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Left ventricular electromechanical dyssynchrony and mortality in cardiothoracic intensive care Academic research paper on "Health sciences"
33rd International Symposium on Intensive Care and Emergency Medicine
Brussels, Belgium, 19-22 March 2013 Published: 19 March 2013
Protective role of autophagy in mouse cecal ligation and puncture-induced sepsis model
W Takahashi1, H Hatano2, H Hirasawa1, S Oda1
'Graduate School of Medicine, Chiba University, Chiba, Japan; 2Biomedical
Research Center, Chiba University, Chiba, Japan
Critical Care 2013, 17 (Suppl 2): P1 (doi: 10.1186 / cc11939)
Introduction Autophagy is well known as one of the biogenic responses against various stresses, which possesses the beneficial roles for survival, but little is known about the dynamics and its significance during the septic condition. We hypothesized that autophagy is induced during the septic condition, and contributes to protect from tissue damage which subsequently leads to organ dysfunction. We confirm whether the autophagic process is accelerated or sustained in an acute phase of sepsis and we also determine its physiological role. Methods Sepsis was induced by cecal ligation and puncture (CLP) in mice. We examined the kinetics of autophagosome and autol ysosome formation which may explain the status of autophagy by western blotting, immunohistochemistry, and electron microscopy. To investigate a precise role of autophagy in CLP-induced sepsis, chloroquine, an autophagy inhibitor, was administered to the CLp-operated mice, and blood chemistry, pathology of the liver and survival were evaluated. Results Autophagy demonstrated by the ratio of LC3-II / LC3-I was induced over the time course up to 24 hours after CLP. The ratio was particularly increased in the liver, heart and spleen. Autophagosome formation became maximal at 6 hours and declined by 24 hours after CLP. Autolysosome formation as evaluated by both fusion of GFP-LC3 dots with LAMP1 immunohistochemistry and electron microscopy was also increased after the procedure. Furthermore, inhibition of autophagy by chloroquine during the CLP procedure resulted in elevation of serum AST levels, and significantly increased mortality in mice.
Conclusion Autophagy was induced in several organs over the time course of the CLP sepsis model and then the process was gradually completed to degradation of the components. Our data suggest autophagy plays a protective role in organ dysfunction in sepsis.
Reversible depressive effect of TNFa on a model of isolated perfused rat heart
BV Nguyen1, M Guillouet2, MA Giroux-Metges2, G Gueret3, M Ould-Ahmed1, JP Pennec2
'Hôpital d'Instruction des Armées Clermont Tonnerre, Brest, France; 2 Laboratory of Physiology, Faculty of Medicine, Brest, France; 3University Hospital, Brest, France
Critical Care 2013, 17 (Suppl 2): P2 (doi: 10.1186 / cc11940)
Introduction Acute myocardial depression in septic shock is common . Myocardial depression is mediated by circulating depressant substances, which until now have been incompletely characterized .
BiOlKled Central © 2013 BioMed Central Ltd
The aim of our study was to observe the effects of TNFa on the model of perfused rat heart.
Methods After profound anesthesia with pentothal, the Wistar rats were killed by exsanguination. After sternotomy, the heart was taken and connected to the Langendorf column. The apex of the heart was hooked to a strength sensor. Biopac student laboratory software was used to record and analyze heart contractions. Contractions were recorded every 5 minutes during periods of 20 minutes. Control measurements were first recorded. We measured four parameters: heart rate, contraction force, speeds of contraction and relaxation for control, during TNFa (20 ng / ml) exposure and after removal of TNFa. We express the variations of parameters as percentage of the control ± SEM. A paired t test was used to compare heart rate, contraction amplitude, speeds of contraction and relaxation with TNFa and control measurements and after removal of TNFa. Results Eight rat hearts Wistar (weight = 325 ± 23 g) were studied. See Table 1.
Table 1 (abstract P2)
TNFa Removal of TNFa
Heart rate 78 ± 6 * 91 ± 5
Contractile 62 ± 8 * 91 ± 4
Speed of contraction 72 ± 6 * 93 ± 2
Speed of relaxation 53 ± 10 * 89 ± 4
Results expressed as percentage of control ± SEM. * P <0.05.
Conclusion TNFa decreases significantly the heart rate, contractile force, speeds of contraction and relaxation on isolated perfused rat heart. TNFa probably plays a role in the pathophysiology of cardiomyopathy during septic shock. The partial reversibility of these effects could explain why left ventricular hypokinesia in patients with septic shock is reversible. References
1. Vieillard-Baron A, et al .: Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 2008, 36: 1701-1706.
2. Hunter JD, et al .: Sepsis and the heart. Br J Anaesth 2010, 104: 3-11.
Effect of cdp-choline on microcirculatory alterations during endotoxemia
K Schmidt1, M Doerr1, T Brenner1, S Hofer1, A Walther2 'Universitatsklinikum Heidelberg, Germany; 2Klinikum Stuttgart, Clinic for Anesthesiology and Operative Intensive Care Medicine, Stuttgart, Germany Critical Care 2013, 17 (Suppl 2): P3 (doi: 10.1186 / cc11941)
Introduction The cholinergic anti-inflammatory pathway (CAP) is a physiological mechanism that inhibits cytokine production and minimizes tissue injury during inflammation. CAP-mediated anti-inflammatory signals in vagal efferent nerve fibers result in the release of acetylcholine, which interacts with innate immune cells that express the nicotinic acetylcholine receptor subunit a7 (a7nAChR).
Endothelial dysfunction during sepsis is responsible for increased endothelial permeability, leukocyte-endothelial interaction and functional breakdown of microvascular perfusion. Endotoxemia-induced endothelial dysfunction can be reduced by cholinergic CAP activation . The aim of this study was to determine the effects of the a7nAChR-agonist cdp-choline on microcirculatory alterations during experimental endotoxemia.
Methods Using fluorescent intravital microscopy, we determined venular wall shear rate, macromolecular efflux and leukocyte adhesion in mesenteric postcapillary venules of male Wistar rats. Endotoxemia was induced over 120 minutes by intravenous infusion of lipopolysaccharide (LPS). Control groups received an equivalent volume of saline. Cdp-choline was applied as an i.v. bolus in treatment groups. Animals received either (i) saline alone, (ii) cdp-choline 10 minutes prior to saline administration, (iii) cdp-choline 10 minutes prior to LPS administration, (iv) cdp-choline 30 minutes after LPS administration or (v) LPS alone.
Results There were no significant differences in venular wall shear rate between the groups after 120 minutes. There was no significant difference in the number of adhering leukocytes between the cdp-choline / LPS groups (iii, iv) and the LPS group after 120 minutes. Macromolecular efflux significantly increased in all groups over 120 minutes. All groups (i, ii, iii, iv) showed a significantly reduced macromolecular efflux compared with the LPS group after 120 minutes. Conclusion Cdp-choline has no effect on leukocyte-endothelial interaction and microhemodynamic alterations during endotoxemia. By activating the CAP, cdp-choline reduces capillary leakage. Thus cdp-choline might have a prophylactic and therapeutic anti-inflammatory effect on LPS-induced endothelial permeability. These findings identify the endothelium as a target of anti-inflammatory cholinergic mediators and cdp-choline as a potential therapeutic substance in sepsis treatment. Reference
1. Peter C, et al .: Shock 2010, 33: 405-411. P4
Immune response after stimulation with wall components of Gram-positive bacteria
S Aloizos1, E Tsigou2, P Myrianthefs2, S Gourgiotis1, A Tsakris3, G Baltopoulos2 'NIMTS Hospital, Athens, Greece; 2A. Anargiroi Hospital, Athens, Greece; 3MedicalSchool, Athens, Greece
Critical Care 2013, 17 (Suppl 2): P4 (doi: 10.1186 / cc11942)
Introduction The purpose of this study was to evaluate the immune response of patients susceptible to infection by Gram-positive bacteria after ex vivo provocation with lipoteichoic acid (LTA) and to compare the reaction with the one of healthy adults.
Methods Blood sample was obtained from 10 healthy volunteers, 10 hemodialysis patients with end-stage chronic renal failure (CRF), 10 patients with type II diabetes mellitus (DM) and 10 ICU patients on the second day of hospitalization, who suffered nonseptic SIRS and had an APACHE II score> 25. After suitable treatment the samples were incubated with 1 mg LTA for 8 hours and maintained at -20 ° C until the measurement of cytokines TNFa, IL-6, IL-1P, and IL-10, using the ELISA method. The results are presented as mean values ± SEM. Graph Pad 4.0 was used, applying a t test to test the variation of each cytokine in each group, and ANOVA to assess the differences between the four groups. Results Baseline cytokine values in the three groups were increased compared with the control group, but the difference was significant only for the ICU group (Table 1, data only for IL-6 and IL-10). The quotient IL-10 / IL-6 of baseline values was between 0.23 and 0.96 among healthy, ESRD and DM persons, and 1.32 among ICU patients. In all examined groups the levels of cytokines increased significantly after stimulation with LTA, although ICU patients showed a differential
Table 1 (abstract P4). Levels of cytokines before and after stimulation with LTA Control baseline LTA ESRD baseline LTA
response (a fivefold to ninefold rise compared with other groups who had an increase of 14-fold to 36-fold).
Conclusion Severely ill patients and secondarily hemodialysis and diabetic patients are in a proinflammatory state. The response of all examined groups to provocation by LTA was sufficient, with a differential expression of severely ill patients, a fact that reflects their different immunologic status.
Correlation of the oxygen radical activity and antioxidants and severity in critically ill surgical patients: preliminary report
J Lee1, H Shim2, JY Jang1
'Yonsei University College of Medicine, Seoul, South Korea; 2Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea Critical Care 2013, 17 (Suppl 2): P5 (doi: 10.1186 / cc11943)
Introduction In septic patients, the oxygen radical (OR) showed toxic effect to induce inflammation and antioxidant activity could affect organ dysfunction. This study was designed to determine the relationship between antioxidant level and severity of organ dysfunction. Methods The medical records of adult patients managed in a surgical ICU from August 2012 to December 2012 were reviewed prospectively. Abstracted data included age, body weight (with BMI), APACHE II scores, SOFA scores, MODS scores, fluid intake, fluid output, nutritional support, shock, antioxidant levels, OR activities, zinc and selenium levels, complication and mortality. In addition, length of stay (LOS) in the ICU and in hospital, and in-hospital mortality were collected. These data were investigated on the first, the third and the seventh day, respectively.
Results A total of 13 patients were enrolled. The in-hospital mortality rate was 7.7% and mean LOS in the ICU and hospital was 6.5 and 27.6, respectively. Mean APACHE II score was 20.2. On the first day of ICU, the mean antioxidant level and OR were 1.5 (± 0.5) mmol / l and 1.6 (± 0.5) mmol / l, respectively. At the same time, SOFA and MODS scores were 7.3 and 5.0, respectively, and zinc and selenium were 32.6 pg / dl and 68.4 ng / ml. On the third day, mean antioxidant and OR were 1.5 (± 0.4) and 1.8 (± 0.7) respectively (SOFA 6.6, MODS 4.9, zinc 50.0, selenium 70.7). On the seventh day, mean antioxidant and OR were 1.4 (± 0.5) and 1.9 (± 0.7), respectively (SOFA 4.3, MODS 3.1, zinc 62.8, selenium 77.3). In the correlation analysis, MODS scores and antioxidant level had significant correlations on the first and seventh days of ICU (P =
0.001. P = 0.009).
Conclusion Antioxidant level had a correlation with organ dysfunction which might be used as a prognostic factor in critically septic patients. To prove this, large-scale data collection is required.
1. Noveanu M, Mebazaa A, Mueller C: Cardiovascular biomarkers in the ICU.
Curr Opin CritCare 2009, 15: 377-383.
2. Piechota M, Banach M, Irzmanski R, Barylski M, Piechota-Urbanska M, Kowalski J, et al .: Plasma endothelin-1 levels in septic patients. J Intensive Care Med 2007, 22: 232-239.
3. Kotsovolis G, Kallaras K: The role of endothelium and endogenous vasoactive substances in sepsis. Hippokratia 2010, 14: 88-93.
Simultaneous analysis of the expression of CD64 and HLA-DR in the peripheral blood and bronchoalveolar lavage fluid in sepsis
T Skirecki1, M Mikaszewska-Sokolewicz2, G Hoser1, U Zielinska-Borkowska1 'The Center of Postgraduate Medical Education, Warsaw, Poland; 2 Medical University of Warsaw, Poland
Critical Care 2013, 17 (Suppl 2): P6 (doi: 10.1186 / cc11944)
Introduction The core pathophysiological changes in sepsis involve systemic activation of the immune system followed by the
DM baseline LTA ICU baseline LTA
8.90 ± 0.76, 245.30 ± 26.68 86.60 ± 45.55, 1,310.00 ± 154.80 1 5.90 ± 1.89, 252.00 ± 35.52 372.40 ± 120.60, 3,659.00 ± 485.20 3.00 ± 1.08, 40.90 ± 7.45 1 9.20 ± 7.14, 273.10 ± 126.50 1 5.30 ± 2.08, 350.50 ± 89.42 492.60 ± 66.72, 2,822.00 ± 432.70
Values in pg / ml.
anti-inflammatory compensatory response. However, controversies exist regarding the status of the immune system in local tissue compartments during sepsis. The aim of this study was to compare selected markers of activation between the systemic circulation and local lung environment.
Methods Twenty patients with severe sepsis were included in this study. Peripheral blood (PB) samples and bronchoalveolar lavage fluid (BALF) samples were obtained on the day of diagnosis (D1). BALF was collected from 11 patients. Samples were stained with antibodies: CD15 / CD64 and CD3 / CD14 / HLA-DR and isotypic control. Cells were analyzed by flow cytometry. Expression of markers of activation was analyzed as the geometric median of fluorescence (GMF). All values are expressed as median values. Comparisons between groups were performed using Mann-Whitney and Wilcoxon tests. Results The mortality of sepsis reached 70%. Nonsurvivors had significantly (P = 0.001) elevated expression of CD64 on neutrophils. Expression of HLA-DR was higher in monocytes from BAL than PB GMF (1.032 vs. 342; P = 0.02) and this tendency was present in sepsis originating from both pneumonia and peritonitis. Percentage of HLA-DR-positive T cells was lower in PB than in BAL (2.9% vs. 6.5%; P = 0.07), but the GMF values for HLA-DR were higher in the circulating T cells (1.904 vs. 1.346; P = 0.004). The expression of CD64 on neutrophils was not significantly different in PB and BAL, but there was a trend towards its higher expression in BAL from patients with pneumonia while its expression was higher in PB of patients with peritonitis. Conclusion In this study we noticed that during sepsis some significant differences in the status of activation of immune cells exist between peripheral blood and lung resident cells. The lung milieu seems to promote activation of monocytes while neutrophil activation is more dependent on the site of infection. However, these observations require further studies in a larger group of patients. Acknowledgments This study was supported by the Center of Postgraduate Medical Education grant no 501-01-02-012 and by the sources of the Medical University of Warsaw.
Anti-inflammatory effects of Kupffer cells through a7-nicotinic acetylcholine receptors
Y Li, X Shi
Changzheng Hospital, Second Military Medical University, Shanghai, China Critical Care 2013, 17 (Suppl 2): P7 (doi: 10.1186 / cc141945)
Introduction Nicotine exerts anti-inflammatory effects in several cell types. a7-nicotinic acetylcholine receptor (a7-nAChR), which has high permeability to calcium, is believed to contribute significantly to nicotinic anti-inflammatory effects. However, the molecular mechanism is largely unknown. Kupffer cells in the liver play an important role in inflammatory response to pathogens invading, but whether there is a7-nAChR expression in Kupffer cells or cholinergic anti-inflammatory pathway involved in this process remains unclear. Methods (1) Kupffer cells, isolated by collagenase digestion and differential centrifugation from mice and labeled with FITC-aBGT, were observed under laser scanning confocal microscope to test the expression of a7-nAChR. Protein level was also tested by western blotting, with RAW264.7 as positive control; (2) 100 nM LPS was given to Kupffer cells, with or without 1 mM nicotine. TNFa, IL-10 and HMGB-1 were tested at 4 hours, 12 hours or 24 hours, respectively; (3) 100 BALB / c mice were randomly divided into four group: Group I (only lethal dose of LPS was given), Group II (nicotine and LPS were given), Group III (LPS, nicotine and GdCl3 were given), and Group IV (LPS and nicotine were given and the left cervical vagus nerve was cut off). The mortality of mice was observed for 72 hours.
Results (1) Expression of a7-nAChR in Kupffer cells was confirmed by confocal microscope and western blotting; (2) after nicotine was administered, the level of TNFa and HMGB-1 increased and the level of IL-10 decreased. Given left cervical vagus nerve cut off or aBGT, the effect of nicotine was weakened; (3) Group I had the highest mortality rate, while in Group II nicotine did reduce the mortality rate dramatically. After the left cervical vagus nerve was cut off or aBGT was given, the effects of nicotine were weakened. Difference for the mortality rate between Group III and Group IV was not significant.
Conclusion Kupffer cells played a crucial rule in modulating inflammation and the anti-inflammatory effect of nicotine was partially weakened after left cervical vagus nerve cut off or aBGT was given. It was verified that left cervical vagus nerve was essential for the anti-inflammatory effect of nicotine and a7 acetylcholine receptors might play a critical role. References
1. Wang H, et al .: Nicotinic acetylcholine receptor a7 subunit is an essential regulator of inflammation. Nature 2003,421: 384-388.
2. Wang H, et al .: Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004, 10: 1216-1221.
Prevention of sepsis by correcting apoptosis
M Puhtinskaya, V Estrin
Research Institute of Obstetrics and Pediatrics, Rostov-on-Don, Russia Critical Care 2013, 17 (Suppl 2): P8 (doi: 10.1186 / cc11946)
Introduction Activation of apoptosis in lymphocytes determines the development of neutropenia and of sepsis [1,2].We investigated prevention of sepsis and correction of lymphocyte apoptosis by recombinant human granulocyte colony-stimulating factor (hr-GCSF, filgrastim) [1,2].
Methods With the permission of the ethics committee, a controlled, randomized, blind clinical trial included 69 term newborns on mechanical ventilation, without neutropenia and clinical signs of infection, with a content of lymphocytes in early apoptosis (AnnexinV-FITC + PI-) of > 9.59%, and in late (AnnexinV-FITC + PI +) of 0.56%. Lymphocytes in apoptosis were detected using antibodies to AnnexinV and propidium iodide staining method of immunophenotyping (flow cytometry; Beckman Coulter Epics XL, USA). The survey was conducted at admission, at 3 to 5 days, and 20 days. The method of random numbers in Group I included 39 newborns who on admission (with written parental consent) received an intravenous infusion of hr-GCSF dose of 10 | g / kg, 3 days. Newborns of Group II (n = 30) did not receive hr-GCSF. Power of the study was 80% (a <0.05). Results For 3 to 5 days, Group I significantly decreased apoptosis of lymphocytes in the early from 16.1% to 7.8%, and in late from 1.3% to 0.1%. The development of sepsis and neutropenia have been reported. We observed no clinical or laboratory signs of adverse effects of the drug. Fatal outcomes (n = 4) are not associated with hr-GCSF, which was confirmed postmortem. Decreased duration of mechanical ventilation (P <0.05). In Group II, 27 patients at 3 to 5 days developed neutropenia and increased lymphocytes in apoptosis (P <0.05). Sepsis was diagnosed in 19 children; eight fatal outcomes. Conclusion hr-GCSF reduces the incidence of septic complications and one of the mechanisms of its clinical effectiveness is the reduction of apoptotic factors affecting the development of neutropenia. References
1. Gillan ER, Christensen RD, Suen Y, et al .: A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia. Blood 1994, 84: 1427-1433.
2. Pukhtinskaya MG, Estrin VV, Gulova ES: Clinical and diagnostic value of apoptosis markers in the pathogenesis of neutropenia and bacterial complications in newborns with respiratory distress syndrome. Cytokines Inflamm 2011, 10: 66-69.
Immune paralysis in trauma patients; implications for prehospital intervention
M Kox, K Timmermans, M Vaneker, GJ Scheffer, P Pickkers Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands Critical Care 2013, 17 (Suppl 2): P9 (doi: 10.1186 / cc11947)
Introduction Multi-trauma is one of the major indications for intensive care admission. Recovery is frequently complicated by post-injury immunological complications, caused by a dysfunctional immune system; for example, sepsis and multiple organ failure. In order to treat
or prevent this immune paralysis, knowledge on the time course of immune paralysis in vivo and the pathophysiological mechanisms of immune paralysis is essential. The aim of this study is to determine factors that could predict and / or induce immunological complications in these patients to ultimately find a suitable target and timeframe for intervention.
Methods Blood was drawn from adult multi-trauma patients (n = 94) admitted to the emergency room (ER) of the Radboud University Nijmegen Medical Center. Blood was drawn at the trauma scene by the helicopter emergency medical services (HEMS), at arrival in the ER and at days 1, 3, 5, 7, 10 and 14 after trauma. Plasma concentrations of TNFa, IL-6, IL-10, IFNy, IL-8 and MCP-1 were determined by Luminex. Ex vivo 24-hour whole blood stimulations with LPS or pam3cys were performed and produced TNFa, IL-6 and IL-10 was measured using ELISA to determine the level of immune paralysis. Clinical data - for example, injury severity scores, trauma mechanism, medication and survival - were collected from electronic patient files. Results The plasma IL-10 concentration at ER was 16.5-fold increased in comparison with time-point HEMS (P <0.01). Similar but less pronounced effects were found for IL-8 and MCP-1. A significant correlation (P = 0.03, R = 0.53) was found between injury severity scores and IL-10 plasma concentration at time-point ER. Time courses of ex vivo produced cytokines suggest that LPS-induced IL-6 and TNFa production is already decreased in the first few hours after trauma and recovering from day 5. Ex vivo IL-10 production shows an inverse pattern.
Conclusion Immune paralysis can be established within hours after trauma. Production of anti-inflammatory IL-10 in the prehospital phase could play a crucial role in the pathogenesis. Patients with a higher injury severity score are more prone to produce excessive IL-10 in this phase. Immune stimulatory strategies applied by the HEMS or early after hospital admission could form a potential future approach to prevent immune paralysis in multitrauma patients in the intensive care ward.
Is hemoglobin concentration affected by sepsis in the acute phase?
G Jansma, H Buter, RT Gerritsen, EC Boerma Medical Center Leeuwarden, the Netherlands Critical Care 2013, 17 (Suppl 2): P10 (doi: 10.1186 / cc11948)
Introduction In the acute phase of sepsis several potential mechanisms may change the hemoglobin (Hb) concentration. On the one hand, endothelial activation may lead to increased vascular permeability and fluid sequestration to the interstitium, leading to hemoconcentration. On the other hand, degradation of the glycocalyx has been reported . Shedding of this carbohydrate-rich layer with an estimated thickness of 0.2 to 0.5 | m may lead to a substantial increase of the intravascular space, and thus to decrease of Hb concentration . The aim of this study is to determine whether there is a decrease in Hb in the acute phase of sepsis.
Methods In this single-center retrospective analysis we identified patients with sepsis as the primary reason for non-elective ICU admission from a standard patient database. Patients who fulfilled the international criteria of sepsis and organ failure during ICU admission were included in the sepsis group (S-group). The control group was formed by patients with other non-elective reasons for ICU admission (C-group). Exclusion criteria were (recent) bleeding, surgery in the last 6 weeks, chronic renal failure (creat> 177 | mol / l, or hemodialysis), untreated chronic anemia, pregnancy, polytrauma, age <18,
Table 1 (abstract P11). Mean RBC fluctuation (daily SOFA score)
Day A B C D
1 4.8 (10) 5.2 (9) - 4.8 (12)
2 4.9 (9) 5.0 (10) 4.6 (13) 5.1 (11)
3 4.0 (6) 5.1 (9) 4.7 (12) 4.8 (11)
4 - 4.8 (7) 4.6 (11) 5.0 (9)
5 - - - 5.1 (6)
hematologic or metastasized malignancies, cardiac arrest, and use of bone marrow suppressive drugs. Laboratory data were collected from blood samples, prior to in-hospital i.v. fluid therapy. In order to detect a difference in Hb concentration of 0.2 mmol / l, we anticipated a sample size of 283 per group, based on a standard deviation (SD) of 1.2, a = 0.05 and p = 0.8. Data are expressed as mean ± SD.
Results We included 296 patients in the S-group and 320 in the C-group. The difference in Hb between the S-group and C-group was not significant (8.76 ± 1.18 mmol / l vs. 8.93 ± 1.16 mmol / l, P = 0.07). After correction for a number of confounders, using a multivariate regression analysis, we observed a significant difference in Hb of -0.23 mmol / l in the S-group in comparison with the C-group (P = 0.01). Conclusion At first presentation, prior to in-hospital i.v. fluid therapy, Hb concentration in patients with sepsis is significantly lower in comparison with controls; however, the difference is very small, without the existence of anemia. References
1. Steppan J, et al .: Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalyx. J Surg Res 2011, 165: 136-141.
2. van den Berg BM, et al .: The endothelial glycocalyx protects against myocardial edema. Circ Res 2003,92: 592-594.
Do changes in red blood cell deformability in patients with septic shock correlate with changes in SOFA scores?
T Clark1, S Jewell2, M Sair1, P Petrov2, P Winlove2 'Derriford Hospital, Plymouth, UK; 2 University of Exeter, UK Critical Care 2013, 17 (Suppl 2): P11 (doi: 10.1186 / cc11949)
Introduction Traditional whole blood experiments suggest that sepsis causes abnormal red blood cell (RBC) deformability. To investigate this at the cellular level, we employed a novel biophysical method to observe individual RBC membrane mechanics in patients with septic shock.
Methods We collected blood samples from patients with septic shock until either death or day 5 of admission. Thermal fluctuations of individual RBCs were recorded allowing a complete analysis of RBC shape variation over time. Mean elasticity of the cell membrane was then quantified for each sample collected.
Results We recruited nine patients with septic shock. Table 1 shows mean RBC thermal fluctuation and SOFA scores. Conclusion RBC thermal fluctuation analysis allows variations in RBC elasticity during sepsis to be quantified at a cellular level. We could not identify any specific trend between sepsis severity and erythrocyte elasticity. Cells demonstrated both increases and decreases in fluctuation independent of SOFA score. This is contrary to current evidence that suggests RBC deformability is reduced during sepsis. Reference
1. Piagnerelli M, et al .: Intensive Care Med 2003, 29: 1052-1061. P12
Do erythrocytes subjected to cardiopulmonary bypass exhibit changes in their membrane mechanical properties?
T Clark1, S Jewell2, M Sair1, P Petrov2, P Winlove2 'Derriford Hospital, Plymouth, UK; 2 University of Exeter, UK Critical Care 2013, 17 (Suppl 2): P12 (doi: 10.1186 / cc11950)
Introduction Whole blood experiments suggest that cardiopulmonary bypass (CPB) causes red blood cell (RBC) trauma and changes in deformability that may contribute to postoperative microcirculatory
E F G H
4.6 (16) 4.9 (13) 5.1 (16) 4.6 (18) 5.1 (15)
4.8 (17) 5.1 (13) 5.0 (16) 4.9 (19) - (16)
4.9 (18) 4.8 (13) 5.0 (16) 4.7 (21) 5.3 (16)
5.9 (19) - - (18) - 5.0 (15)
5.2 (18) - - (19) - 5.0 (10)
Table 1 (abstract P12). Change in RBC thermal fluctuation relative to baseline: two distinct groups seen
Patient Al A2 A3 A4 A5 A6 A7 B8 B9 B10 B11 B12 B13 B14 B15
Post CPB +0.1 -0.4 -0.1 -0.5 -0.1 -0.2 -0.1 +0.5 0 +0.4 +0.1 +0.2 0 +0.2 +0.1
Day i 0 0 +0.1 -0.1 -0.1 +0.1 +0.1 0 +0.5 +0.4 +0.7 +0.4 +0.6 +0.5 +0.7
Day 2 -0.2 +0.1 0 NA NA 0 NA +0.5 -0.1 +0.4 NA +0.1 NA NA NA
dysfunction. We used a novel fluctuation microscopy technique to quantify the effects of CPB on RBC elasticity at a cellular level. Methods We collected blood samples from elective cardiac surgery patients pre (at induction) and post (immediately, each day until CICU discharge) CPB. Thermal fluctuations of individual RBCs were recorded using a high-frame-rate camera allowing a complete analysis of RBC shape variation over time. Mean elasticity of the cell membrane was then quantified for each sample collected.
Results Fifteen patients were recruited. Table 1 displays the results. RBC thermal fluctuation is measured relative to pre-bypass values. An increase in RBC fluctuation marks a decrease in stiffness. CPB caused two distinct changes in RBC elasticity; pre-fix A indicates samples where stiffness increases or shows no change, B those where stiffness decreases. Data on day 2 were not collected in patients discharged from the CICU. CPB type or time had no apparent impact on RBC response to CPB.
Conclusion RBC thermal fluctuation analysis quantifies the impact of CPB on erythrocyte membrane elasticity. We clearly identified two separate RBC elasticity responses to CPB. This finding is contrary to traditional flow measurement techniques that suggest CPB impairs whole blood flow and reduces RBC deformability. Reference
1. Lindmark et al .: J Thoracic Cardiovasc Surg 2002, 123: 381-383. P13
Platelet-associated oxidative stress and ADAMTS-13 levels are inversely associated with a poor prognosis in septic shock
L Montini1, G De Pascale1, MA Pennisi1, ES Tanzarella1, SL Cutuli1, A Occhionero1, R De Cristofaro2, M Antonelli1 'Catholic University School of Medicine, Rome, Italy; 2Haemostasis and Thrombosis Center, Catholic University School of Medicine, Rome, Italy Critical Care 2013, 17 (Suppl 2): P13 (doi: 10.1186 / cc11951)
Introduction Sepsis causes widespread microvascular injury and thrombosis. Some hemostatic factors mediate the mechanisms involved in sepsis-related organ ischemia and failure. Oxidative stress is also increased in sepsis and reactive oxygen species (ROS) favor secretion of von Willebrand factor (vWF) multimers from endothelium and inhibit vWF proteolysis by ADAMTS-13. Moreover, the enzyme indoleamine-2,3-dioxygenase, an important immune regulator, is activated in sepsis and, through generation of kynurenins, promotes antioxidative and anti-infective activities. This study evaluated the relative role of ADAMTS-13, vWF and fibrinogen in the morbidity and mortality of patients with septic shock (SS). The above hemostatic factors were measured together with kynurenine and plasma protein carbonyls, markers of oxidative stress.
Methods One group of 12 patients with SS, defined using standard criteria, was enrolled in the ICU of the 'A. Gemelli 'Hospital (Rome, Italy). Biochemical, hematologic and hemodynamic parameters were measured on days 1 to 4, 7, 14 and 21. A group of 12 age-matched and gender-matched healthy subjects was used as controls. Results Low ADAMTS-13 activity was observed in SS patients (268 ± 123 ng / ml vs. 760 ± 80 ng / ml in controls). vWF levels (antigen and activity) were increased ~ 3-fold compared with controls. Likewise, plasma protein carbonyls and kynurenine were globally increased in patients (2.1 ± 1.5 nmol / mg vs. 0.3 ± 02 nmol / mg and 14.4 ± 9.7 | M vs. 2.3 ± 1.3 | M, respectively). Intra-ICU mortality (3 of 15) was strongly and inversely correlated with carbonyl levels (P = 0.04) and platelets (P = 0.022).
Conclusion Hence, we hypothesize that, in the SS setting, platelets contribute to oxidative stress that counteracts the organ failure-associated mortality. Thus, low platelet count, irrespective of bleedings, may favor mortality in SS patients by generating lower ROS amounts.
1. Strauss R, et al .: Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome. Crit Care Med 2002, 30: 1,765-1771.
Neutrophil gelatinase-associated lipocalin / lipocalin2, derived from gut crypt cells, exerts intestinal antimicrobial effect via bacterial stimulation of Toll-like receptor 4 and 9
K Mori, T Igarashi, K Inoue, T Suzuki, H Morisaki, J Takeda Keio University School of Medicine, Tokyo, Japan Critical Care 2013, 17 (Suppl 2): P14 (doi: 10.1186 / cc11952)
Introduction Neutrophil gelatinase-associated lipocalin (NGAL) / lipocalin2, known as a sensitive biomarker of acute kidney injury, prevents bacterial iron uptake, resulting in the inhibition of its overgrowth . We previously demonstrated that this protein was discharged into gut lumen from crypt cells in septic conditions, and inhibited the growth of Escherichia coli . However, it remains unclear which pathway is associated with the upregulation of NGAL. We therefore designed the present study to reveal whether the pattern-recognition receptor of bacteria, the Toll-like receptor (TLR) family, plays a pivotal role for NGAL secretion from gut crypt cells. Methods With our institutional approval, the ileum and colon of male C57BL / 6J mice (6 to 7 weeks) were everted and washed by Ca2 + and Mg2 + free PBS buffer five times. Tissues were incubated with Ca2 + and Mg2 + free PBS containing 30 mM EDTA for 1 hour to isolate crypt cells of gut. The cell suspension was filtered through a cell strainer (40 | m) twice, and deposited the crypt cells by centrifugation at 700xg. The isolated crypt cells were resuspended in PBS and stained with 0.25% amido black for labeling paneth cells. The 5x105 crypt cells were resuspended in 50 ml HBSS containing 2.5% fetal bovine serum and 1% penicillin-streptomycin. The crypt cells were incubated at 37 ° C with or without TLR ligands: lipopolysaccharide (TLR4 ligand, 10 | g / ml) and CpG-DNA (TLR9 ligand, 8 | g / ml). After a 2-hour incubation period, the crypt cells were deposited and eluted mRNA to measure the expression of both NGAL and TLR mRNA using real-time PCR. Results More than 70 to 80% of collected cells were stained by amido black. LPS significantly upregulated the expression of NGAL and TLR4 mRNA in ileum and colon crypt cells (P <0.05). Although the CpG-DNA did not upregulate NGAL and TLR9 mRNA in ileum crypt cells, the apparent expression of NGAL and TLR9 mRNA was found in colon crypt cells (P <0.05). Conclusion Bacterial stimulation of TLR4 and TLR9 pathways plays a pivotal role in the expression of NGAL mRNA in gut, suggesting that NGAL, derived from gut crypt cells, could contribute to the regulation of the intraluminal microflora in the critically ill. References
1. Nature 2004, 432: 917.
2. Crit Care Med 2011, 39:46.
Lethal influenza virus A H1N1 infection in two relatives with autosomal dominant GATA-2 deficiency
J Sole-Violan1, I Sologuren1, E Betancor2, S Zhang3, C Pérez1, E Herrera-Ramos1, M Martínez-Saavedra1, M López-Rodríguez1, J Pestano2, J Ruiz-Hernández1, J Ferrer1, F Rodríguez de Castro1, J Casanova3 , C Rodríguez-Gallego1
'Hospital GC Dr Negrin, Las Palmas de GC, Spain; 2Universidad Las Palmas de GC, Spain; 3The Rockefeller University, New York, NY, USA Critical Care 2013, 17 (Suppl 2): P15 (doi: 10.1186 / cc11953)
Introduction Most individuals infected with the 2009 pandemic H1N1 influenza A virus (IAV) (H1N1pdm) experienced uncomplicated flu.
However, in a small subset of patients the infection rapidly progressed to primary viral pneumonia (PVP) and a minority of them developed ARDS. Inherited and acquired variability in host immune responses may influence susceptibility and outcome of IAV infection. However, the molecular nature of such human factors remains largely elusive. Methods We report three adult relatives with the autosomal dominant GATA-2 deficiency. P1 and his son P2 had a history of myelodysplastic syndrome and a few episodes of mild respiratory infections. They developed PVP by H1N1pdm which rapidly evolved to ARDS. They died at the age of 54 and 31, respectively.
Results Patients were heterozygous for a novel R396L mutation in GATA2. Like other patients with GATA-2 deficiency, the three relative had absence of peripheral NK and B cells and monocytopenia. However a high number of plasma cells, which were found to be pauciclonal, were observed in peripheral blood from P1 during H1N1pdm infection. P1 and P2 had normal levels of immunoglobulins and IgG antibodies against common viruses. Microneutralization test showed that P1 produced normal titers of neutralizing antibodies against H1N1pdm and against the previous annual H1N1 strain. Our results suggest that a few clones of long-living memory B cells against IAV expanded in P1; and that these cells produced cross-reactive antibodies against H1N1pdm, similar to those recently described.During the flu episode P1 had a strong increase of IFNy-producing T cells and of IFNy production. The Th1-related chemokines CXCL10 and CXCL9, as well as IFNy, MCP-1 and IL-8, were strongly elevated in serum from P1 and P2 in the course of H1N1pdm infection.
Conclusion GATA-2 deficiency is the first described Mendelian inborn error of immunity underlying severe IAV infection. Primary immunodeficiencies predisposing to severe IAV infections may debut, even in adults without a history of previous severe infections. The massive IFNy-mediated cytokine storm may explain the fatal course of H1N1pdm infection in our patients.
Bacterial translocation primes proinflammatory responses and is connected to early death in an experimental model of lethal injury
N Baxevanos, T Tsaganos, A Pistiki, D Droggiti, A Spyridaki, E Giamarellos-Bourboulis University of Athens, Medical School, Athens, Greece Critical Care 2013, 17 (Suppl 2): P16 (doi: 10.1186 / cc11954)
Introduction Some cases of multiple trauma are rapidly deteriorating; the mechanism was investigated.
Methods Forty-one rabbits were assigned into two groups; sham-operated and subject to crush the right femur. Survival was recorded; peripheral blood was sampled for LPS measurement by the kinetic QCL-1000 LAL assay; quantitative tissue growth was assessed after death. Some rabbits were sacrificed at 48 hours; blood was sampled from the portal vein for LPS measurement; splenocytes were
isolated and incubated for 24 hours in the presence of 10 ng / gl LPS of Escherichia coli O55: B5 and of 5 | g / ml phytohemagglutin (PHA); TNFa was measured in supernatants by a bioassay on L929 fibroblasts. Results Fifty percent of rabbits died early; that is, within the first 48 hours. Mean ± SE log10 bacteria in the liver and lung of animals that died early was 2.27 ± 0.62 and 3.16 ± 0.78 cfu / g; respective values of rabbits that started dying late (that is, after 72 hours) were below the limit of detection. Mean circulating LPS at 24 hours was 2.09 EU / ml and 1.99 EU / ml respectively (P = NS). Mean LPS of the portal vein of the sham and of the injury groups were 1.25 and 5.62 EU / ml (P = 0.047). Concentrations of TNFa in splenocyte supernatants are shown in Figure 1.
Conclusion Early death after injury is not related to peripheral endotoxemia and sepsis; bacterial translocation priming for enhanced proinflammatory responses is a likely explanation.
Effects of the common 34C> T variant of the AMPD1 gene on immune function, multiorgan dysfunction and mortality in patients with sepsis
B Ramakers1, E Giamarellos-Bourboulis2, M Coenen1, M Kox1, J Van der Hoeven1, C Routsi2, A Savva2, I Perdios3, F Diamantea4, D Sinapidis5, P Smits1, N Riksen1, P Pickkers1
'Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; 2 University of Athens, Medical School, Athens, Greece; 3Nafplion General Hospital, Nafplio, Greece; 4'G.Gennimatas'General Hospital, Athens, Greece; 5Alexandra General Hospital, Athens, Greece Critical Care 2013, 17 (Suppl 2): P17 (doi: 10.1186 / cc11955)
Introduction Adenosine exerts anti-inflammatory and tissue protective effects during systemic inflammation. While the anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance, the tissue protective effects might limit organ damage. The effects of a common loss-of-function variant of the adenosine monophosphate deaminase 1 gene (AMPD1), which is associated with increased adenosine formation, in patients with sepsis are unknown. Methods In a prospective cohort, genetic-association study, the effects of the presence of the AMPD1 gene on immune function, multiorgan dysfunction and mortality in septic patients was studied. Pneumosepsis patients (n = 402) and controls without infection (n = 101) were enrolled.
Results In pneumosepsis patients and controls, a similar prevalence of the 34C> T (rs17602729) mutation in the AMPD1 gene was found. Univariate logistic regression analysis showed a tendency of increased mortality in patients with the CT genotype, compared with patients with the CC genotype (OR 1.53; 95% CI 0.95 to 2.5). Moreover, carriers of the CT genotype tended to suffer more from multiorgan dysfunction, OR 1.4 (0.84 to 2.3) and 3.0 (0.66 to 13.8), for CT and TT, respectively (P = 0.07). In septic carriers of the CT genotype, the ex vivo production of TNFa by LPS-stimulated monocytes was attenuated (P = 0.005),
Figure 1 (abstract P16). Stimulation of TNFa from isolated splenocytes.
Figure 1 (abstract P17). Kaplan-Meier curve for the 402 sepsis patients.
indicative for more pronounced immunoparalysis in these patients. See Figure 1.
Conclusion The presence of the 34C> T variant of the AMPD1gene is not related to infection susceptibility; However, it is associated with more pronounced immunoparalysis in patients with sepsis, and shows a tendency towards increased mortality. Mechanistically, the anti-inflammatory effects of adenosine may account for this and apparently overrule its tissue protective effects.
Exploring the translational disconnect between the murine and human inflammatory response: in vitro analysis of the dose-response relationship of LPS and NFkB activation in murine and human immune cells
EP McCarron, I Welters, D Williams, D Antoine, A Kipar
University of Liverpool, UK
Critical Care 2013, 17 (Suppl 2): P18 (doi: 10.1186 / cc11956)
Introduction inflammation, as seen in sepsis and systemic inflammatory response, is dependent on the activation of the NFkB pathway through Toll-like receptors (TLRs) . Recreating an inflammatory response using lipopolysaccharide (LPS) can provide results that are different from clinical sepsis . By examining NFkB activation in murine and human cells, a species comparison can be made to investigate differences at the cell level that may contribute to the translational disconnect seen in vivo.
Methods THP1 human monocytes (passages 9 to 11) and RAW 264.7 murine macrophages (passages 15 to 20) were cultured in RPMI-1640 and DMEM respectively and then challenged with LPS. After settling for 24 hours, cells were dosed with six or seven doses of LPS. After 1 hour, nuclear extraction and proteins were separated by acrylamide gel electrophoresis. Membranes where then immunoblotted for actin and p65, followed by densitometric analysis in order to quantify the amount of p65 that had translocated from the cytoplasm to the nucleus (by subtraction from consistent nuclear actin). Results Murine cells required higher doses of LPS compared with human cells in order to detect p65 (human, 1 pg / ml to 100 ng / ml; murine, 30 pg / ml to 1,000 ng / ml). THP1 cells showed a greater fold increase in the p65: actin ratio compared with RAW 264.7 cells. Human cells responded to lower concentrations of LPS. Murine cells appeared to show a molecular resistance to lower doses, but their response was very sensitive at higher doses. A dose-response relationship of LPS dosing and NFkB activation was observed in both cell lines. Conclusion Immunoblotting for p65 is a reliable and reproducible method to determine NFkB activation in cultured cells. Macrophages are more responsive to LPS than monocytes  so differences between cell lines would have been expected to be the reverse of what was observed. The species difference in response to LPS may contribute to the apparent disconnect between human and murine responses to LPS and may partially explain the difficulties of translating therapeutic interventions into clinical human sepsis.
1. Bonizzi G, Karin M: Trends Immunol 2004, 25: 280-288.
2. Remick DG, Ward PA: Shock 2005, 24 (Suppl 1): 7-11.
3. Takashiba S, et al .: InfectImmun 1999, 67 (11): 5573-5578.
Hypogammaglobulinemia in sepsis is not correlated to high circulating angiopoietin-2 levels
U Kovacic1, F Staric2, M Kmet2, M Godnic2, R Kaps2
'Faculty of Medicine, University of Ljubljana, Slovenia; General Hospital Novo
Critical Care 2013, 17 (Suppl 2): P19 (doi: 10.1186 / cc11957)
Introduction Hypogammaglobulinemia has been frequently found in adult patients with severe sepsis and septic shock. Furthermore, it seems that at least a low serum level of IgM is correlated with higher mortality in sepsis. The mechanisms of hypogammaglobulinemia in septic shock have not yet been explained. It has been hypothesized that outflow of immunoglobulins into the extravascular space due to increased capillary permeability could reduce immunoglobulin serum concentrations. Angiopoietin-2, which directly disrupts the endothelial barrier, is markedly elevated in sepsis and other inflammatory states and its serum level has been correlated with microvascular leakage, end-organ dysfunction and death in sepsis.
Methods In the prospective, noninterventional study, we assessed the correlation between the capillary leakage marker angiopoetin-2 and serum levels of IgG and IgM in 41 patients with community-acquired severe sepsis or septic shock on admission. Blood samples were obtained during the first 12 hours after admission to hospital. Results Mean age of patients (17 females) was 70 years. Median APACHE II and SOFA scores at admission were 24 and 11, respectively. The mortality rate was 45%. Thirty-four percent of all patients had level of IgG <650 mg / dl. The median concentration of angiopoietin-2 in the hypo-IgG group was 11.958 pg / ml, which was not statistically different (Mann-Whitney; P> 0.05) than in the rest of patients with normal levels of IgG (15.688 pg / ml) . The concentration of IgM <40 mg / dl was found in only four patients (10%) and all died. Pearson's correlation test showed that the correlation between the concentrations of angiopoietin-2 and IgG (correlation coefficient 0.191) or IgM (correlation coefficient
0.0408., Respectively, were not statistically significant (P <0.05). Conclusion At present the hypothesis that increased microvascular leakage is responsible for hypogammaglobulinemia in septic patients could not be accepted. Studies on larger number of patients are needed. In addition, it is necessary to further explore other possible mechanisms, such as increased catabolism and consumption of antibodies or inadequate synthesis of immunoglobulins, which could also be responsible for hypogammaglobulinemia in sepsis. References
1. Taccone FS, et al .: Gamma-globulin levels in patients with community-acquired septic shock. Shock 2009, 32: 379-385.
2. Werdan K, et al .: Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med 2007, 35: 2693-2701.
TREM-1 levels are elevated in patients with liver cirrhosis
SD Gurney1, CR Graham2, P Kelleher2, N Soni1, M Foxton1, S Singh1 'Chelsea and Westminster Hospital, London, UK; 2Imperial College, London, UK Critical Care 2013, 17 (Suppl 2): P20 (doi: 10.1186 / cc11958)
Introduction Sepsis and spontaneous bacterial peritonitis (SBP) are common sequelae in patients with cirrhosis. Cirrhotics admitted
Figure 1 (abstract P20). TREM-1 expression in healthy controls compared with cirrhotic patients.
to the ICU have an in-hospital mortality of up to 50% . Microbial translocation (MT) is the pathogenic mechanism implicated in SBP. The triggering receptor expressed by myelocytes-1 (TREM-1) modulates the immune response with resultant production of proinflammatory cytokines and has been used as a biomarker in the diagnosis of bacterial infection. We wish to evaluate the role of TREM-1 as a biomarker in cirrhosis.
Methods Blood samples were obtained from 18 healthy controls (HC) and 29 cirrhotic patients (CA) as defined by clinicoradiological criteria. Disease severity was graded according to Child-Pugh class (median 10, range 5 to 13) and modified end-stage liver disease (MELD) score (median 14, range 6 to 21). Simultaneous ascitic fluid samples were taken from 10 patients in the CA group. Soluble TREM-1 and CD14 levels (a surrogate marker of MT) were measured by ELISA. Flow cytometry was used to quantify the expression of TREM-1 on monocytes and neutrophils in blood and ascitic fluid.
Results TREM-1 expression is significantly higher in the CA group compared with HC across all monocyte subsets but not neutrophils, even in the absence of sepsis (see Figure 1). There is no correlation between cell surface TREM-1 expression and severity of cirrhosis by Child-Pugh or MELD score. sTREM and sCD14 levels were elevated in the CA group compared with HC (P = 0.0010 and 0.0016 respectively). In addition, plasma sTREM-1 levels correlated with disease severity according to MELD score (R = 0.71, CI = 0.22 to 0.92 P = 0.012) and serum bilirubin (R = 0.78, CI = 0.36 to 0.94, P = 0.004). There was no correlation with either form of TREM-1 with sCD14 levels. There was no difference in cell surface or soluble TREM-1 expression between blood and ascitic fluid monocytes in culture-negative, non-neutrophilic ascites. Conclusion Blood monocyte and soluble TREm-1 are elevated in cirrhotic patients even in the absence of sepsis. Soluble TREM-1 levels correlate with disease severity in cirrhosis. Further studies are ongoing to ascertain the utility of TREM-1 as a biomarker in cirrhosis. Reference
1. Olson JC, et al .: Intensive care of the patient with cirrhosis. Hepatology 2011, 54: 1864-1872.
Effects of different doses and serotypes of LPS on blood-brain barrier permeability in Sprague-Dawley rats
E Senturk, F Esen, P Ergin Ozcan, G Orhun, N Orhan, N Arican, M Kucuk, M Kaya
University of Istanbul, Turkey
Critical Care 2013, 17 (Suppl 2): P21 (doi: 10.1186 / cc11959)
Introduction The blood-brain barrier (BBB) is highly restrictive of the transport of substances between blood and the central nervous system. Lipopolysaccharide (LPS) from Gram-negative bacteria was reported to affect the permeability of the BBB. BBB disruption using a LPS is used as a model of septic encephalopathy in mice. The present study was designed to investigate the effects of different doses and serotypes of LPS on BBB integrity in Sprague-Dawley rats. Methods Male Sprague-Dawley rats weighing 200 to 250 g were used in the study. Rats were given two different types of LPS (026: B6-L5543 and 026: B6-L2762) in different doses (3, 5, and 10 mg / kg; i.v.). Rectal temperature and arterial blood pressure measurements were recorded for sepsis severity. The changes in the BBB permeability were measured using the Evans blue (EB) and sodium fluorescein (NaFl) dye extravasation techniques 24 hours after LPS administration. Results Both LPS serotypes showed comparable arterial blood pressure and rectal temperature recordings and the severity of the disease increased with the increasing doses (5 mg / kg and 10 mg / kg) of LPS and the mortality rates were found to be 29% and 63% respectively. The extravasated contents of EB and NaFl tracers did not significantly increase in brain parenchyma following the administration of different doses of LPS with different serotypes.
Conclusion Our results showed no disruption to BBB by two different serotypes of LPS even administered in increasing doses. These result indicate that the BBB integrity of Sprague-Dawley rats are resistant to the effects of two different serotypes of LPS.
Bioenergetic imbalance and oxidative stress in the pathophysiology of septic encephalopathy
J D'Avila1, R Rodrigues2, H Castro-Faria-Neto1, M Oliveira3, F Bozza4 'Oswaldo Cruz Foundation - FIOCRUZ, Rio de Janeiro, Brazil; 2Federal University of Rio de Janeiro (UFRJ) and D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil; 3UFRJ, Rio de Janeiro, Brazil; 4Oswaldo Cruz Foundation - FIOCRUZ and IDOR, Rio de Janeiro, Brazil Critical Care 2013, 17 (Suppl 2): P22 (doi: 10.1186 / cc11960)
Introduction Septic encephalopathy is a frequent complication in severe sepsis but its pathogenesis and mechanisms are not fully understood. Oxygen supply and utilization are critical for organ function, especially for the brain, a tissue extremely dependent on oxygen and glucose. Disturbances in oxygen utilization are common in sepsis and a number of mitochondrial dysfunctions have been described in different tissues in septic animals as well as in septic patients. Our group described mitochondrial dysfunctions in the brain during experimental sepsis.
Methods Experimental sepsis was induced by endotoxemia (LPS 10 mg / kg i.p.) in Sprague-Dawley rats and by polymicrobial fecal peritonitis in Swiss mice. Brain glucose uptake was observed in vivo in endotoxemic rats using positron emission tomography with [18F] fluorodeoxyglucose and autoradiography with 2-deoxy-14C-glucose. Results Mice with polymicrobial sepsis present hypoglycemia, hyperlactatemia and long-term cognitive impairment. We observed a rapid increase in the uptake of fluorescent glucose analog 2-deoxy-2 - ((7-nitro-2,1,3-benzoxadiazol-4-yl) amino) -D-glucose in brain slices from septic mice in vitro . A similar increase in brain glucose uptake was observed in vivo in endotoxemic rats. Remarkably, the increase in glucose uptake started 2 hours after LPS injection, earlier than other organs. The brains of mice with experimental sepsis presented neuroinflammation, mitochondrial dysfunctions and oxidative stress, but mitochondria isolated from septic brains generated less ROS in vitro in the first 24 hours. This led us to investigate the role of NADPH oxidase, an enzyme induced during innate immune response, as a potential source of reactive oxygen species in experimental sepsis. Inhibiting NADPH oxidase with apocynin acutely after sepsis prevented cognitive impairment in mice.
Conclusion Our data indicate that a bioenergetic imbalance and oxidative stress is associated with the pathophysiology of septic encephalopathy. We are observing a new metabolic phenotype in the brain during sepsis, characterized by a rapid increase in glucose uptake and mitochondrial dysfunctions that may be secondary to inflammation and hypoxia.
Pathophysiology of sepsis-associated brain dysfunction: an experimental study of cerebral microdialysis and mitochondrial function
P Kurtz1, C Vargas-Lopes1, C Madeira1, I Mello1, R Panizzutti1, L C Azevedo2, F A Bozza1
'Fiocruz, Rio de Janeiro, Brazil; 2Hospital Sirio e Lebanes, Sao Paulo, Brazil Critical Care 2013, 17 (Suppl 2): P23 (doi: 10.1186 / cc11961)
Introduction Pathophysiology of brain dysfunction associated with sepsis is still poorly understood. Potential mechanisms involve oxidative stress, neuroinflammation and blood-brain barrier alterations. Our purpose was to study the metabolic alterations and markers of mitochondrial dysfunction in a clinically relevant model of septic shock.
Methods Twelve anesthetized (midazolam / fentanyl / pancuronium), invasively monitored, and mechanically ventilated pigs were allocated to a sham procedure (n = 5) or sepsis (n = 7), in which peritonitis was induced by intra-abdominal injection of autologous feces . Animals were studied until spontaneous death or for a maximum of 24 hours.In addition to global hemodynamic and laboratory assessment, intracranial pressure and cerebral microdialysis were assessed at baseline, 6, 12, 18 and 24 hours after sepsis induction. After death, brains were removed and brain homogenates were studied to assess markers of mitochondrial dysfunction.
Figure 1 (abstract P23).
Results All septic animals developed a hyperdynamic state associated with lower arterial pressure, fever and organ dysfunction in comparison with control animals. In the septic animals, we observed increased brain dialysate glutamine levels at 12, 18 and 24 hours after sepsis induction, as compared with control animals. Moreover, after analyzing homogenates from the frontal cortex, we found higher concentrations of glutamin and glutamate in septic as compared with control animals (85.67 ± 14.98 vs. 28.77 ± 7.0; P = 0.01 and 132.1 ± 19.72 vs. 53.33 ± 16.83; P = 0.02, respectively). See Figure 1. Conclusion We found higher concentrations of glutamate and glutamin in brain tissues of septic animals as compared with control. Furthermore, glutamin concentrations increased over time in the extracellular space as measured by cerebral microdialysis. These findings suggest an increased excitatory state that is potentially associated with high energy expenditure. However, associations with neuronal injury need further study.
Cholinergic modulation of hippocampal activity during septic encephalopathy
A Zivkovic1, CP Bengtson2, O Sedlaczek1, R Von Haken1, H Bading2, S Hofer '' Universitätsklinikum Heidelberg, Germany; 2Universität Heidelberg, Germany Critical Care 2013, 17 (Suppl 2): P24 (doi: 10. '' 86 / cc''962)
Introduction Septic encephalopathy is a sepsis-related brain dysfunction with a deterioration of cortical functions. The experimental studies in the rat brain revealed a deranged neurotransmitter profile during septic encephalopathy. Glutamatergic synapses, essential in learning and memory, undergo use-dependent changes in synaptic strength, referred to as plasticity. Permanent strengthening of synapses after a brief stimulus, termed long-term potentiation (LTP), was discovered in the hippocampus, and here it has been most thoroughly studied. Cholinergic neurotransmission plays an important role in regulating the cognitive functions of the brain. It acts as a signal-to-noise ratio modulator of sensory and cognitive inputs. The irregularities in brain functions give rise to the symptoms of delirium, including disorganized thinking and disturbances of attention and consciousness, which in turn might affect learning and memory. Possible mechanisms for cholinergic deficiency include impairment of synaptic functions of acetylcholine. Imbalances in the cholinergic system during sepsis might therefore play an extensive role in the septic delirium. Methods By using MRI imaging we identified functional changes in the hippocampal region of patients with severe sepsis. This finding was further supported by the experimental recordings in the rat brains of lipopolysaccharide (LPS) -treated rats using the electrophysiological patch clamp technique.
Results Critically ill ICU patients diagnosed with septic delirium using the CAM-ICU method underwent diagnostic MRI scans. The serial MRI analysis revealed increased signal intensity in the hippocampal region in diffusion-weighted MRI (DWI). We used endotoxemia model to induce sepsis in the rats. Electrophysiological analysis of the hippocampal neurons in LPS-treated rats showed impaired LTP in the excitatory synapses, as compared with controls. Application of physostigmine, a blood-brain barrier permeable cholinesterase inhibitor, resulted in a partial recovery of LTP in the hippocampal synapses of LPS-treated rats. Conclusion The patients with septic delirium show functional changes in the hippocampus. Furthermore, we show that endotoxemia affects synaptic plasticity in the rat hippocampus, suggesting the involvement of this brain region in the pathophysiology of septic delirium. Moreover, the effect of the cholinergic neurotransmission onto the induction and maintenance of synaptic plasticity in the rat hippocampus during endotoxemia suggests that cholinergic neurotransmission might play a critical role in septic encephalopathy.
Neutrophil lymphocyte count ratio as a biomarker of severe sepsis in Escherichia coli infections in adults
LR Ljungstrom1, G Jacobsson1, R Andersson2
'Skaraborgs Sjukhus, Skovde, Sweden; 2Gothenburg University, Gothenburg, Sweden
Critical Care 2013, 17 (Suppl 2): P25 (doi: 10.1186 / cc11963)
Introduction The neutrophil-lymphocyte count ratio (NLCR) is an easy to analyze biomarker reacting very early in the course of acute inflammation. It has previously been reported to correspond to bacteremia and recently to disease severity in community-acquired pneumonia . We have looked at 205 consecutive patients with Escherichia coli infections (ECI) and found the same to be true for ECIs. This may be of great clinical importance since E. coli is the most frequently isolated pathogen in patients with infections requiring in hospital care.
Methods This study is part of a 9-month consecutive study of community-acquired severe sepsis and septic shock in adults at Skaraborg Hospital in the western region of Sweden. The hospital serves a population of 256,000 inhabitants and has approximately 60,000 annual visits to the ED. All patients admitted to the hospital receiving intravenous antibiotic treatment within the first 48 hours of admission were evaluated for severe sepsis and septic shock. Upon admission, two sets of blood cultures and other relevant cultures were obtained from each patient as well as sampling for NLCR and venous plasma lactate. The patient records were evaluated by one infectious diseases specialist. Approximately 2,300 patients were diagnosed as having a bacterial infection. From those, an informed consent to participate in the study could be obtained from approximately 1,600 patients.
Results Of the 1,600 patients who gave consent to participate in the study, 205 had an ECI. Sixty-four had a positive blood culture for E. coli. Fifty of the patients met one or more criteria for severe sepsis or septic shock. The NLCR was significantly higher (P <0.001) within the severe sepsis group (median = 21.1 with quartiles 11.1 to 42.4) compared with the group with no severe sepsis (median = 11.6 with quartiles 7.6 to 18.9).
Conclusion The NLCR can be used as a biomarker of disease severity even in ECIs. The biomarker reacts rapidly, is cheap and needs no extra sampling. The higher the value, the higher the probability for severe sepsis. A high value can even precede the development of severe sepsis or septic shock. However, a low value never excludes neither bacteremia nor severe sepsis. The method cannot be used in patients with disturbances in neutrophil or lymphocyte levels due to other causes than sepsis.
1. de Jager C, et al .: The neutrophil-lymphocyte count ratio in patients with community acquired pneumonia. PLoS ONE 2012, 7: e46561.
Figure 1 (abstract P26).
Obesity and inflammatory markers in severe sepsis
P Simon1, D Thomas-Rüddel2, T Nemes', K Reinhart2, F Bloos2, UX Kaisers' 'University Hospital of Leipzig, Germany; 2 Center for Sepsis Control and Care, Jena, Germany
Critical Care 2013, 17 (Suppl 2): P26 (doi: 10.1186 / cc11964)
Introduction chronic inflammation has recently been recognized as an important factor in the pathophysiology of obesity and associated morbidities . In this clinical study we aimed at identifying possible effects of obesity on inflammatory markers in severe sepsis. Methods With institutional ethical committee approval, 243 consecutive patients treated for severe sepsis or septic shock in the ICUs of two university hospitals over a period of 5 months were studied. Six patients were excluded due to cachexia, syndromal disorders or missing clinical data. Diagnosis of sepsis was made according to SCCM criteria. Serum levels of C-reactive protein (CRP, mg / l) and procalcitonin (PCT, ng / ml) on day 1 of sepsis were compared among five body mass index (BMI) strata according to WHO definitions. Two groups (BMI <30, normal weight, and BMI> 30, obesity) were formed for further analysis, and PCT was logarithmically transformed (LogPCT), resulting in normal distribution. Statistical analysis was performed using a t test. Results Patients with BMI> 30 had higher values of PCT and CRP (Table 1). The difference in LogPCT was of borderline significance (P =
0.052). However, patients with positive blood cultures had significantly higher LogPCT values (P = 0.017) (Figure 1). Difference in CRP was not significant (P = 0.09). The trends over all five BMI strata (Table 1) were not significant.
Conclusion Obesity with BMI> 30 seems to be associated with an increase in inflammatory markers in patients with severe sepsis, particularly in bacteraemia. The role of adipose tissue in severe sepsis should therefore be studied in more detail. Reference
1. Waves K, et al .: Inflammation, stress, and diabetes. J Clin invest 2005, 115: 1111-1119.
Table 1 (abstract P26). PCT and CRP as median (IQR)
BMI n PCT (ng / ml) CRP (mg / l)
18.5 to 24.5 196 4.8 (11.9; 1 53 (189)
>30.0 47 7.3 (24.6) 228 (254)
18.5 to 24.5 101 4.9 (11.7) 147 (175)
25 to 29.9 95 4.4 (12.0) 157 (218)
30 to 34.9 32 6.9 (22.6; 212 (118)
35 to 39.9 7 7.4 (38.3) 241 (264)
>40.0 8 11.4 (32) 278 (272)
Cytokine gene expression can predict infectious complications following severe trauma
HD Torrance, K Brohi, CJ Hinds, MJ O'Dwyer
Bart's Health NHS Trust, London, UK
Critical Care 2013, 17 (Suppl 2): P27 (doi: 10.1186 / cc11965)
Introduction Identifying a group of patients at high risk of developing infectious complications is the first step in the introduction of effective pre-emptive therapies in specific patient groups. Quantifying cytokine gene expression also furthers our understanding of trauma-induced immunosuppression. Our group has already demonstrated that a predictive immunological signature derived from mRNA expression in elective thoracic surgical patients accurately predicts pneumonia risk . Methods In total, 121 ventilated polytrauma patients were recruited. mRNA was extracted from PaxGene tubes collected within 2 hours of the initial insult, at 24 and 72 hours. T-helper cell subtype specific cytokines and transcription factors mRNA was quantified using qPCR. Ten healthy controls served as a comparator.
Results The Median Injury Severity Score (ISS) was 29. Time 0 bloods demonstrated a reduction in TNFaf, IL-12§, IL-23 *, RORyT * and T bet§, and an increase in IL-10 * and IL-4 + mRNA levels in comparison with the control group (* P <0.0001, P <0.001 to 0.0001, * P <0.01 to 0.001, §P <0.05 to 0.01). There was a positive correlation between ISS and IL-10 * whilst both IL-23§
Figure 1 (abstract P27). Cytokine mRNA levels in trauma (time 0) and control groups.
and RORyT * were negatively correlated at time 0. TNFa *, IL-10 * and IL-27 * increased and IFNy *, IL-12 *, IL-17A§, RORyT * and T bet * mRNA levels decreased over the initial 24 hours. Subsequent bacteremia (18/121 patients) was associated with a lower TNFa / IL-10 ratio * at baseline. Similarly, higher IL-10 * and lower T bet * mRNA at 24 hours also predicted later bacteraemic episodes. Development of pneumonia followed a similar pattern. A multivariate logistical regression model proved highly accurate in predicting infectious complications from mRNA analysis of early blood samples. See Figure 1.
Conclusion Cytokine gene expression patterns indicate an immediate and sustained impairment in Th1, Th17 and innate immunity with concurrent upregulation of the Th2 response following major trauma. The magnitude of this response predicts subsequent infectious complications. Reference
1. White M, et al .: Chest 201 1, 139: 626-632. P28
A cohort study of routinely used sepsis biomarkers and 28-day mortality
M De La Torre-Prados1, A Garcia-De la Torre2, C Trujillano-Férnández1 'Hospital Virgen de la Victoria, Málaga, Spain; 2Hospital Puerto Real, Cadiz, Spain
Critical Care 2013, 17 (Suppl 2): P28 (doi: 10.1186 / cc11966)
Introduction The evaluation of sepsis severity is complicated by the highly variable and nonspecific nature of clinical signs and symptoms. We studied routinely used biomarkers together with clinical parameters to compare their prognostic value for severe sepsis and evaluate their usefulness. Methods A cohort study of 150 patients> 18 years with severe sepsis according to the Surviving Sepsis Campaign, in an ICU of a university hospital. Demographic, clinical parameters and coagulation, infection and inflammation parameters during the first 24 hours from severe sepsis or septic shock onset were studied. Descriptive and comparative statistical analysis was performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA).
Results We analyzed 150 consecutive episodes of severe sepsis (16%) or septic shock (84%) in the ICU. The median age of the patients was 64 (interquartile range, 48.7 to 71) years; the main sources of infection were intra-abdomen (45%) and respiratory (38%); 70.7% had medical diseases. The 28-day mortality was 22.7%. The profile of death patients were men (64.7%, n = 22), with significantly higher average age (63 vs. 57 years; P = 0.049), as well as clinical severity scores, APACHE II (29.8 vs. 24.1; P < 0.001) and SOFA (12.1 vs. 8.9; P <0.001) and major dysfunction organ number (4.6 vs. 3.6; P <0.001). Bilirubin was the best predictor of 28-day mortality with the largest AUC (0.71), followed by hemoglobin (0.69) and C3 (0.67). The multivariate logistic regression was adjusted for three risk parameters, hemoglobin (OR: 0.68; 95% CI: 0.51 to 0.94), bilirubin (OR: 1.63; 95% CI: 1.08 to 2.45) and white blood cells (0R: 1.04; 95 % CI: 1.01 to 1.08) and with these parameters a ROC analysis was performed, giving an AUC of 0.77 (0.69 to 0.84). Conclusion The assessment of routine biomarkers (bilirubin, white blood cells and hemoglobin) may be a helpful tool in the decisionmaking process at the bedside, for the evaluation of early ICU admission of recoverable patients, as indicators of inflammatory response, organ dysfunction or catabolism level , and their significant predictive value on mortality. Reference
1. Glickman SW, Cairns CB, Otero RM, et al .: Disease progression in hemodynamically stable patients presenting to the emergency department with sepsis. AcadEmerg Med 2010, 17: 383-390.
Procalcitonin as a prognostic marker of mortality
S Zampieri1, P Bettonte2, M Ortolani1, G Frison1, V Schweiger1, L Gottin3, E Polati1
'Policlinico G.B. Rossi, Verona, Italy; 2Santa Chiara Hospital, Trento, Italy;
3Ospedale Maggiore Civile, Verona, Italy
Critical Care 2013, 17 (Suppl 2): P29 (doi: 10.1186 / cc11967)
Introduction We analyze procalcitonin (PCT) as a prognostic marker, in order to assess the clinical impact of a daily PCT measure.
Methods From November 2010 to November 2011 we collected clinical data, drug administration, scores and PCT values of 420 consecutive patients during hospitalization. Statistical analysis was made using SPSS software. We calculated ICU mortality, 1-month mortality and 1-year mortality. Median percentage daily variation was calculated as: (PCT day after - PCT of the date value) / PCT of the date valuex100. PCT variation in the last 48 hours of hospitalization was calculated as: (PCT at discharge - PCT at 48 hours before discharge) / PCT 48 hours before dischargex100. We compared peak values in dead patients versus alive patients. A logistic regression was performed in order to assess mortality odds ratio.
Results Of the 420 patients, 63 (15%) died in the ICU, 12 (2.86%) died 1 month after ICU discharge and 16 (3.80%) died 1 year after ICU discharge. PCT values were higher during the last day of hospitalization in dead patients versus alive patients. PCT percentage variation during the last 48 hours of hospitalization had a slower trend in patients who died than in those who survived; These differences are even more marked in patients who had a septic event. A slower descending trend of daily PCT values was found in patients who died than in those who survived. PCT peak levels during the ICU stay were higher in dead patients with respect to alive ones. At logistic regression analysis PCT decrease in the last 48 hours <-30% (OR 3.71), PCT peak higher than 10 ng / ml (OR 2.38), and PCT last day / PCT peak ratio> 50% (OR 2.064) were ICU mortality risk factors. PCT values were a higher predictive ICU mortality risk factor than SOFA and APACHE II scores. Other prognostic factors were age and lactate values. Only age was a risk factor in 1-month and 1-year mortality.
Conclusion PCT is a good prognostic marker and is strongly correlated to the clinical status and gravity of the patients, so PCT seems to be a useful marker in an intensive care scenario. References
1. Jensen JU, Heslet L, Jensen TH, et al .: Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med 2006, 34: 2596-2602.
2. Fritz HG, Brandes H, Bredle DL, et al .: Post-operative hypoalbuminaemia and procalcitonin elevation for prediction of outcome in cardiopulmonary bypass surgery. Acta AnaesthesiolScand 2003, 47: 1276-1283.
Changes in circulating procalcitonin versus C-reactive protein in predicting evolution of infectious disease in febrile, critically ill patients
S Hoeboer 1,2, J Groeneveld 1,2
'VU University Medical Center, Amsterdam, the Netherlands; 2Erasmus
Medical Center, Rotterdam, the Netherlands
Critical Care 2013, 17 (Suppl 2): P30 (doi: 10.1186 / cc11968)
Introduction Although absolute values for C-reactive protein (CRP) and procalcitonin (PCT) are well known to predict sepsis in the critically ill, it remains unclear if and how changes in CRP and PCT predict evolution of infectious disease and how they compare in this respect. Methods In 72 critically ill patients with new-onset fever, CRP and PCT were measured on day 0, 1, 2 and 7 after inclusion, and their clinical course was documented over 1 week with follow-up to day 28. Infection was microbiologically defined , as was bloodstream infection; septic shock was defined as infection plus shock. Results From peak at day 0 to 2 to day 7, CRP decreases most when (bloodstream) infection and septic shock (day 0 to 2) resolve and increases most when complications such as a new (bloodstream) infection or septic shock (day 3 to 7) supervene (area under the receiver operating characteristic curve 0.70 or higher, P = 0.04 or lower). PCT decreases most when septic shock resolves (AUC 0.72, P = 0.007) and increases most when a new bloodstream infection or septic shock supervenes (AUC 0.82 or higher, P <0.001). The day 7 value of PCT rather than of CRP was predictive for 28-day outcome (AUC 0.70, P = 0.005).Conclusion The data obtained during ICU-acquired fever and infections, suggest that CRP and PCT changes predict the course of infectious disease and its complications. CRP may be favored over PCT courses in decisions on appropriateness and duration of antibiotic treatment, whereas PCT rather than CRP courses may help predicting complications such as bloodstream infection, septic shock and mortality.
Procalcitonin-guided antibiotic therapy in patients with congestive heart failure and suspicion of lower respiratory tract infection: results from a randomized trial
P Schuetz, E Grolimund, A Kutz, S Haubitz, B Mueller
Aarau Cantonal Hospital, Switzerland
Critical Care 2013, 17 (Suppl 2): P31 (doi: 10.1186 / cc11969)
Introduction Differentiation of acute heart failure from infection in patients with respiratory symptoms and a history of congestive heart failure (CHF) is challenging due to overlap of clinical symptoms and X-ray findings. The BACH study found higher mortality rates if patients presenting with dyspnea were treated with antibiotics and their procalcitonin (PCT) levels were low indicating absence of bacterial infection. Yet the BACH study was observational and causal inference cannot be drawn. Come in, we analyzed the effects of PCT-guided antibiotic stewardship in CHF patients from a previous trial (ProHOSP). Methods This is a secondary analysis of a previous randomized trial of adult ED patients with respiratory symptoms and a history of CHF. Patients were randomized to administration of antibiotics based on a PCT algorithm (PCT group) or standard guidelines without knowledge of PCT levels (control group). The primary endpoint of this analysis is the risk of adverse outcome defined as death or ICU admission within 30 days after ED admission.
Results A total of 233 patients met the inclusion criteria, with 116 in the PCT-guided group and 117 in the control group. In the subgroup of patients with low initial PCT levels <0.25 ng / l (n = 110), PCT-guided patients had a significant reduction in antibiotic exposure (mean 3.7 vs. 6.5 days, difference -2.8 (95% CI -4.4, -1.2), P <0.001). Furthermore, PCT-guided patients had a significant lower risk for death and ICU admission (4% vs. 20%, odds ratio 6.0 (1.3, 28.2), P = 0.02). See Figure 1. Conclusion In CHF patients with suspicion of respiratory infection, use of a PCT protocol resulted in a significant decrease of antibiotic exposure and significantly improved outcomes in patients with low PCT levels indicating absence of bacterial infection. Whether inadequate antibiotic therapy in these CHF patients requiring diuretic treatment explains this difference in clinical outcomes needs verification.
Figure 1 (abstract P31). Time to adverse outcome according to group allocation.
Pro-adrenomedullin as a clinical predictor after cardiac surgery
J Van Fessem, F De Graaf, J Van Paassen, S Arbous LUMC, Leiden, the Netherlands
Critical Care 2013, 17 (Suppl 2): P32 (doi: 10.1186 / cc11970)
Introduction Pulmonary complications after cardiac surgery like ARDS are frequent and linked to high mortality . Pro-adrenomedullin (pro-ADM) has a possible role in the development of ARDS  and a positive correlation between levels of pro-ADM and inflammation was found . In this study we investigated whether intraoperative and postoperative pro-ADM transpulmonary gradient could predict postoperative morbidity.
Figure 1 (abstract P32). Pro-ADM transpulmonary gradient at different time points.
Methods In this prospective cohort study, 39 patients undergoing cardiac surgery using CPB were included. Blood was collected before surgery (T0), after induction of anesthesia (T1), after termination of CPB (T2), at ICU arrival (T3) and 3 hours (T4), 6 hours (T5) and 18 hours (T6) after arrival. Pro-ADM was measured with a sandwich immunoassay. Primary endpoints were length of ICU and hospital stay (ICU-LOS, hospital-LOS).
Results An increase of arterial and venous pro-ADM plasma concentrations was observed after surgery. Immediately after termination of CPB the venous concentration was significantly lower than arterial pro-ADM concentration, but at T6 the venous concentration was significantly higher, indicating a switch from a negative to positive transpulmonary gradient (Figure 1). The pro-ADM venous-arterial difference at T5 was a significant predictor of ICU-LOS (P = 0.032) and the difference at T3 was a significant predictor of hospital-LOS (P = 0.001). Conclusion We found that the transpulmonary gradient of pro-ADM was a predictor for ICU-LOS and hospital-LOS at T3 and T5, respectively. Pro-ADM might be a promising marker for prediction on outcome of patients undergoing cardiac surgery on CPB. The transpulmonary shift of pro-ADM might be caused by an inflammatory response. References
1. Apostolakis E, et al .: J Card Surg 2010, 25: 47-55.
2. Kamei M, et al .: Acta AnaesthesiolScand 2004, 48: 980-985.
3. Ueda S, et al .: Am J Respir Crit Care Med 1 999, 160: 132-136.
Pro-adrenomedullin as a prognostic biomarker in the sepsis
M De La Torre-Prados, A Garcia-De la Torre, A Enguix, M Mayor, N Zamboschi, C Trujillano-Fernández, A Garcia-Alcantara Hospital Virgen de la Victoria, Málaga, Spain Critical Care 2013, 17 (Suppl 2) : P33 (doi: 10.1186 / cc11971)
Introduction Measurement of biomarkers is a potential approach to early assessment and prediction of mortality in septic patients. The purpose of this study was to ascertain the prognostic value of pro-adrenomedullin (pADM), measured in all patients admitted to the ICU of our hospital with a diagnosis of severe sepsis or septic shock during 1 year.
Methods A cohort study of 117 patients> 18 years with severe sepsis according to the Surviving Sepsis Campaign, in an ICU of a university hospital. Demographic, clinical parameters and pADM, C-reactive protein and procalcitonin were studied during 1 year. Descriptive and comparative statistical analysis was performed using the statistical software packages Statistica Stat Soft Inc 7.1 and MedCalc 22.214.171.124. Results We analyzed 117 consecutive episodes of severe sepsis (15%) or septic shock (85%) in the ICU. The median age of the patients was
64 (interquartile range, 53 to 72) years; the main sources of infection were respiratory tract (46%) and intra-abdomen (21%). The 28-day mortality was 32.5%. The profile of death patients had a significantly higher average age (64.7 vs. 57.6 years; P = 0.024), as well as clinical severity scores, APACHE II (26.6 vs. 23; P = 0.006) and SOFA (11.6 vs. 89.2; P <0.001). Kaplan-Meier survival analysis was significant. P = 0.0017 for patients with pADM <1.2 nmol / l. Cox regression analysis also showed statistical significance (P = 0.0033) and a likelihood ratio = 1.18 per each 1 nmol / l increase in pADM.
Conclusion The protein pADM is an important prognostic biomarker of survival when measured on admission of septic patients to the ICU. References
1. Pezzilli R, Barassi A, Pigna A, et al .: Time course of proadrenomedullin in the early phase of septic shock. A comparative study with other proinflammatory proteins. Panminerva Med 2012, 54:21 1-217.
2. Wang RL, Kang FX: Prediction about severity and outcome of sepsis by proatrial natriuretic peptide and pro-adrenomedullin. Chin J Traumatol 2010, 13: 1 52-157.
Early IL-6 response in sepsis is correlated with mortality and severity score
P Srisangthong, A Wongsa, P Kittiworawitkul, A Wattanathum
Phramongkutklao Hospital, Bangkok, Thailand
Critical Care 2013, 17 (Suppl 2): P34 (doi: 10.1186 / cc1 1972)
Introduction IL-6, a proinflammatory cytokine, is synthesized from fibroblasts, T lymphocytes, endothelial cells and monocytes. It serves as an important mediator during the acute phase response to inflammation in sepsis. We hypothesized that the plasma IL-6 is correlated with mortality and severity scores in critically ill patients with sepsis. Methods We conducted a prospective study of plasma IL-6 level at the initial phase of sepsis and the risk of mortality. A total of 203 patients with sepsis, who were admitted to the medical ICU at Phramongkutklao Hospital, Bangkok during January to December 2011, were analyzed. Serum IL-6, C-reactive protein (CRP), and lactate were measured within the first 24 hours of ICU admission. Severity scores (APACHE II, SAP II, and SOFA scores) were measured. The primary outcome variable was 28-day all-cause mortality.
Results We found that the overall 28-day mortality was 46% (93 out of 203 patients). There was a significantly positive correlation between mortality rate and plasma IL-6 (survivors vs. nonsurvivors; 74 (4.4 to 1,718) vs. 206 (19 to 5,000) pg / ml, P <0.05), lactate (survivors vs. nonsurvivors; 1.65 (0.7 to 11.61) vs. 2.47 (0.94 to 19.13) mmol / l, P <0.05), but not CRP levels (P =
0.24 .. Compared with the patients with plasma IL-6 <100 pg / ml, septic patients with IL-6 levels> 100 were associated with an increased 28-day mortality with the odd ratio of 2.99 (95% CI 1.42 to 6.29, P <0.05). We also found that plasma IL-6 levels were well correlated with APACHE II (P <0.05), SAPS II (P <0.05), and SOFA (P <0.05) scores.
Conclusion The initial phase plasma IL-6 levels were correlated with severity and mortality in critically ill patients with sepsis. References
1. Pathan N, et al .: Crit Care Med 2005, 33: 1839-1844.
2. Harbarth S, et al .: Am J Respir Crit Care Med 2001, 164: 396-402.
Compared values of presepsin (sCD14-ST) and procalcitonin as early markers of outcome in severe sepsis and septic shock: a preliminary report from the Albumin Italian Outcome Sepsis (ALBIOS) study
P Caironi1, S Masson2, E Spanuth3, R Thomae4, R Fumagalli5, A Pesenti5, M Romero6, G Tognoni6, R Latini2, L Gattinoni1
'Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Universita degli Studi di Milano, Milan, Italy; 2Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; 3Diagnostic Engineering & Research GmbH, Heildelberg, Germany; 4 Mitsubishi Chemical Europe GmbH, Munich, Germany; 5Ospedale San Gerardo, Monza, Italy; 6 Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy
Critical Care 2013, 17 (Suppl 2): P35 (doi: 10.1186 / cc1 1973)
Introduction Sepsis results from complex interactions between infecting microorganisms and host responses, often leading to multiple organ failures and death. Over the years, its treatment has
been standardized in early goal-oriented therapies, which may benefit from circulating biomarkers for early risk stratification. We aimed to evaluate the prognostic value of presepsin (sCD14-ST), a novel marker of bacterial infection.
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