Lowry, Stephen F.
As always, this edition of Shock has a little something for everyone. Whether your tastes run from the most basic molecular mechanisms to cutting-edge clinical investigations, there are several informative and thought-provoking contributions this month. As has become the custom, this edition leads off with reports of a clinical nature, and several of the themes from these studies are nicely correlated with subsequent basic and translational manuscripts.
A very interesting study from the Denver trauma group has provided an early glimpse into the human proteomic profile of injury-associated mesenteric lymph (1). Although it has long been suspected that such fluids contain bioactive species that could induce systemic and organ site inflammatory damage, there has been little in the way of confirmatory studies in humans. An important parallel of this study was the determination of isolated leukocyte priming by lymph. The authors were thus able to narrow their proteomic analysis by correlations to ex vivo immune cell bioactivity. They identified several classes of potential bioactive proteins among the more than 450 identified protein products. Interestingly, these include some of the usual suspects, such as matrix proteins and proteases, but also markers of cellular glycolysis and hemolysis. Although those ascribing to the cytokine theory of severe inflammatory illness must await more detailed studies, all readers will find something of interest in this article and its materials.
Considering the evidence that products of red blood cell hemolysis appear in inflammatory lymph, another study from Amsterdam by Juffermans et al. (2) observes that red blood cell and platelet transfusions are associated with increased risk of secondary infections among intensive care patients admitted with an initial diagnosis of sepsis. Although there are several caveats to this analysis, including underlying morbidities, this is the largest analysis of this problem to date. Nonetheless, the modest size of their study population should prompt further analyses of databases from prospective clinical trials of sepsis interventions to clarify this important relationship.
Aikawa and colleagues (3) provide a reanalysis of a recent phase 3 trial to determine the effects of thrombomodulin-α treatment in septic patients with disseminated intravascular coagulation (DIC). The relative reduction in 28-day all-cause mortality appears to be similar to that reported for other antagonists of the coagulation activation pathway. Although the number of retrospective study subjects is rather modest (n = 80), their results provide support for an ongoing phase 2 trial to address the efficacy of this approach specifically among patients with infection-induced DIC. The field awaits the results of this prospective study with much interest.
The importance of DIC in the outcome of sepsis is further underscored by a study by Adamzik et al. (4) wherein parameters of thromboelastometry were assessed at the outset of the condition. They determined that these parameters were more informative of 30-day outcome than other commonly applied laboratory measures of DIC. Perhaps this technology will find a place in sepsis diagnosis and management in the same manner as it is currently applied to other systemic insults.
The technique of adipose tissue microdialysis was used by Dimopoulou and colleagues (5) to serially assess differential blood and tissue metabolites among septic patients. Whereas they observed increased tissue lactate and glycerol levels, the lactate-pyruvate ratio remained largely unchanged over the 6-day study period. This suggests that adipose tissue redox and perfusion defects are not a hallmark of sepsis. It would be of interest to determine if a more extensive survey of tissue metabolomic profiles could reveal a characteristic signature.
The sepsis and post-cardiac arrest syndromes share similarities in both physiology and management challenges. A report by Walters and her colleagues (6) provide evidence that a bundled, interdisciplinary approach that applies many principles of acute sepsis care to the post-cardiac arrest condition may improve outcome. Included in the algorithm is therapeutic hypothermia for which clear mechanisms of action have not been defined. As investigations advocating such approaches continue to appear, health care providers will need to balance the implement these protocols amid the emerging science and the many other demands of accountable and cost-effective care.
Several basic science investigations also deal with this management dilemma. Among these is a report from Wagner et al. (7) that questioned whether addition of hydrogen sulfide (H2S) complemented the effects of hypothermia during murine sepsis. In a cecal ligation and puncture model, they determined that H2S had no additional influence upon systemic and lung markers of inflammation, and in fact, H2S increased nuclear factor kB activation in the lung. Clearly, the interaction of these anti-inflammatory strategies is more complex than currently thought.
Luo et al. (8) have addressed the controversy as to whether burn serum factors influence cardiomyocyte excitation-contraction coupling. They observed a transient ex vivo increase in excitation-contraction followed by a more prolonged reduction in a rodent model of burn injury. This late effect was attributed to increased ryodine receptor activity and was also largely preventable by antioxidant treatment.
Whereas there is minimal influence of moderate anemia upon electrocardiographic indices in healthy subjects, the implications of normovolemic anemia under stress are less well defined. Scheller and associates (9) have investigated this in an anesthetized porcine model. At hemoglobin levels less than 8 g/dL, they were able to detect prolongation of the QT interval and a reduction in T-wave amplitude. Although these findings are not correlated with tissue function or metabolism, these subtle changes may have implications for current management algorithms that advocate lower hemoglobin levels in stressed patients.
It is well known that agonism of the nuclear transcription factor, liver X receptor α (LXR-α), exerts anti-inflammatory effects during infectious conditions. A very nice study by Solan and his colleagues (10) have extended this influence to the posthemorrhagic resuscitation phase. Utilizing the LXR-α agonist, T0901317, administered at the time of resuscitation from hemorrhagic shock, they have documented attenuation of adverse events in cardiac and lung tissues as well as reduced production of proinflammatory mediators. This interesting study now extends the list of LXR-α beneficial therapeutic models to include hemorrhage, warranting further study of this approach.
The relationship of prior alcohol intake to increased risks for nosocomial infection in burn and trauma victims is well established. To address this effect, Murdoch and her associates (11) provide a follow-up examination of the influence of alcohol on pulmonary and systemic neutrophil (PMN) function in a murine burn model. They observed both persistently increased pulmonary PMN infiltration and enhanced inflammatory chemokine levels in burn-injured animals instilled with Pseudomonas aeruginosa. They also noted reduced PMN apoptosis in this population, suggesting the combined effects of prior ethanol exposure and systemic injury, enhances the conditions for lung injury after infection.
Although it has been widely reported that lymphatic drainage induces ex vivo cellular injury in some models, the mechanistic basis for this phenomenon has never been established. A report by Qin et al. (12) now calls many of these observations into question by noting that the heparin utilized in many preclinical models appears to induce the lymphatic factors responsible for this effect. Heparin-inducible lipoprotein lipase-inducible mediators may be responsible, and the current studies suggest that we may have, once again, been seduced by our models. Whether gut-derived lymphatic factors are consequential for tissue injury and organ failure after hemorrhage remains an unresolved issue.
A clinical correlation study of femoral venous monitoring during intra-abdominal hypertension (IAH) and positive end-expiratory ventilation is provided by Regli et al. (13). Using a porcine model of controlled IAH, they determined the relationship between femoral venous, superior vena cava, and bladder assessed pressure values and other parameters. They conclude, in concert with current guidelines for IAH monitoring, that femoral venous monitoring is of limited value in the clinical setting.
Although there are numerous ongoing clinical trials that utilize the antioxidant, N-acetyl-l-cysteine, in subjects with free radical-induced illness, the value of this approach in neonates remains uncertain. Lee and colleagues (14) have assessed the impact of 48-h N-acetyl-l-cysteine administration in a piglet model of neonatal asphyxia and reoxygenation. They observed that this longer period of treatment was beneficial in terms of increasing renal blood flow and oxygen delivery as well as reducing renal cell apoptosis.
Finally, an excellent study presented by Belikoff and his associates (15) will be of interest to anyone intrigued by the complex dynamics of systemic inflammation (systemic inflammatory response syndrome) and the so-called compensatory anti-inflammatory response. In a murine two-hit model of chronic CLP and subsequent, acute endotoxin challenge, they observed that animals lacking the adenosine-2α receptor exhibited less local and systemic bacterial loads and variations in inflammatory mediator production. Perhaps most intriguingly, such animals remained responsive to an LPS challenge 5 days after CLP. Their hypothesis that activation of adenosine-2α receptor may be "the switch governing the transition from systemic inflammatory response syndrome to an immunosuppressed phenotype" is clearly worthy of further investigation.
1. Dzieciatkowska M, Wohlauer MV, Moore EE, Damle S, Peltz E, Campsen J, Kelher M, Silliman C, Banerjee A, Hansen KC: Proteomic analysis of human mesenteric lymph. Shock 35:331-338, 2011.
2. Juffermans NP, Prins DJ, Vlaar APJ, Nieuwland R, Binnekade JM: Transfusion-related risk of secondary bacterial infections in sepsis patients: a retrospective cohort study. Shock 35:355-359, 2011.
3. Aikawa N, Shimazaki S, Yamamoto Y, Saito H, Maruyama I, Ohno R, Hirayama A, Aoki Y, Aoki N: Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. Shock 35:349-354, 2011.
4. Adamzik M, Langemeier T, Frey UH, Go¨rlinger K, Saner F, Eggebrecht H, Peters J, Hartmann M: Comparison of thrombelastometry with simplified acute physiology score II and sequential organ failure assessment scores for the prediction of 30-day survival: a cohort study. Shock 35:339-342, 2011.
5. Dimopoulou I, Nikitas N, Orfanos SE, Theodorakopoulou M, Vassiliadi D, Ilias I, Ikonomidis I, Boutati E, Maratou E, Tsangaris I, et al: Kinetics of adipose tissue microdialysis-derived metabolites in critically ill septic patients: associations with sepsis severity and clinical outcome. Shock 35:343-348, 2011.
6. Walters EL, Morawski K, Dorotta I, Ramsingh D, Lumen K, Bland D, Clem K, Nguyen HB: Implementation of a post-cardiac arrest care bundle including therapeutic hypothermia and hemodynamic optimization in patients with return of spontaneous circulation after out-of-hospital cardiac arrest: a feasibility study. Shock 35:360-366, 2011.
7. Wagner F, Wagner K, Weber S, Stahl B, Kno¨ferl MW, Huber-Lang M, Seitz DH, Asfar P, Calzia E, Senftleben U, et al: Inflammatory effects of hypothermia and inhaled H2S during resuscitated, hyperdynamic murine septic shock. Shock 35:396-402, 2011.
8. Luo X, Deng J, Liu N, Zhang C, Huang Q, Liu J: Cellular mechanism underlying burn serum-generated bidirectional regulation of excitation-contraction coupling in isolated rat cardiomyocytes. Shock 35:388-395, 2011.
9. Scheller B, Pipa G, Kertscho H, Lauscher P, Ehrlich J, Habler O, Zacharowski K, Meier J: Low hemoglobin levels during normovolemia are associated with electrocardiographic changes in pigs. Shock 35:375-381, 2011.
10. Solan PD, Piraino G, Hake PW, Denenberg A, O'Connor M, Lentsch A, Zingarelli B: Liver X receptor α activation with the synthetic ligand T0901317 reduces lung injury and inflammation after hemorrhage and resuscitation via inhibition of the nuclear factor κB pathway. Shock 35:367-374, 2011.
11. Murdoch EL, Karavitis J, Deburghgraeve C, Ramirez L, Kovacs EJ: Prolonged chemokine expression and excessive neutrophil infiltration in the lungs of burn-injured mice exposed to ethanol and pulmonary infection. Shock 35:403-410, 2011.
12. Qin Y, Prescott LM, Deitch EA, Kaiser VL: Heparin use in a rat hemorrhagic shock model induces biologic activity in mesenteric lymph separate from shock. Shock 35:411-421, 2011.
13. Regli A, de Beulenaer BL, Hockings LE, Musk GC, Roberts B, van Heerden PV: The role of femoral venous pressure and femoral venous oxygen saturation in the setting of intra-abdominal hypertension: a pig model. Shock 35:422-427, 2011.
14. Lee T-F, Liu J-Q, Li Y-Q, Nasim K, Chaba T, Bigam DL, Cheung P-Y: Improved renal recovery with postresuscitation N-acetylcysteine treatment in asphyxiated newborn pigs. Shock 35:428-433, 2011.
15. Belikoff B, Hatfield S, Sitkovsky M, Remick DG: Adenosine negative feedback on A2A adenosine receptors mediates hyporesponsiveness in chronically septic mice. Shock 35:382-387, 2011.