, which is differentially expressed based on injury severity. There are some expected findings, such as an association between greater injury severity with clinical outcomes, lactate, base deficit, organ dysfunction, and magnitude of systemic inflammation. But the real novelty here is the Bayesian analysis that analyzed not only inflammatory mediators, but also their interactions and influence over one another over time (their roles within the Bnetwork[). They found that interleukin 6 is influenced by different chemokines based on injury severity. So to boil it down, the investigators have shown that the magnitude and character of inflammation change based on injury severity. I am interested to see where they take this. In the next clinical study, van Vught and colleagues (2) studied leukocyte responsiveness in 73 critically ill patients, matching them to control subjects. Whole blood was drawn on the first morning after admission and then stimulated with lipopolysaccharide (LPS) with the aim of determining if reduced leukocyte responsiveness is related to intensive care unit (ICU)Y acquired infections. Compared with control patients, leukocytes from ICU patients did indeed have less cytokine release after LPS stimulation; this did not relate to the subsequent development of ICU-acquired infections, however. The final clinical study is an interesting physiology study on 17 neonates dosed with a milrinone infusion while awaiting cardiac surgery (3). Doppler ultrasound was used to assess the effect of milrinone infusion on splanchnic and cerebral perfusion, two regional vascular beds at risk in critically ill neonates. Milrinone, not surprisingly, increased cardiac output with subsequent improvement 99
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
100
SHOCK VOL. 44, NO. 2
activity and the proinflammatory role they may have in lung injury and organ failure. Specifically, because !-enolase plays a role in other inflammatory conditions, does !-enolase have a role in critically ill patients with respect to neutrophil priming and organ failure? Blood from two trauma patients was compared with four control subjects. Injury was associated with increased !-enolase levels, as was storage of red blood cells. Furthermore, !-enolase primed neutrophils and contributed to proinflammatory activation of pulmonary vascular endothelium. This suggests that this protein may play a role in ARDS development. The next study deals with the favorite drug for many of us: caffeine (7). Citing some background data to suggest that caffeine may be proinflammatory and have deleterious immune effects via adenosine antagonism, Bauza´ and Remick (7) conducted this study to assess caffeine_s effect on immunity in sepsis. In this cecal ligation and puncture model of sepsis, caffeine had no impact on survival or inflammatory cytokines, but increased chemokine KC, and did have some physiologic effects on heart rate and blood pressure. I wonder how many other routinely ingested substances need to be studied for their effect on critical care outcomes? Geng and colleagues (8) give us our second study on heat and examined the thermoregulatory profile in exertional heat stroke versus passive heat stroke. Exertion did indeed alter the thermoregulatory profile of rats and contributed to increased mortality. Tawadros and colleagues (9) give us in vivo and in vitro data on oxidative stress. They hypothesized that ceramide has an important role in oxidant-induced TLR4 translocation, and their data support this hypothesis, providing maybe another target in the future for organ failure prevention. Often what we do while taking care of the critically ill is all about timing of interventions and assessment of physiologic response in a short-loop feedback manner. Many therapies used early should not be used later as they are, at best, not effective and potentially harmful. The study by Mai and colleagues (10) sings a similar tune. Cell-free DNA (cfDNA) has been associated with worse outcome in severe sepsis, but the effect of counter-regulating cfDNA with DNase therapy is uncertain. In a study that is reported really nicely, mice given DNase soon after cecal ligation and puncture had increased inflammation and organ failure. Mice given DNase later experienced less inflammation, organ failure, and mortality. These results suggest that the clearance of cfDNA later in sepsis can ameliorate its injurious effects. Wouldn_t it be nice if we could give our patients a therapy that improved mitochondrial dysfunction in organ failure? Wang and colleagues (11) administered resveratrol, a naturally occurring polyphenol with antioxidant and anti-inflammatory properties, to rats in hemorrhagic shock. Animals given resveratrol showed an improved acid-base profile and renal mitochondrial function and respiratory capacity. Longer-term studies are needed, but this therapy may have some promise moving forward. Methane is commonI we all know that. But we don_t know yet if it has a role treatment of illness. Ye and colleagues (12) gave methane-rich saline to rats to test the hypothesis that methane could protect against hepatic ischemia-reperfusion injury. The results seem to show some
FULLER
pleiotropic effects of methane, as it exhibited antiapoptotic, antioxidant, and anti-inflammatory actions. Our last basic science investigation is from Yi and colleagues (13) in China. They tested the hypothesis that sinomenine, a naturally occurring plant alkaloid possessing immunomodulatory and antiinflammatory properties, may act on nicotinic acetylcholine receptors to reduce inflammation. Sinomenine was found to decrease inflammatory cytokines, with the effect being blocked by antagonism at the !-7 nicotinic acetylcholine receptors. Can this drug, currently used for rheumatoid arthritis in China, have efficacy in critical illness? Too early to tell, but an interesting study nonetheless. So that_s it. I hope you all enjoy these investigations as much as I have. I would like to thank the investigators for inching us closer to improved phenotyping of our critical care syndromes and getting us a little closer to individualizing critical care to improve outcomes. I am also very thankful to Dr. Chaudry and the journal for this opportunity to tell you all what_s new in Shock! REFERENCES 1. Almahmoud K, Namas RA, Abdul-Malak O, Zaaqoq AM, Zamora R, Zuckerbraun BS, Sperry J, Peitzman AB, Billiar TR, Vodovotz Y: Impact of injury severity on dynamic inflammation networks following blunt trauma. Shock 44:101Y109, 2015. 2. van Vught LA, Wiewel MA, Hoogendijk AJ, Scicluna BP, Belkasim-Bohoudi H, Horn J, Schultz MJ, van der Poll T: Reduced responsiveness of blood leukocytes to lipopolysaccharide does not predict nosocomial infections in critically ill patients. Shock 44:110Y114, 2015. 3. Bianchi MO, Cheung PY, Phillipos E, Aranha-Netto A, Joynt C: The effect of milrinone on splanchnic and cerebral perfusion in infants with congenital heart disease prior to surgery: an observational study. Shock 44:115Y120, 2015. 4. Sturtevant RA, Sharma P, Pavlovsky L, Stewart EJ, Solomon MJ, Younger JG: Thermal augmentation of vancomycin against staphylococcal biofilms. Shock 44:121Y127, 2015. 5. Hsu AT, Barrett CD, DeBusk MG, Ellson CD, Gautam S, Talmor DS, Gallagher DC, Yaffe MB: Kinetics and role of plasma matrix metalloproteinase-9 expression in acute lung injury and the acute respiratory distress syndrome. Shock 44:128Y136, 2015. 6. Bock A, Tucker N, Kelher MR, Khan SY, Gonzalez E, Wohlauer M, Hansen K, Dzieciatkowska M, Sauaia A, Banerjee A, et al.: !-Enolase causes proinflammatory activation of pulmonary microvascular endothelial cells and primes neutrophils through plasmin activation of protease-activated receptor-2. Shock 44: 137Y142, 2015. 7. Bauza´ G, Remick D: Caffeine improves heart rate without improving sepsis survival. Shock 44:143Y148, 2015. 8. Geng Y, Peng N, Li X-G, Liu Y-N, Li B-l, Peng L-Q, Ma Q, Su L: Physical effort affects heatstroke thermoregulatory response and mortality in rats. Shock 44:149Y156, 2015. 9. Tawadros PS, Powers KA, Ailenberg M, Birch SE, Marshall JC, Szaszi K, Kapus A, Rotstein OD: Oxidative stress increases surface Toll-like receptor 4 expression in murine macrophages via ceramide generation. Shock 44: 157Y165, 2015. 10. Mai SHC, Khan M, Dwivedi DJ, Ross CA, Zhou J, Gould TJ, Gross PL, Weitz JI, Fox-Robichaud AE, Liaw PC, for the Canadian Critical Care Translational Biology Group: Delayed but not early treatment with DNase reduces organ damage and improves outcome in a murine model of sepsis. Shock 44:166Y172, 2015. 11. Wang H, Guan Y, Karamercan MA, Ye L, Bhatti T, Becker LB, Baur JA, Sims CA: Resveratrol rescues kidney mitochondrial function following hemorrhagic shock. Shock 44:173Y180, 2015. 12. Ye Z, Chen O, Zhang R, Nakao A, Fan D, Zhang T, Gu Z, Tao H, Sun X. Methane attenuates hepatic ischemia-reperfusion injury in rats through antiapoptosis, anti-inflammatory and anti-oxidative. Shock 44:181Y187, 2015. 13. Yi L, Luo JF, Xie BB, Liu JX, Wang JY, Liu L, Wang PX, Zhou H, Dong Y. !7 Nicotinic acetylcholine receptor is a novel mediator of sinomenine antiinflammation effect in macrophages stimulated by lipopolysaccharide. Shock 44:188Y195, 2015.
Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
