University of North Carolina at Charlotte, Charlotte, North Carolina
The June 2014 issue of Shock presents a particularly exciting combination of reviews and clinical and basic science reports. The first of the three reviews is a multiauthored perspective on the recent controversy regarding the appropriateness of mouse models for sepsis research (1). This excellent critique should be a required reading for all sepsis researchers. Particularly useful will be the table provided on discoveries made in the mouse model subsequently shown to be valid in human patients.
Two other review articles this month address specific mechanisms in the response to injury. Liu et al. (2) provide an excellent summary of the potential role of neutrophil extracellular traps in various injury models. It is well known that neutrophils are important components of both the defense response and subsequent tissue damage after injury. The formation of these neutrophil extracellular traps from neutrophil DNA and cytoplasmic proteins may be an important modulator of the neutrophil effects. Another sequela of trauma is coagulopathy. Christiaans et al. (3) provide a review of the literature on coagulopathy in pediatric trauma patients. They point out that it seems to be more common than previously recognized and its management is complicated by the very small blood sample sizes often available in pediatric patients. This review should provide a framework for the further investigation of the unique properties of coagulopathy in the pediatric population.
This month’s issue of Shock also presents four clinical reports. Continuing with the theme of coagulopathy, Cardenas et al. (4) investigated the mechanisms of hyperfibrinolysis after trauma. Regulators of fibrinolysis were assessed in blood samples collected from 163 trauma patients on admission. They found that hyperfibrinolysis occurred in 10% of the patients, and that this was associated with a more complicated intensive care unit course. The hyperfibrinolysis was associated with an upregulation of tissue plasminogen activator and an absence of compensatory plasminogen activator inhibitor 1, suggesting that their dysregulation was the cause of the hyperfibrinolysis. Another important aspect of management of critically ill patients is oxygen delivery. This month, we have two clinical reports focused on assessment of adequacy of oxygen delivery. Mari et al. (5) evaluated the reliability of the oxygen challenge test (OCT) in evaluating peripheral perfusion in 56 mechanically ventilated patients. Transcutaneous O2 (tcO2) was measured at baseline and after increasing inspired O2 to 100% (FiO2 = 1.0). Although the OCT response was found to correlate with outcome, this seemed to be largely related to pulmonary exchange problems rather than just tissue perfusion. The authors suggest that arterial PO2 values also need to be considered in interpreting the result of the OCT. Legrand et al. (6) similarly emphasized the importance of PaO2 in their article. Central venous oxygen saturation is often used to estimate the adequacy of oxygen delivery to tissues with the assumption that the oxygen content of arterial blood is adequately estimated by hemoglobin saturation. They found that increasing FiO2 resulted in a significant increase in central venous saturation even with no changes in either cardiac output or hemoglobin content, suggesting that the dissolved oxygen in the arterial blood is a significant contribution to the venous saturation.
Various pattern recognition receptors are expressed on many cells to allow them to sense the presence of pathogens or tissue injury. Danger-associated molecular patterns (DAMPs) are intracellular molecules that signal tissue injury when released. One of these proposed DAMPs is mitochondrial DNA (mtDNA). Because astrocytes and microglia in the CNS express DAMP receptors, Walko et al. (7) hypothesized that injured cells in the CNS release mtDNA and that its levels might predict outcome in pediatric trauma patients. They found measureable mtDNA in the cerebrospinal fluid of pediatric trauma patients and its levels were higher in nonsurvivors than those in survivors. Mitochondrial DNA levels also correlated with levels of high-mobility box group 1 levels, suggesting that it may serve as a novel DAMP in pediatric traumatic brain injury.
The June issue of Shock also offers four basic science reports. Lemarié et al. (8) investigated the effect of treatment with activated protein C (APC) and dexamethasone on cardiac function in a rat model of experimental sepsis. They found that delayed treatment with either molecule significantly improved depressed cardiac function whereas combination treatment showed no consistent additional benefit. Treatment with either APC or dexamethasone was associated with decreased nitric oxide and reactive oxygen production, suggesting that the mechanism might be related to limiting their production. Although neither APC nor steroids have produced uncomplicated clinical benefit, the authors point out that the mechanisms related to nitric oxide and reactive oxygen may lead to clinically viable treatments. In addition to myocardial failure, pulmonary dysfunction including microthrombi and neutrophil accumulation are common after hemorrhage. Conhaim et al. (9) tested the efficacy of inhaled thrombolytics in reducing these sequelae. They administered tissue plasminogen activator, Ringer’s lactate solution, or ipratropium bromide (a negatively charged anticholinergic) by nebulizer 6 h after removal of 30% of calculated blood volume. Tissue plasminogen activator or Ringer’s lactate solution decreased microthrombi and neutrophil accumulation compared with no treatment of ipratropium bromide. The Ringer’s lactate solution effect was ascribed to the effect of its positive charge on thrombolysis. They conclude that the microthrombi are at least in part responsible for neutrophil accumulation in the lung after hemorrhage, and that this can be attenuated by inhaled thrombolytics.
In addition to the effect of neutrophils in damaging the microvasculature in shock, intracellular signaling in response to multiple inflammatory mediators results in decreased endothelial cell barrier function. Based on the observation that agents that increase cAMP production protect barrier function, Flemming et al. (10) tested the effect of phosphodiesterase 4 inhibitor rolipram that would stabilize cAMP levels on the barrier function in a rat sepsis model. Treatment was initiated 12 h after cecal ligation and stent placement with either a low or a high dose of rolipram. Both doses of rolipram improved barrier function, but the high dose decreased flow. However, rolipram produced diverse effects on inflammatory mediators that did not correlate with its effect on barrier function. The final report by Duburcq et al. (11) in this month’s issue of Shock addresses obesity as a preexisting condition in the response to endotoxemia in a swine model. Pigs were maintained on either a lean diet or a “Western diet” high in carbohydrates and fats to produce obesity and then were challenged with endotoxin. The obese group showed a more severe macrocirculatory and microcirculatory injury that was associated with increased peak values of tumor necrosis factor-α and interleukin 6. They conclude that obesity exacerbates vascular injury in response to endotoxin probably via its effects on inflammatory mediators. However, Radermacher et al. (12), in an insightful editorial comment, point out that this is a very complicated area with mixed results in different models, indicating the need for further research.
This issue also offers two additional commentaries. Osuchowski et al. (13) comment on some limitations of an article by Prunet et al. (14) that appeared in the February 2014 issue of Shock. Finally, Ron Maier provides an excellent summary of the Third Annual Conference of the Trauma Hemostasis and Oxygenation Research (THOR) Network from June 17 to 19, 2013, near Bergen, Norway, that appears as a supplement to the May issue of Shock.
1. Osuchowski MF, Remick DG, Lederer JA, Lang CH, Aasen AO, Aibiki M, Azevedo LC, Bahrami S, Boros M, Cooney R, et al.: Abandon the mouse research ship? Not just yet!
Shock 41: 463–475, 2014.
2. Liu F-C, Chuang Y-H, Tsai Y-F, Yu H-P: Role of neutrophil extracellular traps following injury. Shock 41: 492–499, 2014.
3. Christiaans SC, Duhachek-Stapelman AL, Russell RT, Lisco SJ, Kerby JD, Pittet J-F: Coagulopathy after severe pediatric trauma. Shock 41: 476–491, 2014.
4. Cardenas JC, Matijevic N, Baer LA, Holcomb JB, Cotton BA, Wade CE: Elevated tissue plasminogen activator and reduced plasminogen activator inhibitor promote hyperfibrinolysis in trauma patients. Shock 41: 515–522, 2014.
5. Mari A, Vallee F, Bedel J, Riu B, Ruiz J, Sanchez-Verlaan P, Geeraerts T, Genestal M, Silva S, Fourcade O: Oxygen challenge test in septic shock patients: prognostic value and influence of respiratory status. Shock 41: 505–510, 2014.
6. Legrand M, Vallee F, Mateo J, Payen D: Influence of arterial dissolved oxygen level on venous oxygen saturation: don’t forget the PAO2
! Shock 41: 511–514, 2014.
7. Walko TD III, Bola RA, Hong JD, Au AK, Bell MJ, Kochanek PM, Clark RSB, Aneja RK: Cerebrospinal fluid mitochondrial DNA—a novel DAMP in pediatric traumatic brain injury. Shock 41: 500–504, 2014.
8. Lemarié J, Blet A, Bouazza Y, Boisrame-Helms J, Meziani F, Levy B: Dexamethasone and recombinant human activated protein C improve myocardial function and efficiency during experimental septic shock. Shock 41: 523–528, 2014.
9. Conhaim RL, Watswon KE, Dovi WF, Bates ML: Inhaled thrombolytics reduce lung microclot and leukocyte infiltration after acute blood loss. Shock 41: 529–537, 2014.
10. Flemming S, Schlegel N, Wunder C, Meir M, Baar W, Wollborn J, Roewer N, Germer C-T, Schick MA: Phosphodiesterase 4 inhibition dose dependently stabilizes microvascular barrier functions and microcirculation in a rodent model of polymicrobial sepsis. Shock 41: 538–546, 2014.
11. Duburcq T, Hubert T, Saint-Leger P, Mangalaboyi J, Favory R, Gmyr V, Quintane L, Tailleux A, Staels B, Tournoys A, et al.: Impact of endotoxin challenge in obese pigs. Shock 41: 547–554, 2014.
12. Radermacher P, Huber-Lang M, Knippschild U, Thiemermann C: The obesity paradox revisited: does increased body mass protect against circulatory shock? [Editorial Comment]. Shock 41: 555–556, 2014.
13. Osuchowski MF, Radermacher P, Thiemermann C: Caught between a rock and a hard place: seeking an optimal resuscitation strategy for hemorrhaging patients with lung injury [Editorial Comment]. Shock 41: 557–558, 2014.
14. Prunet B, Prat N, Couret D, Cordier P-Y, De Bourmont S, Asencio Y, Meaudre E, Michelet P: Midterm effects of fluid resuscitation strategies in an experimental model of lung contusion and hemorrhagic shock. Shock 41 (2): 159–165, 2014.