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Severe Sepsis (severe + sepsis)

Distribution by Scientific Domains

Medical Sciences	92%

Distribution within Medical Sciences

Anesthesia & Pain Management	19%
Immunology	8%
Hematology	4%
13 Other Subdomains	65%

Selected Abstracts

Tissue Oxygenation Does Not Predict Central Venous Oxygenation in Emergency Department Patients With Severe Sepsis and Septic Shock

ACADEMIC EMERGENCY MEDICINE, Issue 4 2010
Anthony M. Napoli MD
Abstract Objectives:, This study sought to determine whether tissue oxygenation (StO2) could be used as a surrogate for central venous oxygenation (ScVO2) in early goal-directed therapy (EGDT). Methods:, The study enrolled a prospective convenience sample of patients aged ,18 years with sepsis and systolic blood pressure <90 mm Hg after 2 L of normal saline or lactate >4 mmol, who received a continuous central venous oximetry catheter. StO2 and ScVO2 were measured at 15-minute intervals. Data were analyzed using a random coefficients model, correlations, and Bland-Altman plots. Results:, There were 284 measurements in 40 patients. While a statistically significant relationship existed between StO2 and ScVO2 (F(1,37) = 10.23, p = 0.002), StO2 appears to systematically overestimate at lower ScVO2 and underestimate at higher ScVO2. This was reflected in the fixed effect slope of 0.49 (95% confidence interval [CI] = 0.266 to 0.720) and intercept of 34 (95% CI = 14.681 to 50.830), which were significantly different from 1 and 0, respectively. The initial point correlation (r = 0.5) was fair, but there was poor overall agreement (bias = 4.3, limits of agreement = ,20.8 to 29.4). Conclusions:, Correlation between StO2 and ScVO2 was fair. The two measures trend in the same direction, but clinical use of StO2 in lieu of ScVO2 is unsubstantiated due to large and systematic biases. However, these biases may reflect real physiologic states. Further research may investigate if these measures could be used in concert as prognostic indicators. ACADEMIC EMERGENCY MEDICINE 2010; 17:349,352 © 2010 by the Society for Academic Emergency Medicine [source]

Complement Activation in Emergency Department Patients With Severe Sepsis

ACADEMIC EMERGENCY MEDICINE, Issue 4 2010
John G. Younger
Abstract Objectives:, This study assessed the extent and mechanism of complement activation in community-acquired sepsis at presentation to the emergency department (ED) and following 24 hours of quantitative resuscitation. Methods:, A prospective pilot study of patients with severe sepsis and healthy controls was conducted among individuals presenting to a tertiary care ED. Resuscitation, including antibiotics and therapies to normalize central venous and mean arterial pressure (MAP) and central venous oxygenation, was performed on all patients. Serum levels of Factor Bb (alternative pathway), C4d (classical and mannose-binding lectin [MBL] pathway), C3, C3a, and C5a were determined at presentation and 24 hours later among patients. Results:, Twenty patients and 10 healthy volunteer controls were enrolled. Compared to volunteers, all proteins measured were abnormally higher among septic patients (C4d 3.5-fold; Factor Bb 6.1-fold; C3 0.8-fold; C3a 11.6-fold; C5a 1.8-fold). Elevations in C5a were most strongly correlated with alternative pathway activation. Surprisingly, a slight but significant inverse relationship between illness severity (by sequential organ failure assessment [SOFA] score) and C5a levels at presentation was noted. Twenty-four hours of structured resuscitation did not, on average, affect any of the mediators studied. Conclusions:, Patients with community-acquired sepsis have extensive complement activation, particularly of the alternative pathway, at the time of presentation that was not significantly reversed by 24 hours of aggressive resuscitation. ACADEMIC EMERGENCY MEDICINE,2010; 17:353,359 © 2010 by the Society for Academic Emergency Medicine [source]

The Use of Impedance Cardiography in Predicting Mortality in Emergency Department Patients With Severe Sepsis and Septic Shock

ACADEMIC EMERGENCY MEDICINE, Issue 4 2010
Anthony M. Napoli MD
Abstract Objectives:, Pulmonary artery catheterization poses significant risks and requires specialized training. Technological advances allow for more readily available, noninvasive clinical measurements of hemodynamics. Few studies exist that assess the efficacy of noninvasive hemodynamic monitoring in sepsis patients. The authors hypothesized that cardiac index, as measured noninvasively by impedance cardiography (ICG) in emergency department (ED) patients undergoing early goal-directed therapy (EGDT) for sepsis, would be associated with in-hospital mortality. Methods:, This was a prospective observational cohort study of patients age over 18 years meeting criteria for EGDT (lactate > 4 or systolic blood pressure < 90 after 2 L of normal saline). Initial measurements of cardiac index were obtained by ICG. Patients were followed throughout their hospital course until discharge or in-hospital death. Cardiac index measures in survivors and nonsurvivors are presented as means and 95% confidence intervals (CI). Diagnostic performance of ICG in predicting mortality was tested by receiver operating characteristic (ROC) curve and areas under the ROC curves (AUC) were compared using Wilcoxon test. Results:, Fifty-six patients were enrolled; one was excluded due to an inability to complete data acquisition. The mean cardiac index in nonsurvivors (2.3 L/min·m2, 95% CI = 1.6 to 3.0) was less than that for survivors (3.2, 95% CI = 2.9 to 3.5) with mean difference of 0.9 (95% CI = 0.12 to 1.71). The AUC for ICG in predicting mortality was 0.71 (95% CI = 0.58 to 0.88; p = 0.004). A cardiac index of < 2 L/min·m2 had a sensitivity of 43% (95% CI = 18% to 71%), specificity of 93% (95% CI = 80% to 95%), positive likelihood ratio of 5.9, and negative likelihood ratio of 0.6 for predicting in-hospital mortality. Conclusions:, Early, noninvasive measurement of the cardiac index in critically ill severe sepsis and septic shock patients can be performed in the ED for those who meet criteria for EGDT. There appears to be an association between an initial lower cardiac index as measured noninvasively and in-hospital mortality. ACADEMIC EMERGENCY MEDICINE 2010; 17:452,455 © 2010 by the Society for Academic Emergency Medicine [source]

The Utility of a Quality Improvement Bundle in Bridging the Gap between Research and Standard Care in the Management of Severe Sepsis and Septic Shock in the Emergency Department

ACADEMIC EMERGENCY MEDICINE, Issue 11 2007
H. Bryant Nguyen MD
The research in the management of severe sepsis and septic shock has resulted in a number of therapeutic strategies with significant survival benefits. These results also emphasize the primary importance of early hemodynamic resuscitation, or early goal-directed therapy (EGDT), and place the emergency physician in the center of the multidisciplinary team caring for patients with this disease. However, in a busy emergency department, the translation of research into clinical practice is far from ideal. While the benefits are significant, the successful implementation of EGDT is filled with challenges and obstacles. In this article, we will discuss the steps taken at our institution to create, implement, measure, and improve on a six-hour severe sepsis and septic shock treatment bundle incorporating EGDT in the emergency department setting, resulting in significant mortality benefit. [source]

Severe sepsis in critically ill patients: early recognition and outcome

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2010
D. M. Vandijck
No abstract is available for this article. [source]

The Use of B-Type Natriuretic Peptides in the Intensive Care Unit

CONGESTIVE HEART FAILURE, Issue 2008
Christian Mueller MD
B-type natriuretic peptide levels are quantitative markers of cardiac stress and heart failure that summarize the extent of systolic and diastolic left ventricular dysfunction, valvular dysfunction, and right ventricular dysfunction. Initial observational pilot studies have addressed 7 potential indications in the intensive care unit: identification of cardiac dysfunction, diagnosis of hypoxic respiratory failure, risk stratification in severe sepsis and septic shock, evaluation of patients with shock, estimation of invasive measurements, weaning from mechanical ventilation, as well as perioperative and postoperative risk prediction. Although additional studies are required to better define the clinical utility of B-type natriuretic peptide values in the intensive care unit, current data suggest that the diagnosis of hypoxic respiratory failure and timing of extubation seem to be the most promising indications. Congest Heart Fail. 2008;14(4 suppl 1):43,45. ©2008 Le Jacq [source]

Serum vascular endothelial growth factor in adult haematological patients with neutropenic fever: a comparison with C-reactive protein

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2009
Sari Hämäläinen
Abstract Objectives:, Vascular endothelial growth factor (VEGF) is considered to be of importance in patients with sepsis. No data are available on VEGF kinetics in haematological patients with neutropenic fever. Methods:, Forty-two haematological patients were included into this prospective study. Median age was 57 yr (range 18,70). Fifteen patients received therapy for acute myeloid leukaemia and 27 patients received autologous stem cell transplantation for haematological malignancy. Laboratory samples for the determination of C-reactive protein (CRP) and VEGF were collected at the start of fever (d0) and then daily. Results:, The median serum VEGF concentrations were low in all study patients. In patients with severe sepsis (n = 5) the median VEGF on d0 was higher than in septic patients without signs of hypoperfusion or hypotension (n = 37) (77 pg/mL vs. 52 pg/mL, P = 0.061). Also on d1 the median VEGF concentration was higher in patients with severe sepsis (82 pg/mL vs. 56 pg/mL, P = 0.048). There were no statistically significant differences in CRP values on any day during the study period between patients with severe sepsis and those without. Time from d0 to the peak VEGF concentration (mean 1.02, SE 0.18 d) was shorter than that to the peak CRP concentration (mean 1.93, SE 0.15 d) (P = 0.002). Conclusion:, Compared to CRP, serum VEGF was a more rapid indicator for sepsis in our haematological patients with neutropenic fever. Those with severe sepsis had higher VEGF concentrations than those without on d0 and d1 after the onset of fever. Further studies on VEGF are warranted in haematological patients. [source]

Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010
William F. Carson
Abstract Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4+ T-cell responses remains unclear. In the present study, CD4+ T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4+CD62L+ T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4+CD62L+ T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the TH1 or TH2 lineage. Repressive histone methylation marks were also evident at promoter regions for the TH1 cytokine IFN-, and the TH2 transcription factor GATA-3 in naïve CD4+ T cells from CLP mice. These results provide evidence that CD4+ T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription. [source]

Adrenal Insufficiency in Critically Ill Emergency Department Patients: A Taiwan Preliminary Study

ACADEMIC EMERGENCY MEDICINE, Issue 7 2001
Shy-Shin Chang MD
Objective: Unrecognized adrenal insufficiency can have serious consequences in critically ill emergency department (ED) patients. This prospective pilot study of adrenal function in patients with severe illness was undertaken to determine the prevalence of adrenal dysfunction and any relation to prior herbal drug use. Methods: In a high-volume urban tertiary care ED, adult patients with sepsis or acute myocardial infarction (AMI) were eligible for the study. Over a two-month period, a convenience sample was enrolled by the authors on arrival to the ED. Inclusion criteria were systemic inflammatory response syndrome (SIRS) criteria plus evidence of at least one organ dysfunction or cardiac marker plus electrocardiogram-proven AMI. Exclusion criteria included known corticosteroid use. Serum cortisol was measured on arrival and for those patients with a level of <15 ,g/dL (<414 nmol/L), an adrenocorticotropic hormone (ACTH) stimulation test was performed. Results: Of the 30 enrolled patients, 23 (77%) were suffering from severe sepsis and the other seven (23%) had an AMI. Thirteen of the 30 patients (43%; 95% CI = 25% to 65%) had serum cortisol levels of <15 ,g/dL, consistent with adrenal insufficiency, nine with severe sepsis and four with an AMI. Eight (62%; 95% CI = 32% to 86%) of the 13 patients with low cortisol levels reported using herbal medications, while only two (12%; 95% CI = 1% to 36%) of the 17 with normal cortisol levels reported taking herb drugs (p = 0.01). Only two (15%; 95% CI = 2% to 45%) of the patients with low cortisol levels failed their corticotropin stimulation test, suggestive of true adrenocortical insufficiency. Both reported using herbal preparations. Conclusions: These results indicate that adrenal dysfunction is common among a group of critically ill patients seen in this Taiwanese ED. Moreover, the use of herbal drugs was high in the patients with low serum cortisols. Further studies are required to both confirm these findings and clarify whether a number of herbal medications contain corticosteroids. [source]

Complement Activation in Emergency Department Patients With Severe Sepsis

Disease Progression in Hemodynamically Stable Patients Presenting to the Emergency Department With Sepsis

ACADEMIC EMERGENCY MEDICINE, Issue 4 2010
Seth W. Glickman MD
Abstract Background:, Aggressive diagnosis and treatment of patients presenting to the emergency department (ED) with septic shock has been shown to reduce mortality. To enhance the ability to intervene in patients with lesser illness severity, a better understanding of the natural history of the early progression from simple infection to more severe illness is needed. Objectives:, The objectives were to 1) describe the clinical presentation of ED sepsis, including types of infection and causative microorganisms, and 2) determine the incidence, patient characteristics, and mortality associated with early progression to septic shock among ED patients with infection. Methods:, This was a multicenter study of adult ED patients with sepsis but no evidence of shock. Multivariable logistic regression was used to identify patient factors for early progression to shock and its association with 30-day mortality. Results:, Of 472 patients not in shock at ED presentation (systolic blood pressure > 90 mm Hg and lactate < 4 mmol/L), 84 (17.8%) progressed to shock within 72 hours. Independent factors associated with early progression to shock included older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection. Early progression to shock (vs. no progression) was associated with higher 30-day mortality (13.1% vs. 3.1%, odds ratio [OR] = 4.72, 95% confidence interval [CI] = 2.01 to 11.1; p , 0.001). Among 379 patients with uncomplicated sepsis (i.e., no evidence of shock or any end-organ dysfunction), 86 (22.7%) progressed to severe sepsis or shock within 72 hours of hospital admission. Conclusions:, A significant portion of ED patients with less severe sepsis progress to severe sepsis or shock within 72 hours. Additional diagnostic approaches are needed to risk stratify and more effectively treat ED patients with sepsis. ACADEMIC EMERGENCY MEDICINE 2010; 17:383,390 © 2010 by the Society for Academic Emergency Medicine [source]

The systemic inflammatory response syndrome in acute liver failure

HEPATOLOGY, Issue 4 2000
Nancy Rolando
The systemic inflammatory response syndrome (SIRS) in acute liver failure (ALF), in which infection is common, has not been studied. In this study, SIRS components were recorded on admission and during episodes of infection, in 887 ALF patients admitted to a single center during an 11-year period. Overall, 504 (56.8%) patients manifested a SIRS during their illness, with a maximum of 1, 2, and 3 concurrent SIRS components in 166, 238, and 100 patients, respectively. In 353 (39.8%) patients who did not become infected, a SIRS on admission was associated with a more critical illness, subsequent worsening of encephalopathy, and death. Infected patients more often developed a SIRS and one of greater magnitude. The magnitude of the SIRS in 273 patients with bacterial infection correlated with mortality, being 16.7%, 28.4%, 41.2%, and 64.7% in patients with 0, 1, 2, and 3 maximum concurrent SIRS components, respectively. Similar correlations with mortality were seen for SIRS associated with fungal infection, bacteremia, and bacterial chest infection. Fifty-nine percent of patients with severe sepsis died, as did 98% of those with septic shock. A significant association was found between progressive encephalopathy and infection. Infected patients with progressive encephalopathy manifested more SIRS components than other infected patients. For patients with a SIRS, the proportions of infected and noninfected patients manifesting worsening encephalopathy were similar. In ALF, the SIRS, whether or not precipitated by infection, appears to be implicated in the progression of encephalopathy, reducing the chances of transplantation and conferring a poorer prognosis. [source]

The Use of Impedance Cardiography in Predicting Mortality in Emergency Department Patients With Severe Sepsis and Septic Shock

Early predictors of morbidity and mortality in trauma patients treated in the intensive care unit

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2010
O. BRATTSTRÖM
Background: We investigated the incidence and severity of post-injury morbidity and mortality in intensive care unit (ICU)-treated trauma patients. We also identified risk factors in the early phase after injury that predicted the later development of complications. Methods: A prospective observational cohort study design was used. One hundred and sixty-four adult patients admitted to the ICU for more than 24 h were included during a 21-month period. The incidence and severity of morbidity such as multiple organ failure (MOF), acute lung injury (ALI), severe sepsis and 30-day post-injury mortality were calculated and risk factors were analyzed with uni- and multivariable logistic regression analysis. Results: The median age was 40 years, the injury severity score was 24, the new injury severity score was 29, the acute physiology and chronic health evaluation II score was 15, sequential organ failure assessment maximum was 7 and ICU length of stay was 3.1 days. The incidences of post-injury MOF were 40.2%, ALI 25.6%, severe sepsis 31.1% and 30-day mortality 10.4%. The independent risk factors differed to some extent between the outcome parameters. Age, severity of injury, significant head injury and massive transfusion were independent risk factors for several outcome parameters. Positive blood alcohol was only a predictor of MOF, whereas prolonged rescue time only predicted death. Unexpectedly, injury severity was not an independent risk factor for mortality. Conclusions: Although the incidence of morbidity was considerable, mortality was relatively low. Early post-injury risk factors that predicted later development of complications differed between morbidity and mortality. [source]

Lactate concentrations in the rectal lumen in patients in early septic shock

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2010
M. IBSEN
Background: Previously, we observed that rectal luminal lactate was higher in non-survivors compared with survivors of severe sepsis or septic shock persisting >24 h. The present study was initiated to further investigate this tentative association between rectal luminal lactate and mortality in a larger population of patients in early septic shock. Methods: A prospective observational multicentre study of 130 patients with septic shock at six general ICU's of university hospitals. Six to 24 h after the onset of septic shock, the concentration of lactate in the rectal lumen was estimated by a 4-h equilibrium dialysis. Dialysate concentrations of lactate were determined using an auto-analyser. Results: The overall 30-day mortality was 32%, with age and Simplified acute physiology scores II and sequential organ failure assessment scores being significantly higher in non-survivors. In contrast, there were no differences in concentrations of lactate in the rectal lumen [2.2 (1.4,4.1) and 2.8 (1.6,5.1) mmol/l (P=0.34)] (medians and 25th,75th percentiles) or arterial blood [2.1 (1.4,4.2) and 2.0 (1.3,3.2) mmol/l (P=0.15)] between non-survivors and survivors. The rectal,arterial difference of the lactate concentration was higher in survivors. There were no differences in blood pressure, noradrenaline dose or central venous oxygen saturation between the groups. Conclusion: In this prospective, observational study of unselected patients with early septic shock, there was no difference in the concentration of lactate in the rectal lumen between non-survivors and survivors. Trial Registration: Clinicaltrials.gov (no: NCT00197938). [source]

The interleukin-6 (IL6),174 G/C promoter genotype is associated with the presence of septic shock and the ex vivo secretion of IL6

INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2007
J. J. W. Tischendorf
Summary Septic shock is associated with a high mortality and an excessive activation of immune cascades. Interleukin (IL)-6 has been found to be a key cytokine in the pathogenesis of severe sepsis, but the importance of a regulatory polymorphism within the IL6 promoter has been controversial in these patients. The aim of the study was therefore to systematically investigate the IL6,174 G/C promoter genotype with regard to the presence of shock in patients with sepsis, the IL6 serum levels, and the ex vivo secretion of IL6, respectively. Overall, 112 consecutive subjects with severe sepsis and septic shock according to consensus criteria were enrolled. The ex vivo secretion of IL6 after stimulation with lipopolysaccharide (LPS) in a whole blood assay and the IL6 serum concentrations were determined after admission of the patients. Among the 112 subjects with severe sepsis, 85 patients fulfilled the criteria of septic shock. In these patients, the frequency of the mutated C-allele of the IL6 promoter polymorphism was significantly (P = 0.04) higher compared to that in individuals without shock. IL6 serum concentrations were highest in patients with the GG genotype (mean 2209 pg mL,1), followed by CG genotype (mean 1113 pg mL,1), and lowest in individuals with the CC genotype (mean 256 pg mL,1). Interestingly, a significantly (P = 0.005) higher ex vivo secretion of IL6 is detected in heterozygote individuals (535 pg mL,1) and patients with the IL6 CC genotype (555 pg mL,1) compared to patients with the ,174 GG genotype (276 pg mL,1). In conclusion, the IL6,174 G/C promoter genotype is associated with shock in patients with sepsis. Functionally, the mutated C-allele is correlated with low IL6 serum concentrations, but a high ex vivo secretion after LPS stimulation. These results further indicate a complex regulation of the expression of IL6 during infection and have implications for the design of immune intervention trials. [source]

Fournier's gangrene: Report of thirty-three cases and a review of the literature

INTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2006
LUTFI TAHMAZ
Background:, Fournier's gangrene (FG) is an extensive fulminant infection of the genitals, perineum or the abdominal wall. The aim of this study is to share our experience with the management of this difficult infectious disease. Methods:, Thirty-three male patients were admitted to our clinic with the diagnosis of FG between February 1988 and December 2003. The patient's age, etiology and predisposing factors, microbiological findings, duration of hospital stay, treatment, and outcome were analyzed. The patients were divided into two groups. The first 21 patients (Group I) were treated with broad-spectrum triple antimicrobial therapy, broad debridement, exhaustive cleaning, and then they underwent split-thickness skin grafts or delayed closure as needed. The other 12 patients (Group II) were treated with unprocessed honey (20,50 mL daily) and broad-spectrum triple antimicrobial therapy without debridement. Their wounds were cleaned with saline and then dressed with topical unprocessed honey. The wounds were inspected daily and the honey was reapplied after cleaning with normal saline. Then, the patients' scrotum and penis were covered with their own new scrotal skin. Results:, The mean age of the patients was 53.9 ± 9.56 years (range = 23,71). The source of the gangrene was urinary in 23 patients, cutaneous in seven patients, and perirectal in three patients. The predisposing factors included diabetes mellitus for 11 patients, alcoholism for 10 patients, malnutrition for nine patients, and medical immunosuppression (chemotherapy, steroids, malignancy) for three patients. The mean duration of hospital stay was 41 ± 10.459 (range = 14,54) days. Two patients in Group I died from severe sepsis. The clinical and cosmetic results were better in Group II than Group I. Conclusions:, Necrotizing fasciitis of the perineum and genitalia is a severe condition with a high morbidity and mortality. Traditionally, good management is based on aggressive debridement, broad-spectrum antibiotics, and intensive supportive care but unprocessed honey might revolutionize the treatment of this dreadful disease by reducing its cost, morbidity, and mortality. [source]

Effects of recombinant human activated protein C on the coagulation system: a study with rotational thromboelastometry

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2008
C. U. NILSSON
Background: Recombinant human activated protein C (rhAPC) is an anticoagulant that can be used for treatment of patients with severe sepsis. The use of rhAPC is accompanied by an increased risk of severe bleeding. Rotational thromboelastometry is a method for measuring the status of the coagulation. The aim of the study was to investigate whether rotational thromboelastometry could be used for monitoring the effects of rhAPC on the coagulation. Methods: Whole blood was mixed in vitro with concentrations of rhAPC ranging from 0 to 75 ng/ml and analysed with rotational thromboelastometry. Results: The parameter Coagulation Time was significantly prolonged by increasing the concentrations of rhAPC (P=0.002). Other parameters were not significantly affected. Conclusion: rhAPC dose dependently affects the early humoral parts of the coagulation, while platelet function and fibrinogen to fibrin conversion seem virtually unaffected. [source]

Activated protein C (Xigris®) treatment in sepsis: a drug in trouble

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2006
B. Gårdlund
Drotrecogin alfa (activated) or recombinant human activated protein C (rhAPC) has been registered for use as adjuvant treatment in severe sepsis since 2001 under the trade name Xigris® essentially based on the results from one large clinical trial (the PROWESS trial). In a recently published second randomized clinical trial (the ADDRESS trial), enrolling patients with severe sepsis but with less risk of death, no effect of the treatment was shown, not even a trend to a positive effect in the subgroup of patients with a high risk of death that would match the present prescription label for Xigris®. In addition, a large randomized, placebo-controlled trial with rhAPC in paediatric sepsis has recently been terminated prematurely because of lack of efficacy. Altogether, the robustness of the data supporting the use of rhAPC in treating patients with severe sepsis may indeed be questioned. A confirmatory clinical trial is required before rhAPC can be used with confidence. The side-effects and the cost of rhAPC are well documented but its efficacy is not. [source]

Vascular and dendritic cell coagulation signaling in sepsis progression

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009
W. RUF
Summary., The intrinsic signaling networks of the coagulation pathways have recently emerged as crucial determinants for survival in sepsis and systemic inflammatory response syndromes. Protease activated receptor (PAR) 1 is central to both lethality promoting and vascular protective signaling. In the vascular anticoagulant pathway, EPCR/aPC-PAR1 signaling prevents vascular leakage and genetic or acute deficiencies in this pathway promote lethality. In addition, coagulation signaling acts directly on cells of the innate immune system. Dendritic cell (DC) thrombin-PAR1 signaling is coupled to the migration promoting sphingosine 1 phosphate receptor 3 (S1P3). Thrombin generated in the lymphatic compartment perturbs DCs to promote systemic inflammation and disseminated intravascular coagulation in severe sepsis. Signaling-selective aPC variants and selective modulators of the S1P receptor system attenuate sepsis lethality, suggesting novel therapeutic approaches that can be employed to rebalance alterations in the coagulation signaling pathways in severe inflammatory disorders. [source]

von Willebrand factor is a major determinant of ADAMTS-13 decrease during mouse sepsis induced by cecum ligation and puncture

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2009
N. LEROLLE
Summary.,Background:,During sepsis, von Willebrand factor (VWF) is abundantly secreted; the main mechanism regulating its size involves specific proteolysis by the metalloprotease ADAMTS-13. Objectives:,To determine whether ADAMTS-13 consumption due to its binding to, and/or cleavage, of VWF contributes to its decrease during sepsis and whether abrogating or enhancing ADAMTS-13 activity influences sepsis outcome. Methods:,ADAMTS-13 activity was evaluated in a model of sepsis induced by cecum ligature and puncture (CLP) in wild-type and Vwf,/, mice. Sepsis outcome was studied in those mice and in Adamts-13,/, mice. Finally, survival was studied in wild-type mice injected hydrodynamically with the human ADAMTS-13 gene. Results:,In wild-type mice, CLP-induced sepsis elicited a significant ADAMTS-13 decrease, and a strong negative correlation existed between VWF and ADAMTS-13. In Vwf,/, mice, CLP also induced severe sepsis, but ADAMTS-13 was not significantly diminished. Notably, Vwf,/, mice lived significantly longer than wild-type mice. In contrast, Adamts-13,/, mice and wild-type mice were comparable with regard to thrombocytopenia, VWF concentrations, absence of thrombi, and survival. Hydrodynamic hADAMTS-13 gene transfer with the pLIVE expression vector resulted in high and stable ADAMTS13 activity in CLP mice; however, no impact on survival was observed. Conclusions: VWF secretion is a major determinant of ADAMTS-13 decrease in the CLP model, and plays an important role in sepsis-induced mortality, but the complete absence of its regulating protease, ADAMTS-13, had no detectable impact in this sepsis model. Furthermore, increasing ADAMTS-13 activity had no impact on survival. [source]

ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2007
J. A. KREMER HOVINGA
Summary. Background:,Insufficient control of von Willebrand factor (VWF) multimer size as a result of severely deficient ADAMTS-13 activity results in thrombotic thrombocytopenic purpura associated with microvascluar thrombosis and platelet consumption, features not seldom seen in severe sepsis and septic shock. Methods:,ADAMTS-13 activity and VWF parameters of 40 patients with severe sepsis or septic shock were compared with those of 40 healthy controls of the same age and gender and correlated with clinical findings and sepsis outcome. Results:,ADAMTS-13 activity was significantly lower in patients than in healthy controls [median 60% (range 27,160%) vs. 110% (range 63,200%); P < 0.001]. VWF parameters behaved reciprocally and both VWF ristocetin cofactor activity (RCo) and VWF antigen (VWF:Ag) were significantly (P < 0.001) higher in patients compared with controls. Neither ADAMTS-13 activity nor VWF parameters correlated with disease severity, organ dysfunction or outcome. However, a contribution of acute endothelial dysfunction to renal impairment in sepsis is suggested by the significantly higher VWF propeptide and soluble thrombomodulin levels in patients with increased creatinine values as well as by their strong positive correlations (creatinine and VWF propeptide rs = 0.484, P < 0.001; creatinine and soluble thrombomodulin rs = 0.596, P < 0.001). Conclusions:,VWF parameters are reciprocally correlated with ADAMTS-13 activity in severe sepsis and septic shock but have no prognostic value regarding outcome. [source]

Platelet function in sepsis

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2004
A. YAGUCHI
Summary.,Background: Coagulation abnormalities and thrombocytopenia are common in severe sepsis, but sepsis-related alterations in platelet function are ill-defined. Objectives: The purpose of this study was to elucidate the effect of sepsis on platelet aggregation, adhesiveness, and growth factor release. Patients and methods: Agonist-induced platelet aggregation was measured in platelet-rich plasma separated from blood samples collected from 47 critically ill patients with sepsis of recent onset. Expression of platelet adhesion molecules was measured by flow cytometry and the release of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) was measured by ELISA in the supernatant of platelet aggregation. Results: Septic patients had consistently decreased platelet aggregation compared with controls, regardless of the platelet count, thrombin generation, or overt disseminated intravascular coagulation (DIC) status. The severity of sepsis correlated to the platelet aggregation defect. Adhesion molecules, receptor expression (CD42a, CD42b, CD36, CD29, PAR-1), and ,-granule secretion detected by P-selectin expression remained unchanged but the release of growth factors was differentially regulated with increased VEGF and unchanged PDGF after agonist activation even in uncomplicated sepsis. Conclusions: Sepsis decreases circulating platelets' hemostatic function, maintains adhesion molecule expression and secretion capability, and modulates growth factor production. These results suggest that sepsis alters the hemostatic function of the platelets and increases VEGF release in a thrombin-independent manner. [source]

Superantigens from Staphylococcus aureus induce procoagulant activity and monocyte tissue factor expression in whole blood and mononuclear cells via IL-1,

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2003
E. Mattsson
Summary.,Background:,Staphylococcus aureus is one of the most common bacteria in human sepsis, a condition in which the activation of blood coagulation plays a critical pathophysiological role. During severe sepsis and septic shock microthrombi and multiorgan dysfunction are observed as a result of bacterial interference with the host defense and coagulation systems. Objectives:,In the present study, staphylococcal superantigens were tested for their ability to induce procoagulant activity and tissue factor (TF) expression in human whole blood and in peripheral blood mononuclear cells. Methods and results:,Determination of clotting time showed that enterotoxin A, B and toxic shock syndrome toxin 1 from S. aureus induce procoagulant activity in whole blood and in mononuclear cells. The procoagulant activity was dependent on the expression of TF in monocytes since antibodies to TF inhibited the effect of the toxins and TF was detected on the surface of monocytes by flow cytometry. In the supernatants from staphylococcal toxin-stimulated mononuclear cells, interleukin (IL)-1, was detected by ELISA. Furthermore, the increased procoagulant activity and TF expression in monocytes induced by the staphylococcal toxins were inhibited in the presence of IL-1 receptor antagonist, a natural inhibitor of IL-1,. Conclusions:,The present study shows that superantigens from S. aureus activate the extrinsic coagulation pathway by inducing expression of TF in monocytes, and that the expression is mainly triggered by superantigen-induced IL-1, release. [source]

An updated view of hemostasis: mechanisms of hemostatic dysfuntion associated with sepsis

JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 2 2005
DACVECC, Kate Hopper BVSc
Abstract Objective: To review the current understanding of mechanisms involved in normal hemostasis and to describe the changes associated with pro-inflammatory disease processes such as sepsis. Data sources: Original research articles and scientific reviews. Human data synthesis: Organ damage caused by sepsis is created in part by the interdependent relationship between hemostasis and inflammation. Markers of coagulation have been found to have prognostic value in human patients with sepsis and there are both experimental and clinical investigations of the therapeutic potential of modulating the hemostatic system in sepsis. Improvement of 28-day all-cause mortality in severe sepsis by treatment with recombinant human activated Protein C strongly supports the interdependence of hemostasis and inflammation in the pathophysiology of sepsis. Veterinary data synthesis: Publications reporting clinical evaluation of the hemostatic changes occurring in septic dogs or cats are minimal. Experimental animal models of sepsis reveal significant similarity between human and animal sepsis and may provide relevance to clinical veterinary medicine until prospective clinical evaluations are published. Conclusions: It is now apparent that inflammation and the coagulation system are intimately connected. Understanding this relationship provides some insight into the pathogenesis of the hemostatic changes associated with sepsis. This new updated view of hemostasis may lead to the development of novel therapeutic approaches to sepsis and disseminated intravascular coagulation in veterinary medicine. [source]

Seventh Day Syndrome , acute hepatocyte apoptosis associated with a unique syndrome of graft loss following liver transplantation,

LIVER INTERNATIONAL, Issue 1 2001
Muhammed Ashraf Memon
Abstract:Aim: The aim of this study is to describe a unique 7th day syndrome (7DS), quite different from other causes of post-transplantation allograft dysfunction in a group of orthotopic liver transplant (OLT) patients who needed retransplantation. Methods: A retrospective analysis of 594 consecutive OLT over an 8-year period revealed that 10 patients developed allograft dysfunction approximately 7 days following an initially normal graft function. Results: The features included: (a) severe liver failure; (b) sudden peak of extremely high liver enzymes at approximately day 7; (c) serial liver biopsy findings of central lobular hemorrhage with minimal inflammatory cell infiltrate and (d) an explant with no evidence of vascular thrombosis. The biochemical and morphometric pathological data of these patients were compared with data of patitents who had early acute rejection (AR), hepatic artery thrombosis (HAT), primary non-function (PNF), severe sepsis and no dysfunction. Lastly, serial liver core biopsies and explants were tested for evidence of apoptosis, which revealed a significantly higher number of apoptotic hepatocytes in 7DS compared to all control groups. Conclusions: Seventh Day Syndrome is a distinct entity associated with early graft dysfunction characterized by a marked apoptosis of hepatocytes. Fas receptor activation or other pathways of program cell death may be implicated in occurrence of 7DS. [source]

Use of activated protein c in liver transplantation patients with septic shock,

LIVER TRANSPLANTATION, Issue 11 2008
Laura Rinaldi
Recombinant human activated protein C (rhAPC) has been approved for use in patients with severe sepsis at high risk of death. Because of the high risk of bleeding, liver transplantation (LT) patients have been excluded from the randomized control trials that evaluated efficacy and safety of rhAPC and, thus, few data are available on the use of this drug in LT patients with severe sepsis. We describe our experience with 5 LT recipients treated for septic shock with the best conventional therapy and rhAPC. Before rhAPC therapy, all the patients showed septic shock, with ,3 organ dysfunctions and thrombocytopenia with impairment of coagulation. rhAPC therapy started within 30 hours after septic shock onset in all the patients who recovered from sepsis-induced circulatory failure, improved organ dysfunction, and completed the 96 hours of rhAPC therapy. During rhAPC infusion, 4 patients received fresh frozen plasma and/or platelet concentrates because of thrombocytopenia and severe hemostasis dysfunction. No major bleeding occurred and only 1 patient presented with minor bleeding events. Liver Transpl 14:1598,1602, 2008. © 2008 AASLD. [source]

Surviving Sepsis campaign , outcome of severe sepsis can be improved by revising procedural standards

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2005
E. Ruokonen
No abstract is available for this article. [source]

Implementing the severe sepsis care bundles outside the ICU by outreach

NURSING IN CRITICAL CARE, Issue 5 2007
Chris Carter
Abstract Sepsis is not a new challenge facing the health care team, it remains a complex disease, which is difficult to identify and treat. Mortality from sepsis remains high and continues to be a common cause of death among critically ill patients, despite advances in critical care. Sepsis accounts for an estimated 27% of all intensive care admissions in England, Wales and Northern Ireland, and accounted for 46% of all intensive care bed days. Recent research studies and the surviving sepsis campaign have shown that identifying and providing key interventions to patients with severe sepsis and septic shock prior to their admission to the intensive care unit significantly improve outcomes. The aim of this paper was to identify how the Critical Care Outreach Team at one local hospital implemented the severe sepsis resuscitation care bundle for patients in the emergency department (ED) and on the general wards. It will include a presentation on the various ways the team raised the profile of severe sepsis and the care bundle at hospital and at national level. It also includes audit data that have been collected. The results showed that if the resuscitation care bundle was implemented within the first 24 h of hospital admission, mortality was 29%, whereas if the care bundle was instigated after this time mortality was more than at 49%. Audit data showed that the commonest sign of severe sepsis seen in patients in the ED and on wards was tachypnoea. This article discusses the successful implementation of the severe sepsis resuscitation care bundle and the positive impact an Outreach team can have in changing practice in the way patients are managed with severe sepsis. The audit data support the need for regular physiological observations and the use of a Patient At Risk Trigger scoring tool to identify patients at risk of deterioration. This allows referral to the Outreach team, who assess the patient and if appropriate initiate the care bundle. [source]

Ascites in infants with severe sepsis , treatment with peritoneal drainage

PEDIATRIC ANESTHESIA, Issue 12 2006
ANDRZEJ PIOTROWSKI MD PhD
Summary Background:, Ascites in neonates and infants is usually caused by cardiac failure and urinary or biliary tract obstruction. The objective of this study was to characterize our experience with ascites as a complication of sepsis. Methods:, We retrospectively collected and analyzed data of patients treated in the intensive care unit (ICU) of the university-based children's hospital, in whom ascites developed during nosocomial sepsis. Ten infants admitted to the ICU in the first 2 days of life developed sepsis on the mean 31.5 (±21.9) postnatal day. Gram-negative bacteria were the causative organism in nine cases, and Staphylococcus hemolyticus in one. Because of sepsis, reintubation and mechanical ventilation were necessary. All patients received broad spectrum antibiotics (including meropenem and ciprofloxacin), blood transfusions, catecholamines and intravenous immunoglobulin preparations. Ascites was observed on the median 13.5 day of sepsis (range 3,36), and severely compromised gas exchange. Continuous peritoneal drainage was applied by means of an intravascular catheter placed in the right lower abdominal quadrant. Results:, The mean drained fluid volume was 44.7 (±20.4) ml·kg,1·day,1, drainage was continued for a median of 5.5 (range 1,56) day, and enabled significant reduction of ventilator settings 24 h after its implementation. No severe complications related to drainage occurred; six of 10 babies survived. Conclusions:, Ascites can develop in infants with sepsis and cause respiratory compromise. Continuous drainage of ascitic fluid by means of an intravenous catheter is relatively safe and can improve gas exchange. [source]