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WHAT'S NEW IN SHOCK, October 2007?

Thiemermann, Christoph

doi: 10.1097/shk.0b013e31814a54f8

Centre for Translational Medicine & Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom

The current issue of SHOCK comprises 3 excellent and timely review articles, 4 clinical studies, and 10 basic science studies aimed at gaining a better understanding of either pathophysiology or experimental treatment of septic/endotoxic shock, trauma-hemorrhagic shock, burns, and smoke inhalation or I/R injury. Let me start by introducing you to the topics reviewed in this issue of SHOCK, which discuss the potential beneficial effects of stem cell therapy in cardiac surgery, the gut as the motor of critical illness, and the beneficial and adverse effects of the inhibition of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in shock. Stem cells are defined as unspecialized or undifferentiated precursor cells with the capacity for long-term division without differentiation (self-renewal) and the power to differentiate into multiple different specialized cell types (pluripotency). In the last decade, it has become apparent that stem cells may restore cardiac function in animals and patients with cardiac injury and heart failure. Although it was initially proposed that undifferentiated stem cells regardless of lineage (hematopoietic, bone marrow, cardiac, etc.) are able to differentiate into cardiac myocytes, there is more recent evidence to suggest that the observed beneficial effects of stem cells are, at least in part, secondary to paracrine effects of these cells. In their excellent and timely review article, Crisostomo et al. (1) discuss (1) the history of stem cell research in cardiac disease, (2) the mechanism(s) underlying the cardioprotective effects with particular focus on the signals responsible for the paracrine protective effects of stem cells, and (3) the ongoing human studies designed to use stem cells to improve outcome in patients with cardiac disease.

For more than 20 years, the gut has been implicated in the development of the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) caused by major trauma, shock, or burn injury. Over the years, many disparate mechanisms have been discussed by which the gut may play a pivotal role in the origin and propagation of critical illness. The purpose of the review by Clark et al. (2) is to present a unifying theory as to how the gut drives critical illness by proposing that the intestinal epithelium, the intestinal immune system, and the intestine's endogenous bacteria all play vital roles in driving the development of MODS. The authors propose that the complex cross talk between these three interrelated portions of the gastrointestinal tract is what cumulatively makes the gut a motor of critical illness. The final review by Lange et al. (3) discusses the role of KATP channels in septic and hemorrhagic shock. Excessive vasodilatation and vascular hyporesponsiveness to vasopressor agents plays a pivotal role in the pathophysiology of many forms of shock. The KATP channels located in vascular smooth muscle cells are activated by hypoxia-induced falls in intracellular ATP concentrations, resulting in vasodilatation, which in turn results in an increase in blood flow to the hypoxic tissue. There is good evidence that both septic and hemorrhagic shock results in the activation of KATP channels, and this results in vasodilatation and, when excessive, hypotension. Thus, pharmacological inhibition of KATP channels may represent a therapeutic option to stabilize h`modynamics in shock. The authors critically review both preclinical and-the more controversial-clinical findings relating to the use of inhibitors of the activation of KATP channels in shock.

The following four original research articles highlight some important clinical aspects of the pathophysiology, diagnosis, and therapy of shock and multiple organ failure. For instance, coagulopathy and thrombocytopenia often occurs in critically ill patients, and disseminated intravascular coagulation may contribute to the development of multiple organ dysfunction and poor outcome. Ogura et al. (4) evaluated the relationship between coagulation, organ dysfunction, and SIRS (over 4 consecutive days) in 273 critically ill patients from 13 centers (in Japan) with thrombocytopenia. Both entry and maximum SIRS score correlated positively with "Sequential Organ Failure Assessment" score, and both SIRS and Sequential Organ Failure Assessment scores correlated positively with the degree of coagulopathy (thrombocytopenia, disseminated intravascular coagulation). The authors conclude that SIRS-associated coagulopathy may play a key role in the organ dysfunction in critically ill patients with thrombocytopenia. There is also evidence that excessive inflammation contributes to the hemostatic alterations associated with hepatic surgery. Pulitano et al. (5) have evaluated the effects of preoperative administration of methylprednisolone (500 mg) on changes (measured over 5 days) in coagulation and systemic inflammation in 73 patients undergoing liver resection. Treatment of patients with methylprednisolone resulted in decreases in antithrombin III, platelet count and fibrinogen levels, prolongation of prothrombin time, and increases in the plasma fibrin degradation products. The postoperative increase in the proinflammatory cytokines IL-6 and TNF-α were also reduced by treatment with this steroid. The authors conclude that (1) systemic inflammation correlates positively with alterations in coagulation and (2) preoperative methylprednisolone inhibits the impairment in coagulation in patients undergoing liver resection, possibly through suppressing the production of inflammatory cytokines.

Elective cardiac surgery with cardiopulmonary bypass may, even in the absence of infection, be associated with SIRS, adrenal dysfunction, and coagulopathy. Thus, Adip-Conquy et al. (6) evaluated the plasma levels of two markers on infection, namely, soluble-triggering receptor expressed on myeloid cells 1 (sTREM-1) and procalcitonin (PCT), in (1) 76 patients undergoing elective heart surgery with cardiopulmonary bypass, (2) 54 patients admitted after out-of-hospital cardiac arrest, (3) 55 patients with sepsis, and (4) 31 healthy volunteers. Plasma levels of PCT were higher in sepsis patients than in patients who survived after cardiac arrest or cardiac surgery, but the peak levels of sTREM-1 were similar in patients with cardiac surgery, patients who survived a cardiac arrest, or patients with sepsis. Interestingly, in patients who survived cardiac arrest associated with refractory shock, the levels of sTREM-1 and PCT were similar to those in the patients with severe sepsis. Thus, the authors conclude that sTREM-1 and PCT are not specific for infection and can increase markedly in patients with SIRS without infection. The final clinical study in this issue of SHOCK relates to the immunoparalysis that is often associated with sepsis and septic shock. This immunoparalysis (exemplified by a reduction in monocyte human leukocyte antigen-DR expression) can be triggered by endotoxin, IL-6, and complement-activation product 5a (C5a), and this immunoparalysis may result in uncontrolled infection, multiple organ dysfunction, and death. In a prospective, controlled trial in patients with severe sepsis or septic shock, Schefold et al. (7) evaluated whether the simultaneous reduction of the systemic levels of endotoxin, IL-6, and C5a can be achieved by daily (for 7.5 h for 5 days) selective extracorporeal immunoadsorption would restore monocyte function and improve organ function. Immunoadsorption therapy reduced the circulating levels of IL-6, C5a, and two indices of endotoxemia as well as C-reactive protein and "Acute Physiology and Chronic Health Evaluation" II scores at day 7. Most notably, in patients who received immunoadsorption therapy (but not in controls), monocytic human leukocyte antigen-DR improved and recovered in all patients with immunoparalysis. Thus, the authors conclude that an immunoadsorption therapy aimed at simultaneously reducing circulating levels of endotoxin, IL-6, and C5a reverses monocytic deactivation (immune paralysis) and improves organ system functions.

The final 10 preclinical studies published in this issue of SHOCK relate to the pathophysiology and treatment of trauma-hemorrhagic shock, shock caused by burns and smoke inhalation, endotoxic shock, and alveolar hypoxia and reoxygenation. The loss of gut barrier function caused by trauma-hemorrhagic shock has been suggested to be a major contributor to the development of distant organ injury and subsequent MODS (2). Previous studies aimed at gaining an insight into the mechanism(s) underlying this phenomenon have focused on the potential toxic effects of lymph, but have largely ignored the nonbacterial factors contained within the lumen of the intestine. Caputo et al. (8) have investigated whether pancreatic proteases are necessary for the trauma-hemorrhage-induced gut injury and the production of biologically active mesenteric lymph by determining the extent to which pancreatic duct ligation would limit gut injury and mesenteric lymph bioactivity. In male rats subjected to trauma (laparotomy) and hemorrhagic shock (30 mmHg for 90 min), ligation of the pancreatic duct (1) protected the intestine against the injury and dysfunction caused by trauma-hemorrhage and (2) reduced the ability of lymph obtained from animals subjected to trauma-hemorrhage to kill endothelial cells or to prime naive neutrophils for an augmented respiratory burst. Thus, it appears that intraluminal pancreatic proteases play a pivotal role in the pathogenesis of the gut injury and the generation of bioactive lymph after trauma-hemorrhage. We know relatively little about the mechanism(s) by which tissue injury initiates inflammation. Hoth et al. (9) have developed a murine model of pulmonary contusion that is similar (based on histological, morphological, and biochemical criteria) to that observed clinically in humans with acute lung injury. When compared with wild-type mice, Toll-like receptor (TLR) 2-deficient mice subjected to lung contusion exhibited reduced pulmonary edema and inflammation, and this was associated with reduced circulating levels of the chemokine (CXC motif) ligand 1. These results support the view that pulmonary contusion and injury generates a hitherto unidentified, noninfectious ligand that activates TLR-2 to generate an inflammatory response. It is still unclear whether animal models of either uncontrolled or controlled hemorrhage are the most appropriate for studying the pathophysiology and therapy of hemorrhagic shock. To address this important question, Sondeen et al. (10) evaluated hemodynamic and metabolic changes (for 3 h in the absence of fluid resuscitation) in anesthetized immature female pigs subjected to uncontrolled hemorrhage (vascular injury) and compared the observed changes to those in animals subjected to controlled hemorrhages that mimicked either the blood pressure profile or the blood volume loss of uncontrolled hemorrhage by using a computer-driven feedback control system. Although not one particular model was better than any other for subsequent studies of hemorrhage and resuscitation, the authors report that (1) using a controlled hemorrhage model to match the blood pressure response of an uncontrolled hemorrhage was the hardest to reproduce, (2) the fixed-volume hemorrhage was the easiest to reproduce and may be most appropriate to study the efficacy of different resuscitation strategies to replace volume and study the effect of whole-body ischemia, (3) to study the aspect of trauma and tissue injury, especially if the effect on the inflammatory and coagulation status is of interest, a model incorporating an uncontrolled hemorrhage model with tissue injury should be used. Clearly, adequate volume replacement is a cornerstone in the management of trauma because hypovolemia may lead to MODS, but the question as to which fluid should be used is still controversial. To address this issue, Cabrales et al. (11) have compared the effects of low molecular weight hydroxyethyl starch (L-HES) or high molecular weight HES (H-HES) on rheological properties, restoration of perfusion, and coagulation in a model of moderate hemorrhagic shock (hypovolemia to 50% of blood volume for 1 h) in the hamster. When compared with L-HES, replacement of 25% of the shed blood volume with H-HES improved blood pressure, microcirculatory flow, and metabolic recovery, but thrombus formation was impaired in both groups. The authors conclude that fluid resuscitation with HES may increase the risk of bleeding secondary to hemodilution, but that the molecular weight of the HES does not explain the bleeding tendency.

Acute airway injury caused by smoke inhalation results in airway complications, such as cast formation and poor gas exchange, which have the potential to be fatal to exposed patients. Interestingly, in severely burned patients, the levels of L-arginine, the critical substrate for NO formation by NOS, are depleted. Using their well-established ovine model of burn and smoke inhalation (40% area full-thickness flame burn combined with 48 breaths of smoke from burning cottons), Murakami et al. (12) have investigated whether infusion of L-arginine (57 mg·kg−1·h−1) affects the lung injury and dysfunction caused by burn and smoke inhalation in ventilated ewes. Infusion of l-arginine reduced the (1) fall in plasma L-arginine, (2) fall in the Pao2/Fio2 ratio, (2) degree of airway obstruction, and (4) the formation of nitrotyrosine caused by burn and smoke inhalation. The observed reduced formation of peroxynitrite may be secondary to a reduced formation of superoxide anions by NOS in the absence of sufficient amounts of its physiological substrate L-arginine. In my opinion, these findings are exciting, but it would have been interesting to see the effects (if any) of an infusion of an equal amount of D-arginine, which is not a substrate for NOS.

The following three studies focus on the pathophysiology and treatment of endotoxic shock. Activated protein C (APC) is an important modulator of vascular function that has antithrombotic and anti-inflammatory properties. In addition, there is evidence in humans that APC attenuates the hypotension caused by LPS by a hitherto unknown mechanism. Gupta et al. (13) report here that APC suppresses the expression of the mRNA of the potent vasoactive peptide adrenomedullin in vitro. In a rat model of endotoxemia, APC (100 mg·kg−1) prevented the formation of adrenomedullin, hypotension, expression of iNOS, formation of nitrite/nitrate, and the formation of interferon-γ. Most notably, in human volunteers challenged with LPS, APC prevented the formation of adrenomedullin and reduced the hypotension afforded by LPS. These findings support the view that APC prevents the formation of adrenomedullin and reduces the formation of NO by iNOS; and both of these effects may contribute to prevention by APC of the hypotension caused by LPS in rat and man. The mechanisms leading to cardiac myocyte dysfunction in shock of various etiologies are not entirely clear, but there is some evidence that local mediators, including endothelin 1 and NO may play an important role. In this issue of SHOCK, Patel et al. (14) report their discovery of a novel phenotype of the ventricular cardiac myocyte that does not contract appropriately on electrical stimulation. These noncontractile cardiac myocytes are viable, have normal calcium transients, and the proportion of these myocytes is increased by activation of either TLR-2/6 by Staphylococcus aureus or of TLR-4 by Escherichia coli. The observed transition to the noncontractile phenotype was largely attenuated by an inhibition of the ETA receptor, but not NOS, suggesting that endothelin 1 (but not NO) mediates this phenomenon. These results are the first to describe the characteristics of this noncontractile phenotype and the mechanisms of its induction by bacteria. The description of the myocyte population, instead of effects only on individual cells, will be more relevant to the prediction of the depression of cardiac function.

There is good evidence that mechanical ventilation with a high tidal volume can cause or exacerbate lung injury in critically ill patients. Lin et al. (15) have investigated whether the tidal volume affects the inflammatory response caused by LPS. Thus, LPS (0.5 mg·kg−1) was given into the trachea of rats, and this was followed by mechanical ventilation for 4 h with low (control, 60 strokes per min; tidal volume, 10 mL·kg−1 for 4 h) or high tidal volume (30 strokes per min; tidal volume, 20 mL·kg−1). The authors demonstrate that ventilation with a high tidal volume alone caused neutrophil recruitment and pulmonary edema, whereas LPS alone caused lung injury, neutrophil recruitment, and formation of cytokines and chemokines. Intratracheal administration of LPS followed by mechanical ventilation with high (but not low) tidal volume caused a synergistic increase in IL-1 formation, up-regulation of intercellular adhesion molecule 1, and neutrophil recruitment, and these effects were reduced by a monoclonal antibody directed against intercellular adhesion molecule 1.

Every year, there are more than 1 million neonates suffering from asphyxia worldwide. After the initial resuscitation, the clinical course may be complicated by cardiovascular compromise with shock and hypotension potentially leading to I/R injury of hypoperfused organs, including the kidney and the intestine. Cheung et al. (16) have compared the systemic and regional hemodynamic effects of high-dose epinephrine with those of dopamine combined with low-dose epinephrine infusions in a model of hypoxia reoxygenation. Alveolar hypoxia in neonatal piglets (1 - 3 days) resulted in falls in cardiac index, arterial blood pressure, and regional perfusion, as well as acidosis. Infusions for 2 h of either epinephrine (1·μg·kg−1·min−1) alone or dopamine (10μg·kg−1·min−1) plus epinephrine (0.2 μg·kg−1·min−1) enhanced cardiac index, arterial pressure, pulmonary vascular resistance, systemic oxygen delivery and consumption (to a similar degree), and decreased lactate. There were no differences in heart rates, pulmonary artery pressures, and regional blood flows between both treatment groups. Thus, the authors conclude that infusion of high-dose epinephrine alone is as effective as the coadministration of dopamine and low-dose epinephrine for the treatment of the alterations in systemic hemodynamics in piglets subjected to severe alveolar hypoxia and reoxygenation. Using their model of hypoxia reoxygenation, Johnson et al. (17) have evaluated whether therapeutic administration of N-acetylcysteine (i.v. bolus of 150 mg kg−1 given at 10 min of reoxygenation followed by 100 mg·kg−1·h−1 infusion) improves cardiac function and renal blood flow in anesthetized piglets (1 - 4 days of age). Alveolar hypoxia was induced for 2 h, followed by resuscitation with 100% oxygen for 1 h and 21% oxygen for 3 h. When compared with control, N-acetylcysteine prevented the decrease in cardiac index, stroke volume, mean blood pressure, systemic oxygen delivery, renal artery flow index, and renal oxygen delivery at 2 to 4 h of reoxygenation. Interestingly, both myocardial and renal tissue glutathione content were significantly higher after treatment with N-acetylcysteine, and cardiac index and renal artery flow index (at 4 h of reoxygenation) correlated with the tissue glutathione redox ratio. Thus, the therapeutic administration of N-acetylcysteine (during early reoxygenation) improved cardiac function, renal perfusion, and tissue glutathione content in piglets subjected to hypoxia and reoxygenation.

Clearly, I have only been able to highlight some of the key aspects of each study in this relatively brief editorial comment and very much hope that our readers will enjoy the original articles published in this issue of SHOCK as much as I have. As always, I would like to take this opportunity to congratulate the authors and coauthors of the articles reviewed here for their important efforts, which hopefully will help us to gain a better understanding of the complexity of the pathophysiology of shock and injury caused by sepsis, trauma, hemorrhage, burns and smoke inhalation, and I/R, and help to improve the therapy of patients.

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1. Crisostomo PR, Wang M, Markel TA, Lahm T, Abarbanell AM, Herrmann JL, Meldrum DR: Stem cell mechanisms and paracrine effects: potential in cardiac surgery. Shock 28:375-383, 2007.
2. Clark JA, Coopersmith CM: Intestinal crosstalk: a new paradigm for understanding the gut as the "motor" of critical illness. Shock 28:384-393, 2007.
3. Lange M, Morelli A, Ertmer C, Brkling K, Rehberg S, Van Aken H, Traber DL, Westphal M: Role of adenosine triphosphate-sensitive potassium channel inhibition in shock states: physiology and clinical implications. Shock 28:394-400, 2007.
4. Ogura H, Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, Mayumi T, Murata A, Ikeda T, et al, Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Study Group: SIRS-associated coagulopathy and organ dysfunction in critically ill patients with thrombocytopenia. Shock 28:411-417, 2007.
5. Pulitan C, Aldrighetti L, Arru M, Finazzi R, Catena M, Guzzetti E, Soldini L, Comotti L, Ferla G: Preoperative methylprednisolone administration maintains coagulation homeostasis in patients undergoing liver resection: importance of inflammatory cytokine modulation. Shock 28:401-405, 2007.
6. Adib-Conquy M, Monchi M, Goulenok C, Laurent I, Thuong M, Cavaillon J-M, Adrie C: Increased plasma levels of soluble triggering receptor expressed on myeloid cells 1 and procalcitonin after cardiac surgery and cardiac arrest without infection. Shock 28:406-410, 2007.
7. Schefold JC, von Haehling S, Corsepius M, Pohle C, Kruschke P, Zuckermann H, Volk H-D, Reinke P: A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5A. Shock 28:418-425, 2007.
8. Caputo FJ, Rupani B, Watkins AC, Barlos D, Vega D, Senthil M, Deitch EA: Pancreatic duct ligation abrogates the trauma hemorrhage-induced gut barrier failure and the subsequent production of biologically active intestinal lymph. Shock 28:441-446, 2007.
9. Hoth JJ, Hudson WP, Brownlee NA, Yoza BK, Hiltbold EM, Meredith JW, McCall CE: Toll-like receptor 2 participates in the response to lung injury in a murine model of pulmonary contusion. Shock 28:447-452, 2007.
10. Sondeen JL, Dubick MA, Holcomb JB, Wade CE: Uncontrolled hemorrhage differs from volume- or pressure-matched controlled hemorrhage in swine. Shock 28:426-433, 2007.
11. Cabrales P, Tsai AG, Intaglietta M: Resuscitation from hemorrhagic shock with hydroxyethyl starch and coagulation changes. Shock 28:461-467, 2007.
12. Murakami K, Enkhbaatar P, Yu Y-M, Traber LD, Cox RA, Hawkins HK, Tompkins RG, Herndon D, Traber DL: L-Arginine attenuates acute lung injury after smoke inhalation and burn injury in sheep. Shock 28:477-483, 2007.
13. Gupta A, Berg DT, Gerlitz B, Richardson MA, Galbreath E, Syed S, Sharma AC, Lowry SF, Grinnell BW: Activated protein C suppresses adrenomedullin and ameliorates lipopolysaccharide-induced hypotension. Shock 28:468-476, 2007.
14. Patel TA, Belcher E, Warner TD, Harding SE, Mitchell JA: Identification and characterization of a dysfunctional cardiac myocyte phenotype: role of bacteria, Toll-like receptors, and endothelin. Shock 28:434-440, 2007.
15. Lin S-M, Lin H-C, Lee K-Y, Huang C-D, Liu C-Y, Wang C-H, Kuo H-P: Ventilator-induced injury augments interleukin-1β production and neutrophil sequestration in lipopolysaccharide-treated lungs. Shock 28:453-460, 2007.
16. Cheung P-Y, Abozaid S, Al-Salam Z, Johnson S, Li Y, Bigam D: Systemic and regional hemodynamic effects of high-dose epinephrine infusion in hypoxic piglets resuscitated with 100% oxygen. Shock 28:491-497, 2007.
17. Johnson ST, Bigam DL, Emara M, Obaid L, Slack G, Korbutt G, Jewell LD, Van Aerde J, Cheung P-Y: N-Acetylcysteine improves the hemodynamics and oxidative stress in hypoxic newborn pigs reoxygenated with 100% oxygen. Shock 28:484-490, 2007.
©2007The Shock Society