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Purpose The clinical significance of septic myocardial dysfunction is controversial, a fact that may be explained by the influence of loading conditions. Many indices may be useful to characterize cardiac function during septic shock, but their feasibility and physiological coherence in the clinical setting are unknown. Methods Hemodynamic and echocardiographic data with tissue Doppler and speckle tracking were prospectively recorded on the first 3 days of human septic shock. Hypokinesia, normokinesia, and hyperkinesia were defined as a left ventricular ejection fraction (LVEF) of 60%, respectively. Twelve hemodynamic indices exploring contractility and loading conditions were assessed and analyzed. Results Two hundred and ninety-seven echocardiographies were performed in 132 patients. During the first 24 h (H.sub.1-24), 48 (36.4%) patients were hyperkinetic, 55 (41.7%) were normokinetic, and 29 (22.0%) patients were hypokinetic. Thirteen patients had a secondary hypokinesia absent at H.sub.1-24 but present at H.sub.25-48 or H.sub.49-72, for an overall incidence of 42 (31.8%) during the first 3 days. Despite a limited feasibility (70%) of the patients assessed, including all those with depressed LVEF, and declined early in patients whose LVEF secondarily deteriorated. Most contractility indices were inversely correlated with afterload indices. Hyperkinetic patients exhibited the worst reduction in afterload indices. Hospital mortality was significantly higher in patients with LV hyperkinesia than in their counterparts: 30 (62.5%) vs. 35 (41.7%), p = 0.02. Conclusions Speckle tracking-derived strain was reduced in the majority of patients with septic shock, revealing covert septic myocardial dysfunction, but had poor feasibility. We found an inverse correlation between most of the contractility and afterload indices. Precise evaluation of afterload is crucial for adequate interpretation of LV systolic function in this setting., Author(s): Florence Boissier [sup.1] [sup.2] [sup.4] [sup.5], Keyvan Razazi [sup.1] [sup.2], Aurélien Seemann [sup.1] [sup.3], Alexandre Bedet [sup.1] [sup.2], Arnaud W. Thille [sup.1] [sup.4] [sup.5], Nicolas de Prost [sup.1] [sup.2], [...]

Author(s): Anders Aneman [sup.1], Antoine Vieillard-Baron [sup.2] Author Affiliations: (1) grid.1005.4, 0000000449020432, Intensive Care Unit, Liverpool Hospital, South Western Sydney Local Health District, South Western Sydney Clinical School, University of [...]

Sepsis and septic shock are the chief cause of death in intensive care units, with mortality rates between 30 and 70%. In a large animal model of septic shock, we have demonstrated hypotension, increased cardiac output, and tachycardia, together with renal vasodilatation and renal failure. The changes in cardiac sympathetic nerve activity (CSNA) that may contribute to the tachycardia have not been investigated, and the changes in renal SNA (RSNA) that may mediate the changes in renal blood flow and function are unclear. We therefore recorded CSNA and RSNA during septic shock in conscious sheep. Septic shock was induced by administration of Escherichia coli, which caused a delayed hypotension and an immediate, biphasic increase in heart rate (HR) associated with similar changes in CSNA. After E. coli, RSNA decreased for over 3 h, followed by a sustained increase (180%), whereas renal blood flow progressively increased and remained elevated. There was an initial diuresis, followed by oliguria and decreased creatinine clearance. There were differential changes in the range of the arterial baroreflex curves; it was depressed for HR, increased for CSNA, and unchanged for RSNA. Our findings, recording CSNA for the first time in septic shock, suggest that the increase in SNA to the heart is not driven solely by unloading of baroreceptors and that the increase has an important role to increase HR and cardiac output. There was little correlation between the changes in RSNA and renal blood flow, suggesting that the renal vasodilatation was mediated mainly by other mechanisms. acute renal failure; renal blood flow doi: 10.1152/ajpregu.00437.2009.

We previously showed that lysozyme (Lzm-S), derived from leukocytes, caused myocardial depression in canine sepsis by binding to the endocardial endothelium to release nitric oxide (NO). NO then diffuses to adjacent myocytes to activate the cGMP pathway. In a canine right ventricular trabecular (RVT) preparation, Lzm-S also decreased the inotropic response to field stimulation (FSR) during which the sympathetic and parasympathetic nerves were simulated to measure the adrenergic response. In the present study, we determined whether the pathway by which Lzm-S decreased FSR was different from the pathway by which Lzm-S reduced steady-state (SS) contraction. Furthermore, we determined whether the decrease in FSR was due to a decrease in sympathetic stimulation or enhanced parasympathetic signaling. In the RVT preparation, we found that the inhibitory effect of Lzm-S on FSR was prevented by NO synthase (NOS) inhibitors. A cGMP inhibitor also blocked the depressant activity of Lzm-S. However, in contrast to the Lzm-S-induced decline in SS contraction, chemical removal of the endocardial endothelium by Triton X-100 to eliminate endothelial NO release did not prevent the decrease in FSR. An inhibitory G protein was involved in the effect of Lzm-S, since FSR could be restored by treatment with pertussis toxin. Atropine prevented the Lzm-S-induced decline in FSR, whereas [[beta].sub.1]- and [[beta].sub.2]-adrenoceptor function was not impaired by Lzm-S. These results indicate that the Lzm-S-induced decrease in FSR results from a nonendothelial release of NO. NO then acts through inhibitory G protein to enhance parasympathetic signaling. adrenergic [beta]-receptors; septic shock; myocardial depression; sympathetic response

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions, particularly in septic shock. The intracellular mechanisms involved in the effect of ADM on adult rat ventricular myocytes are still to be elucidated. Ventricular myocytes were isolated from adult rats 4 h after an intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Membrane potential and L-type calcium current ([I.sub.Ca, L]) were determined using whole cell patch-clamp methods. APD in LPS group was significantly shorter than control values (time to 50% repolarization: LPS, 169 [+ or -] 2 ms; control, 257 [+ or -] 2 ms, P < 0.05; time to 90% repolarization: LPS, 220 [+ or -] 2 ms; control, 305 [+ or -] 2 ms, P < 0.05). [I.sub.ca,L] density was significantly reduced in myocytes from the LPS group (-3.2 [+ or -] 0.8 pA/pF) compared with that of control myocytes (-6.7 [+ or -] 0.3 pA/pF, P < 0.05). The ADM antagonist ADM-(22-52) reversed the shortened APD and abolished the reduction of [I.sub.Ca.L] in shock myocytes. In myocytes from control rats, incubating with ADM for 1 h induced a marked decrease in peak [I.sub.Ca,L] density. This effect was reversed by ADM-(22-52). The [G.sub.i] protein inhibitor, pertussis toxin (PTX), the protein kinase A (PKA) inhibitor, KT-5720, and the specific cyclo-oxygenase 2 (COX-2) inhibitor, nimesulide, reversed the LPS-induced reduction in peak [I.sub.Ca.L]. The results suggest a COX-2-involved PKA-dependent switch from [G.sub.s] coupled to PTX-sensitive [G.sub.i] coupling by ADM in adult rat ventricular myocytes. The present study delineates the intracellular pathways involved in ADM-mediated effects on [I.sub.Ca.L] in adult rat ventricular myocytes and also suggests a role of ADM in sepsis. pertussis toxin; protein kinase A inhibitor

A shock canine pneumonia model that permitted relief of discomfort with the use of objective criteria was developed and validated. After intrabronchial Staphylococcus aureus challenge, mechanical ventilation, antibiotics, fluids, vasopressors, sedatives, and analgesics were titrated based on algorithms for 96 h. Increasing S. aureus (1 to 8 x [10.sup.9] colonyforming units/kg) produced decreasing survival rates (P = 0.04). From 4 to 96 h, changes in arterial-alveolar oxygen gradients, mean pulmonary artery pressure, IL-1, serum sodium levels, mechanical ventilation, and vasopressor support were ordered based on survival time [acute nonsurvivors ([less than or equal to]24 h until death, n = 8) [greater than or equal to] subacute nonsurvivors (>24 to 96 h until death, n = 8) [greater than or equal to] survivors ([greater than or equal to] 96 h until death, n = 22) (all P < 0.05)]. In the first 12 h, increases in lactate and renal abnormalities were greatest in acute nonsurvivors (all P < 0.05). Compared with survivors, subacute nonsurvivors had greater rises in cytokines and liver enzymes and greater falls in platelets, white cell counts, pH, and urine output from 24 to 96 h (all P < 0.05). Importantly, these changes were not attributable to dosages of sedation, which decreased in nonsurvivors [survivors vs. nonsurvivors: 5.0 [+ or -] 1.0 vs. 3.8 [+ or -] 0.7 ml x [h.sup.-1] x [(fentanyl/midazolam/ medetomidine).sup.-l]; p = 0.02]. In this model, the pain control regimen did not mask changes in metabolic function and lung injury or the need for more hemodynamic and pulmonary support related to increasing severity of sepsis. The integration into this model of both specific and supportive titrated therapies routinely used in septic patients may provide a more realistic setting to evaluate therapies for sepsis. sepsis; dog; Staphylococcus aureus

Previous studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This response is mediated, in part, through circulating TNF-[alpha]-induced, nitric oxide-dependent, depression of basal myocyte contractility. Other mechanisms of early myocardial dysfunction involving decreased response to adrenergic stimulation may exist. This study evaluated the presence and nitric oxide dependence of impaired adrenergic response to TNF-[alpha] in in vitro cardiac myocytes. The contraction of electrically paced neonatal rat cardiac myocytes in tissue culture was quantified using a closed-loop video tracking system. TNF-[alpha] induced depression of baseline contractility over the first 20 min of cardiac myocyte exposure. This effect was blocked by N-methyl-arginine (NMA), a nitric oxide synthase inhibitor, in all studies. Contractile and cAMP response to increasing concentrations of isoproterenol was deficient in cardiac myocytes exposed to TNF-[alpha] regardless of the presence of NMA. In contrast, increasing concentrations of forskolin (a direct stimulant of adenylate cyclase) and dibutyryl cAMP (a metabolically active membrane-soluble analog of cAMP) completely reversed TNF-[alpha]-mediated depression, though only in the presence of NMA. Forskolin-stimulated cAMP generation remained intact regardless of NMA. Increasing concentrations of exogenous calcium chloride, unlike other inotropic agents, corrected TNF-[alpha]-mediated defects of contractility independent of the presence of NMA. These data suggest that TNF-[alpha] exposure is associated with a second nitric oxide-independent but calcium-dependent early depressant mechanism that is manifested by reduced contractile and cAMP response to [beta]-adrenergic stimulation. sepsis; septic shock; adrenoreceptor; myocardial depression; myocyte; heart; myocardial depressant substance; cytokine doi:10.1152/ajpregu.00146.2006

Arginine metabolism involves various organs such as the kidney, the intestines, and the liver, which act together in an interorgan axis. Major pathways for arginine production are protein breakdown and de novo arginine production from citrulline; disposal of arginine is mainly used for protein synthesis or used by the enzymes arginase and nitric oxide synthase (NOS). To assess in vivo organ arginine metabolism under normal conditions and during endotoxemia we used a mouse model, and analyzed for gender and strain differences. Male and female inbred FVB and C57BL6/J mice were anesthetized and catheterized to study whole body, gut, liver, renal and muscle metabolism, using a stable isotope infusion protocol. Animals were treated with saline or lipopolysaccharide. Plasma arginine levels tended to be higher in female mice, although levels were not significantly different from male mice (P = 0.09). Although not all significantly different, whole body arginine production and arginine clearance tended to be higher in C57BL6/J mice (P < 0.1), while citrulline (P = 0.05), NO (P = 0.08), and de novo arginine (P < 0.01) production were higher in FVB mice. During endotoxemia, NO production increased in general (P < 0.05), while whole body arginine clearance increased in FVB mice, but decreased in C57BL6/J mice (P < 0.01). At the organ level, portal-drained viscera (PDV) arginine metabolism was higher in FVB than in C57BL6/J mice (P < 0.05). During endotoxemia, liver arginine metabolism decreased in general (P < 0.05), while strain differences existed for PDV, muscle, and renal arginine metabolism. In conclusion, stable isotope techniques in multicatheterized mice allow measurements of arginine metabolism on whole body and organ level. Strain and gender differences are present in arginine metabolism under physiological conditions and during endotoxemia. J. Nutr. 134: 2768S-2774S, 2004. KEY WORDS: * arginine * gut * liver * muscle * kidney

Neutrophils can cause liver injury during endotoxemia through generation of reactive oxygen species. However, the enzymatic source of the oxidant stress and the nature of the oxidants generated remain unclear. Therefore, we investigated the involvement of NADPH oxidase in the pathophysiology by using the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) in the galactosamine/endotoxin (700 mg/kg Gal: 100 [micro]g/kg ET) model of liver injury. In addition, we measured chlorotyrosine as indicator for hypochlorous acid formation by myeloperoxidase. Gal/ET treatment of male C3HeB/FeJ mice resulted in sinusoidal neutrophil accumulation and parenchymal cell apoptosis (14 [+ or -] 3% of cells) at 6 h. At 7 h, 35% of neutropbils had transmigrated. The number of apoptotic cells increased to 25 [+ or -] 2%, and the overall number of dead cells was 48 [+ or -] 3%; many of them showed the characteristic morphology of necrosis. Hepatocytes, which colocalized with extravasated neutrophils, stained positive for chlorotyrosine and 4-hydroxynonenal (4-HNE) protein adducts. In contrast, animals pretreated with DPI (2.5 mg/kg) were protected against liver injury at 7 h (necrosis = 20 [+ or -] 2%). These livers showed little chlorotyrosine or 4-HNE staining, but apoptosis and neutrophil accumulation and extravasation remained unaffected. However, DPI-treated animals showed serious liver injury at 9 h due to sustained apoptosis. The results indicate that NADPH oxidase is responsible for the neutrophil-derived oxidant stress, which includes formation of hypochlorous acid by myeloperoxidase. Thus NADPH oxidase could be a promising c therapeutic target to prevent neutrophil-mediated liver injury. However, the long-term benefit of this approach needs to be investigated in models relevant for human liver disease. chlorotyrosine protein adducts; apoptotic cell death; diphenyleneiodonium chloride; neutrophil-induced liver injury; 4-hydroxynonenal

Byline: Ahmad D. Chishti (1), Brian K. Shenton (1), John A. Kirby (1), Simon V. Baudouin (1,2) Keywords: Septic shock; Neutrophil leukocyte; Chemokine; Chemotaxis; Interleukin-8; Chemokine receptor Abstract: Objective To examine the hypothesis that neutrophil chemotaxis to interleukin-8 (IL-8) is reduced in septic shock. Surface expression of neutrophil CXC chemokine receptors and the adhesion molecule CD11b were also examined and associations between disease severity, gas exchange and receptor expression were studied. Design Prospective cohort clinical study. Setting Intensive care unit in a tertiary referral teaching hospital. Patients Patients with septic shock (n=15) and healthy controls (n=8) were studied. Measurements and results Daily (for 5 consecutive days) flow cytometric measurements of chemokine and [beta] integrin surface expression. 'In vitro' neutrophil chemotaxis to IL-8 was also compared between patients with sepsis and healthy controls. CXCR2 expression significantly fell, CD11b expression increased and CXCR1 expression was unchanged throughout the study in the septic group compared with healthy controls. CD11b positively correlated with increasing APACHE II scores (p Conclusions Surface expression of the chemokine receptor CXCR2 and the [beta]-integrin CD11b, but not CXCR1, were reduced on neutrophils isolated from patients with septic shock compared with healthy controls. Chemotaxis to IL-8 was also reduced in neutrophils from septic patients compared with healthy controls. The changes in receptor expression correlated with measures of disease severity. Author Affiliation: (1) University Departments of Reproductive and Surgical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE1 7RU, UK (2) Department of Anaesthesia and Intensive Care, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK Article History: Registration Date: 09/01/2004 Received Date: 17/07/2003 Accepted Date: 31/12/2003 Online Date: 28/02/2004

Byline: Martijn Poeze (1), Barbara C. J. Solberg (1), Jan Willem M. Greve (1), Graham Ramsay (1) Keywords: Intestinal ischemia; Gastric intramucosal carbon dioxide partial pressure; l-Lactate; d-Lactate; Septic shock Abstract: Objective Intestinal ischemia causes an increase in lactate production and gastric intramucosal carbon dioxide partial pressure (PgCO.sub.2). However, no linear relationship between systemic l-lactate levels and gastric tonometry during intestinal ischemia has been found, probably since l-lactate is rapidly cleared from the circulation by the liver. In contrast, the rate of d-lactate clearance from the circulation by the liver is considerably lower than that of l-lactate, and d-lactate may therefore be more closely related to measurements of gastric tonometry than l-lactate values. Design and setting Prospective, observational study in a university-affiliated mixed intensive care unit. Subjects Twenty critically ill patients with septic shock. Measurements and results During the first 24 h of admission to the intensive care unit at least two blood samples were taken for d- and l-lactate measurements and arterial blood gases, Simultaneously, gastric PgCO.sub.2 was measured using capnographic tonometry. The intramucosal-arterial PCO.sub.2 gap was calculated using gastric intramucosal PgCO.sub.2 and arterial PCO.sub.2 from arterial blood. d-Lactate was significantly correlated to PgCO.sub.2 values and to the mucosal-arterial PCO.sub.2 gap. There was no relationship between l-lactate and PgCO.sub.2 or the mucosal-arterial PCO.sub.2 gap. d-lactate and l-lactate values were significantly correlated. Conclusions During sepsis intestinal production of d-lactate is related to gastric intramucosal PCO.sub.2. No such relationship was found between l-lactate values and PgCO.sub.2 Author Affiliation: (1) Department of Surgery and Intensive Care Medicine, University Hospital Maastricht, Maastricht, The Netherlands Article History: Received Date: 14/02/2003 Accepted Date: 16/07/2003 Online Date: 08/10/2003

Leptin deficiency in ob/ob mice increases susceptibility to endotoxic shock, whereas leptin pretreatment protects them against LPS-induced lethality. Lack of the long-form leptin receptor (Ob-Rb) in db/db mice causes resistance. We tested the effects of LPS in C57BL/6J [db.sup.3J]/ [db.sup.3J] (BL/3J) mice, which express only the circulating leptin receptors, compared with C57BL/6J db/db (BL/6J) mice, which express all short-form and circulating isoforms of the leptin receptor. Intraperitoneal injections of LPS significantly decreased rectal temperature and increased leptin, corticosterone, and free TNF-[alpha] in fed and fasted BL/3J and BL/6J mice. TNF-[alpha] was increased three- and fourfold in BL/3J and BL/6J, respectively. LPS (100 [micro]g) caused 50% mortality of fasted BL/6J mice but caused no mortality in fasted BL/3J mice. Pretreatment of fasted BL/3J mice with 30 [micro]g leptin prevented the drop in rectal temperature, blunted the increase in corticosterone, but had no effect on TNF-[alpha] induced by 100 [micro]g LPS. Taken together, these data provide evidence that fasted BL/3J mice are more resistant than BL/6J mice to LPS toxicity, presumably due to the absence of leptin receptors in BL/3J mice. This resistance may be due to high levels of free leptin cross-reacting with other cytokine receptors. tumor necrosis factor-[alpha]; leptin receptor; lipopolysaccharides

Free radicals have been implicated in the etiology of cardiac dysfunction during sepsis, but the actual species responsible remains unclear. We studied the alterations in myocardial nitric oxide (NO), superoxide, and peroxynitrite generation along with cardiac mechanical function and efficiency in hearts from lipopolysaccharide (LPS)-treated rats. Six hours after LPS (4 mg/kg ip) or saline (control) treatment, hearts were isolated and perfused for 1 h with recirculating Krebs-Henseleit buffer and paced at 300 beats/min. Cardiac work, [O.sub.2] consumption, and cardiac efficiency were markedly depressed in LPS hearts compared with controls. Plasma nitrate/nitrite level was elevated in LPS rats, and ventricular NO production was enhanced as measured by electron spin resonance spectroscopy, [Ca.sup.2+]-independent NO synthase (NOS) activity, and inducible NOS immunohistochemistry. Ventricular superoxide production was also enhanced in LPS-treated hearts as seen by lucigenin chemiluminescence and xanthine oxidase activity. Increased nitrotyrosine staining (immunohistochemistry) and higher lipid hydroperoxides levels were also detected in LPS-treated hearts, indicating oxygen radical-induced stress. Enhanced generation of both NO and superoxide, and thus peroxynitrite, occur in dysfunctional hearts from endotoxemic rats. sepsis; cardiac dysfunction; nitric oxide; superoxide and peroxynitrite

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two mediators synthesized by immune cells, specially under inflammatory and antigen stimulation conditions. Reports have shown that neuropeptides attenuate the deleterious consequences of septic shock both by down-regulating the production of proinflammatory mediators and by stimulating the production of anti-inflammatory cytokines by activated macrophages. In this study, we used a knockout for the PACAP receptor ([PAC1.sup.-/-]) to demonstrate an important protective role for PAC1 receptor in endotoxic shock. Moreover, our results indicate that PAC1 receptor acts in vivo as an anti-inflammatory receptor, at least in part, by attenuating lipopolysaccharide (LPS)induced production of proinflammatory IL-6, which appears to be the main cytokine regulating the expression of the majority of the acute phase protein genes, which are an important deleterious component of septic shock. Besides, our findings point to endogenously produced VIP and PACAP as participants of the natural anti-inflammatory machinery. Because VIP and PACAP are two attractive candidates for the development of therapies against acute and chronic inflammatory diseases, septic shock, and autoimmune diseases, this paper represents a contribution to the understanding of the mechanism of action of these anti-inflammatory agents.

Byline: Guenther Fischer (1), Elisabeth Schneider (2), Lyle L. Moldawer (3), Christian Karcher (1), Eberhard Barth (1), Heidemarie Suger-Wiedeck (1), Michael Georgieff (1), Manfred Weiss (1) Keywords: Granulocyte colony-stimulating factor Sepsis Shock, septic CD64 Neutrophils Abstract: Objective: To clarify the changes in total leukocyte counts, CD64 neutrophil receptor expression and serum granulocyte colony-stimulating factor (G-CSF) concentrations in critically ill patients without infection and sepsis and in patients with septic shock. Design: Prospective study. Setting: Intensive care unit (ICU) and research laboratory of a university hospital. Patients: Eleven critically ill patients without infections and 22 patients with proven infections in septic shock for the first time and of at least 3 days' duration. Measurements and results: Over a 6month period, a longitudinal analysis of expression of the monomeric Fc receptor type I (CD64, FcI3RI) on neutrophils was performed by flow cytometric analysis on a daily basis in all postoperative/post-traumatic patients admitted to the ICU until discharge from the ICU or death. Out of 273 patients, 11 patients without sepsis had organ failure and 22 patients with proven infections had septic shock for the first time and of at least 3 days' duration. Ten out of the 22 patients survived, 12 died. CD64 expression was greater in patients with septic shock than in patients without sepsis. Moreover, CD64 expression was only initially and transiently elevated in most survivors (9/10) and non-survivors (8/12) of septic shock. In survivors, G-CSF serum concentrations were markedly decreased in the 2nd week. Conclusions: Decreased neutrophil CD64 expression in an acutely ill population with septic shock may reflect the development of a non-responsive state as well as the early downregulation of neutrophil activation prior to the resolution of an ongoing infection. Author Affiliation: (1) Universitaetsklinik fur Anaesthesiologie, Universitaetsklinikum fur Anaesthesiologie, Steinhoevelstrasse 9, 89075 Ulm, Germany (2) Universitaetsklinik fur Experimentelle Anaesthesiologie, Universitaetsklinikum fur Anaesthesiologie, Steinhoevelstrasse 9, 89075 Ulm, Germany (3) Department of Surgery, University of Florida College of Medicine, Gainesville FL 32610, USA Article History: Received Date: 02/02/2001 Accepted Date: 12/09/2001 Article note: Final revision received: 16 July 2001 Electronic Publication

Byline: R. Matyal (1), Y. Vin (1), R. Delude (1), C. Lee (1), A. Creasey (2), M. Fink (1) Keywords: Peritonitis Coagulation Escherichia coli Disseminated intravascular coagulation Tissue factor pathway inhibitor Abstract: Objective: We sought to determine the lowest dose of recombinant human tissue factor pathway inhibitor (TFPI) that can provide protection from lethality in a rabbit model of septic shock. Methods: Sepsis was induced in New Zealand white rabbits by intraperitoneal implantation of 7.0 ml of a solution containing hemoglobin (4.8 g/dl), porcine mucin (6 g/dl), and 0.8--1.4x10.sup.4 viable Escherichia coli (strain O:18 K+). Gentamicin (5 mg/kg) was administered 4 h following surgery, and this dose was repeated every 12 h for 3 days. Beginning 4 h following the induction of sepsis, animals were treated with a bolus (1 ml) plus a continuous infusion (100 ml over 24) of either TFPI (various doses) or its vehicle. Four different doses of TFPI were studied, and each experiment included a contemporaneous control group. The primary outcome parameter was survival time. Results were analyzed using the Wilcoxen log rank test. Results: The average survival time for rabbits treated with the highest dose of TFPI tested (50 Aug/kg bolus and 0.5 Aug/kg per minute infusion) was 118 h, as compared to 81 h in vehicle-treated controls). The average survival time for septic rabbits treated with a much lower dose of TFPI (100 ng/kg bolus and 1.0 ng/kg per minute infusion) was 119 h as compared to 57 h in surviving vehicle-treated controls. Treatment with an even lower dose of TFPI (10 ng/kg bolus and 0.1 ng/kg per minute infusion) still produced a marginally significant prolongation of average survival time (80 h) relative to contemporaneously studied controls (47 h). When the dose of TFPI was decreased still further (1.0 ng/kg bolus and 0.01 ng/kg per minute infusion), average survival times were not significantly different between TFPI-treated and vehicle-treated rabbits (77 and 51 h, respectively). Conclusions: Delayed infusion with remarkably low doses of recombinant human TFPI prolongs survival in a rabbit model of antibiotic-treated Gram-negative bacterial sepsis. In planning human trials of TFPI as an adjuvant treatment for sepsis it may be reasonable to use much lower doses of the agent than were heretofore contemplated. Author Affiliation: (1) Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA (2) Chiron Corporation, Emeryville, CA 94608, USA (3) Mailing address: Division of Crit Care Med, 616 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA Article History: Received Date: 28/06/2000 Accepted Date: 30/04/2001 Article note: Final revision received: 4 April 2001 Electronic Publication

Byline: C. Venet (1), F. Zeni (1), A. Viallon (1), A. Ross (2), P. Pain (1), P. Gery (1), D. Page (1), R. Vermesch (1), M. Bertrand (1), F. Rancon (1), J. C. Bertrand (1) Keywords: Key words Endotoxaemia; Severe sepsis; Septic shock; Clinical study; Outcome; Bacteraemia; Gram-negative bacteria infection Abstract: Objective: To examine the incidence and the bacteriological and clinical significance of endotoxaemia in ICU patients with severe sepsis or septic shock. Design: Prospective review. Setting: A 15-bed general ICU in a university hospital. Patients: One hundred sixteen patients hospitalised in our ICU fulfilling Bone's criteria for severe sepsis or septic shock and with an available early endotoxin assay (chromogenic limulus assay). Interventions: None. Measurements and results: The clinical characteristics of the population were: age 63.6 +- 11.4 years SAPS II: 45.4 +- 15.6 mechanical ventilation: 72.4 % septic shock: 51.7 % (n = 60) bacteraemia: 28.4 % (n = 33) gram-negative bacteria (GNB) infection 47.4 % (n = 55) ICU mortality: 39.6 % (n = 46). Detectable endotoxin occurred in 61 patients (51.2 % mean level: 310 +- 810 pg/ml). There was no relationship between detectable endotoxin and severity of infection at the moment of the assay. Endotoxaemia was associated with a higher incidence of bacteraemia (39.3 % vs 16.3 % p = 0.01). There was a trend (p = 0.09) towards an association between positive endotoxin and gram-negative bacteraemia or GNB infection but this was non-significant. This relationship became significant only in the case of bacteraemia associated with GNB infection irrespective of the site of infection. Conclusion: Early detection of endotoxaemia appeared to be associated with GNB infection only in cases of bacteraemic GNB infection. Early endotoxaemia correlated neither to occurrence of organ dysfunction nor mortality in patients with severe sepsis or septic shock. This study suggests that the use of endotoxaemia as a diagnostic or a prognostic marker in daily practice remains difficult. Author Affiliation: (1) Intensive Care Unit, Hopital Bellevue, Boulevard Pasteur, F-42055 Saint-Etienne Cedex 2, France, FR (2) Department of Microbiology, Hopital Nord, F-42055 Saint-Etienne Cedex 2, France, FR Article note: Received: 28 September 1999 Final revision received: 31 January 2000 Accepted: 1 February 2000

Byline: M. -A. Dugas (1), F. Proulx (1), A. de Jaeger (1), J. Lacroix (1), M. Lambert (1) Keywords: Key words Sepsis; Lactate; Pyruvate; Ketone bodies; Carnitine; Gastric mucosa; Child Abstract: Objective: To describe measurements of global oxygenation parameters, markers of splanchnic hypoperfusion and those of metabolic activity related to cellular energy production among critically ill children with septic shock.APDesign: Clinical study of a series of cases.APPatients and participants: 11 previously healthy children with septic shock admitted to the pediatric intensive care unit (ICU) of a university hospital.APInterventions: None.APMeasurements and results: Oxygen consumption, oxygen delivery (DO.sub.2), serum bicarbonate, arterial pH, gastric intramucosal pH (pHi), gastroarterial carbon dioxide tension gradient, serum lactate, pyruvate, lactate to pyruvate ratio (L/P), ketone body ratio, and the esterified to free carnitine ratio were measured serially at 0, 6, 12, 24, 36, and 48 h after admission to the pediatric ICU. All children survived. One patient failed to show supranormal DO.sub.2 ( > 570 ml/min per m.sup.2). Normalization of serum bicarbonate and lactate were associated with patient recovery. One patient presented an increasingly abnormal L/P ratio with normal lactate levels, suggesting an increased utilization of pyruvate rather than an increased cytosolic redox potential. Although values of gastric pHi < 7.30 were observed in 43 % of samples, serial measurements in individuals showed significant variability and unpredictable trends. Free fatty acid concentrations, ketone body production, and carnitine levels remained within the normal range.APConclusions: In this study, trends in serum bicarbonate and lactate somewhat characterized the recovery of children with septic shock. Based on our data, it is unclear how other markers may have been used to modify therapy. Author Affiliation: (1) Department of Pediatrics, Section of Pediatric Intensive Care Unit, Sainte-Justine Hospital, University of Montreal, Montreal, Canada, H3T 1C5 Tel.: + 1-5 14-3 45-46 75 Fax: + 1-5 14-3 45-48 22, CA Article note: Received: 14 May 1999/Final revision received: 5 September 1999/Accepted: 24 September 1999

Changes in beta2-adrenergic receptor (beta2-AR) gene expression in the rat liver during various phases of sepsis were investigated. Septic rats showed two metabolically distinct phases: an initial hyperglycemic followed by a hypoglycemic phase. Results showed that the transcriptional and posttranscriptional regulation of beta2-AR gene related with decreases in beta2-AR number and its protein expression may offer a molecular mechanistic explanation for the development of hypoglycemia during the late stage of sepsis.

Author(s): Pierre Asfar [sup.1], Peter Radermacher [sup.2], Marlies Ostermann [sup.3] Author Affiliations: (1) 0000 0001 2248 3363, grid.7252.2, Département de Médecine Intensive-Réanimation, Centre Hospitalo Universitaire Angers, , 49933 cedex 9, [...]

The function of the endotoxin lipopolysaccharide (LPS) and nitric oxide in hepatic oxygen metabolism was studied in 36 pigs receiving the non-selective inhibitor of NO synthase activity, N(super G)-nitro-L-arginine methyl ester (L-NAME). Results showed that L-NAME has detrimental circulatory effects in the above model. However, neither endotoxin nor L-NAME appeared to inhibit the ability of the still circulated parts of the liver to raise the hepatic oxygen extraction ratio to almost maximum when oxygen delivery was decreased.

The effect of subcutaneous injection of lipopolysaccharide on the synthesis of the acute phase proteins complement C3 and serum amyloid A and the synthesis of messenger RNA for these proteins was investigated in mouse jejunal mucosa using enzyme-linked immunosorbent assay, Northern blot and competitive polymerase chain reaction. Results reveal that endotoxemia increases the expression of these acute phase proteins probably via transcriptional activation.

Rats exhibiting lipopolysaccharide (LPS)-induced hypotension were analyzed to determine the effects of heat shock protein induction and nitric oxide synthase (iNOS) inhibition on hypotension. LPS-induced hypotension and vasoplegia were mediated by NO synthetic pathway and iNOS activity. Furthermore, LPS-vasoplegia in rats were inhibited by the expression of HSP 70, heme oxygenase-1 and inhibition of NO synthetic pathway or iNOS activity.

The role of glycine in the treatment of lipopolysaccharide (LPS)-induced endotoxin shock was investigated in a model using rats fed a glycine diet. Rats fed control diet died 24 hrs. after injection of LPS, whereas rats fed a glycine diet survived endotoxin shock. It is suggested that glycine feeding reduced the deleterious effects of LPS such as elevation of serum transaminase levels, hepatic necrosis, and lung and liver injury.

The cardiac effects of nitric oxide synthase inhibitor N(super omega)-nitro-L-arginine (L-NNA) in endotoxemia are the reduction of the endotoxin-induced decrease in contractility and impairment of function. Nitric oxide causes a decrease in left ventricular contractility in the intact animal. Nitric oxide synthase inhibition enhances right and left ventricular afterloads, which damages cardiac function. Pretreatment of the pigs with L-NNA raises pulmonary arterial pressure and prevents reduction in mean arterial pressure.

Fluid resuscitation during treatment of septic shock may have some negative effects on systemic arterial mechanical properties, which are already compromised by bacterial endotoxins. Rabbits treated with endotoxin alone had elevated total peripheral resistance (TPR), lowered cardiac output and increased cardiac impedance. Rabbits treated with both endotoxin and and fluid resuscitation had decreased TPR, somewhat increased cardiac output and a lesser rise in cardiac impendence.

Systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock may represent increasingly severe stages of the body's inflammatory response to infection. During a nine-month period, researchers reviewed the medical records of 3,708 adults who were admitted to one of six hospital wards. Of these, 2,527 patients had at least two symptoms of SIRS. Within the 28-day follow-up period, 26% of the patients with SIRS symptoms developed sepsis, 18% developed severe sepsis, and 4% developed septic shock. Forty-four percent of the patients with sepsis, 58% of patients with severe sepsis, and 71% of patients with septic shock had progressed from a milder stage of inflammatory response to a more serious stage. The patients' rates of positive blood cultures for bacteria, end-organ failures, and death increased with each progressive stage of the body's inflammatory response to infection., Objective. - Define the epidemiology of the four recently classified syndromes describing the biologic response to infection: systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock. Design. - Prospective cohort study with a follow-up of 28 days or until discharge if earlier. Setting. - Three intensive care units and three general wards in a tertiary health care institution. Methods. - Patients were included if they met at least two of the criteria for SIRS: fever or hypothermia, tachycardia, tachypnea, or abnormal white blood cell count. Main Outcomes Measures. - Development of any stage of the biologic response to infection: sepsis, severe sepsis, septic shock, end-organ dysfunction, and death. Results. - During the study period 3708 patients were admitted to the survey units, and 2527 (68%) met the criteria for SIRS. The incidence density rates for SIRS in the surgical, medical, and cardiovascular intensive care units were 857, 804, and 542 episodes per 1000 patient-days, respectively, and 671, 495, and 320 per 100 patient-days for the medical, cardiothoracic, and general surgery wards, respectively. Among patients with SIRS, 649 (26%) developed sepsis, 467 (18%) developed severe sepsis, and 110 (4%) developed septic shock. The median interval from SIRS to sepsis was inversely correlated with the number of SIRS criteria (two, three, or all four) that the patients met. As the population of patents progressed from SIRS to septic shock, increasing proportions had adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, and shock. Positive blood cultures were found in 17% of patients with sepsis, in 25% with severe sepsis, and in 69% with septic shock. There were also stepwise increases in mortality rates in the hierarchy from SIRS, sepsis, severe sepsis, and septic shock: 7%, 16%, 20%, and 46%, respectively. Of interest, we also observed equal numbers of patients who appeared to have sepsis, severe sepsis, and septic shock but who had negative cultures. They had been prescribed empirical antibiotics for a median of 3 days. The cause of the systemic inflammatory response in these culture-negative populations is unknown, but they had similar morbidity and mortality rates as the respective culture-positive populations. Conclusions. - This prospective epidemiologic study of SIRS and related conditions provides, to our knowledge, the first evidence of a clinical progression from SIRS to sepsis to severe sepsis and septic shock.

Anesthetized endotoxemic rats are used to examine organ perfusion and accumulation of high-energy phosphates (ATP and creatine phosphate (Crp)) of kidney, heart, skeletal muscle and liver, and to analyze the influence of improving organ blood flow and cardiac output (CO) with two cardiostimulatory drugs, dobutamine (DB) and dopexamine (DX). The amount of high-energy phosphates decreases in all the four organs during endotoxin shock. The decrease is maximum in renal and hepatic blood flow. CrP is revived in skeletal muscle, heart and kidney by DX and DB.

Metabolism of all vasoconstrictors is presented by endotoxemia, with the exception of neuropeptide Y, NPY. Hemodynamics is enhanced when NPY is constantly injected in an endotoxin-stimulated shock process. Norepinephrine (NE) is added in large amounts, but does not produce the same reaction. Alpha-adrenergic functions control a portion of NPY action, probably through the influence of endogenous catecholamines by NPY. Rats with a lethal dose of lipopolysaccharide, accept the injection of lower pressor doses of NPY.

The effects of endotoxin shock on endothelial structure and the function of large arteries were studied using rat cremaster muscles. Arteriolar endothelia of cremaster muscles showed minimal adverse effects and vasodilation upon adminstration of acetylcholine (ACh). Nitric oxide (NO) antagonist hydroquinone was also observed to partially inhibit ACh postendotoxin and extend the survival of endotoxin-treated rats by blocking effects of inducible NO synthase.

The effect of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1alpha (IL-1a) on cardiopulmonary function were examined. Eicosanoid mediation in cardiopulmonary dysfunction induced by TNF-alpha and IL-1a was also studied in cytokine-infused pigs pretreated with 5-lipoxygenase inhibitor (CGS 8515) and cyclooxygenase inhibitor. TNF-alpha and IL-1alpha coinfusion triggered synergistic physiological reactions and CGS 8515 and cyclooxygenase inhibitor acted as mediators in cardiopulmonary dysfunction.

Elevated blood somatostatin level in the early stages of endotoxicosis in the rat causes an initial hyperglycemia which can correct the hypoglycemia that occurs in the more advanced stages of septic shock. This was confirmed in blocking studies using control, endotoxin-treated and blocker-endotoxin-treated rats. Results imply that somatostatin has an important function in the regulation of blood glucose concentration in septic shock.