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PubMed2004

Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C.

OBJECTIVE: Coagulation activation is part of the acute innate host response to infection that, when uncontrolled, may contribute to organ dysfunction and death. Activated protein C limits excessive coagulation activation by inactivating factors Va and VIIIa. The factor V Leiden mutation (R506Q), a prothrombotic gene polymorphism, disrupts the activity of this natural anticoagulant by rendering factor Va partially resistant to inactivation by activated protein C. Previous findings in the mouse factor V Leiden endotoxemia model and in patients with severe sepsis suggest that factor V Leiden constitutes a rare example of a balanced gene polymorphism that may provide a survival advantage for heterozygous carriers with severe sepsis. We sought to confirm that carriers of this prothrombotic factor V Leiden mutation do not have an increased risk of developing severe sepsis and that carriers with severe sepsis derive similar treatment benefit from recombinant human activated protein C (drotrecogin alfa [activated]) as non-factor V Leiden carriers. DESIGN: Prospective collection of factor V Leiden status from two clinical studies of severe sepsis (PROWESS and ENHANCE). SETTING: : A total of 447 clinical sites across 25 countries. PATIENTS: A total of 3894 adult patients with severe sepsis. INTERVENTION: Either 24 microg x kg x hr drotrecogin alfa (activated) (n = 3063) or placebo (n = 800) for 96 hrs or no exposure to the study drug (n = 31). MAIN RESULTS: The effect of the factor V Leiden carrier status in severe sepsis in the PROWESS study has been previously reported. The combined data on factor V Leiden status from 3894 adult patients with severe sepsis from the PROWESS and ENHANCE (a single-arm, open-label study of drotrecogin alfa [activated]) studies are reported here. At study entry, 3.9% of patients (150/3894) presenting with severe sepsis were heterozygous carriers. No homozygous factor V Leiden carriers were identified. The proportion of factor V Leiden carriers in patients with severe sepsis differs slightly from that predicted (allelic frequency of 2.5%) by the Hardy-Weinberg equation for the general white population (p =.05). There was no significant difference in baseline disease severity (Acute Physiology and Chronic Health Evaluation II score or number of organ dysfunctions) between heterozygous carriers and non-Leiden carriers. There was no significant difference in serious bleeding or thrombotic event rates with drotrecogin alfa (activated) treatment between heterozygous carriers and non-Leiden carriers. The 28-day mortality rates for heterozygous carriers and non-Leiden carriers with drotrecogin alfa (activated) treatment were 20.3% and 24.9%, respectively (risk ratio, 0.82; 95% confidence interval, 0.57-1.17). CONCLUSIONS: : Compared with non-Leiden carriers, factor V Leiden heterozygous carriers may have a slightly decreased risk of developing severe sepsis from infection, do not seem to have increased mortality in severe sepsis, and derive similar benefit and risk profiles from drotrecogin alfa (activated) treatment. Therefore, factor V Leiden carriers should not be excluded from this new sepsis therapy.

Anti-Infective Agents↗
PubMed2004

Epidemiology of sepsis in patients with traumatic injury.

OBJECTIVE: To characterize the epidemiology of sepsis in trauma. DESIGN: Analysis of a prospectively collected administrative database (Pennsylvania trauma registry). SETTING: All trauma centers in the state of Pennsylvania (n = 28) PATIENTS: All patients (n = 30,303) with blunt or penetrating injury admitted to Pennsylvania trauma centers over a 2-yr period (January 1996-December 1997). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Incidence of sepsis in trauma, independent predictors of sepsis, and associated mortality were evaluated. Analyses controlled for age, gender, preexisting disease, injury type, Revised Trauma Score, Injury Severity Score, and admission vital signs. Sepsis occurred in 2% of all patients and was associated with a significant increase in mortality (23.1% vs. 7.6%, p < .001) compared with nonseptic patients. Respiratory tract infections were the most common cause of sepsis. Septic trauma patients had increased ICU length of stay (21.8 vs. 4.7 days, p < .001) and hospital length of stay (34.1 vs. 7.0 days, p < .001). Logistic regression identified Injury Severity Score, Revised Trauma Score, lower admission Glasgow Coma Scale score, and preexisting diseases as significant independent predictors of sepsis, whereas female gender was associated with a decreased risk of sepsis. Increasing injury severity measured by Injury Severity Score was associated with increased incidence of sepsis. Moderate (Injury Severity Score 15-29) and severe injury (Injury Severity Score >/=30) had a six-fold and 16-fold, respectively, increased incidence of sepsis compared with mild injury. Multivariate analysis confirmed that the effect of sepsis on mortality was greater in trauma patients with mild injury than those with moderate or severe injury. CONCLUSIONS: This study reports the incidence of sepsis and its associated mortality and critical care resource utilization in a large, state-wide population-based trauma registry. Increasing injury severity, measured by Injury Severity Score, was a significant independent predictor of sepsis in trauma and was associated with increased intensive care unit resource utilization and mortality. These results suggest that future studies should attempt to delineate interventional strategies to prevent sepsis in trauma patients with moderate and severe injury, given their significantly increased risk.

Adult↗
PubMed2006

Global fibrinolytic capacity in pediatric patients with sepsis and disseminated intravascular coagulation.

There are many complex pathophysiologic changes of the coagulation system in sepsis. The fibrinolytic system was evaluated in septic children using the global fibrinolytic capacity (GFC), a new technique reflecting the overall fibrinolytic activity. The study consisted of 24 children with sepsis, 36 children with sepsis plus disseminated intravascular coagulation (DIC), and 20 healthy age-matched control individuals. Compared with controls, 86% of sepsis patients and 87% of sepsis plus DIC patients had decreased GFC levels. Between the sepsis plus DIC and sepsis groups there was no significant difference in terms of GFC levels. While 19 patients (52.7%) died in the sepsis plus DIC group, only three patients (12.5%) died in the sepsis group. When survivors and nonsurvivors were compared in terms of coagulation tests, there were significant differences for protein C, antithrombin, platelet, fibrinogen, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and white blood cell values. In conclusion, the level of GFC reduced in most of the pediatric sepsis patients but no difference was observed between patients with sepsis and patients with sepsis plus DIC. While inhibition of fibrinolysis is an important finding in sepsis, the mortality is mainly associated with the presence of end-organ damage and the status of coagulation parameters.

Blood Coagulation Tests↗
PubMed2003

G protein and adenylate cyclase complex-mediated signal transduction in the rat heart during sepsis.

Changes in the protein level of various subunits of GTP-binding protein and the activity of adenylate cyclase in the rat heart during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP. The protein levels of various subunits of GTP-binding protein were determined by Western blot analysis. The activity of adenylate cyclase was measured based on the rate of formation of cAMP from [alpha-32P]ATP. The results show that protein levels of G alphas and G beta remained stable during the early and the late phases of sepsis. The protein levels of G alpha i-2 and G alpha i-3 remained relatively unaltered during the early phase of sepsis, but they were increased by 46.5% (P < 0.05) and 61.3% (P < 0.01), respectively, during the late phase of sepsis. The basal adenylate cyclase activity remained unchanged during the early phase while it was decreased by 25.7% (P < 0.05) during the late phase of sepsis. The isoproterenol-stimulated adenylate cyclase activity was unchanged during early sepsis while it was decreased by 44.6% (P < 0.01) during late sepsis. These data demonstrate that during the late hypodynamic phase of sepsis, myocardial G alpha i-2 and G alpha i-3 protein levels were increased and the increases were coupled with a reduction in adenylate cyclase activity. Because GTP-binding proteins mediate sympathetic control of cardiac function, the present findings may have a pathophysiological significance in contributing to the understanding of the pathogenesis of cardiac dysfunction during the late stage of sepsis.

Adenylyl Cyclases↗
PubMed2004

Transcriptional regulation of cardiac sarcoplasmic reticulum calcium-ATPase gene during the progression of sepsis.

Changes in sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene expression in the rat heart during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Septic rats were divided into two groups: the early hyperdynamic (9 h after CLP, early sepsis) and the late hypodynamic (18 h after CLP; late sepsis) groups. Western blot analyses reveal that SERCA2a protein level remained unaltered during early sepsis but was decreased by 59% during late sepsis. Northern blot analyses show that the steady-state level of SERCA2a mRNA stayed unchanged during the early phase but was decreased by 43% during the late phase of sepsis. Nuclear runoff assays show that the transcription rate of SERCA2a gene transcript remained unaffected during early sepsis but was decreased by 34% during late sepsis. The actinomycin D pulse-chase studies indicate that the half-life of SERCA2a mRNA was unaffected during the early and the late phases of sepsis. These findings demonstrate that during the early phase of sepsis, the protein level, the mRNA abundance, and the transcription rate of SERCA2a remained unaltered, whereas during the late phase of sepsis, the rate of transcription of SERCA2a was decreased, and the decreased transcription rate was associated with decreases in SERCA2a mRNA abundance and SERCA2a protein level in the rat heart. Based on these data, it is concluded that SERCA2a gene expression decreased during the late phase of sepsis in the rat heart and that the decreased expression was regulated at the transcriptional level.

Animals↗
PubMed2004

Adrenomedullin and adrenomedullin binding protein-1 attenuate vascular endothelial cell apoptosis in sepsis.

OBJECTIVE: To determine whether vascular endothelial cell apoptosis occurs in the late stage of sepsis and, if so, whether administration of a potent vasodilatory peptide adrenomedullin and its newly reported specific binding protein (AM/AMBP-1) prevents sepsis-induced endothelial cell apoptosis. SUMMARY BACKGROUND DATA: Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Our recent studies have shown that administration of AM/AMBP-1 delays or even prevents the transition from the hyperdynamic phase to the hypodynamic phase of sepsis, attenuates tissue injury, and decreases sepsis-induced mortality. However, the mechanisms responsible for the beneficial effects of AM/AMBP-1 in sepsis remain unknown. METHODS: Polymicrobial sepsis was induced by cecal ligation and puncture in adult male rats. Human AMBP-1 (40 microg/kg body weight) was infused intravenously at the beginning of sepsis for 20 minutes and synthetic AM (12 microg/kg body weight) was continuously administered for the entire study period using an Alzert micro-osmotic pump, beginning 3 hours prior to the induction of sepsis. The thoracic aorta and pulmonary tissues were harvested at 20 hours after cecal ligation and puncture (ie, the late stage of sepsis). Apoptosis was determined using TUNEL assay, M30 Cytodeath immunostaining, and electromicroscopy. In addition, anti-apoptotic Bcl-2 and pro-apoptotic Bax gene expression and protein levels were assessed by RT-PCR and Western blot analysis, respectively. RESULTS: Vascular endothelial cells underwent apoptosis formation at 20 hours after cecal ligation and puncture as determined by three different methods. Moreover, partial detached endothelial cell in the aorta was observed. Bcl-2 mRNA and protein levels decreased significantly at 20 hours after the onset of sepsis while Bax was not altered. Administration of AM/AMBP-1 early after sepsis, however, significantly reduced the number of apoptotic endothelial cells. This was associated with significantly increased Bcl-2 protein levels and decreased Bax gene expression in the aortic and pulmonary tissues. CONCLUSION: The above results suggest that vascular endothelial cell apoptosis occurs in late sepsis and the anti-apoptotic effects of AM/AMBP-1 appear to be in part responsible for their beneficial effects observed under such conditions.

Adrenomedullin↗
PubMed2003

Plasma nitrite/nitrate and endothelin-1 concentrations in neonatal sepsis.

AIM: To determine the changes in plasma nitrite/nitrate (NOx) and endothelin-1 (ET-1) concentrations during neonatal sepsis. METHODS: In a prospective study, 60 consecutive newborns meeting the criteria for sepsis and without receiving exogenous nitric oxide (25 haemoculture-positive [HC+] and 35 haemoculture-negative [HC-]) were compared with 68 healthy newborns (46 full-term and 22 preterm). NOx and ET-1 concentrations were measured in each newborn within 48 h of diagnosis of sepsis and then every third day up to three determinations. SNAP-II and SNAPPE-II severity scores were performed at the moment of highest clinical severity. RESULTS: At the beginning of the sepsis period, controls and septicaemic newborns had similar NOx and ET-1 levels, with the exception of infants with severe HC+ sepsis. Throughout the sepsis period, NOx increased in moderate HC+ sepsis and decreased in HC--sepsis, reaching a significant difference at the end of the study period (59.9 +/- 72.7 vs 33.9 15.3 micromol/L; p = 0.036). Meanwhile, ET-1 in newborns with severe HC+ sepsis remained higher than that in the moderate HC+ sepsis group and HC--group, reaching significant differences in all the periods. The highest ET-1 value was positively correlated with SNAP-II and SNAPPE-II scores. CONCLUSION: NOx concentrations increased throughout the neonatal HC+ sepsis period, reaching significant differences after 7-9 d. The highest ET-1 levels in neonatal HC+ sepsis emerged before the NOx peak, at 3-5 d, and later decreased. Only newborns with severe HC+ sepsis presented a significant increase in ET-1 concentrations from the beginning of the septicaemic process.

Birth Weight↗
PubMed1999

Transcriptional and posttranscriptional regulation of beta(2)-adrenergic receptor gene in rat liver during sepsis.

Changes in beta(2)-adrenergic receptor (beta(2)-AR) gene expression in the rat liver during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Septic rats exhibit two metabolically distinct phases: an initial hyperglycemic (9 h after CLP; early sepsis) followed by a hypoglycemic phase (18 h after CLP; late sepsis). The [(3)H]dihydroalprenolol binding studies show that the density of beta(2)-AR was decreased by 12 and 35% during the early and late phases of sepsis, respectively. Western blot analyses depict that the beta(2)-AR protein level was reduced by 37 and 72% during early and late sepsis, respectively. The reverse transcription polymerase chain reaction and Southern blot analyses reveal that the steady-state level of beta(2)-AR mRNA was decreased by 37% during early phase and 77% during late phase of sepsis. Nuclear run-off assays show that the rate of transcription of beta(2)-AR mRNA was reduced by 36% during early sepsis and 64% during late sepsis. The stability assays indicate that the half-life of beta(2)-AR mRNA was shortened by 21 and 50% during the early and late phases of sepsis, respectively, indicating that the rate of degradation of beta(2)-AR mRNA was progressively enhanced during sepsis. These findings demonstrate that the beta(2)-AR gene was underexpressed in the liver during the progression of sepsis, and, furthermore, the underexpression of the beta(2)-AR gene was the result of a reduction in the rate of transcription coupled with an enhancement in the rate of degradation of beta(2)-AR gene transcripts. Thus our findings that the transcriptional and posttranscriptional regulation of beta(2)-AR gene associated with decreases in beta(2)-AR number and its protein expression may provide a molecular mechanistic explanation for the development of hypoglycemia during the late stage of sepsis.

Animals↗
PubMed2002

Neonatal sepsis of nosocomial origin: an epidemiological study from the "Grupo de Hospitales Castrillo".

A prospective multicenter study was designed to assess the frequency, etiology, and mortality of nosocomial neonatal sepsis diagnosed between 1996 and 1997 in the neonatology services of 27 acute-care hospitals in Spain ("Grupo de Hospitales Castrillo"). Nosocomial sepsis is defined in the literature using chronological criteria (> 3-7 days of life at the onset of symptoms); accordingly, there is the possibility of including late-onset maternally acquired sepsis or of excluding early-onset nosocomial sepsis (< 3-7 days of life). For these reasons, in this study, cases of nosocomial sepsis that developed at < or = 3-7 days after birth (early onset) were also recorded and maternally acquired sepsis diagnosed beyond 3-7 days of life were excluded. Using these criteria in a total of 30,993 admissions to the neonatal units of the participating hospitals, the nosocomial sepsis rate was 2.1% with an incidence density of 0.89 per 1000 patient days. Sepsis rate was significantly more frequent among very low birth weight (VLBW) infants (15.6%) than among those weighing > or = 1500 g (1.16%) (P < 0.001). Fifty-eight percent of all isolates were Gram-positive organisms, mainly Staphylococcus epidermidis (42%). Gram-negative organisms were isolated in 29.5% of cases (Escherichia coli and Klebsiella spp. were the most commonly isolated pathogens) and fungal infections in 12%, with absolute predominance of Candida spp. The overall mortality rate was 11.8% and the following subgroups had significantly higher (P < 0.001) mortality rates: sepsis caused by Gram-negative organisms (19% vs. 5.1% in Gram-positive pathogens) and sepsis caused by Pseudomonas aeruginosa (33.3% vs. 9.4% for the total number of sepsis caused by the remaining causative pathogens). Sepsis caused by S. epidermidis showed a significantly lower mortality rate (5.5%) compared with overall sepsis for the remaining etiologies (14.2%) (P < 0.001). In VLBW infants, the mortality rate was significantly higher than in infants weighing > 1500 g (17.3% vs. 6.5%, P < 0.001).

Birth Weight↗
PubMed1998

Decline in sepsis-associated neonatal and infant deaths in the United States, 1979 through 1994.

BACKGROUND: Infant mortality in the United States has continued to decline in recent years, but changes in sepsis-associated deaths among infants have not been evaluated previously. METHODS: Data from US death records were analyzed for the period 1979 through 1994 to assess trends in sepsis-associated deaths among newborns and older infants. RESULTS: Annual neonatal mortality associated with sepsis declined by 25% from 50.5 deaths per 100 000 live births in 1979 through 1981 to 38.0 deaths per 100 000 live births in 1992 through 1994. Although infant mortality associated with sepsis declined from 71.7 to 56.4 per 100 000 live births over the same period, this decline was attributable to lower sepsis-related mortality among newborns. The rates of sepsis-associated deaths declined for both preterm and term deliveries. Approximately 2260 infants (1521 of whom were newborns) died of sepsis per year in 1992 through 1994. Sepsis-associated death was more likely to occur among infants who were male, black, preterm, or born in the South. Among black infants, the racial gap in sepsis-associated mortality was greater for term than for preterm infants. CONCLUSIONS: Despite declines in the overall sepsis-related mortality among newborns, racial and regional gaps in mortality persisted over the 16-year study period. Almost half of the sepsis-related deaths occurred among infants who were born prematurely. Disproportionate rates of prematurity among blacks and infants born in the South may have contributed to persistently high sepsis-related mortality in these groups. Future efforts to reduce the incidence of sepsis-associated deaths will depend on targeting higher risk populations and reducing prematurity.

Age Distribution↗
PubMed2006

[Investigation on epidemiology in 645 cases with sepsis in surgical intensive care unit].

OBJECTIVE: To investigate the epidemiology of sepsis in surgical intensive care unit. METHODS: The clinical data of 645 intensive care unit cases, admitted during January 2003 to December 2004 in Shanghai Integrated Traditional Chinese and Western Medicine Hospital, were analyzed. The incidence and mortality of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and septic shock, as well as the relationship between them, and age, sex were studied. The hospital stay time was compared among the patients with sepsis, severe sepsis, septic shock and the patients without sepsis. RESULTS: The incidence of SIRS at the first day and second day in surgical intensive care unit was 63.7% and 49.8% respectively, while 74.3% of the cases developed SIRS in surgical intensive care unit. There was no death in non-SIRS group, while the mortality was 6.26% in SIRS group. The incidences of sepsis, severe sepsis, septic shock were 27.0%, 10.9%, 7.0% respectively, and their mortality was 14.94%, 34.29%, 51.11% respectively. The elderly and the male had more chance to develop sepsis (both P<0.01). The sepsis group stayed longer in surgical intensive care unit than non-sepsis group (P<0.01). CONCLUSION: Sepsis is not uncommon in surgical intensive care unit and elderly and male are more susceptible to develop it and carry a poor prognosis. More attention should be given to sepsis in surgical intensive care unit.

Adolescent↗
PubMed2006

Survival analysis of 314 episodes of sepsis in medical intensive care unit in university hospital: impact of intensive care unit performance and antimicrobial therapy.

AIM: To evaluate epidemiology of sepsis in medical intensive care unit (ICU) in a university hospital, and the impact of ICU performance and appropriate empirical antibiotic therapy on survival of septic patients. METHODS: Observational, partly prospective study conducted over 6 years assessed all patients meeting the criteria for sepsis at ICU admission at the Sisters of Mercy University Hospital. Clinical presentation of sepsis was defined according to 2001 International Sepsis Definitions Conference. Demographic data, admission category, source of infection, severity of sepsis, ICU or hospital stay and outcome, ICU performance, and appropriateness of empirical antibiotic therapy were analyzed. RESULTS: The analysis included 314 of 5022 (6.3%) patients admitted to ICU during the study period. There were 176 (56.1%) ICU survivors. At the ICU admission, sepsis was present in 100 (31.8%), severe sepsis in 89 (28.6%), and septic shock in 125 (39.8%) patients with mortality rates 17%, 33.7%, 72.1%, respectively. During ICU treatment, 244 (77.7%) patients developed at least one organ dysfunction syndrome. Of 138 (43.9%) patients who met the criteria for septic shock, 107 (75.4) were non-survivors (P<0.001). Factors associated with in-ICU mortality were acquisition of sepsis at another department (odds ratio [OR] 0.06; 95% confidence interval [CI], 0.02-0.19), winter season (OR 0.42; 0.20-0.89), limited mobility (OR 0.28; 0.14-0.59), ICU length of stay (OR 0.82; 0.75-0.91), sepsis-related organ failure assessment (SOFA) score on day 1 (OR 0.80; 0.72-0.89), history of global heart failure (OR 0.33; 0.16-0.67), chronic obstructive pulmonary disease (COPD)-connected respiratory failure (OR 0.50; 0.27-0.93), septic shock present during ICU treatment (OR 0.03; 0.01-0.10), and negative blood culture at admission (OR 2.60; 0.81-6.23). Microbiological documentation of sepsis was obtained in 235 (74.8%) patients. Urinary tract infections were present in 168 (53.5%) patients, followed by skin or soft tissue infections in 58 (18.5%) and lower respiratory tract infections in 44 (14.0%) patients. Lower respiratory tract as focus of sepsis was connected with worse outcome (P<0.001). Empirical antibiotic treatment was considered adequate in 107 (60.8%) survivors and 42 (30.4%) non-survivors. Patients treated with adequate empirical antibiotic therapy had significantly higher survival time in hospital (log-rank, P=0.001). CONCLUSION: The mortality rate of sepsis was unacceptably high. The odds for poor outcome increased with acquisition of sepsis at another department, winter season, limited mobility, higher SOFA score on day 1, history of chronic global heart failure, COPD-connected respiratory failure, and septic shock present during ICU treatment, whereas longer ICU length of stay, positive blood culture, and adequate empirical antibiotic therapy were protective factors.

Adult↗
PubMed1993

Externalization and internalization of (Na+ + K+)-ATPase in rat heart during different phases of sepsis.

Changes in the distribution of (Na+ + K+)-ATPase in two subcellular fractions, the sarcolemma and the light vesicle, of rat heart during sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). The alpha-subunit of (Na+ + K+)-ATPase was photoaffinity labeled with [alpha-32P]8-N3ATP. The results show that septic rat heart exhibits hyperdynamic (hypermetabolic) phase during early (9 hr post-CLP), followed by hypodynamic (hypometabolic) phase during late (18 hr post-CLP) sepsis. Marker enzyme and beta-adrenergic receptor assays depict that the light vesicle fraction is the intracellular site of surface receptor. The incorporation of the photolabel into the alpha-subunit (M(r) = 98,000) of the (Na+ + K+)-ATPase in sarcolemmal fraction was increased by 60% (P < 0.01) during early sepsis, but was decreased by 63% (P < 0.01) during late sepsis. In contrast, the binding of 98,000-M(r) peptide in light vesicles was decreased by 40% (P < 0.01) in early sepsis, but was increased by 102% (P < 0.01) during late sepsis. The ouabain-sensitive (Na+ + K+)-ATPase activity was increased by 31% (P < 0.05) during the early sepsis, but was decreased by 32% (P < 0.01) during late sepsis in the sarcolemmal fraction; while in the light vesicle fraction, the (Na+ + K+)-ATPase activity was decreased by 21% (P < 0.01) during early sepsis, but was increased by 47% (P < 0.01) during the late phase of sepsis. The yield of membrane proteins for each specific fraction remained unchanged for control, early sepsis, and late sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1999

Selective downregulation of neutrophils by a phosphatidic acid generation inhibitor in a porcine sepsis model.

Effects of lisofylline (1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine), a functional inhibitor of phosphatidic acid (PA) generation derived from de novo synthesis, on neutrophil function were examined in a porcine sepsis model. Hanford minipigs (18-25 kg) were randomly separated into six groups of six animals each: (1) saline control group; (2) sepsis control group, infused with Pseudomonas aeruginosa (1 x 10(6) colony-forming units/kg/min) for 2 h; (3) lisofylline control group, given a 25 mg/kg bolus of lisofylline 30 min prior to time zero, followed by a continuous infusion of 10 mg/kg/h throughout the study; (4) lisofylline pretreatment sepsis group, given lisofylline 30 min prior to sepsis, (5) lisofylline 1-h post-treatment sepsis group, and (6) lisofylline 2-h post-treatment sepsis group. All animals were studied for 6 h. Neutrophils were isolated at -0.5, 2, and 6 h. In the pretreatment and 1-h post-treatment groups, sepsis-induced neutrophil attachment to fibronectin was significantly attenuated. Sepsis-enhanced phagocytic activity was significantly reduced in the lisofylline pretreatment sepsis group, but not in the post-treatment groups. No treatment affected phorbol 12-myristate 13-acetate-induced chemiluminescence and basal filamentous actin content, which increased in sepsis, and cap formation, which declined in sepsis. Sepsis caused neutropenia, pretreatment produced neutrophilia, and 1-h post-treatment caused the neutropenia to recover to control levels. Interestingly, toward the end of the 6-h period, the neutrophil count was higher in the lisofylline control group than in the saline control groups. Thus, the inhibition of PA generation from de novo synthesis during sepsis not only can selectively downregulate some neutrophil functions but can also reverse neutropenia.

Actins↗
PubMed2004

Coagulase-negative staphylococcal sepsis as a predictor of bronchopulmonary dysplasia.

AIM: To determine whether sepsis caused by coagulase-negative staphylococci (CoNS) is a risk factor for developing bronchopulmonary dysplasia (BPD) in premature newborns. METHODS: All newborns born at < or = 30 wk of gestation at Orebro University Hospital during 1994-2001 with clinical sepsis caused by CoNS (group A, n = 22) or by other bacteria (group B, n = 17) were included and compared with premature newborns without sepsis (group C, n = 53). Clinical sepsis was defined as a positive blood culture (monoculture) plus clinical symptoms and laboratory findings. BPD was defined as treatment with oxygen > 21% for at least 28 d. RESULTS: The incidence of BPD differed between the three groups, as follows: CoNS sepsis (A) 64%, other sepsis (B) 41% and control (C) 24%. The difference between the control group and the sepsis groups was highly significant (p = 0.006). In a univariate model the crude estimates of relative risk (RR) for occurrence of BPD increased with presence of sepsis and particularly with presence of sepsis with CoNS (A: RR 2.6, 95% CI 1.5-4.6, p = 0.001; B: RR 1.7, CI 0.8-3.5, p = 0.17). When regression was performed with two additional predictive variables in multivariate models including sepsis, gestational age and mechanical ventilation (group A: RR 1.5, CI 1.1-2.0, p = 0.004; group B: RR 0.9, CI 0.6-1.4, p = 0.67), the estimates were lower. CONCLUSION: The relative risk for BPD is significantly increased in premature newborns with sepsis caused by CoNS compared with those with sepsis caused by other bacteria and compared with premature newborns with no sepsis.

Anti-Infective Agents↗
PubMed1992

Differential alterations in microvascular perfusion in various organs during early and late sepsis.

Although cellular dysfunction occurs very early in sepsis, it remains controversial whether this is solely due to a decrease in tissue perfusion. Recent studies have indicated that while active hepatocellular function was depressed, hepatic surface microvascular blood flow (MBF) increased in early sepsis but decreased in late sepsis as produced by cecal ligation and puncture (CLP). However, it is not known whether microvascular hyperperfusion in early sepsis and microvascular hypoperfusion in late sepsis are common events in other organs under such conditions. To study this, rats were subjected to sepsis by CLP, after which these and the corresponding shams received 3 ml/100 g body wt normal saline. Microvascular perfusion and MBF in various tissues were assessed by colloidal carbon infusion and laser-Doppler flowmetry, respectively, at 5 h (i.e., early sepsis) or 20 h (late sepsis) after CLP or sham operation. Carbon-perfused areas were quantitated by an Optomax image analyzer. The results indicate that the carbon-perfused areas and MBF in the liver, renal cortex, spleen, and small intestinal serosa (only MBF) increased significantly 5 h after CLP. In late sepsis, however, the carbon-perfused areas and MBF were found to be significantly decreased. A highly linear relationship was observed between the changes of carbon-perfused areas and MBF during sepsis in the tested organs. Thus the microvascular responses in the fluid-resuscitated sepsis model are characterized by hyperperfusion in the early stage and hypoperfusion in the late stage of sepsis in the tested tissues. The cellular dysfunctions observed during the early stage of sepsis are, therefore, not due to any reduction in tissue perfusion.

Animals↗
PubMed1998

Phosphorylation of beta-adrenergic receptor leads to its redistribution in rat heart during sepsis.

The role of receptor phosphorylation on the redistribution of beta-adrenergic receptors (beta-ARs) in rat hearts during different phases of sepsis was investigated. Sepsis was induced by cecal ligation and puncture (CLP). Changes in the distribution of beta-ARs in the sarcolemmal and light vesicle fractions were studied using (-)-[4,6-propyl-3H]dihydroalprenolol ([3H]DHA). Phosphorylation of beta-ARs was studied by perfusing hearts with [32P]H3PO4 followed by identification of the phosphorylated beta-ARs with immunoprecipitation using anti-beta 1-AR antibody. The results show that septic rat hearts exhibit an initial hypercardiodynamic (9 h after CLP; early sepsis) and a subsequent hypocardiodynamic (18 h after CLP; late sepsis) state. [3H]DHA binding studies show that, during early sepsis, the maximum binding capacity (Bmax) was increased by 26% in sarcolemma but was decreased by 30% in light vesicles, whereas, during late sepsis, the Bmax was decreased by 39% in sarcolemma but increased by 31% in light vesicles. These data indicate that beta-ARs in the rat heart were externalized from light vesicles to sarcolemma during early sepsis but were internalized from surface membranes to intracellular sites during late sepsis. The immunoprecipitation studies reveal that the externalization of beta-ARs during early sepsis was coupled with a concomitant decrease (-28.5 to -30.6%, P < 0.01) in the receptor phosphorylation, whereas the internalization of beta-ARs during late sepsis was accompanied by a simultaneous increase (30.3 to 33.8%, P < 0.01) in the receptor phosphorylation. Because the phosphorylation/dephosphorylation of beta 1-ARs regulate their functional coupling and may reflect their subcellular distribution, it is suggested that the increase in receptor phosphorylation seen in late sepsis leads to the receptor internalization observed in late sepsis; similarly, externalization of (dephosphorylated) receptors in early sepsis may give rise to the apparent decrease in sarcolemmal receptor phosphorylation observed during this interval.

Adenosine Triphosphate↗
PubMed2006

Sepsis in European intensive care units: results of the SOAP study.

OBJECTIVE: To better define the incidence of sepsis and the characteristics of critically ill patients in European intensive care units. DESIGN: Cohort, multiple-center, observational study. SETTING: One hundred and ninety-eight intensive care units in 24 European countries. PATIENTS: All new adult admissions to a participating intensive care unit between May 1 and 15, 2002. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic data, comorbid diseases, and clinical and laboratory data were collected prospectively. Patients were followed up until death, until hospital discharge, or for 60 days. Of 3,147 adult patients, with a median age of 64 yrs, 1,177 (37.4%) had sepsis; 777 (24.7%) of these patients had sepsis on admission. In patients with sepsis, the lung was the most common site of infection (68%), followed by the abdomen (22%). Cultures were positive in 60% of the patients with sepsis. The most common organisms were Staphylococcus aureus (30%, including 14% methicillin-resistant), Pseudomonas species (14%), and Escherichia coli (13%). Pseudomonas species was the only microorganism independently associated with increased mortality rates. Patients with sepsis had more severe organ dysfunction, longer intensive care unit and hospital lengths of stay, and higher mortality rate than patients without sepsis. In patients with sepsis, age, positive fluid balance, septic shock, cancer, and medical admission were the important prognostic variables for intensive care unit mortality. There was considerable variation between countries, with a strong correlation between the frequency of sepsis and the intensive care unit mortality rates in each of these countries. CONCLUSIONS: This large pan-European study documents the high frequency of sepsis in critically ill patients and shows a close relationship between the proportion of patients with sepsis and the intensive care unit mortality in the various countries. In addition to age, a positive fluid balance was among the strongest prognostic factors for death. Patients with intensive care unit acquired sepsis have a worse outcome despite similar severity scores on intensive care unit admission.

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