SHOCK, Vol. 44, No. 6, pp. 503–504, 2015

Commentary WHAT’S NEW IN SHOCK, DECEMBER 2015? Mark G. Clemens University of North Carolina at Charlotte, Charlotte, North Carolina

superior to PPI in predicting compensation. Assuming that determination of PPI was the same in this study and the one by Rasmy, one factor that may account for the different utility of PPI is the difference between severe sepsis and LBNP. While both of these studies support the utility of this type of hemodynamic monitoring for predicting decompensation, further studies are needed to determine the best approach for specific pathologies. The final clinical report in this issue by Ramakers et al. (6) examined the role of increased production of adenosine resulting from a 34C>T single-nucleotide polymorphism in the gene for AMP deaminase (AMPD1). They examined the incidence of community (CAP) or ventilator (VAP) acquired pneumonia in a large cohort of patients with CAP or VAP in multiple institutions. Their findings showed that the CT variant was associated with higher susceptibility to CAP but not VAP which was associated with suppressed proinflammatory cytokine production by stimulated monocytes. Another theme in this month’s issue is that of mitochondrial dysfunction. Martin et al. (7) examined the effect of heparan sulfate in the serum from septic patients on mitochondrial function in the HL-1 cardiomyocyte cell line. Native serum but not serum depleted of heparan sulfate caused impaired mitochondrial respiration, increased mitochondrial reactive oxygen, and decreased cellular ATP. This was associated with upregulation of PPARa and g and PGC-1a and dependent on TLR4 expression. This suggests that circulating heparan sulfate may contribute to myocardial depression in severe sepsis through a TLR4-dependent impairment of mitochondrial function. Hansen et al. (8) studied the effect of LPS on mitochondrial function in skeletal muscle. Specifically, they tested the importance of specific sphingolipids on LPS-induced mitochondrial function changes in myotubes or muscles of LPS injected mice. LPS caused significant effects of dihydroceramides and ceramides in both models, but the directions of the changes were opposite in the two models. Experiments stimulating myotubes with conditioned medium from LPS-stimulated macrophages produced similar results to in vivo LPS indicating mediation by cytokines rather than directly by LPS. The response was marked by mitochondrial fission and dependent upon de novo sphingolipid biosynthesis indicating a central role for sphingolipid accumulation in mitochondrial injury. Mitochondria are also central regulators of reactive oxygen production and apoptosis. Hara et al. (9) examined this relationship in brain tissue in sepsis by doing a metabolomics analysis following treatment with an ROS scavenger edavarone in a

The December 2015 issue of Shock offers another excellent combination of reviews, clinical and basic science reports including a strong theme related to mechanisms and application of hemodynamic monitoring. The lead article in this month’s issue is a review by Pati et al. (1) summarizing the current state of the art and future directions for cellular therapies in trauma and critical care. They review the different stem cell sources used as well as application to clinical entities such as brain and spinal cord injury as well as other organ injuries resulting from traumatic or hemorrhagic shock. This review will provide comprehensive resources to help guide future studies in the area of cell therapies. The second review in the December issue introduces a theme of hemodynamic function and monitoring. Duan et al. (2) provided an excellent overview of the development of vascular hyporeactivity in shock including the mediators, cell signaling pathways, and perspectives for management of these changes. In a related opinion piece, McGee et al. (3) discussed the importance of more sophisticated dynamic hemodynamic monitoring for the management of shock. In contrast to the report of Duan et al. who focused on the vasculature, they emphasized the importance of dynamic monitoring of cardiac function using techniques such as ultrasound to assess the parameters such as the variability of stroke volume and pulse pressure, as well as arterial waveform analysis to more comprehensively stage cardiac status. Two clinical studies in this month’s issue then evaluate some of these parameters in human studies. Rasmy et al. (4) studied 36 patients with severe sepsis and examined the utility of perfusion index to predict vasopressor requirements. Although it is not clear from the report exactly how perfusion index was determined, this parameter and plasma lactate were the only parameters measured that significantly predicted the need for vasopressors. In a related study, Janak et al. (5) compared peripheral perfusion index (PPI), pulse pressure variability (PPV), and compensatory reserve index (CRI) as predictors of hemodynamic decompensation in response to central hypovolemia. Functional hypovolemia was produced in normal subjects using lower body negative pressure (LBNP). Compensatory reserve index is an index recently described by this group based on analysis of the arterial waveform from a pulse oximeter and is designed to detect impending hemodynamic decompensation. Their results showed both CRI and PPV to be E-mail: [email protected] DOI: 10.1097/SHK.0000000000000498 Copyright ß 2015 by the Shock Society

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cecal ligation and puncture model in mice. Metabolomic analysis showed impairment of redox regulation pathways which was prevented by edavarone. CLP also caused increased neuronal death associated with an increased Bax/Bcl2 ratio. This was also ameliorated by edavarone. The authors conclude that edavarone prevents neuronal cell death by inhibiting the proapoptotic phenotype. Tao et al. (10) also examined metabolic responses to inflammation and relationship to ROS. Several recent reports have shown that administration of hydrogen-rich saline (HRS) has antioxidant effects. This group looked at the mechanism of HRS on ameliorating cardiac dysfunction in an LPS model in rats. LPS decreased fraction shortening (FS) in the left ventricle which was prevented by HRS. Decreased FS was associated with decreased expression of fatty acid oxidation enzymes and this was also prevented by HRS in a manner that was associated with decreased activation of JNK. This month we also have three reports related to lung injury. Quilez et al. (11) examined the effect of moderate positive end expiratory pressure (PEEP) on lung injury and neuronal activation in a rat model of LPS instillation into the trachea. 7 cm but not 2 cm of PEEP ameliorated LPS-induced lung and systemic inflammation but increased neuronal activation as indicated by c-Fos expression in most areas of the brain. Interestingly, in the central amygdala and nucleus of the tractus solitarius, 7-cm PEEP increased c-Fos expression in control but not LPS-treated rats. Petroni et al. (12) also studied the timing of hypertonic saline (HS) administration on acute lung injury induced by intraperitoneal LPS in rats. Early (15 min after LPS) but not late (90 min after LPS) decreased mortality. Moreover, late resuscitation with either HS or normal saline increased lung injury. Given that the 90 min treatment option is considered to be more relevant to a clinical situation, the authors stress the importance of the very small therapeutic window for HS treatment. The final research report in this month’s issue looks at the effect of low-dose heparin during extracorporeal membrane oxygenation (ECMO) life support for ARDS. In a sheep model of oleic acid-induced ARDS, Prat et al. (13) tested whether low-dose heparin could produce effective anticoagulation on ECMO since higher doses can produce unacceptable bleeding risk in trauma patients with ARDS. Their results showed that a single bolus of low-dose heparin produced effective prevention of clot formation without significant

CLEMENS

bleeding, suggesting that this modality may be safe and effective for trauma patients. REFERENCES 1. Pati S, Pilia M, Grimsley JM, Karanikas AT, Oyeniyi B, Holcomb JB, Cap AP, Rasmussen TE: Cellular therapies in trauma and critical care medicine: forging new frontiers. Shock 44:505–523, 2015. 2. Duan C, Yang G, Li T, Liu L: Advances in vascular hyporeactivity after shock: the mechanisms and managements. Shock 44:524–534, 2015. 3. McGee WT, Raghunathan K, Adler AC: Utility of functional hemodynamics and echocardiography to aid diagnosis and management of shock. Shock 44:535– 541, 2015. 4. Rasmy I, Mohamed H, Nabil N, Abdalah S, Hasanin A, Eladawy A, Ahmed M, Mukhtar A: Evaluation of perfusion index as a predictor of vasopressor requirement in patients with severe sepsis. Shock 44:554–559, 2015. 5. Janak JC, Howard JT, Goei KA, Weber R, Muniz GW, Hinojosa-Laborde C, Convertino VA: Predictors of the onset of hemodynamic decompensation during progressive central hypovolemia: comparison of the peripheral perfusion index, pulse pressure variability, and compensatory reserve index. Shock 44:548–553, 2015. 6. Ramakers BP, Giamarellos-Bourboulis EJ, Tasioudis C, Coenen MJH, Kox M, Vermeulen SH, Groothuismink JM, van der Hoeven JG, Routsi C, Savva A, et al.: Effects of the 34C>T variant of the AMPD1 gene on immune function, multi-organ dysfunction and mortality in sepsis patients. Shock 44:542–547, 2015. 7. Martin L, Peters C, Schmitz S, Moellmann J, Martincuks A, Heussen N, Lehrke M, Mu¨ller-Newen G, Marx G, Schuerholz T: Soluble heparan sulfate in serum of septic shock patients induces mitochondrial dysfunction in murine cardiomyocytes. Shock 44:569–577, 2015. 8. Hansen ME, Simmons KJ, Tippetts TS, Thatcher MO, Saito RR, Hubbard ST, Trumbull AM, Parker BA, Taylor OJ, Bikman BT: Lipopolysaccharide disrupts mitochondrial physiology in skeletal muscle via disparate effects on sphingolipid metabolism. Shock 44:585–592, 2015. 9. Hara N, Chijiiwa M, Yara M, Ishida Y, Ogiwara Y, Inazu M, Kuroda M, Karlsson M, Sjovall F, Elme´r E, et al.: Metabolomic analyses of brain tissue in sepsis induced by cecal ligation reveal specific redox alterations—protective effects of the oxygen radical scavenger edaravone. Shock 44:578–584, 2015. 10. Tao B, Liu L, Wang N, Tong D, Wang W, Zhang J: Hydrogen-rich saline attenuates lipopolysaccharide-induced heart dysfunction by restoring fatty acid oxidation in rats by mitigating c-Jun N-terminal kinase activation. Shock 44:593–600, 2015. 11. Quilez ME, Rodriguez-Gonza´lez R, Turon M, Fernandez-Gonzalo S, Villar J, Kacmarek RM, Go´mez MN, Oliva JC, Blanch L, Lo´pez-Aguilar J: Moderate PEEP after tracheal lipopolysaccharide instillation prevents inflammation and modifies the pattern of brain neuronal activation. Shock 44:601–609, 2015. 12. Petroni RC, Biselli PJC, de Lima TM, Velasco IT, Soriano FG: Impact of time on fluid resuscitation with hypertonic saline (NACL 7.5%) in rats with LPSinduced acute lung injury. Shock 44:610–616, 2015. 13. Prat NJ, Meyer AD, Langer T, Montgomery RK, Parida BK, Batchinsky AI, Cap AP: Low-dose heparin anticoagulation during extracorporeal life support for acute respiratory distress syndrome in conscious sheep. Shock 44:560–568, 2015.

Copyright © 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.

What's New in Shock, December 2015?

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