The May pages of SHOCK contain significant new data on resuscitation issues, clinical, and preclinical models of organ dysfunction, along with myocardial metabolism and protection among the topics addressed. An exciting new feature is summaries from the Master Class presented at the recent meeting of our Society.
An important initial paper discusses acidosis. Acidosis is seen as both a marker and mediator of various forms of cell and organ injury. Rudnick et al. (1) provide an excellent overview on the potential for sodium bicarbonate to blunt the effects of acidosis. A brief discussion of the etiologies of lactic acidosis is presented. Topics include the impact of acidosis on myocardial contractility, vasodilatation, and a variety of endocrinopathies. Sodium bicarbonate is an obvious means to change the pH which has both intracellular and extracellular effects. While the authors summarize the potential benefit sodium bicarbonate for control of pH changes, they also present the limits of this therapy as seen in less effective oxygen transport, increased concentration of non-bicarbonate buffers, and reduced cardiac output related to the fall of intramyocardial pH.
An impressive group of papers examine myocardial function in a variety of shock states beginning with the right ventricle, long a neglected neighbor of the left. In the lead clinical paper in this issue, Winkelhorst et al. (2) examine pulmonary artery catheter (PAC) data in patients admitted with sepsis. A correlation was found between right ventricular ejection fraction and 1-year all-cause mortality. As the authors acknowledge, this is a selected group of patients and acute mortality may not purely reflect myocardial outcome. However, this work highlights the importance of the right heart association with outcome and provides data which is not available in many studies due to the relatively infrequent use of the PAC.
Many papers discuss specific organ dysfunction. Fujishima and the JAAM FORECAST ARDS Study group examine the demographics of 157 patients fulfilling the Berlin ARDS Definition (3). The majority of these patients had high acuity ARDS with mortality of approximately 40%. While this study, similar to other ARDS demographic work, reflects our limitations of understanding for this clinical syndrome, an important observation is the correlation of glucocorticoid use with mortality. This finding could reflect the subtype of ARDS examined.
Included among papers in this issue of SHOCK is a series of observations which examine the impact of the ICU environment and sepsis on changes in chronobiology. Acuña-Fernández et al. (4) examined metabolism of melatonin in septic and non-septic patients. While their findings do not refute the critical care literature that the ICU environment may compromise clock function of patients, sepsis with inflammatory mediators is a significant factor based on comparisons made in this study of melatonin metabolite production which is increased in septic versus non-septic ICU subjects.
The Colorado group has long had an interest in coagulation changes associated with various disease states. Using thromboelastography, Samuels et al. (5) demonstrate an association between complement pathway activation and a hypercoagulable state. Specimens studied in this project were managed with Cobra Venom Factor to activate the alternative complement pathway, produce a hypercoagulable state, and reduce fibrinolysis.
Standard response of normal volunteers to dehydration associated with administration of furosemide is compared with controlled blood withdrawal by Hahn et al. (6) Ringers acetate solution was administered to treat these two types of volume depletion. Endothelial effects of hemorrhage were suggested by differing kinetics of extravascular fluid accumulation. Extravascular fluid accumulation decreased in the dehydration group in comparison with volunteers subjected to graded hemorrhage. Another surrogate for end organ function, urinary output, was inhibited to a greater degree by hemorrhage than by dehydration. These models do not fully reflect injury or other forms of shock; however, they do allow comparison of fluid shifts between the two patterns of intravascular insults.
The May issue of SHOCK includes a unique contribution in the Methodological Aspects. Hackam (7) introduces summaries of a collection of presentations from the Annual Conference on Shock intended to provide our readers with insight into contemporary techniques in biomedical research. Four of these topics are listed as a “Master Class in Shock Research.” A theme of these papers is “connectivity” reflecting organ interaction in shock development.
Wu et al. (8), in a pertinent review paper, associate the use of fibrinogen and cryoprecipitate for control of bleeding in the injured patient and discuss mechanisms for these agents to treat endothelial injury. This paper can be recommended as an elegant review of alternative pathways to support the endothelium and resuscitate the underlying glycocalyx.
Kilpatrick and Kiani (9) review strategies to evaluate interaction of leukocytes and endothelium in sepsis and other inflammatory states. This work can be recommended for thoughtful examination of neutrophil adhesion and methods for evaluating endothelial permeability in association with differential neutrophil traffic. In vitro and in vivo models are discussed. The authors, in summary comments, argue the urgent need for further model development representing human disease and allowing identification of therapy for endotheliopathy, particularly that associated with sepsis.
This collection of papers from Shock Research Masters also discusses concerns specific to pediatrics. Nolan et al. (10) examine neonatal shock and necrotizing enterocolitis, an important source of morbidity in the premature infant. Immunologic differences in neonates and adults are compared and available animal models evaluated. One important theme developed in this paper is the impact of relative immaturity on the neonatal immune system for response to polymicrobial sepsis and associated survival. These authors call for and suggest tools for building improved preclinical models which could enhance study quality.
Rupert et al. (11), in the fourth presentation on methodology, examine mechanisms of muscle growth regulation as a means to find interventions promoting reduction in morbidity and mortality after insults including trauma, sepsis, and other sources of inflammation. This review highlights clinical problems, tools for muscle mass evaluation, and potential for genetic manipulation.
Papers from the Basic Science portion of this issue of SHOCK shed additional light on myocardial dysfunction in a variety of settings. Vasques-Nóvoa et al. (12) begin a discussion of septic cardiomyopathy with clinical experience in three middle-aged patients presenting without previous cardiovascular disease. A commonality in these patients was subepicardial edema with associated reduction in myocardial contraction and relaxation at a time when these patients faced significant metabolic challenges. Associating myocardial edema with extracellular matrix disruption, these authors noted increased oxygen diffusion distance, capillary compression, and accumulation of cellular waste products as potential mechanisms of myocardial edema related to functional deterioration. This set of clinical observations, while not clearly organized as a clinical trial, suggests complementary clinical data for preclinical work already done by these investigators. Lackner et al. (13) change the focus of investigation for cardiac dysfunction from sepsis to trauma by examining myocardial glucose and fatty acid transport in experimental porcine mono- and polytrauma. The monotrauma model employed is a standard femur fracture. Polytrauma animals, on the other hand, received a combination of blunt chest injury, penetrating liver injury, and femur fracture. Polytrauma animals also underwent controlled hemorrhage using a Wiggers model to a mean arterial pressure of approximately 40 mm Hg with withdrawal of at most 45% of calculated total blood volume. Polytrauma animals demonstrated hyperglycemia. By 72 h after injury, all animals were hypoglycemic and hepatic glycogen stores decreased. The authors suggest that trauma induces a protective state of myocardial hibernation with down regulation of oxygen consumption and a shift to anaerobic glycolysis for cardiac ATP production. They further propose that this adaptive response allows maintained viability of cardiac myocytes when energy deficiency is induced by injury.
Yang et al. (14) examine a third model of myocardial injury, that following cardiac arrest. Using echocardiography for monitoring, they study an ivabradine protocol to reduce the risk of heart failure in this model. Study animals underwent ventricular fibrillation which was untreated for several minutes. Defibrillation was attempted after cardiopulmonary resuscitation. Ivabradine and saline were utilized in animals with return of spontaneous circulation and myocardial function analyzed by echocardiography obtained up to 24 h after resuscitation. Evidence of myocardial injury was reduced in animals receiving ivabradine as opposed to placebo and neurologic deficits were also reduced with this agent.
Hyperglycemia and its effects on ischemic preconditioning and cardioprotection are examined in another basic science paper in this issue of SHOCK. Goergens et al. (15) utilize male Wistar rats subjected to myocardial ischemia and subsequent reperfusion. Animals in the ischemic preconditioning group received three brief ischemic periods and 5 min of reperfusion before a larger ischemic insult. This study examined the impact of hyperglycemia achieved by glucose administration on ischemic preconditioning. Ischemic preconditioning reduced infarct size in animals subjected to the standard myocardial injury. However, hyperglycemia limited the cardioprotective effects of ischemic preconditioning. The authors also studied traffic of neutrophils in this model. Hyperglycemia reversed reduction in neutrophil accumulation in injured tissue which was associated with ischemic preconditioning.
In related work, Yu et al. (16) examine the protective effect of fresh frozen plasma (FFP), and particularly fibrinogen as a means to protect endothelial cells in a series of in vitro studies. They appropriately point out that FFP contains over 3,000 proteins and that additional work is needed to identify those components causing anti-apoptotic activity leading to development of resuscitation tools protecting the endothelium in patients experiencing trauma. This report on the clinical benefits of FFP utilizes specimens obtained from both rodents and injured patients. Apoptosis was readily identified in hemorrhagic shock along with protective effects of FFP administration. While this may be seen as preliminary work, fibrinogen becomes an attractive resuscitation tool.
Finally, Ahmad et al. (17) examine safety and efficacy of enzyme inhibitors in a murine model of cerulein-induced pancreatitis. Enzymatic blockade, as studied, reduced inflammatory mediator levels in the plasma and improved gross and histologic appearance of the pancreas. The authors argue in favor of further preclinical study of enzymatic manipulation in treatment of pancreatitis.
Readers of the May contributions in our Journal will enjoy this spectrum of clinical studies, preclinical examination of promising treatment strategies, and reviews from the “Master Class in Shock Research” which should stimulate further engaging contributions.
1. Rudnick MR, Blair GJ, Kuschner WG, Barr J. Lactic acidosis and the role of sodium bicarbonate: a narrative opinion. Shock
2. Winkelhorst JC, Bootsma IT, Koetsier PM, de Lange F, Boerma EC. Right ventricular function and long-term outcome in sepsis: a retrospective cohort study. Shock
3. Fujishima S, Gando S, Saitoh D, Kushimoto S, Ogura H, Abe T, Shiraishi A, Mayumi T, Sasaki J, Kotani J, et al. Demographics, treatments, and outcomes of acute respiratory distress syndrome: the focused outcomes research in emergency care in acute respiratory distress syndrome, sepsis, and trauma (FORECAST) study. Shock
4. Acuña-Fernández C, Marín JS, Díaz-Casado ME, Rusanova I, Darias-Delbey B, Pérez-Guillama L, Florido-Ruiz J, Acuña-Castroviejo D. Daily changes in the expression of clock genes in sepsis and their relation with sepsis outcome and urinary excretion of 6-sulfatoximelatonin. Shock
5. Samuels JM, Coleman JR, Moore EE, Bartley M, Vigneshwar N, Cohen M, Silliman CC, Sauaia A, Banerjee A. Alternative complement pathway activation provokes a hypercoagulable state with diminished fibrinolysis. Shock
6. Hahn RG, Drobin D, Li Y, Zdolsek J. Kinetics of ringer's solution in extracellular dehydration and hemorrhage. Shock
7. Hackam DJ. A master class in shock research. Shock
8. Wu F, Chipman A, Pati S, Miyasawa B, Corash L, Kozar RA. Resuscitative strategies to modulate the endotheliopathy of trauma: from cell to patient. Shock
9. Kilpatrick LE, Kiani MF. Experimental approaches to evaluate leukocyte-endothelial cell interactions in sepsis and inflammation. Shock
10. Nolan LS, Wynn JL, Good M. Exploring clinically-relevant experimental models of neonatal shock and necrotizing enterocolitis. Shock
11. Rupert JE, Jengelley DHA, Zimmers TA. In vitro
, in vivo
, and in silico
methods for assessment of muscle size and muscle growth regulation. Shock
12. Vasques-Nóvoa F, Laundos TL, Madureira A, Bettencourt N, Nunes JPL, Carneiro F, Paiva JA, Pinto-do-Ó P, Nascimento DS, Leite-Moreira AF, et al. Myocardial edema: an overlooked mechanism of septic cardiomyopathy? Shock
13. Lackner I, Weber B, Knecht D, Horst K, Reija B, Gebhard F, Pape H-C, Huber-Lang M, Hildebrand F, Kalbitz M. Cardiac glucose and fatty acid transport after experimental mono- and polytrauma. Shock
14. Yang M, Chen L, Hua T, Zou Y, Yang Z. Beneficial effects of ivabradine on post-resuscitation myocardial dysfunction in a porcine model of cardiac arrest. Shock
15. Goergens JI, Heinen NM, Zoller J, Preckel B, Bauer I, Huhn R, Ebel D, Raupach A. Influence of hyperglycemia during different phases of ischemic preconditioning on cardioprotection––a focus on apoptosis and aggregation of granulocytes. Shock
16. Yu Q, Yang B, Davis JM, Ghosn J, Deng X, Doursout M-F, Dong J-f, Wang R, Holcomb JB, Wade CE, et al. Identification of fibrinogen as a key anti-apoptotic factor in human fresh frozen plasma for protecting endothelial cells in vitro
17. Ahmad A, Haas De Mello A, Szczesny B, Törö G, Marcatti M, Druzhyna N, Liaudet L, Tarantini S, Salomao R, Garcia Soriano F, et al. Effects of the poly(ADP-ribose) polymerase inhibitor olaparib in cerulein-induced pancreatitis. Shock