A survey of fever management in febrile intensive care patients without neurological injury

OBJECTIVE
To determine the attitudes of critical care clinicians in Australia and New Zealand towards fever management for critically ill patients with sepsis but without neurological injury.


DESIGN
Online scenario-based survey distributed to members of the Australian and New Zealand Intensive Care Society Clinical Trials Group and their intensive care colleagues.


MAIN OUTCOME MEASURES
The choice of intervention and preferred threshold temperature for modification of temperature in clinical practice and in a clinical trial.


RESULTS
Most respondents indicated a preference for the use of interventions to lower temperature at or below 39.0°C (80%; 337/423), with first-line preference being a combination of paracetamol and physical cooling. Secondline interventions included the addition of intensive physical cooling. Doctors chose higher temperature thresholds for intervention (32% [43/134] below 38.5°C and 27% [36/134] above 39.5°C) than nurses (78% [226/289] and 7% [19/289], respectively), who, in turn, indicated stronger preferences for the use of physical cooling. There is support (78%) for a clinical trial of fever management, with respondents suggesting randomising patients to a mean intensive control of temperature to 38.0°C versus a permissive approach with a threshold for intervention of between 38.8°×C (SD, 0.6°C) (nurses) and 39.5°C (SD, 0.7°C) (doctors).


CONCLUSION
There is considerable variability in attitudes to fever management with a reported tendency to act to reduce fever in febrile patients with sepsis. There was broad support for a clinical trial of fever management.

Introduction Anti-endotoxin immunity (AEI) has many biological eff ects but the problem of conjugation and elimination of lipopolysaccharides (LPS) in peritonitis patients is not discussed. We investigated the role of IgA, IgM and IgG in peritonitis and their association with humoral immunity (HI). Methods We investigated 33 patients (male:female = 25:8) with abdomi nal sepsis (total peritonitis in appendicitis, perforated duodenal ulcer, pancreonecrosis). Anti-endotoxin (AE) antibodies (anti-LPS-IgA, anti-LPS-IgM, anti-LPS-IgG) were determined by original modifi cation of hard-phase immunoenzyme analysis. Escherichia coli K30 LPS was used as antigen for AE antibody detection. The level of general immunoglobulin was determined by the microturbidimetric method with human monospecifi c sera to IgG, IgA and IgM. All data were compared with healthy donors (99 patients). Results A high level of AEI and HI was determined in 24% of patients who recovered rapidly without complication after surgery, discharged in 9 to 10 days. This was confi rmed by clinical data (normalization of body temperature, peristalsis, spontaneous stool) by 4 to 5 days. A low level of AEI and HI was found in 42% of patients who recovered slowly; in a favorable course of peritonitis, the increase of parameters was marked by 8 to 10 days; in several with suppuration of wounds, discharge was in 14 to 16 days. A few patients with a low level of immunity against the background of abdominal sepsis required therapy with sandoglobulin H that was accompanied with a sharp positive change of a postoperative course of peritonitis and an increase of immunity indices. See Table 1. An evident decrease of AE antibodies may be a background for translocation of endotoxin from the intestine to the portal and systemic circulation. Disorder of AE mechanisms of endotoxin conjugation may activate other mechanisms of neutralization (endotoxin-conjugating protein) that stimulate CD14-receptor structures and mechanisms of active production of proinfl ammatory cytokines and starting systemic infl ammatory response syndrome. Conclusion Abdominal sepsis patients are determined dysfunction of AEI (decrease of AE IgM and IgG). Successful treatment of peritonitis is accompanied with normalization of the IgM and IgG concentration and an increase of IgA above standard. Dynamics of AE antibodies may be a marker of the clinical course and forecast of abdominal sepsis. Comparative analysis of HI and AEI demonstrates parallelism of the dynamic concentration of immunoglobulins during treatment.  Introduction Tight glycemic control is a major concern in critical care. The objective of this study in the ICU was to evaluate the eff ectiveness and safety of the Yale insulin infusion protocol in sepsis patients. Methods A retrospective, before-after cohort study. Selected endpoints were mean blood glucose levels, time to reach the target range of 100 to 150 mg/dl, percentage of blood glucose in the target range, and hypoglycemia incidence.

P O S T E R P R E S E N TAT I O N S
Results Were studied 78 patients: 42 in the control group (CG) and 36 in the protocol group (PG). Bedside blood glucose was measured 3,755 times for a mean value of 134.1 ± 15.4 mg/dl in the PG versus 1,730 times for a mean value of 172.7 ± 33.6 mg/dl in the CG. Blood glucose values were in the target range 63% and 37% of the times, respectively, for the PG and the CG (P <0.001). The median time to reach the glucose target range was 8 hours (range 5 to 17 hours) for the PG and 53 hours (range 23 to 218 hours) for the CG (P <0.001). The incidence of severe hypoglycemia reached a statistically signifi cant diff erence: one patient in the PG versus four patients in the CG (P <0.01). All patients reached the target in 72 hours of insulin infusion in the PG while only 29 patients in the CG reached this target. Conclusion The Yale insulin infusion protocol was eff ective and safe in sepsis patients admitted to the ICU.
Introduction Vasopressin is frequently used to maintain blood pressure in refractory septic shock. We hypothesized that early infusion of vasopressin compared with norepinephrine would decrease the mortality rate and severity of septic status. Methods In this randomized, double-blind study, we assigned patients who need vasopressors and randomized to receive norepinephrine (0.05 to 2.0 μg/kg/minute) or vasopressin (0.01 to 0.03 U/minute) with norepinephrine. Both groups had the vasoactive drug infusions titrated and tapered to maintain a mean blood pressure between 65 and 75 mmHg. Results A total of 387 patients underwent randomization with 191 patients receiving vasopressin and 196 receiving norepinephrine. There was no signifi cant heterogeneity between these two study groups. There was a signifi cant diff erence between the vasopressin and norepinephrine groups in the mortality rate of 14 days (29.3% vs. 36.7%, respectively, P = 0.05) and 28 days (34% and 42.3%, respectively, P = 0.03); however, in 7-day mortality there were no signifi cant diff erences in the overall rates (21.2% vs. 23.9%, respectively; P = 1.1). Also note a reduction in the incidence of single organ dysfunction (37.7% vs. 49.2%, respectively, P = 0.02) and multiple organ dysfunction using vasopressin and norepinephrine (17.8% vs. 26%, P = 0.05; P = 0.03). The length of stay in the ICU was 14 and 17 days (P = 0.29) and the time of hospitalization was 23 and 28 days (P = 0.11), respectively, in the vasopressin and norepinephrine groups. Conclusion Early application of vasopressin reduced mortality rates in 14 and 28 days as compared with norepinephrine alone, and also a diff erence in incidence of organ dysfunction. This observed diff erence can be attributed to early restoration of tissue perfusion and vascular smooth muscle responsiveness that directly infl uenced patient survival.
Introduction Many symptoms of septic shock are due to the presence of endotoxin in the bloodstream. The biological activity of endotoxins is associated with lipopolysaccharide (LPS). LPS induces systemic infl ammatory response and a high level of endotoxin in blood is associated with worse clinical outcome. Reduction of the level of circulating endotoxins with hemoperfusion through the fi lter with high affi nity for LPS could potentially interrupt the biological cascade of sepsis. The aim of the study was to evaluate the effi ciency of extracorporeal endotoxin elimination in patients with Gram-negative septic shock. Methods The study was conducted at the Department of Anesthesiology and Intensive Therapy, Wroclaw Medical University, Poland. Patients with septic shock, documented or suspected Gram-negative infection, and with high endotoxin activity (EA >0.6 units) were eligible for the study. The endotoxin activity in blood was measured with chemiluminescent activity assay. Based on the enrolment criteria and EA level, patients were assigned to the conventional treatment group (Group 1) or the conventional plus hemoperfusion therapy with LPS adsorber (Alteco Medical AB, Lund, Sweden) group (Group 2). Hemoperfusion was performed for 2 hours with blood fl ow maintained at 150 ml/minute. Results Seventeen patients with low EA (0.42 ± 0.14, Group 1) and 12 patients with high EA (0.76 ± 0.13, Group 2) (P <0.05) were included. There were no signifi cant diff erences between Group 1 and 2 regarding age (63 ± 2 and 61 ± 21), APACHE II score (22.7 ± 8.6 and 24.5 ± 7.2), SOFA score (9.8 ± 3.0 and 11.3 ± 4.1), mean arterial pressure (MAP, 66.2 ± 8.1 mmHg and 71.5 ± 7.3 mmHg), and PaO 2 /FiO 2 (255 ± 59 and 216 ± 105) at entry to the study. In the hemoperfusion group, nine patients had Gram-negative and three had Gram-positive infection; seven patients survived to the 28-day follow-up. High endotoxin activity at baseline decreased signifi cantly 24 hours after hemoperfusion to 0.5 ± 0.1 (P <0.01) in those who survived, but remained high (0. 7  Introduction Urinary proteomics have recently identifi ed hepcidin, a key regulator of iron homeostasis, as a potential marker of tubular stress [1]. It appears to be released in response to situations that predispose to acute kidney injury (AKI), and greater concentrations of hepcidin in the blood and in the urine have been associated with reduced risk of AKI [2]. Catalytic iron is a biologically plausible mechanism for the development of AKI as a consequence of tubular oxidative stress [3]. The relationship between serum creatinine, urinary hepcidin and CRP may help defi ne whether urinary hepcidin is more likely to refl ect systemic infl ammation or renal events. The relationship in septic patients has not yet been described. Patients with SIRS, oliguria and a 25 μmol/l increase from baseline creatinine are known to be at an increased risk of AKI [4]. We sought to determine if hepcidin correlated more strongly with CRP or creatinine in these patients with a diagnosis of sepsis and those without. Methods Patients meeting the inclusion criteria within 48 hours of admission had their CRP, urinary hepcidin, and serum and urinary creatinine measured. The strength of the relationship between serum creatinine or CRP and urinary hepcidin corrected for urinary creatinine was determined using Spearman's rank correlation coeffi cient.

Results
We enrolled 103 patients between 31 August 2010 and 17 November 2010; 22 of whom had an APACHE III diagnosis of sepsis. Serum creatinine only correlated weakly with direct and inverse urinary hepcidin measurements in septic and nonseptic patients alike. However, there was a moderately strong correlation between CRP and urinary hepcidin in septic patients, a relationship not demonstrated in the nonseptic group (Table 1). Conclusion Hepcidin is only weakly inversely correlated with serum creatinine. A stronger relationship exists between hepcidin and CRP in septic patients, suggesting that hepcidin may primarily be a marker of infection that is fi ltered in the urine when the glomerular fi ltration rate (GFR) is preserved and fi ltered in lower amounts when the GFR is lost. That this relationship is not replicated in nonseptic patients with clinical evidence of SIRS suggests that the underlying pathophysiological processes are diff erent. Further investigation of the natural history of AKI and biomarker release is warranted. References patients [1]. Serum and urinary NGAL have been shown to be elevated in patients with SIRS, sepsis and septic shock [2], and the predictive ability of NGAL in these patients is not so certain [3]. It is unclear, however, whether this predictive relationship is due to the fact that NGAL is produced by neutrophils and is, therefore, a biomarker of infl ammation and infection, or whether NGAL in blood and/or urine mostly refl ects tubular release. It is also unclear if the type of AKI that develops in SIRS is diff erent from that developing in septic patients. Methods To test these hypotheses, we studied ICU patients with SIRS and oliguria or a 25 μmol/l increase in serum creatinine. We sought to determine whether blood and urine NGAL correlated more closely with CRP or creatinine at the time of enrolment. The strength of the relationship between serum creatinine or CRP and urine and serum NGAL, as well as urinary NGAL corrected for urinary creatinine, was determined using Spearman's rank correlation coeffi cient. Results We recruited 105 patients between 31 August 2010 and 17 November 2010; 22 of these had an APACHE III diagnosis of sepsis. In nonseptic patients NGAL in blood or urine correlated only weakly with CRP, but a stronger and statistically signifi cant relationship was observed between serum and/or urine NGAL and serum creatinine. A similar strength of relationship was observed between creatinine and NGAL and CRP and NGAL in septic patients, although it failed to reach signifi cance. See Table 1.

Introduction
The utility of urinary biochemistry has recently been challenged [1], while there is emerging evidence that renal biomarkers may accurately quantify the risk of development of acute kidney injury (AKI) [2]. Neutrophil gelatinase-associated lipocalin (NGAL) is a marker of renal tubular damage [3]. Fractional excretion of sodium (FENa) is a marker of renal tubular function, and is a signifi cantly cheaper investigation [4]. Insults damaging the tubules and resulting in AKI should both stimulate NGAL production and prevent resorption of sodium. Given the diff erent pathological mechanisms underlying septic and nonseptic AKI, it is plausible that the relationship between these variables could be diff erent in these two groups of patients [5].
Methods To test this hypothesis, we studied ICU patients developing SIRS and oliguria or a 25 μmol/l increase in serum creatinine within 48 hours of ICU admission. We sought to determine if a relationship existed between FENa and NGAL in patients, with and without sepsis, developing AKI. We measured the serum and urinary NGAL, creatinine and sodium of patients with SIRS and either oliguria or an increase in creatinine within 48 hours of admission to a tertiary referral ICU. Pointof-care creatinine measurements were used to identify the maximum RIFLE category of AKI developed within the fi rst 5 days of admission. The strength of the relationship between variables was determined using Spearman's rank correlation coeffi cient. Introduction Multiple biomarkers have been proposed for identifying patients at risk of developing the syndrome of acute kidney injury (AKI) [1]. These biomarkers include urine and serum NGAL, and urinary hepcidin. The pathophysiology of AKI in sepsis appears to be primarily mediated by immunological, toxic and infl ammatory factors as opposed to renal ischaemia [2]. Diff erent aetiologies of AKI are likely to lead to diff erential release of serum and urinary biomarkers. We sought to determine if the predictive ability of several renal biomarkers for predicting AKI varied in the presence of sepsis in the context of routine ICU practice. Methods We measured serum and urinary NGAL and urinary hepcidin in patients admitted to the ICU of a tertiary referral hospital with SIRS and either oliguria or a 25 μmol/l serum creatinine increase within 48 hours of admission. We used point-of-care creatinine measurements to identify the maximum RIFLE category of AKI within the fi rst 5 days of enrolment. We corrected both urinary biomarkers for urinary creatinine. We calculated the reciprocal of hepcidin measurement and noted if serum NGAL was greater than the upper limit of normal (149 ng/ml). We derived the area under the curve (AUC) for the receiver operating characteristic curve (ROC) for all biomarkers. Results Between 31 August 2010 and 17 November 2010, we enrolled 92 patients; 17 of these patients had APACHE II diagnoses of sepsis. In patients with a diagnosis of sepsis, the predictive ability of all of the biomarkers measured was worse than in those without (Table 1). Conclusion Although the sample size is limited, there is a marked diff erence in the predictive ability of the measured biomarkers to predict AKI between septic and nonseptic patients. All patients admitted met the criteria for a diagnosis of SIRS, suggesting that infl ammation and sepsis contribute to the development of AKI via diff erent pathways. The ability of these biomarkers to predict AKI in patients with a diagnosis of sepsis in our cohort is limited. Further investigation is needed into whether the combination of specifi c biomarker patterns and clinical features can better identify patients at risk, particularly in the setting of sepsis. In addition, further work examining the relationship between the various biomarkers and the aetiology and natural history of AKI is required.

Results
Introduction While cancer patients are known to be at higher risk for infection and subsequent complications, there is a scarcity of data regarding incidence and outcome of septic cancer patients admitted to ICUs. Hence, we aimed to assess the incidence of cancer patients admitted with sepsis to an onco-medical ICU and study their ICU course and outcome. Methods Data were collected prospectively from all cancer patients admitted to a specialized onco-medical ICU of a tertiary care hospital, over a period of 6 months. Sepsis was defi ned as per the international guidelines. Cancer patients were divided into two groups on the basis of presence of sepsis on ICU admission and compared with regard to their need for organ support, length of ICU stay and mortality. Severity of illness was assessed by APACHE II score and organ failure by SOFA score. Qualitative data were analyzed using the chi-squared test or Fisher exact test as appropriate and quantitative data were analyzed using Student's t test. P <0.05 was considered signifi cant. Results Out of 104 cancer patients admitted during the study period, 43 (41.3%) patients were admitted with sepsis. Even though there was no diff erence in age (P = 0.13), sex (P = 0.382) and presence of metastasis (P = 0.314) among the septic and nonseptic groups of patients, septic patients had comparatively higher admission APACHE II (21.4 ± 7 vs. 18.21 ± 6.9; P = 0.023) and SOFA (6.4 ± 3.8 vs. 4.56 ± 3; P = 0.007) scores, required invasive mechanical ventilation (65.1% vs. 19.7%; P = 0.000) and vasopressor support (74.4% vs. 19.7%; P = 0.000) more often, had a longer ICU stay (10.77 ± 8.4 vs. 7.44 ± 5.5; P = 0.017) and had a higher ICU mortality (62.8% vs. 18%; P = 0.000). The odds ratio and relative risk Introduction Certain colloids like albumin and plasma protein fraction (PPF) have been derived from human plasma and they are used as plasma expanders to treat patients with shock. PPF, which more closely resembles plasma in its constituents, contains albumin plus α and β globulins. We conducted this study to assess the eff ect of PPF on need for vasopressors, organ support and ICU mortality in patients with septic shock. Methods A retrospective study was conducted and data were collected from the records of patients admitted to a 16-bed neuro and medical ICU over a 1.5-year period. All adult patients admitted with septic shock and requiring vasopressor support (for more than 6 hours) in spite of aggressive fl uid resuscitation were enrolled. Patients who were transferred from some other ICU or ward and those who developed shock during their ICU course were excluded from the analysis. Patients were divided into two groups: patients in whom PPF was used along with resuscitative fl uids comprised the study group, whereas others formed the control group. Patients in these groups were compared according to need for organ support, ICU mortality and time taken to stop vasopressor agents. PPF (Plasmanate®) was administered in a protocolized way at the dosage of 10 to 20 ml/hour for the fi rst 48 hours. Development of any complication like allergy or hypotension associated with PPF was also noted. Results There was no signifi cant diff erence in the baseline characteristics of patients in both groups in terms of age (P = 0.154), sex (P = 0.479), severity of illness (APACHE II score, P = 0.356), and presence of organ failure (SOFA score, P = 0.105). Among the outcome parameters there was no signifi cant diff erence in terms of need for renal support (P = 0.814), mechanical ventilation (P = 0.776), ICU stay (P = 0.122), hospital stay (P = 0.054) and ICU mortality (P = 0.091). However, there was a signifi cant diff erence in time taken to stop the vasopressors (P = 0.030) ( Table 1). There were no incidences of any complications or side eff ects in any group. Conclusion PPF may be used safely and eff ectively for initial resuscitation of patients with septic shock requiring vasopressor support. It may lead to early termination of vasopressor support; however, it did not translate to lesser need for organ support or reduced ICU mortality in our patient cohort. To demonstrate such benefi ts, larger multicenter trials are warranted.
Introduction Disease-severity scoring systems have been developed for stratifi cation of ICU patients. These systems have been tested and validated in various general medical and surgical ICU patients. However, the validity and effi cacy of these systems, especially the newer generation, has not been assessed in patients with sepsis, which is the commonest indication for admission to a medical ICU. Hence, we conducted this study to assess the performance of various ICU scoring systems -Acute Physiology and Chronic Health Evaluation (APACHE) II, III, IV; Simplifi ed Acute Physiology Score (SAPS) II, III; Mortality Prediction Model (MPM) II 0 , III 0 ; and Sequential Organ Failure Assessment (SOFA) scores -in septic patients admitted to a medical ICU.
Methods A prospective, observational study was conducted in a tertiary care medical ICU and consecutive patients fulfi lling the diagnostic criteria for sepsis during the fi rst 24 hours of ICU admission were included over a 2-year period. Data related to patient demographics and that required to compute various scores were recorded. Predicted mortality was calculated using original regression formulas. The standardized mortality ratio (SMR) was computed for mortality prediction. Calibration was assessed by calculating the Lemeshow-Hosmer goodness-of-fi t C-statistic. Discrimination was assessed by calculating the area under the receiver operating characteristic (AUROC) curves. ICU mortality was the primary outcome measure. Results Data were analyzed for 438 septic patients. The mean age of patients was 64.5 ± 16.3 years and 301 (68.7%) were male. The mean ICU and hospital length of stay was 6.39 ± 9.7 and 9.99 ± 10.5 days, respectively. The observed ICU mortality was 107/438 (24.4%). Mortality predicted by SAPS III score was closest to that of actual mortality with a SMR of 0.98 followed by that of MPM III 0 (SMR -1.13) and APACHE IV (SMR -1.18) scores (Table 1). APACHE IV (χ 2 = 4.416; P = 0.818) had the best calibration followed by SAPS II (χ 2 = 6.073; P = 0.639) and SAPS III scores (χ 2 = 6.538; P = 0.587). There was no statistically signifi cant diff erence between the AUROCs of these scores; SOFA (AUROC = 0. 0.889) performed the best followed closely by APACHE IV (AUROC = 0.882) and APACHE III (AUROC = 0.880) scores (Table 2). Conclusion Overall, the newer generation of scoring systems performed better than their older counterparts and was more accurate. Older scoring systems had a tendency to overpredict mortality. However, all the scores tested had good effi cacy and the diff erence in effi cacy was not statistically signifi cant.

Introduction
The aim was to study the impact of infl ammation/ sepsis on the concentrations of cystatin-C and neutrophil gelatinaseassociated lipocalin (NGAL) in plasma and urine in adult ICU patients and to estimate the predictive properties of cystatin-C and NGAL in plasma and urine for early detection of acute kidney injury (AKI) in patients with sepsis. Methods The RIFLE class for AKI was calculated daily, while plasma and urinary Cys-C and NGAL were determined on days 0 and alternate days until ICU discharge. Test characteristics were calculated to assess the diagnostic performance of urinary and plasma Cys-C and NGAL. The diagnostic and predictive performances of the markers were assessed from the area under the receiver operator characteristic curve (AUC).
Although plasma NGAL performed less well (AUC = 0.58). Conclusion Plasma and urinary Cys-C are useful markers in predicting AKI in sepsis. pNGAL is raised in patients with sepsis, and should be used with caution as a marker of AKI in ICU patients with sepsis. uNGAL is more useful in predicting AKI as the levels are not elevated in septic patients without AKI. Introduction Sodium selenite (Na 2 SeO 3 ) has been proposed as an early treatment of septic shock with discrepant results [1][2][3]. Benefi cial action is mainly believed through improvement of major antioxidant selenoenzymes, but could on the contrary be related to a therapeutic oxidant action reducing activity of hyperactivated circulating phagocytic cells [4]. It has been suggested that the absence of benefi cial eff ect of high-dose Na 2 SeO 3 continuously administered [2] might be related to toxicity, especially on the lung, of too much selenium (Se) as mentioned in recent parenteral nutrition guidelines in intensive care [5]. On additional clinical and biological data, our purpose was to assess if there was argument for Na 2 SeO 3 toxicity, especially on the lung, under continuous administration of high-dose Na 2 SeO 3 in the SERENITE study.

Clinical and biological eff ects of high-dose sodium selenite, continuously administered in septic shock
Methods In a randomized, double-blind multicenter study performed in 60 septic shock patients [2], the effi cacy and tolerance of Na 2 SeO 3 (4 mg Se on day 1 (D1), then 1 mg/day during 9 days or placebo) were evaluated on all components of the SOFA score measured daily, infection rate, and plasma Se, selenoprotein-P (Sel-P), glutathione peroxidase (GPx), lipid peroxidation, cytokines, and procalcitonin measured at D0, D4, D7, D10 and D14.
Results No deleterious eff ect of Na 2 SeO 3 especially on the lung was observed for any clinical or biological variables. PaO 2 /FiO 2 was strictly identical between groups ( Table 1). As compared with placebo, mean time occurrences of infections were delayed in the treated group (18 ± 24 days vs. 34 ± 28 days, respectively; P <0.0001). Plasma Se, Sel-P and GPx concentrations were increased at D4 in the treated group, achieving the high reference value for the plasma Se concentration (Figure 1). Conclusion Continuous administration of high doses of Na 2 SeO 3 (4 mg Se D1) did not induce any deleterious eff ect in septic shock patients. We did not observe a benefi cial eff ect, contrasting with a comparable study administering Na 2 SeO 3 in bolus, potentially more toxic [1]. In agreement with results obtained on a peritonitis sheep model [6], our data support a therapeutic oxidant action of Na 2 SeO 3 , opening a new fi eld in septic shock treatment based on oxidant selenocompounds. Data presented as mean ± SD (KPa).

Introduction
The use of pharmacological and physical antipyretic therapies to reduce fever in febrile patients is common in hospital settings. Actual evidence on the frequency of antipyretic use is limited, however, both in general hospital populations and, more specifi cally, in adult intensive care [1][2][3]. We undertook a prospective point prevalence study with the aim of identifying the prevalence of physical and pharmacological antipyretic therapies in intensive care patients with sepsis and infl ammation. We also recorded the indication for antipyretic therapies, temperature measurement site, and mean temperatures on the study day.
Methods We conducted a single-day observational point prevalence study in 38 ICUs in Australia and New Zealand. All patients in participating ICUs at a 10:00 am census point were studied. Data were collected for the 24-hour study day that included the 10:00 am time point.

Results
We studied 506 patients, with a mean age 59 years (SD = 17 years); 65% male; APACHE II score 17 (SD = 7), 28-day mortality 14%. Eighty percent of the ICU admissions were unplanned. Of the 506 patients, 311 patients had sepsis and infl ammation with mean peak temperature of 37.3°C (SD = 0.8°C). Of these, 35% (n = 100/311) had a mean peak temperature above 38°C. In the 24-hour period, paracetamol was used 50% (n = 152/311) of the time, nonsteroidal anti-infl ammatory drugs (NSAIDs) 0.6% (n = 2/311) and physical cooling 1% (n = 3/311) ( Figure 1). Of patients that had an indication for paracetamol recorded, 64% was for pain (n = 92/152), 18% for both pain and fever (n = 26/152); and 10% for fever alone (n = 14/152) ( Figure 2). Sixty-four percent (n = 92/152) of the patients who had paracetamol were prescribed regular paracetamol and 36% (n = 51/143) had a PRN order. Of the 40 patients who received paracetamol for an indication of fever, the mean peak temperature was 38.3°C (SD = 0.8°C; range 36.1 to 40.2°C). Of the three patients who received physical cooling, the mean peak temperature was 39.2°C (SD = 0.9°C; range 38.5 to 40.2°C). Temperature measurement sites were mainly noncore (n = 251/311) with axillary (37%; n = 116/311) and tympanic (35%; n = 110/311) most common ( Figure 3). Conclusion This point prevalence study of intensive care patients with sepsis and infl ammation identifi ed pharmacological antipyretics are used regularly for pain management rather than fever management, with paracetamol the most common therapy. The use of physical cooling was rare, and noncore temperature measurements were common. These results are important in understanding current temperature management practice in intensive care and will aid in designing future clinical trials on the subject.
Introduction Fever is a common observation during critical illness [1,2] and may be due to many possible causes such as infection, sterile infl ammation and neurological injury. Clinical trials of fever management lack suffi cient methodological quality to answer the question of whether attempts at reduction in temperature improves patient-centred outcomes in patients with sepsis, infl ammation or neurological injury [3][4][5][6][7]. We undertook a survey to describe the attitudes of critical care clinicians in Australia and New Zealand towards fever management in critically ill patients without neurological injury or hyperthermic syndromes. Methods An online scenario-based questionnaire survey was distributed to medical and nursing members of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG) and their intensive care colleagues. Main outcome measures: the choice of drug and preferred threshold temperature for intervention with antipyretics in clinical practice and in a clinical trial. Results There were 588 email invitations distributed through the ANZICS-CTG and Research Coordinator mailing list. Four hundred and forty-seven responses were received from 308 nurses (69%), 137 doctors (31%), and two others (0.5%). The majority of respondents having more than 8 years of experience (62%) worked in mixed medical and surgical units (84%) in a metropolitan or tertiary hospital setting (77%). The primary fi ndings of our survey suggest that fever management is highly variable. Most clinicians administer an intervention to reduce temperature at or below 39°C ( Figure 1); and initially use a combination of both pharmacological and physical interventions, with an increase in intensity of physical interventions for persistent fever ( Figure 2). There were diff erences between the professions, with doctors choosing higher temperature thresholds for intervention and nurses generally using more physical cooling ( Figure 1 and Table 1); fourthly, temperature thresholds for a clinical trial were 39.0°C (SD = 0.7°C) for a permissive strategy and 38.0°C (SD = 0.75°C) for an intensive strategy; fi nally, there was broad support for a clinical trial of fever management. Conclusion This survey suggests there is considerable clinical variability in fever management in patients with sepsis and without neurological injury or hyperthermic syndromes. At present, no particular management strategy is known to be superior to any other and it remains possible that current practice may be harming substantial numbers of patients. A temperature threshold of up to 40°C may be acceptable to clinicians for the design of a future randomized controlled trial. Further observational data may be informative for the design of such clinical trials.   Introduction Sepsis is a life-threatening condition characterized by a whole-body infl ammatory state. The early diagnosis and treatments of sepsis will improve the outcome of patients. The aim of this study was to compare blood levels of presepsin (renamed from soluble CD14 subtype), procalcitonin (PCT), IL-6 and C-reactive protein (CRP) and to investigate the most useful biomarker for early diagnosis of sepsis. Methods A single-center, prospective, observational study. Patients who had one or more systemic infl ammatory response syndrome criteria were included in this study. The blood samples for measuring the biomarkers were collected and the severity of sepsis was evaluated at the time of admission and every other day for a week. Forty-two patients were enrolled for the prospective study from June 2010 to December 2010. Results Twenty-three patients were diagnosed with sepsis and 19 patients were without sepsis. In the receiver operating characteristics (ROC) curve analysis, the area under the curve (AUC) to distinguish sepsis was the largest for presepsin (0.930) followed by IL-6 (0.896), PCT (0.854) and CRP (0.840). Presepsin may be able to discriminate between patient groups with or without sepsis. From the ROC curve analysis, a cut-off value of presepsin was 929 pg/ml with sensi tivity and specifi city of 76% and 81%, respectively, with odds ratios and 95% CIs of 0.996 (0.992 to 0.998) and 3.376 (1.497 to 6.094). And the presepsin values were signifi cantly higher in the patients with the more severe septic condition (for example, sepsis, severe sepsis, septic shock). In addition, a signifi cant correlation was found between the Sepsis-related Organ Failure Assessment scores and the presepsin values (r 2 = 0.320; P = 0.0003). But there was a no signifi cant correlation between APACHE II scores and the presepsin values.
Conclusion In this study, presepsin is the most valuable predictor about sepsis compared with PCT, IL-6 and CRP. Moreover, the results suggest that presepsin values can serve as a parameter that closely refl ects the pathology. So we strongly suggest that the presepsin will be not only a very useful new biomarker of the diagnosis of sepsis, but also useful for monitoring the severity of the disease in the near future.

Introduction
The UK national body, which reviews maternal mortality (Centre for Maternal and Child Enquiries (CMACE)), has recently published their 2006 to 2008 report. This highlighted an increase in maternal sepsis, making it the leading cause of direct death amongst peripartum women in the UK (26 out of a total 107 direct deaths) [1]. The Surviving Sepsis Campaign (SSC) published updated sepsis resuscitation and management bundles in 2008 [2]. We decided to audit awareness about sepsis amongst staff caring for perpartum women.
Methods A questionnaire was devised and distributed to midwives, obstetricians and anaesthetists. This asked the criteria for the systemic infl ammatory response syndrome (SIRS), common sites of maternal sepsis, the initial duties of care ('sepsis six' resuscitation bundle: delivery of oxygen, intravenous fl uids, intravenous antibiotics, taking of blood cultures, measurement of plasma haemoglobin, lactate and urine output) and recognition and management of severe sepsis. Results There was a 98% response rate with 41 completed questionnaires returned, 15 from midwives, 13 from obstetricians and 13 from anaesthetists. We found that awareness was suboptimal within all groups. Of the six criteria for SIRS, suggested by the SSC, two criteria (altered consciousness and hyperglycaemia) were poorly identifi ed and few responders were aware that two or more criteria indicated SIRS (Figure 1). Most healthcare professionals correctly identifi ed genital tract infection as the leading source of maternal sepsis. The majority of responders had not heard of the 'sepsis six' (Figure 2). Out of the initial duties of care, delivery of oxygen and monitoring urine output were poorly identifi ed. Respondents were not confi dent in identifying features of severe sepsis and with the exception of hypotension despite fl uids, other markers of end organ dysfunction were underreported. Conclusion It is all of our responsibilities to focus eff orts on the emerging threat of maternal sepsis as highlighted by CMACE. Historically, we have seen a signifi cant improvement in maternal mortality rates when specifi c interventions have targeted those issues raised in previous  Critical Care 2011, Volume 15 Suppl 3 http://ccforum.com/supplements/15/S3 S10 CMACE reports (for example, venous thromboembolism). We therefore propose to develop local clinical guidelines, posters and factsheets with formal teaching sessions and multidisciplinary simulator workshops to raise awareness, optimise care and minimise preventable deaths from maternal sepsis. We will re-audit awareness in 6 months time to complete the audit cycle.
Introduction Vitamin D plays an important role in immune and cardiovascular function. There is evidence that low 25-hydroxyvitamin D (25(OH)D) levels are associated with an increased risk of lifethreatening infections [1,2]. Our objective was to determine the prevalence of 25(OH)D defi ciency (<20 ng/ml) in critically ill children and to identify any association with illness severity and infection. Conclusion The overall prevalence of vitamin D defi ciency in critically ill children is high, and patients with severe septic shock had signifi cantly lower vitamin D levels than the general population. This association between vitamin D and septic shock may be due to the cardiovascular eff ects of vitamin D or to increased severity of infection with diminished 25(OH)D levels. These results suggest a role for the vitamin D axis in sepsis and hemodynamic instability that deserves further investigation.

Introduction
The endothelial glycocalyx is a recently discovered structure at the luminal side of blood vessels consisting of proteoglycans and glycosaminoglycans, which play an important role in vascular barrier function and cell adhesion. Due to its vulnerability, the endothelial glycocalyx may easily be altered by hypoxia [1], TNFα [2], oxidized lipoproteins [3] and other nonphysiological conditions. We raised the question of whether the glycocalyx may be shed from the endothelium in dependence of severity of sepsis. Methods This clinical prospective study -approved by the local ethics committee -was performed to assess plasma levels of the glycocalyx components (hyaluronane, syndecan, heparan sulfate) by ELISA technique and polymorphonuclear leukocyte (PMN) function by fl ow cytometry in eight healthy volunteers (HV) and 37 patients who were prospectively enrolled within 24 hours of onset of signs of infection, if they met the criteria for sepsis (n = 10), severe sepsis (n = 9) and septic shock (n = 18) as defi ned by the members of the ACCP/SCCM Consensus Conference Committee (Table 1). Blood was drawn within  Critical Care 2011, Volume 15 Suppl 3 http://ccforum.com/supplements/15/S3 S11 24 hours after onset of sepsis. Informed consent was obtained from all patients or their legal representatives, respectively. Results Plasma levels of the glycocalyx components were signifi cantly higher in septic patients than in healthy volunteers and even more pronounced in patients with severe sepsis and septic shock (all P <0.05; Figure 1). Hyaluronan and syndecan plasma levels correlated positively with the APACHE II, SOFA and MOD scores ( Figure 1 and Table 2). Hyaluronan displayed a positive correlation with the C-reactive protein, procalcitonin and IL-6 in plasma ( Table 3). The PMN dysfunctioncharacterized by an increase in cytotoxic capability and a decrease in microbicidity -showed a parallel course to the heparan sulfate plasma levels.
Conclusion Elevated plasma levels of hyaluronan, syndecan and heparan sulfate are suggestive of a glycocalyx shedding from endothelium with increasing sepsis severity. This process might contribute to the vascular dysfunction and development of edema in septic patients.   Conclusion Peak temperature in the fi rst 24 hours in the ICU is associated with decreased in-hospital mortality in critically ill patients with an infection; randomised trials are needed to compare the eff ect on mortality of controlling fever against a permissive approach to fever management in such patients.  Conclusion These observations indicate that PCT is a better prognostic indicator than hsCRP and is also a better predictor of bacteremia in the newly admitted critically ill patients of sepsis. Hence, routine use of PCT as a monitoring tool may aid in appropriate therapeutic intervention in patients with sepsis.
Introduction Over the past several years, the early identifi cation and aggressive treatment of sepsis patients has become a standard of care in the hospital setting. A relatively small number of emergency medical service (EMS) systems have started programs to screen for sepsis; an even smaller number provide treatment based on that screening process in the prehospital setting.
Objective The purpose of this study is twofold. First, the study aims to determine how eff ectively paramedics working in the county EMS system can use a screening tool to identify potential sepsis patients and provide an alert to the receiving hospital. Second, the study will examine whether or not an early identifi cation process in the fi eld leads to improved treatment of sepsis. The end goal is to reduce morbidity and mortality of sepsis patients in the hospital setting.
Methods This is a multi-site prospective observational study with comparison to retrospective cohort. Patient data will be collected to determine whether or not the alert process leads to early obtaining of a serum lactate measurement and early goal-directed therapy. Results Data points being analyzed from prehospital care reports: criteria from the sepsis screening tool include evidence of infection, temperature, heart rate, respiratory rate; and EMS fi eld clinical impression (for comparison with emergency department (ED) admitting diagnosis). Data points being analyzed in the hospitals include the following: ED admitting diagnosis; serum lactate values, blood culture, timestamps; evidence of early goal-directed therapytimestamps/values for fl uid and antibiotic administration; hospital admitting diagnosis; and discharge diagnosis. The results of the study will be available by 2012/2013. Conclusion Preliminary anecdotal and early data analysis reports from EMS and hospital staff suggest that patients are being identifi ed as septic prior to ED arrival and have lower lactate levels. Patients are also treated more timely on arrival to the ED for sepsis. Final data analysis will shed more light on our hypothesis. Early identifi cation of septic patients has implications for further research both in the fi eld and hospital settings.
Introduction Despite extensive research in the fi eld of sepsis pathogenesis and its management, mortality associated with sepsis in hospitals remains very high. For example, more than 18 million people are aff ected by sepsis worldwide and have an expected 1% increase annually in ICUs. Sepsis is the outcome of a deregulated immune system occurring during systemic bacterial (that is, Gram-negative or Gram-positive) infection. So modulating the immune system by an immunomodulatory approach may prove benefi cial to sepsis patients.
In the present study, we evaluated the protective immunomodulatory eff ect of thalidomide alone or with augmentin in Klebsiella pneumoniae B5055-induced sepsis in BALB/c mice. Methods The mouse model of sepsis was developed by placing K. pneumoniae B5055 entrapped in fi brin and thrombin clots in the peritoneal cavity of mice. The septic mice were treated with thalidomide alone (30 mg/kg/day p.o.), with augmentin alone (20 μg/ml i.p.) and with their combination. The bacterial load in blood was estimated by blood culture on MacConkey's agar plates along with measuring the other systemic infl ammatory parameters. For example, lipid peroxidation was measured in terms of malondialdehyde (MDA) and nitric oxide (NO) levels in serum by biochemical methods. Levels of proinfl ammatory cytokines (that is, TNFα and IL-1α) and antiinfl ammatory cytokine (that is, IL-10) levels in serum were measured by ELISA.

Results
The thalidomide-alone-treated mice showed 75% survival whereas 60% of the augmentin-alone-treated group survived. However, their combination (thalidomide + augmentin) treatment provided 100% survival. Treatment with thalidomide alone signifi cantly (P <0.05) decreased TNFα, IL-1α, NO and MDA levels in the serum without signifi cantly (P <0.05) decreasing the bacterial count in blood. However, levels of IL-10 in serum were found to be signifi cantly (P <0.05) elevated upon thalidomide treatment. Augmentin alone only decreased the bacterial load in blood signifi cantly (P <0.05), while no signifi cant decrease was observed on infl ammatory mediators studied. However, a combination thalidomide with augmentin signifi cantly (P <0.05) decreased both the bacterial count as well as infl ammatory mediators (that is, TNFα, IL-1α, NO and MDA) and provided 100% protection to animals. Conclusion Thalidomide can be used as an immunomodulatory agent along with antibiotics for sepsis management.

Introduction
In septic shock, iNOS activation and nitric oxide (NO) overproduction contribute to vascular hyporeactivity to adrenergic vasopressors. The consequent hypotension often necessitates high doses of catecholamine administration. However, this may lead to detrimental eff ects on tissue perfusion, immune function and myocardial function. Asymmetric dimethlyarginine (ADMA), an endo ge nous inhibitor of NO synthase, is extensively metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Competitive inhi bi tion of the DDAH-1 isoform should thus reverse hypotension but, as this isoform is absent in immune cells, it should not compromise the immune eff ects of NO. Hence, we investigated whether L257, a novel DDAH-1 inhibitor, could spare norepinephrine dosing in a rat endotoxic shock model. Methods Anaesthetised, spontaneously breathing male Wistar rats (body weight 270 to 330 g) had their left carotid artery and right internal jugular vein cannulated for arterial pressure monitoring and fl uid infusion, respectively. Then 40 mg/kg Klebsiella pneumoniae lipopolysaccharide was administered intravenously over 30 minutes followed by fl uid resuscitation at a rate of 10 ml/kg/hour thereafter. When the mean arterial pressure fell over 20% below baseline, they received norepinephrine titrated to maintain arterial pressure at ±10% baseline. Thirty minutes post commencement of norepinephrine, animals were randomized to receive either L-257 (3 mg/kg bolus then infusion of 125 μg/hour) or, in controls, an equivalent volume of saline. Experiments were terminated 3 hours post commencement of norepinephrine titration, before which echocardiography was performed and serum samples were collected for biochemistry. Results L-257-treated animals (n = 8) required a signifi cantly lower total dose of noradrenaline over 3 hours compared with the eight control animals (38 ± 9 vs. 48 ± 4 μg, P <0.05). The heart rate was signifi cantly lower in the treatment group (P <0.05), which associated with a trend of increased stroke volume and cardiac output. Serum BUN and urea were also signifi cantly lower in the treatment group (P <0.05, Table 1). Conclusion In this acute endotoxic rat model, we demonstrate that DDAH-1 inhibition by L-257 could reduce norepinephrine dosage and ameliorate its harmful eff ects. This agent warrants further study as a putative therapy for septic shock.
Introduction Excessive NOS activity and NO overproduction are believed to play an important role in sepsis-induced macrocirculatory and microcirculatory dysfunction. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, is extensively metabolised by dimethylarginine dimethylaminohydrolase (DDAH).  The DDAH-1 isoform is present in vascular smooth muscle so its inhibition should theoretically reverse sepsis-induced hypotension. We thus investigated the dose-dependent cardiovascular eff ects of a novel DDAH-1 competitive inhibitor, L-257, in experimental sepsis. Methods Anaesthetised, spontaneously breathing male Wistar rats (body weight 270 to 330 g) had their left carotid artery and right internal jugular vein cannulated for arterial pressure monitoring and fl uid infusion, respectively. Then 40 mg/kg Klebsiella pneumoniae lipopolysaccharide was administered intravenously over 30 minutes followed by fl uid resuscitation at a rate of 10 ml/kg/hour thereafter. When the mean arterial pressure fell over 20% below baseline, groups (n = 6) were randomized to receive a bolus dose of L-257 of 0 (control), 3, 30 or 300 mg/kg. Animals were sacrifi ced 2 hours later with prior measurement of gastrocnemius muscle microcirculatory perfusion and with collection of plasma samples for biochemistry, arginine, ADMA and nitrate/nitrite measurements.

Results
The bolus doses of L-257 were given after approximately 60 to 90 minutes post endotoxin when the mean BP fell over 20%. Arterial pressure, perfused capillary density and microcirculatory fl ow index were better maintained than in controls, especially at higher doses (Figure 1, P <0.05). Signifi cantly higher plasma ADMA concentrations and ADMA/ arginine ratios were seen in the 30 mg/kg bolus group (Figure 2, P <0.05). Plasma nitrate/nitrite levels in the treated animals were signifi cantly lower compared with those in controls (Figure 2, P <0.05). Conclusion In this short-term rat model of endotoxaemia, we demonstrated protective dose-dependent eff ects of a novel DDAH-1 inhibitor, L-257, on cardiovascular function. This was associated with an elevation of plasma ADMA level and a resultant reduction of plasma nitrate/nitrite level.
Introduction Sepsis remains a major and increasing healthcare problem with a mortality exceeding 25%. The early detection of infection is important in treating sepsis. Nucleic acid amplification methods have the potential to improve the timeliness, sensitivity, and accuracy of the tests used to detect respiratory pathogens. We used a quantitative realtime PCR (rt-PCR) to detect the enteric bacterial counts in blood from patients in the emergency room. Methods EDTA samples were collected from patients with systemic infl ammatory response syndrome (SIRS) presenting to the emergency room after obtaining informed consent. Enteric bacterial loads in blood samples were assayed by rt-PCR to quantitate the bacterial 23S rDNA and EB rDNA loads. Descriptive and clinical data were collected from the medical records and compared with 23S and EB rDNA results. Results From January 2011 to April 2011, 39 patients (mean age 71.15 ± 17.12, range 22 to 93) were enrolled in the study. There was no correlation between serum lactate and enteric bacterial load in patients with SIRS. However, in a subgroup comprising patients presenting with respiratory distress and abnormal blood white cell count, the enteric bacterial rDNA load was higher and showed correlation with serum lactate level. The serum enteric bacterial rDNA loads were signifi cantly higher in patients with positive cultures and in patients presenting with higher serum lactate. Correlations between serum lactate and enteric bacterial rDNA load were also signifi cant in the patients with positive culture results. Conclusion The quantitative assay for enteric bacterial rDNA could be a useful tool to detect early enteric bacterial translocation in patients presenting to the emergency room with elevated serum lactate level or with respiratory distress and abnormal white blood cell counts.  because these drugs sometimes trigger excessive hypotension due to direct eff ects on heart function in addition to their β 1 blocking eff ects.
Since little is known about their acute direct eff ects on mammalian heart, we therefore evaluated the direct eff ects of esmolol, ultrashort-acting β-blockers, on cardiac performance and single cellelectrophysiology in guinea pig hearts, and compared these eff ects with those of landiolol. Methods All animal experiments were approved by the University Animal Ethics Committee. Under deep anesthesia with pentobarbital, the heart was excised and mounted on a Langendorff apparatus to measure the coronary perfusion pressure (CPP). The saline-fi lled balloon was inserted into the left ventricle to measure the heart rate (HR) and systolic left ventricular pressure (sLVP). The coronary fl ow was maintained at a constant value during the experiments. Single ventricular cells were enzymatically isolated from hearts and cardiac ion currents were investigated by the patch clamp methods. Group comparisons were conducted by one-way repeated-measures analysis of variance with Dunnett's or Turkey's multiple comparison test. Diff erences at P <0.05 were considered to denote signifi cance. Results Esmolol increased CPP in a concentration-dependent manner, and decreased both the sLVP and HR signifi cantly at concentrations >10 μM. Esmolol also shortened the action potential duration (APD) in a concentration-dependent manner, and inhibited the inward rectifi er K + current (I K1 ), while the L-type Ca 2+ current (I CaL ) and outward current (I Ks and I Kr ) and ATP-sensitive K + current were hardly aff ected. Furthermore, with the application of BAPTA from patch pipettes, the chelation of intracellular calcium ion did not antagonize APD shortening by esmolol. On the other hand, landiolol had minimal eff ects on cardiac coronary perfusion, cardiac contractility, action potential, and cardiac ionic currents. In the Kyoto Model computer simulation, sole inhibition of I K1 or I CaL failed to simulate APD shortening induced by esmolol.
Conclusion The present fi ndings demonstrated that esmolol has more direct eff ects on the heart than landiolol; that is, the elevation of coronary perfusion pressure and negative inotropic action. The negative inotropic action is accompanied with the APD shortening in single cardiomyocytes. Inhibition of I K1 and I CaL , and inhibition of ionic current systems other than those we identifi ed may be involved in the APD shortening caused by esmolol. Introduction Pulmonary fi brosis is a major and common medical condition, characterized by progressive scaring and decline in lung function. Persistent infl ammation and acute lung injury in response to sepsis are potential triggers of the fi brotic response. Recently, we have reported that Escherichia coli sepsis in baboons strongly induces procoagulant responses and aff ects the integrity of the lung. These eff ects are diminished by the treatment with compstatin, a C3 convertase complement inhibitor [1]. Methods Here we used the baboon model described [1] in conjunction with detailed gene expression analysis, as well as biochemical and histological assays to determine if E. coli sepsis triggered metabolic and signaling pathways related to lung remodeling and fi brosis, and whether complement inhibition could attenuate these pathways.

Sepsis-induced lung fi brosis in baboons is reduced by the treatment with a complement inhibitor
Results Microarray gene expression analysis shows that sepsis augments several fi brotic gene clusters in the lung as early as 24 hours post E. coli challenge. Immunochemical and biochemical analysis reveals enhanced collagen synthesis, induction of profi brotic factors and increased cell recruitment and proliferation. Compstatin treatment decreases sepsis-induced expression of extracellular matrix genes, including eight collagen genes. Sirius Red and immunofl uorescence staining for procollagens 1 and 3 confi rms the collagen deposition in the lung. Ingenuity® pathway analysis of transcriptomics data shows that compstatin treatment reduces sepsis-induced expression of genes involved in fi broblast transformation and connective tissue production, cell chemotaxis, migration and proliferation (see Table 1). Immunocytochemistry and pathway-oriented transcriptomics and phospho-proteomics analysis reveal changes of multiple processes mediated by transforming growth factor beta (TGF-β), connective tissue growth factor and other TGF-β controlled proteins. Immunostaining for cell proliferation markers demonstrates that compstatin treatment strongly reduces cell proliferation in fi broblastic foci. Moreover, biochemical analysis shows decreased production in the compstatintreated group of two chemokines responsible for fi brocyte recruitment (CCL2 and CXCL12) and of the type 1 tissue inhibitor of metalloproteases that controls extracellular matrix remodeling. Conclusion Our data demonstrate that bacterial sepsis initiates pulmonary collagen deposition, and complement inhibition eff ectively attenuates the fi brotic response. This suggests that complement inhibitors could be used for prevention of sepsis-induced pulmonary fi brosis. Acknowledgements The authors thank Dr Bart Frank (OMRF) for help with protein array scanning and quantitation. This work was supported by grants from the National Institutes of Health (GM097747-01 to FL and JL; 2P20RR018758-06A2 and 1RC1GM09739-02 to FL; AI068730 and GM062134 to JL).  Introduction In sepsis, sympathetic nerve activity is diff erentially increased in individual organs. The increased cardiac sympathetic nerve activity is partly responsible for the increase in heart rate (HR) and cardiac output (CO) opposing the development of hypotension [1].
Recently, in a rat septic model, β-blockade appeared safe and decreased the infl ammatory response and mortality [2]. Accordingly, we sought to investigate the cardiovascular eff ects of selective β1-receptor blockade in a sheep model of sepsis. Methods Eight merino ewes were studied in a university-affi liated research institute in Melbourne. The study design was a prospective interventional crossover animal study. The animals had renal and cardiac fl ow probes implanted to continuously measure CO and renal blood fl ow (RBF). Every animal was randomly allocated to receive sepsis and atenolol (atenolol group, AG) or sepsis alone (control group, CG) and then crossed over. After 24 hours of baseline period, sepsis was induced through a bolus of live Escherichia coli by a continuous infusion for a total 24 hours of sepsis. After the fi rst 8 hours of sepsis (development sepsis period, DS), a bolus of atenolol (10 mg bolus) was given followed by a continuous infusion of 0.125 mg/kg/hours for 16 hours. Two-way repeated-measure ANOVA was performed to compare the average of periods and group interaction. P <0.05 was considered signifi cant (not signifi cant (NS), P >0.05).
Results Animals in the AG and CG had similar baseline values and developed a similar hyperdynamic state in the DS (Figure 1 and Table 1). Atenolol reduced CO and HR without changes in stroke volume. Hypotension was slightly greater in the AG than in the CG (MAP: 81.5 vs. 86.1 mmHg) with a greater decrease in total peripheral conductance (16.8 vs. 22.1 l/minute/mmHg). Changes in lactate level were similar. Similar increases in RBF and in renal vascular conductance (RVC) were observed in the AG and CG and after an initial increase in diuresis in the DS, oliguria similarly subsequently developed in both groups. Creatinine clearance decreased in a similar way in the AG and CG from 59.2 (± 2.8) to 32 (± 5.7) ml/minute and from 65.2 (± 9.9) to 36 (± 7) ml/minute, respectively (P = 0.381). One animal in the AG and two in the CG died in the 24 hours after the end of sepsis. Conclusion β-blockade in hyperdynamic sepsis appears safe. It results in only limited decreases in mean arterial pressure, and does not increase lactate levels or worsen renal function.
Introduction Previously our group has developed neural net progression models to characterize the development of organ failure in an ovine only as well as an integrated human/ovine model of acute lung injury using early clinical information. The goal of this study was to expand our model of disease progression using clinically available data as well as more exploratory biomarkers, such as the endotoxin activity assay (EAA), cytokines, D-dimer, copeptin, and procalcitonin, in an adult population with sepsis. Methods Three North American study sites enrolled adult patients within 24 hours of meeting at least two SIRS criteria with clinical evidence of infection. Biomarker sampling occurred daily on days 1 to 7 and on days 14, 21, and 28. Clinical data from the 24 hours preceding the fi rst sampling point as well as the baseline biomarker values were used as model inputs. Model outputs were serum creatinine (Scr) and organ metric (OM) over the study duration. OM is a composite parameter similar to the SOFA score with the CNS category removed and a continuous rather than categorical value. A neural net was used to perform a multiple parameter logistic regression while allowing for non-linear (usually sigmoidal) dependence on input parameters. Input parameters are fi rst used individually to model the output and are then ranked based on the minimum mean squared error (MMSE) in these single-parameter models. The two parameters with the lowest MMSE are used to create the fi nal multi-parametric model, which yields a lower modeling error than the original single-parameter models.
Results Thirty patients were enrolled with the two most common infection types being pneumonia and bloodstream. Seventy per cent of patients had at least one organ failure at enrollment. Diastolic blood pressure (DBP), red blood cell count (RBC), and copeptin had the smallest MMSE when individually predicting OM. Combining DBP and RBC yielded good agreement between the modeled and actual OM value (r 2 = 0.60). Individually, the prothrombin time (PT), copeptin, and phosphorus had the smallest MMSE when modeling Scr. The r 2 value between the model and actual Scr was 0.64 when combining PT and copeptin.
Conclusion When analyzed using a neural net model, changes in overall organ dysfunction and serum creatinine were predicted from early clinical data in a population of adult patients with sepsis. Identifying predictive biomarker patterns and coupling this information with known drug/intervention response could aid in optimizing treatment timing for greatest clinical benefi t.

Introduction
We have reported that nitric oxide (NO) production and microvascular hyperpermeability were signifi cantly higher in septic sheep with methicillin-resistant Staphylococcus aureus (MRSA) than with Pseudomonas aeruginosa. We hypothesize that peroxynitrite, a byproduct of NO, causes vascular hyperpermeability in MRSA sepsis via promoting vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). The hypothesis was tested, using both a well-established ovine sepsis model and cultured human umbilical endothelial cells (HUVECs). Methods Female ewes were chronically instrumented with multiple catheters and live MRSA (USA300, 10 11 CFU) was instilled into the both lungs by bronchoscope under deep isofl urane anesthesia. The sheep were then randomly allocated to control and treated (nonspecifi c NOS inhibitor L-NAME, 25 mg/kg, i.v., every 12 hours) groups and monitored for 24 hours for cardiopulmonary hemodynamics. The cells were challenged with 10 5 CFU of live MRSA or 50 μM peroxynitrite and coincubated with or without L-NAME, peroxynitrite scavenger FeTMPyP, Tie-2 and Ang-2 antibody, and VEGF and its antibody. At diff erent times after the treatment, the permeability was measured by quantifying the amount of FITC-Dextran that passed through the confl uent HUVEC monolayer (n = 4). Ang-2 mRNA was determined by RT-PCR in those cells with or without treatment as well (n = 4). Statistical analysis: oneway ANOVA (Bonferroni).

Results
In vivo, L-NAME signifi cantly reduced MRSA-induced fl uid accumulation and requirement, as well as expression of VEGF. HUVEC permeability was time-dependently increased following MRSA coincubation, reaching a plateau at 2 and 4 hours. These permeability changes (73 ± 4 RFUs) were signifi cantly (P <0.001) inhibited by 1 mM L-NAME (28 ± 1), 5 μM FeTMPy (34 ± 2), 5 μg/ml Tie-2 antibody (32 ± 2), and 5 μg/ml Ang-2 antibody (30 ± 1). In HUVECs, the Ang-2 mRNA was time-dependently (picks at 30 minutes) and dose-dependently increased by peroxynitrite (highest at 50 μM  Introduction Severe sepsis is major health problem with a high mortality rate, and still its incidence continues to rise [1][2][3][4][5]. Lactate clearance, measurement of the lactate level at two consecutive times, is an inexpensive and simple clinical parameter that can be obtained by a minimally invasive means [6][7][8]. This parameter represents kinetic alteration of the anaerobic metabolism that makes it a potential parameter to evaluate disease severity and intervention adequacy. Lactate clearance early in the hospital course may indicate a resolution of global tissue hypoxia and is associated with improved outcome [7][8][9]. Nevertheless, the relationship between lactate clearance and short-term mortality in severe septic patients is still poorly understood.
Understanding the presence of confounder factors is also important to strengthen the role of lactate clearance in the treatment of severe septic patients.
Objective To evaluate the clinical course between lactate clearance groups, and determine the role of confounder variables that infl uence its relationship. Methods This is a prospective cohort study conducted in Ciptomangunkusumo Hospital, from March to May 2011. Patients were categorized into the high lactate clearance group if there were diff erences in 6-hour lactate levels ≥10%, and conversely were categorized into the low lactate clearance group [7,8]. Deaths were observed within the fi rst 10 days. After data collection, the statistical methods were analyzed using survival analysis. Analysis of confounder variables was performed by multivariate Cox regression test. Results During the research period there were 60 patients recruited, consisting of 30 patients grouped into high lactate clearance and the remainder grouped into low lactate clearance. The survival rates in high and low lactate clearance groups were 60.0% versus 26.7% (see Figure 1). In the low lactate clearance group the median survival was 3 days, while the mortality rate did not reach 50% in the high lactate clearance group. The fi rst interquartile was 1 day and 4 days. The hazard ratio between groups was 2.87 (95% CI = 1.41 to 5.83). Steps taken to analyze the role of variables that potentially act as confounder factors were by using bivariate analysis, in which variables that infl uenced the occurrence of deaths (indicated by P <0.25) underwent multivariate analysis subsequently. On multivariate analysis the presence of septic shock, degree of organ dysfunction, vasoactive drug usage, blood transfusion, and fl uid resuscitation change the hazard ratio by no more than 10% ( Table 1). For that reason, these parameters were not considered as confounders.
Conclusion Severe septic patients with high lactate clearance have a better survival rate compared with the low lactate clearance group, and its relationship is not infl uenced by the presence of confounder variables.
Introduction The use of low-dose corticosteroids in sepsis early stages is still debated. The association of LPS-LBP complexes to CD14 receptors and will interact with TLR4 to induce NF-κB as a signal and transcription of proinfl ammatory cytokines [1,2]. Excessive production of infl ammatory cytokines will cause activation of SIRS, especially in gut-associated lymphoid tissues [3], which induces metabolic changes leading to apoptosis network, MOF, septic shock and death [3][4][5]. Changes in apoptosis are mediated by caspases, including caspase-3 that acts as an eff ector caspase [6,7]. Low-dose corticosteroids can inhibit the production of proinfl ammatory cytokines, production of infl ammatory mediators, and lower adhesion of leukocytes to the endothelium [8].
Objective The aim of this study was to analyse NF-κB and caspase-3 intestinal expression, and also survival from use of low-dose steroid in the early stages of sepsis in the Balb/C mouse model of sepsis. Methods Male Balb/C mice were inoculated with lipopolysaccharide for the sepsis mouse model. Sepsis mouse model grouping was to a sepsis group (Group I) and to sepsis with steroid (methylprednisolone 1 to 1.5 mg/kg BW/day) (Group II). Detection of intestinal NF-κB and caspase-3 expression used the immunohistochemistry technique on days 1, 3, 5 and 7. Survival was seen until the 7th day. The two-tailed Fisher exact test for the analysis of mortality, independent-sample t test for intestinal NF-κB and caspase-3 expression, and P <0.05 were used to determine signifi cant diff erences.
Results Acute infl ammatory response occurs in the early stages of sepsis (the fi rst 5 days of exposure) and the process of death occurs in advanced stages of sepsis (after the fi rst 5 days of exposure) [9]. This study shows that the use of low-dose corticosteroids in sepsis early stages (fi rst 5 days) signifi cantly inhibited the expression of NF-κB (see Table 1), so cytokine production of proinfl ammatory cytokines was not excessive. Reduced product proinfl ammatory cytokines would reduce the expression of intestinal caspase-3 (see Table 2), which will reduce the excessive apoptosis in the intestinal tract. Decreased expression of NF-κB and caspase-3 in the intestinal tract would further reduce the excessive mucosal cell death. This situation will block the destruction and disruption of mucosal defense function of the digestive tract, thereby increasing immune response. The end result will be seen that low-dose corticosteroids can reduce mortality. This study found dead animals for Group I were 70%, while Group II were 10% (P = 0.020). Conclusion Low-dose steroids can reduce NF-κB and caspase-3 intestinal expression and also mortality in early sepsis. Data presented as mean ± standard deviation.