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Thiemermann, Christoph

doi: 10.1097/SHK.0b013e3180546b6b

Centre for Experimental Medicine, Nephrology & Critical Care, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK

This issue of Shock comprises 1 excellent review of the role of genes located on the X chromosome in the host response to injury, 4 studies investigating clinical aspects of shock and trauma, and 11 experimental studies aimed at gaining a better insight into the pathophysiology and experimental therapy of shock.

There is now substantial evidence that women are of better health and live longer than men, and it is thought that this is-at least in part-due to the modulating effects of sex hormones on the inflammatory response. In his excellent review, Dr. Spolarics (1) provides a summary of the unique nature of the X chromosome and its potential role in causing sex-related differences in the host response to injury and infection, which are independent from those related to the actions of sex hormones. Several genes encoding key metabolic and regulatory proteins reside on the X chromosome, and the products of these genes may play a beneficial role in the innate immune response. Because women carry both parental X chromosomes (whereas men carry only one), women have to be regarded as cellular mosaics for their X-linked polymorphic genes. Dr. Spolarics argues that this cellular mosaicism in women represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response. Finally, this review discusses the unique inheritance patterns of X-linked polymorphisms and their potential confounding effects in clinical trials and highlights potential biomarkers for studying mosaic cell populations of innate immunity.

The four studies relating to clinical aspects of shock cover very different research topics, including the mathematical modeling of clinical outcome, a clinical trial comparing values for oxygen delivery with those of transcutaneous pressure of oxygen as potential resuscitation goals, a clinical study into the role of endothelin 1 (ET-1) in traumatic brain injury, and an experimental study into the mechanisms by which the complement factor C5a modulates the responses of human monocytes to LPS. Infections of intensive care unit (ICU) patients with multidrug-resistant gram-negative bacteria, including Acinebacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumonie, have become more common. Because these bacteria respond to intravenous polymyxins, it has been argued that polymyxins should be used in the initial empirical antibiotic regimen in the ICU patient with fever that is thought to be due to infection. By retrieving data from the literature and the WHONET Greece (data from the Greek system for the surveillance of antimicrobial resistance in the period from January 2005 to June 2005), Falagas and Rafailidis (2) have developed a mathematical model to estimate the probability that a gram-negative bacterium susceptible only to polymyxins is isolated from an ICU patient. Based on the mathematical model developed, the authors propose that 4% to 5% of ICU patients with fever secondary to infection may die if the attending physicians do not include polymyxin in the initial treatment regimen. Thus, they propose that polymyxins should be included in the empirical antibiotic regimen in the ICU setting in hospitals, where the observed probability that a gram-negative bacterium is susceptible only to polymyxin is approximately 50% and, thus, similar to that assumed when developing their mathematical model.

In the absence of shock, transcutaneous pressure of oxygen (PtcO2) correlates with arterial pressure, but in conditions associated with shock, PtcO2 mirrors the changes in cardiac output and oxygen delivery (DO2), with no response to increasing fractions of inspired oxygen and arterial pressure of oxygen. Although an incremental change of more than 21 mmHg in PtcO2 in response to a fraction of inspired oxygen of 1.0 indicates adequate tissue perfusion, a lack of response in PtcO2 has been associated with increased mortality. In this issue of Shock, Yu et al. (3) have randomized patients with severe sepsis and septic shock into two groups: the first group was treated to a DO2 and mixed venous oxygen saturation goals, and the second group, the PtcO2 group, was treated to achieve a value of 40 mmHg or more in the oxygen challenge test. Although the DO2 and PtcO2 groups were similar in baseline characteristics, the mortality rates were 40% in the DO2 group and only 13% in the PtcO2 group. Based on subsequent logistic regression analysis of their data, the authors conclude that treating patients with severe sepsis/septic shock to an oxygen challenge test value of 25 mmHg or more may provide a specific end point of resuscitation that may be associated with better survival than resuscitating to the central hemodynamic parameters of DO2 and mixed venous oxygen saturation.

Severe traumatic brain injury is characterized by a high mortality rate and poor outcome, but the role of the potent vasopressor peptide ET-1 in the pathophysiology of the deterioration of cerebral perfusion after trauma is largely unclear. Maier et al. (4) have compared the alterations in the levels of ET-1 in the cerebrospinal fluid (CSF) and plasma in patients with either traumatic brain injury (TBI) alone or TBI in the presence of subarachnoid hemorrhage. ET-1 levels in both plasma and CSF were elevated in the first 2 to 3 days after TBI, but thereafter declined toward baseline values. Interestingly, in those patients in which the TBI was associated with subarachnoid hemorrhage, a second rise in the ET-1 levels in the CSF occurred at day 7, and ET-1 levels remained significantly elevated in the CSF until day 14. Thus, patients with TBI with associated subarachnoid hemorrhage exhibit persistent elevations in the ET-1 levels in the CSF, and this appears to be associated with a worsened outcome.

There is some evidence that ligands of Toll-like receptors (TLRs) such as the Toll-like receptor 4 ligand LPS and anaphylatoxins C3a or C5a, produced upon activation of the complement system, may synergize to activate the inflammatory response to injury, which-when excessive-may contribute to the development of acute lung injury and multiple organ dysfunction syndrome. When challenged with LPS in the presence of C5a, macrophages, Kupffer cells, and peripheral blood mononuclear cells (PBMCs) produce larger amounts of the proinflammatory cytokines TNF-α and IL-6, but the mechanism(s) underlying this "priming" effect of C5a are largely unclear. Schaeffer et al. (5) report here that the C5a receptor is expressed on human PBMCs. Interestingly, priming of adherent PBMCs with C5a led to a rapid phosphorylation and, thus, activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase, p38 and c-Jun NH2-terminal kinase. Specific inhibition of the activation of p38 MAPK with SB203580 prevented the priming effect of C5a on human PBMCs, whereas inhibition of the activation of extracellular signal-regulated kinase or c-Jun NH2-terminal kinase was without effect. Thus, the authors propose that the activation of the p38 MAPK cascade by C5a importantly contributes to the enhancement of the formation of TNF-α and IL-6 by PBMCs challenged with LPS in the presence of C5a.

The first 6 of 12 of the experimental studies reported in this issue of SHOCK relate to the pathophysiology or experimental treatment of sepsis, endotoxemia, septic shock, trauma, and heatstroke. Let us start with the two studies aimed at improving outcome in rodent models of cecal ligation and puncture (CLP). Butyrate is a short (4-carbon) chain fatty acid produced by bacterial fermentation of fiber in the mammalian intestine, which has proapoptotic and anti-inflammatory properties. Zhang et al. (6) have investigated the effects of sodium butyrate on the expression of high-mobility group box 1 protein (HMGB1) and outcome in a rat model of CLP. Sepsis resulted in an increase in the expression of HMGB1 in the liver, lung, intestine, and (to a lesser extent) kidney, which was attenuated by treatment of septic rats with sodium butyrate (500 mg kg−1, i.v., at 0.5 and 4 h after CLP). Interestingly, sodium butyrate moderately reduced the liver injury and renal dysfunction and reduced the mortality caused by CLP-sepsis (significant on days 1-6, but not thereafter). Butyrate also reduced the accumulation of neutrophils in the lung, but this was not secondary to prevention of the expression of TNF-α because the latter was not affected by butyrate. The authors imply that prevention of HMGB1 expression by butyrate contributes to the beneficial effects of this short chain fatty acid in experimental polymicrobial sepsis.

Although the loss of skeletal muscle protein is often associated with sepsis, there are currently no safe and effective medicines available to treat muscle atrophy. Catecholamines exert an inhibitory effect on muscle protein degradation through a pathway involving the cyclic adenosine monophosphatase (cAMP) cascade. Thus, Lira et al. (7) have investigated the effects of cAMP-phosphodiesterase inhibitors on protein metabolism in skeletal muscle from rats subjected to a model of polymicrobial sepsis. Within 3 h, CLP resulted in lactate acidosis, hypotension, a reduction in muscle blood flow, and muscle catabolism (measured as an increase in tyrosine levels in the interstitium and arterial plasma). Infusion (starting 1 h after CLP) of the cAMP-phosphodiesterase inhibitor pentoxifylline (50 mg kg−1 of body weight, i.v.) had no effect on muscle blood flow, but reduced the rise in TNF-α and the muscle catabolism caused by CLP. Incubation of muscle biopsies with the phosphodiesterase inhibitor isobutylmethylxanthine reduced muscle catabolism, and this effect was blocked by inhibition of protein kinase A with H-89. The authors conclude that novel therapeutic approaches aimed at activating either cAMP-dependent pathways or protein kinase A may reduce the muscle protein catabolism associated with sepsis and septic shock.

There is evidence that the neuropeptide cholecystokinin octapeptide (CCK-8) reduces the expression of the proinflammatory cytokines TNF-α and IL-1β in animal models of endotoxemia, but the mechanism(s) underlying these effects of CCK-8 are largely unclear. To address this issue, Li et al. (8) have investigated the potential signaling pathways by which CCK-8 may inhibit the formation of IL-1β caused by LPS in rat pulmonary interstitial macrophages. The authors report that pretreatment of rat pulmonary macrophages with CCK-8 attenuated the LPS-induced activation of p38 MAPK and nuclear factor-κB as well as the associated formation of IL-1β. Interestingly, these effects of CCK-8 were attenuated by an inhibitor of protein kinase A (H-89) and by specific antagonists of the CCK-1 receptor and-to a lesser extent-the CCK-2 receptor. Thus, activation by CCK-8 of the CCK-1 receptor (and to a lesser degree, CCK-2 receptor), with subsequent activation of the adenosine monophosphate-protein kinase A signaling pathway, importantly contributes to the observed anti-inflammatory effects of CCK-8 in rat pulmonary macrophages.

Activation of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels plays a role in the pathogenesis of the excessive vasodilation associated with shock, and bolus injections of inhibitors of KATP channels cause transient increases in blood pressure. In this issue of SHOCK, Lange et al. (9) have investigated the effects of the sulfonylurea glipizide, which inhibits KATP channels, in an ovine model of endotoxemia. At 16 h after the onset of endotoxin infusion (Salmonella typhosa, 10 ng kg−1 min−1), surviving sheep were treated with either glipizide (5 mg kg−1, followed by a continuous infusion of 8 mg kg−1 h−1 for 3 h) or placebo (saline). Infusion of glipizide reversed the endotoxin-induced hypotensive-hyperdynamic circulation (e.g., increase in blood pressure and systemic vascular resistance associated with decreases in cardiac index and heart rate) and increased urine output. The decrease in plasma glucose caused by this sulfonylurea was prevented by infusion of 5% glucose. The authors propose that infusion of glipizide should be considered as a novel therapeutic strategy to combat the excessive arterial hypotension associated with sepsis.

There is evidence that the adequate oxygen delivery alone does not necessarily result in improved organ function or survival of patients with septic shock. Thus, Schenkman et al. (10) have investigated whether optical spectroscopy may be able to detect changes in intracellular oxygenation in isolated perfused hearts obtained from guinea pigs subjected to endotoxemia for 4 h. When compared with control, endotoxemia resulted in an increase in myoglobin saturation, reduction in myocardial performance (left ventricular developed pressure), and reduced myocardial oxygen consumption. After a 30-s challenge with ischemia, myoglobin saturation decreased to 15% in hearts from control animals, but only to 60% in animals subjected to endotoxemia. Thus, in hearts obtained from guinea pigs with endotoxemia, oxygen consumption was lower, resulting in relatively high levels of intracellular oxygenation. Thus, the authors propose that the cellular dysfunction seen in patients with sepsis or septic shock may be secondary to impairment in oxygen usage, rather than oxygen delivery.

Head injury remains the leading cause of traumatic death in the United States, and the outcome of head trauma is worsened when associated with hypotension. Kerby et al. (11) have therefore investigated the effects of a polymerized hemoglobin-based oxygen-carrying solution (HBOC) as a resuscitation therapy in a rat model of combined hemorrhagic shock and brain injury. Anesthetized rats were subjected to a controlled degree of brain injury followed by a 30-min period of hemorrhagic hypotension (MAP of 30 mmHg) and subsequent resuscitation with HBOC-201, autologous shed blood, or lactated Ringer solution (RL). Rats subjected to trauma/hemorrhage resuscitated with HBOC-201 required less resuscitation volumes than rats resuscitated with shed blood or RL. Although cerebral blood flow was diminished at 60 min after resuscitation in rats with trauma/hemorrhage, which were resuscitated with HBOC-201, those animals resuscitated with HBOC-201 (or shed blood) maintained their vasoreactivity to hypercapnia and had significantly smaller contusion volumes than those treated with RL alone. Thus, in the prehospital environment where autologous blood is not readily available, low-volume resuscitation of patients with TBI with HBOC-201 may reduce secondary brain injury.

The multiple organ dysfunction caused by severe heatstroke in humans includes hypotension, hepatic and renal failure, activation of the coagulation system, excessive systemic inflammation, and cerebral ischemia. Chen et al. (12) have investigated whether a therapy with human umbilical cord blood-derived CD34+ cells improves the survival rate in a rodent model of heatstroke. When compared with normothermic controls, rats subjected to heatstroke (increase in body temperature to 43°C) that were treated with CD34− cells (negative control) exhibited hypotension, hepatic and renal failure, excessive activation of the coagulation system, systemic inflammation, and cerebral ischemia and injury. In contrast, treatment of rats with CD34+ cells significantly improved survival time and reduced all of the above signs of organ injury/dysfunction and inflammation. In addition, therapy with CD34+ cells increased the plasma levels of the anti-inflammatory cytokine IL-10 and the levels of glial-cell line-derived neurotrophic factors in the brain. Thus, the authors speculate that resuscitation of patients suffering from heatstroke with CD34+ cells derived from human umbilical cords may reduce the incidence or severity of multiple organ failure and, thus, improve outcome.

The studies discussed in the following section of my commentary relate to the pathophysiology and experimental treatment of ischemia (hypoxia)- and reperfusion (reoxygenation)-related injury. Zacharowski et al. (13) have investigated the effects of a fibrin-derived peptide Bβ15-42 (28 amino acids corresponding to the N-terminal sequence of the fibrin β-chain) in acute and chronic rodent models of ischemia/reperfusion (I/R) in three different study centers. The fibrin-derived peptide reduced infarct size caused by ligation of the left anterior descending coronary artery, followed by reperfusion (for up to 30 days) in rodents. The magnitude of the reductions in infarct size afforded by this peptide was similar to the one afforded by the radical scavenger tempol, an antibody against C5a, and by preconditioning of the hearts with ischemia. The cardioprotective peptide also reduced the ischemia-induced rise in the plasma levels of IL-1β, IL-6, and TNF-α. Thus, the authors provide convincing evidence that the fibrin-derived peptide Bβ15-42, reduces myocardial infarct size, scar formation, and inflammation when given upon reperfusion of the previously ischemic myocardium. Although positive end-expiratory pressure (PEEP) is used in patients with severe acute myocardial infarction to prevent the development of lung edema, it has been suggested that the use of PEEP may impair left ventricular contractility by reducing ventricular loading. To address this issue, Kubitz et al. (14) have evaluated the effects of PEEP (5 or 10 cm H2O) on myocardial contractile performance in anesthetized pigs subjected to occlusion and reperfusion of the left anterior descending coronary artery. In the absence of myocardial ischemia, PEEP reduced cardiac output secondary to a reduction in end-diastolic volume, whereas the preload-recruitable stroke work remained unchanged, and end-systolic elastance increased. Myocardial I/R resulted in a marked deterioration in cardiac output and preload-recruitable stroke work, but not in end-systolic elastance. Under those conditions, PEEP (10 cm H2O) reduced cardiac output but improved preload-recruitable stroke work and end-systolic elastance. The authors conclude that PEEP impairs global left ventricular function in the absence and, to a lesser degree, presence of myocardial I/R. This impairment in left ventricular function appears to be due to a reduction in left ventricular filling and not due to a reduction in contractile force. I/R of the liver importantly contributes to the liver injury associated with liver transplantation or liver resections as well as cardiogenic and hemorrhagic shock. Duenschede et al. (15) have evaluated theeffects of the naturally occurring, lipophilic antioxidant α-lipoic acid in a rodent model of liver ischemia and reperfusion. Pretreatment of rats 15 min before the onset of liver ischemia with α-lipoic acid (500 μmol) attenuated hepatocyte necrosis and hepatocyte apoptosis, and increased survival. In sections of the liver subjected to I/R, α-lipoic acid also attenuated the fall in tissue ATP, the activation of the caspases 3, 8, and 9, as well as the expression of proapoptotic protein Bax, but enhanced the expression of the antiapoptotic protein Bcl-2. Interestingly, α-lipoic acid also aided liver regeneration, an effect that may be secondary to an enhanced formation of liver TNF-α, which functions as a key growth factor during the early phase of liver regeneration.

Neonatal asphyxia is associated with hypoxia-reoxygenation injury of many organs, including the liver, but the effects of resuscitation with a low (21%) or a high (100%) concentration of oxygen are largely unknown. Using newborn piglets subjected to 2 h of hypoxia, Stevens et al. (16) have investigated the effects of the subsequent resuscitation with either 21% or 100% oxygen (for 1 h, followed by 1 h resuscitation with 21% oxygen in both groups) on hepatic hemodynamics and oxygen metabolism. Hypoxia caused a fall in cardiac index, reductions in portal venous flow index and total hepatic blood flow, hypotension, and metabolic acidosis. Within 15 min of reoxygenation with either 21% or 100% oxygen, cardiac index improved, portal venous flow index recovered, and hepatic artery flow index was maintained, but the hypoxia-induced rise in lactate was not affected by resuscitation with either concentration of oxygen. Hypoxia resulted in a decrease in oxygen consumption and an increase in oxygen extraction. Resuscitation with 100% oxygen resulted in a greater oxygen delivery (portal vein) when compared with resuscitation with 21% oxygen, whereas the hepatic oxygen extraction was lower in animals resuscitated with 100% oxygen. The authors conclude that resuscitation with 21% oxygen is sufficient to restore hepatic hemodynamics and oxygen consumption.

I hope that you will enjoy the articles published in this issue of Shock as much as I have. I would like to stress that I have only been able to highlight some of the key aspects of each study in this relatively brief editorial comment, and I would therefore urge the interested reader to find more detailed information in the original articles and reviews published in this issue of Shock. I would like to take this opportunity to congratulate the authors and coauthors of the articles reviewed here for their important efforts, which hopefully ultimately help to improve the treatment of patients with shock.

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1. Spolarics Z: The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection. Shock 27:597-604, 2007.
2. Falagas ME, Rafailidis PI: When to include polymyxins in the empirical antibiotic regimen in critically ill patients with fever? A decision analysis approach. Shock 27:605-609, 2007.
3. Yu M, Chapital A, Ho HC, Wang J, Takanishi D Jr: A prospective randomized trial comparing oxygen delivery versus transcutaneous pressure of oxygen values as resuscitative goals. Shock 27:615-622, 2007.
4. Maier B, Lehnert M, Laurer HL, Marzi I: Biphasic elevation in cerebrospinal fluid and plasma concentrations of endothelin 1 after trauma brain injury in human patients. Shock 27:610-614, 2007.
5. Schaeffer V, Cuschieri J, Garcia I, Knoll M, Billgren J, Jelacis S, Bulger E, Maier R: The priming effect of C5A on monocytes is predominantly mediated by the p38 MAPK pathway. Shock 27:623-630, 2007.
6. Zhang L-T, Yao Y-M, Lu J-Q, Yan X-J, Yu Y, Sheng Z-Y: Sodium butyrate prevents lethality of severe sepsis in rats. Shock 27:672-677, 2007.
7. Lira EC, Graça FA, Gonçalves DAP, Zanon NM, Baviera AM, Strindberg L, Lo¨nnroth P, Migliorini RH, Kettelhut IC, Navegantes LCC: Cyclic adenosine monophosphate-phosphodiesterase inhibitors reduce skeletal muscle protein catabolism in septic rats. Shock 27:687-694, 2007.
8. Li S, Ni Z, Cong C, Gao W, Xu S, Wang C-Y, Yao Y, Ma C, Ling Y: CCK-8 inhibits LPS-induced IL-1β production in pulmonary interstitial macrophages by modulating PKA, p38, and NF-κβ pathway. Shock 27:678-686, 2007.
9. Lange M, Williams W, Bone H-G, van Aken H, Bro¨king K, Morelli A, Hucklenbruch C, Daudel F, Ertmer C, Stubbe H, et al.: Continuously infused glipizide reverses the hyperdynamic circulation in ovine endotoxemia. Shock 27:701-706, 2007.
10. Schenkman KA, Arakaki LSL, Ciesielski WA, Beard DA: Optical spectroscopy demonstrates elevated intracellular oxygenation in an endotoxic model of sepsis in the perfused heart. Shock 27:695-700, 2007.
11. Kerby JD, Sainz JG, Zhang F, Hutchings A, Sprague S, Farrokhi FR, Son M: Resuscitation from hemorrhagic shock with HBOC-201 in the setting of traumatic brain injury. Shock 27:652-656, 2007.
12. Chen S-H, Chang F-M, Chang H-K, Chen W-C, Huang K-F, Lin M-T: Human umbilical cord blood-derived CD34+ cells cause attenuation of multiorgan dysfunction during experimental heatstroke. Shock 27:663-671, 2007.
13. Zacharowski K, Zacharowski PA, Friedl P, Mastan P, Koch A, Boehm O, Rother RP, Reingruber S, Henning R, Emeis JJ, et al.: The effects of the fibrin-derived peptide Bβ15-42 in acute and chronic rodent models of myocardial ischemia-reperfusion. Shock 27:631-637, 2007.
14. Kubitz JC, Annecke T, Hinkel R, Reuter DA, Kronas N, Forkl S, Boekstegers P, Goetz AE, Kemming GI: Positive end-expiratory pressure does not compromise myocardial contractility in myocardial ischemia/reperfusion. Shock 27:638-643, 2007.
15. Duenschede F, Erbes K, Kircher A, Westermann S, Schad A, Riegler N, Ewald P, Dutkowski P, Kiemer AK, Kempski O, et al.: Protection from hepatic ischemia/reperfusion injury and improvement of liver regeneration by α-lipoic acid. Shock 27:644-651, 2007.
16. Stevens JP, Haase E, Churchill T, Bigam DL, Cheung P-Y: Resuscitation with 21% or 100% oxygen is equally effective in restoring perfusion and oxygen metabolism in the liver of hypoxic newborn piglets. Shock 27:657-662, 2007.
©2007The Shock Society