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Clemens, Mark G. PhD

doi: 10.1097/SHK.0b013e3181a4cdbc

University of North Carolina at Charlotte, Charlotte, North Carolina

Each month, Shock presents us with an excellent selection of articles, out of which several relevant themes emerge. This month's issue presents particularly strong themes. The lead-off article from Karvunidis et al. (1) is a review of the very timely topic of proteomics in critical illness. The article provides an excellent overview of the technical approaches and then summarizes recent reports using these techniques in the study of the response to critical illness. This article is then followed by six articles reporting clinical studies. Four of these address topics of diagnostic parameters in critically ill patients, and the other two introduce the other main themes of this issue: integrity of microcirculation and endogenous mediators. Two of the clinical reports investigate the use of procalcitonin (PCT) measurements in diagnosis and outcome prediction in patients. Nakamura et al. (2) measured PCT levels in 116 patients suspected of having sepsis. They found that PCT was significantly elevated in patients with bacteremia with a positive predictive cutoff value of 0.83ng/mL. Schneider et al. (3) surveyed 220 consecutive patients and related PCT levels to mortality, morbidity, and length of stay. Procalcitonin levels were found to be an independent predictor of these end points and were better predictors of mortality than Advanced Physiological and Chronic Health Evaluation II score or IL-6 levels with a predictive cutoff point of 1.44 ng/mL. These two studies combined indicate that PCT may be a good indicator of sepsis at lower levels and mortality at higher levels.

Two additional clinical studies address technical aspects of patient monitoring. Monitoring central oxygen and lactate concentrations can allow calculation of whole body oxygen consumption and provide an assessment of metabolic state; however, sampling from the pulmonary artery to get true central values is not always possible. Kopterides et al. (4) rigorously compared central venous and pulmonary artery parameters in septic shock patients to evaluate the acceptability of the easier central venous sampling site. Significant differences in both parameters were found in the patient, indicating that these simplifications must be done with caution. Respiratory rate (RR) is another important vital sign but is difficult to monitor reliably. Chen et al. (5) examined an automated method for selecting reliable periods for monitoring of respiratory rate in trauma victims being transported by helicopter. This method significantly improved the use of RR for predicting which patients would need a respiratory intervention in the hospital. They conclude that, when combined with other relevant data, RR may be a useful parameter for predicting need for respiratory intervention in trauma patients.

Matejec et al. (6) provide another clinical report that introduces the next theme for this month-mediators, good and bad. These authors examined the adequacy of pituitary function in septic shock patients by measuring coritcotroph- and melanotroph-type proopiomelanocortin derivatives in these patients. Their results showed a suppression on the melanotroph-type proopiomelanocortin that have anticytokine effects in septic shock patients, suggesting that these deficiencies may contribute to the increased risk of mortality in these patients. Mirjana et al. (7) examined another putative endogenous protectant, α2-macroglobulin, in protection against radiation injury in a rat model. Based on the finding that amifostine, a radioprotectant, increases plasma α2-macroglobulin levels in plasma, they tested whether exogenous α2-macroglobulin would be similarly protective. Using a median lethal dose model of whole-body irradiation, they found that intraperitoneal administration of α2-macroglobulin raise plasma levels by 15-fold and increased survival to 80% to 100%. This suggests that α2-macroglobulin is an important endogenous mediator or radioprotection after amifostine administration. Another well-recognized protectant in shock is estrogen. Kitagawa et al. (8) investigated the mechanisms by which estrogen promotes liver regeneration of remnant lobe after portal vein branch ligation. Estrogen administration significantly increased liver regeneration and expression of regeneration-related genes as well as serotonin receptor gene expression. A serotonin receptor antagonist significantly inhibited regeneration, suggesting that activation of the serotonin system in the liver is an essential component of the estrogen-induced enhancement of regeneration. Another important mediator of endogenous protection is maintenance of clotting activity. Because factor XIII is needed to stabilize fibrin clots and may have anti-inflammatory effects, Zaets et al. (9) tested the effect of exogenous recombinant factor XIII after intestinal I/R. Administration of factor XIII at the beginning of reperfusion resulted in improved organ function and microvascular integrity as well as decreased neutrophil activation. In vitro, factor XIII increased endothelial monolayer resistance in response to thrombin. Together, these results indicated that factor XIII protects against multiple organ failure largely via anti-inflammatory effects especially on endothelial cells and neutrophils. Finally, in the mediator theme, Cuzzocrea et al. (10) examine the role of an injurious mediator. Ceramide is a sphingolipid with proinflammatory actions. Therefore, these investigators investigated the potential role of ceramide in spinal cord injury. Treatment of rats with inhibitors of various steps in the ceramide synthetic pathway had significant protective effects on markers of spinal cord inflammatory injury and on recovery of motor function in the injury rats, suggesting an important role for ceramide in propagating spinal cord injury and suggesting a potential protective strategy through ceramide inhibition.

The final theme in this month's issue is that of integrity of the microcirculation and includes one clinical and four laboratory investigations. Many studies in animal models have shown that endotoxemia impairs vascular reactivity. Draisma et al. (11) tested whether this is true in humans as whether it is affected by the development of endotoxin tolerance. Using a variety of methods, they examined flow at rest and response to acetylcholine in normal human volunteers. After a single dose of endotoxin, resting blood flow was decreased in medium and large microvessels, and endothelium-dependent vasodilation in response to acetyl choline was attenuated. These changes were prevented by induction of endotoxin tolerance by daily injection of endotoxin. These results indicate that endotoxemia produces readily detectable defects in microvascular regulation, and that these responses can be prevented by induction of tolerance. Another approach to preventing deleterious effects of stress is through preconditioning such as with thermal stress (heat shock). Rücker et al. (12) tested whether localized thermal stress could help protect against photochemically induced thrombus in the microcirculation. Contrary to their hypothesis, thermal stress preconditioning actually increased thrombus formation in this model. It would be interesting to determine whether this effect is model specific or if this is a generalized effect of hypercoagulability.

It is becoming clear that shock and inflammation of various etiologies share many common mechanisms. One of these is the involvement of Toll-like receptors (TLRs). Khandoga et al. (13) investigated the role of TLR-2 and TLR-4 in mediating increased vascular permeability and leukocyte migration after ischemia. Using specific TLR knockout mice, they studied these parameters in postcapillary venules of the hamster cremaster muscle. Their finding that permeability changes were attenuated in both TLR-2 and TLR-4 knockouts, but leukocyte migration attenuated only in TLR-2 knockouts indicates a somewhat complex involvement of multiple TLRs in mediating microvascular damage after ischemia. The last two articles in this month's issue address issues of blood oxygenation. Villela et al. (14) examined the effect of changing hemoglobin oxygen affinity (P50) on microvascular integrity and oxygen delivery during hemorrhagic shock. This is relevant because of the altered P50 of stored blood often used for transfusion. They produced controlled alterations in P50 by electroporation of allosteric regulators of hemoglobin into fresh red blood cells and then used the cells for resuscitation. Although low P50 is commonly thought to impair oxygen delivery because of decreased off-loading in the tissues, resuscitation with low P50 blood resulted in improved microvascular flow compared with high P50, which resulted in a higher tissue PO2. These results suggest that a lowered P50 may be advantageous because of the improved perfusion, resulting in improved tissue oxygenation. The final article addresses the effect of erythropoietin (EPO) on tissue oxygenation in partially ischemic areas of skin flaps in rats (15). In a relatively short-term experiment (8 h total, 5 h after EPO) in which there was no change in hematocrit, EPO treatment resulted in a significant improvement in tissue perfusion and decrease in leukocyte adhesion and transmigration. This was associated with increased expression of eNOS in vessels of EPO-treated rats, and the effect was abolished by a NOS inhibitor. This suggests that EPO exerts its actions through anti-inflammatory effects, and that these effects are mediated at least in part by up-regulation of eNOS.

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1. Karvunidis T, Mares J, Thongboonkerd V, Matejovic M: Recent progress of proteomics in critical illness. Shock 31:545-552, 2009.
2. Nakamura A, Wada H, Ikejiri M, Hatada T, Sakurai H, Matsushima Y, Nishioka J, Maruyama K, Isaji S, Takeda T, et al.: Efficacy of procalcitonin in the early diagnosis of bacterial infections in a critical care unit. Shock 31:586-591, 2009.
3. Schneider CP, Yilmaz Y, Kleespies A, Jauch K-W, Hartl WH: Accuracy of procalcitonin for outcome prediction in unselected postoperative critically ill patients. Shock 31:568-573, 2009.
4. Kopterides P, Bonovas S, Mavrou I, Kostadima E, Zakynthinos E, Armaganidis A: Venous oxygen saturation and lactate gradient from superior vena cava to pulmonary artery in patients with septic shock. Shock 31:561-567, 2009.
5. Chen L, Reisner AT, Gribok A, McKenna TM, Reifman J: Can we improve the clinical utility of respiratory rate as a monitored vital sign? Shock 31:574-580, 2009.
6. Matejec R, Löcke G, Mühling J, Harbach H-W, Langefeld T-W, Bödeker R-H, Hempelmann G: Release of melanotroph- and corticotroph-type proopiomelanocortin derivatives into blood after administration of corticotrophin-releasing hormone in patients with septic shock without adrenocortical insufficiency. Shock 31:553-560, 2009.
7. Mirjana M, Silva D, Goran P, Milodrag P, Aleksandra U, Jelena A, Desanka B: The acute-phase protein α2-macroglobulin plays an important role in radioprotection in the rat. Shock 31:607-614, 2009.
8. Kitagawa T, Yokoyama Y, Kokuryo T, Kawai T, Watanabe K, Kawai K, Nagino M: Estrogen promotes hepatic regeneration via activating serotonin signal. Shock 31:615-620, 2009.
9. Zaets SB, Xu D-Z, Lu Q, Feketova E, Berezina TL, Gruda M, Malinina IV, Deitch EA, Olsen EHN: Recombinant factor XIII diminishes multiple organ dysfunction in rats caused by gut ischemia-reperfusion injury. Shock 31:621-626, 2009.
10. Cuzzocrea S, Deigner H-P, Genovese T, Mazzon E, Esposito E, Crisafulli C, Di Paola R, Bramanti P, Matuschak G, Salvemini D: Inhibition of ceramide biosynthesis ameliorates pathological consequences of spinal cord injury. Shock 31:634-644, 2009.
11. Draisma A, Bemelmans R, van der Hoeven JG, Spronk P, Pickkers P: Microcirculation and vascular reactivity during endotoxemia and endotoxin tolerance in humans. Shock 31:581-585, 2009.
12. Rücker M, Laschke MW, Stamm A, Harder Y, Vollmar B, Menger MD: Local preconditioning by thermal stress accelerates microvascular thrombus formation. Shock 31:627-633, 2009.
13. Khandoga AG, Khandoga A, Anders H-J, Krombach F: Postischemic vascular permeability requires both TLR-2 and TLR-4, but only TLR-2 mediates the transendothelial migration of leukocytes. Shock 31:592-598, 2009.
14. Villela NR, Cabrales P, Tsai AG, Intaglietta M: Microcirculatory effects of changing blood hemoglobin oxygen affinity during hemorrhagic shock resuscitation in an experimental model. Shock 31:645-652, 2009.
15. Contaldo C, Elsherbiny A, Lindenblatt N, Plock JA, Trentz O, Giovanoli P, Menger MD, Wanner GA: Erythropoietin enhances oxygenation in critically perfused tissue through modulation of nitric oxide synthase. Shock 31:599-606, 2009.
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