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PubMed2000

Fulminant late-onset sepsis in a neonatal intensive care unit, 1988-1997, and the impact of avoiding empiric vancomycin therapy.

OBJECTIVE: To determine the pathogens associated with fulminant (lethal within 48 hours) late-onset sepsis (occurring after 3 days of age) in a neonatal intensive care unit (NICU) and the frequency of fulminant late-onset sepsis for the most common pathogens. METHODS: A retrospective study was conducted of sepsis in infants in a NICU over a 10-year period (1988-1997). RESULTS: There were 825 episodes of late-onset sepsis occurring in 536 infants. Thirty-four of 49 (69%; 95% confidence interval [CI]: 55%-82%) cases of fulminant late-onset sepsis were caused by Gram-negative organisms, including Pseudomonas sp., 20 (42%); Escherichia coli, 5 (10%); Enterobacter sp., 4 (8%); and Klebsiella sp., 4 (8%). The frequency of fulminant sepsis was highest for Pseudomonas sp., 20 of 36 (56%; 95% CI: 38%-72%) and lowest for coagulase-negative staphylococci, 4 of 277 (1%; 95%CI: 0%-4%). The very low frequency of fulminant sepsis caused by coagulase-negative staphylococci did not increase during the period when oxacillin was used instead of vancomycin as the empiric antibiotic for Gram-positive organisms. CONCLUSIONS: These data suggest that empiric antibiotics selected for treatment of suspected sepsis in infants >3 days old need to effectively treat Gram-negative pathogens, particularly Pseudomonas sp., because these organisms, although less frequent, are strongly associated with fulminant late-onset sepsis in the NICU. Avoiding empiric vancomycin therapy seemed to be a reasonable approach to late-onset sepsis, because of the very low frequency of fulminant sepsis caused by coagulase-negative staphylococci.

Abnormalities, Multiple↗
PubMed2006

Neonatal sepsis-- a global problem: an overview.

Neonatal sepsis is one of the major health problems throughout the world. Every year an estimated 30 million newborns acquire infection and 1-2 million of these die. The present review provides updates regarding neonatal sepsis to help paediatricians to protect the newborn from this deadly problem. The onset of sepsis within first 48 hours of life (early onset sepsis) is frequently associated with pre and perinatal predisposing factors while onset after 48-72 hours of life (late onset sepsis) frequently reflects infection acquired nosocomially. Some literatures say that early onset disease presents in the first 5-7 days of life. Klebsiella pneumoniae is the leading pathogen causing neonatal sepsis in Bangladesh and neighbouring countries. Among many risk factors the single most important neonatal risk factor is low birth weight. Other main risk factors are invassive procedures in the postnatal period and inadequate hand washing before and after handling babies. Sepsis score is a useful method for early and rapid diagnosis of neonatal sepsis which was developed by Tollner U in 1982. Antibiotics should be given to most of the neonates suspected of infection. Ampicillin and gentamicin are the first drug of choice. In Bangladesh context sepsis score may be used as a good parameter for the early and rapid diagnosis of sepsis and that will guide the treatment plan. Clean and safe delivery, early and exclusive breastfeeding, strict postnatal cleanliness following adequate handwashing and aseptic technique during invasive procedure might reduce the incidence of neonatal sepsis. Prompt use of antibiotic according to standard policy is warranted to save the newborn lives from septicaemia.

Ampicillin↗
PubMed2000

[Interleukin-6, procalcitonin, C-reactive protein and the immature to total neutrophil ratio (I/T) in the diagnosis of early-onset sepsis in low birth weight neonates].

OBJECTIVE: To determine the influence of early-onset neonatal sepsis on interleukin-6 (IL-6) and procalcitonin (PCT) levels in cord blood. To evaluate the significance of usually used infection markers--C-reactive protein (CRP) and immature to total neutrophil ratio (I/T)--and new markers (PCT, IL-6) for the diagnosis of early-onset neonatal sepsis. DESIGN: Prospective clinical study. SETTING: Institute for the Care of Mother and Child, Prague. METHODS: The serum levels of IL-6 and PCT were measured in cord blood in 37 low birht weight infants less than 35 week of gestation born in our institute. IL-6 and PCT levels were further evaluated together with CRP and I/T in neonatal blood within 2 hours after delivery. Neonatal sepsis within the first 72 hours of life was monitored. RESULTS: Differences in mean values of CRP, I/T, IL-6, and PCT between "sepsis proven" and "sepsis not proven" groups were not statistically significant. Only the difference between groups in cord blood PCT was of borderline significance (p = 0.06, higher in "sepsis proven" group). Fisher test showed significant dependence on sepsis in cord blood PCT only (cut-off point 0.4 ng/ml, p < or = 0.05). Other parameters did not show significant dependence on sepsis. Sensitivity for early onset sepsis above 50% was found in cord blood PCT only (sensitivity 60%, specificity 85.2%). PCT predictive accuracy for sepsis expressed as AUC value was 0.74 +/- 0.06. CONCLUSION: The only relatively sensitive marker and moderate predictor of early-onset sepsis in premature low birthweight infant was in our study cord blood PCT.

Biomarkers↗
PubMed1987

The benefits of Isolator cultures in the management of suspected catheter sepsis.

Until recently, when a patient receiving total parenteral nutrition (TPN) was suspected of having catheter-related sepsis, the catheter was removed and the tip and the patient's blood was cultured. Using this method at our institution, greater than two thirds of the central venous catheters (CVC) removed were sterile, or if colonized, proved not to be the source of sepsis. This practice led to the unwarranted removal of numerous catheters and posed a clinical dilemma because it necessitated replacement of the catheter with its attendant risks, cost, and inconvenience. To address this problem, we instituted a protocol for determining in situ catheter-related sepsis based on a quantitative blood culture method using lysis centrifugation (Isolator; Dupont Co., Wilmington, Del.). When catheter-related sepsis was clinically suspected, quantitative blood cultures were obtained simultaneously via a peripheral (PER) vein and through the CVC suspected as the source of sepsis. The CVC, however, remained in situ pending culture results (approximately 16 to 24 hours). A CVC colony of greater than or equal to five times the PER colony count was considered significant and the catheter was removed. Equivocal colony counts between the CVC and PER cultures were interpreted as incriminating a source of sepsis other than the CVC. An 8-month prospective study was undertaken to evaluate the efficacy of this method for determining in situ catheter sepsis. One hundred third-eight patients received TPN by means of 160 catheters. In 113 patients no sepsis-related problems were noted. In the remaining 25 patients, 28 catheters were suspected as the source of sepsis. Twenty-six catheters were evaluated by the Isolator culture method. In eight instances significant differences in colony counts between the CVC and PER cultures were seen, implicating the CVC as the source of infection. In all these cases the CVC was removed and the patients underwent defervescence. In 18 cases, the CVC samples revealed either no growth or insignificant differences between the CVC and PER colony counts. Nine of these CVCs were removed without clinical improvement. The remaining nine catheters were left in place, and another source of sepsis was ultimately identified and treated. These results confirm the use of the quantitative blood culture method for determining in situ catheter-related sepsis. In all cases, when the catheter was incriminated by culture data, removal of the CVC led to patient improvement.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1997

Epidemiology of sepsis syndrome in 8 academic medical centers.

CONTEXT: Sepsis syndrome is a leading cause of mortality in hospitalized patients. However, few studies have described the epidemiology of sepsis syndrome in a hospitalwide population. OBJECTIVE: To describe the epidemiology of sepsis syndrome in the tertiary care hospital setting. DESIGN: Prospective, multi-institutional, observational study including 5-month follow-up. SETTING: Eight academic tertiary care centers. METHODS: Each center monitored a weighted random sample of intensive care unit (ICU) patients, non-ICU patients who had blood cultures drawn, and all patients who received a novel therapeutic agent or who died in an emergency department or ICU. Sepsis syndrome was defined as the presence of either a positive blood culture or the combination of fever, tachypnea, tachycardia, clinically suspected infection, and any 1 of 7 confirmatory criteria. Estimates of total cases expected annually were extrapolated from the number of cases, the period of observation, and the sampling fraction. RESULTS: From January 4, 1993, to April 2, 1994, 12759 patients were monitored and 1342 episodes of sepsis syndrome were documented. The extrapolated, weighted estimate of hospitalwide incidence (mean+/-95% confidence limit) of sepsis syndrome was 2.0+/-0.16 cases per 100 admissions, or 2.8+/-0.17 per 1000 patient-days. The unadjusted attack rate for sepsis syndrome between individual centers differed by as much as 3-fold, but after adjustment for institutional differences in organ transplant populations, variation from the expected number of cases was reduced to 2-fold and was not statistically significant overall. Patients in ICUs accounted for 59% of total extrapolated cases, non-ICU patients with positive blood cultures for 11%, and non-ICU patients with negative blood cultures for 30%. Septic shock was present at onset of sepsis syndrome in 25% of patients. Bloodstream infection was documented in 28%, with gram-positive organisms being the most frequent isolates. Mortality was 34% at 28 days and 45% at 5 months. CONCLUSIONS: Sepsis syndrome is common in academic hospitals, although the overall rates vary considerably with the patient population. A substantial fraction of cases occur outside ICUs. An understanding of the hospitalwide epidemiology of sepsis syndrome is vital for rational planning and treatment of hospitalized patients with sepsis syndrome, especially as new and expensive therapeutic agents become available.

Adult↗
PubMed1987

Superoxide dismutase in rats with sepsis. Effect on survival rate and amino acid transport.

In a recent study, administration of the free radical scavenger superoxide dismutase (SOD) improved survival in rats with sepsis when administered two hours before induction of sepsis. The present study was designed to determine whether free radical-induced membrane damage is involved in the pathogenesis of decreased muscle amino acid uptake, noted in sepsis. Additionally, the effect on survival rate of SOD given after the onset of sepsis was studied. Sepsis was induced by cecal ligation and puncture in rats. Amino acid transport in incubated soleus muscles was studied using tritiated alpha-aminoisobutyric acid. Amino acid uptake was significantly reduced in muscle from rats with sepsis. Administration of SOD before induction of sepsis or added in vitro to incubated muscles with sepsis had no effect on alpha-aminoisobutyric acid uptake. Survival rate was not increased when SOD was given two hours after cecal ligation and puncture. The results suggest that free radical-induced membrane damage is not the mechanism of inhibited muscle amino acid transport in sepsis. Since survival was not improved by SOD administered after induction of sepsis, the role of the enzyme in the treatment of sepsis may be questioned.

Amino Acids↗
PubMed1996

Pulmonary artery endothelial cell function in swine pseudomonas sepsis.

A substantial increase in pulmonary vascular resistance is associated with sepsis and its sequelae (sepsis syndrome and septic shock). It is postulated that increased resistance may result from sepsis-induced endothelial cell injury or altered vasoreactivity secondary to pulmonary hypertension. We, therefore, tested the hypothesis that sepsis causes endothelial cell injury and that increased pulmonary pressure alters vascular reactivity. Young swine (15-25 kg) were anesthetized and ventilated. Septic animals received a 1-hr infusion of live Pseudomonas aeruginosa (n = 11), and the control cohort received 0.9% NaCl (n = 7). All animals were studied for 300 min following the infusion. Postmortem branches of peripheral pulmonary arteries were prepared and tested in a vessel myograph. Ring segments were set to 90% of the circumference the vessels would have at pressures of 20, 30, 40, or 50 mmHg (L90), corresponding to varying pulmonary pressures observed in sepsis. A high dose of potassium was used to obtain maximum possible contraction. Prostaglandin was used to precontract the vessels before testing endothelial cell responses to acetylcholine or bradykinin. Sodium nitroprusside was added at the end of each experiment to obtain maximum possible smooth muscle relaxation. No differences in contraction or relaxation were observed when vessels were set to different pressures (i.e., 20 vs 50 mmHg). Maximum possible contraction to KCl was significantly decreased after 300 min of sepsis compared to control. No differences between groups were found in contractility to prostaglandin. Bradykinin-induced EDRF/NO production, mediated by BK2 receptors, was not altered in Pseudomonas sepsis (97-98% of total relaxation control and 91-95% septic cohort). Response to acetylcholine was significantly decreased after sepsis (89-95% of total relaxation control and 51-61% of septic cohort relaxation). Decreased response to acetylcholine could not be attributed to decreased smooth muscle sensitivity to nitric oxide because the response to bradykinin plus sodium nitroprusside was not altered following sepsis. Vessel reactivity was not altered by increasing pressure settings reflective of changing pulmonary pressure in vivo. These results strongly suggest a sepsis-induced alteration in pulmonary artery endothelial cell receptor sensitivity to acetylcholine, independent of changing pulmonary arterial pressures. This is the first time this decrease has been shown in pseudomonas sepsis.

Animals↗
PubMed1998

Phospholipase A2 activities are decreased during early but increased during late phases of sepsis in rat heart.

BACKGROUND: Changes in the activities of secretory phospholipase A2 (sPLA2) and cytosolic phospholipase A2 (cPLA2) in the rat heart during early hyperdynamic and late hypodynamic phases of sepsis were studied in an attempt to understand the pathophysiology of cardiac dysfunction during sepsis. METHODS: 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. PLA2 activity was measured based on the rate of hydrolysis of 1-palmitoyl-2-[1-(14)C]-oleoyl phosphatidylcholine. RESULTS: The results show that under physiological conditions, sPLA2 and cPLA2 activities were time and protein dependent. The optimal Ca2+ concentrations for sPLA2 and cPLA2 activities were 3 mM and 40 microM, respectively. During sepsis, sPLA2 activity was decreased by 25% (P < 0.01) during early phase while it was increased by 49% (P < 0.01) during late phase of sepsis. Similarly, cPLA2 activity was decreased by 23% (P < 0.01) during early sepsis while it was increased by 60% (P < 0.01) during late sepsis. CONCLUSIONS: Since PLA2 functions to maintain cell membrane integrity and function, a biphasic change in sPLA2 and cPLA2 activities may contribute to the development of the two cardiodynamically distinct phases during the progression of sepsis.

Animals↗
PubMed1998

Scope and limitations of antimicrobial therapy of sepsis in surgery.

OBJECTIVE: The goal of antibiotic therapy for surgical sepsis is to kill bacteria that intermittently or continuously reach the bloodstream from the residue of an operatively treated focus. While sepsis and conditions leading to sepsis compromise the immune system, antibiotics may become a fundamental determinant of the host's defense. No data from sound prospective randomized clinical antibiotic trials dealing with sepsis are available. Therefore we tested the hypothesis that treatment recommendations can be based on pharmacodynamics comparing in vitro activity of commonly used antimicrobials with concentrations sustained in vivo to provide for full coverage for bacteria of concern. RESULTS: The application of strict criteria for antibiotic choice to avoid selection of primary resistant strains reveals that most commonly used antibiotics render insufficient activity to eliminate pathogens that commonly cause surgical sepsis. Antibiotics that sustain in vivo concentration exceeding fourfold the MIC100 (highest minimal inhibitory concentration for all (100%) species tested) of Escherichia coli, for example, are 400 mg ciprofloxacin IV (MIC100 of 1224 strains=0.06 mg/dl, in vivo concentration=1 mg/dl for 12 h), and 1000 mg imipenem/cilastatin (MIC100 of 3142 strains=0.14 mg/dl, in vivo concentration=2 mg/dl for 6 h). The third choice is one of the fourth- or, less convincingly, third-generation cephalosporins. Similar data for most pathogens causing sepsis are provided. First- and second-generation cephalosporins and penicillin beta-lactamase inhibitor combinations generally do not achieve sufficient concentrations to cover the most important pathogens of sepsis. CONCLUSION: Sepsis is defined as a whole body's inflammatory response that is characterized by systemic signs and symptoms secondary to a focal infection. While many antibiotic trials have dealt with a focal infection, no prospective randomized antibiotic trial has dealt with sepsis per se. Antibiotic trials on focal infections generally exclude patients when their focal infection has progressed to sepsis. To circumvent the lack of controlled clinical trials we show that pharmacodynamics may provide sound foundation for antibiotic choice for sepsis.

Anti-Bacterial Agents↗
PubMed1987

Mortality associated with multiple organ system failure and sepsis in pediatric intensive care unit.

Seven hundred twenty-six patients from five pediatric intensive care units were studied to determine the association of multiple organ system failure (MOSF) with mortality and to test the hypothesis that MOSF associated with sepsis has a higher mortality rate than MOSF without sepsis. There were 177 (24%) patients with MOSF and 83 (11%) nonsurvivors of MOSF. The mortality rates for two, three, or four or more failed organ systems were 26%, 62%, and 88%, respectively (P less than 0.001). Eighty-four (47%) patients with MOSF had associated sepsis. Sepsis (both bacteremia and clinical sepsis syndrome) did not significantly increase mortality rates in the groups with organ system failure. Mortality rates for patients with sepsis before or within 24 hours of development of MOSF (early sepsis) did not differ from mortality rates for those patients with onset of sepsis more than 24 hours after developing MOSF (late sepsis, 53% vs 33%, P = NS). We conclude that underlying pathophysiologic mechanisms of MOSF other than sepsis are as important as sepsis in critically ill pediatric patients.

Child↗
PubMed2003

Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle.

Muscle wasting during sepsis reflects increased expression and activity of the ubiquitin-proteasome proteolytic pathway and is at least in part mediated by glucocorticoids. The ubiquitination of proteins destined to be degraded by the proteasome is regulated by multiple enzymes, including ubiquitin ligases. We tested the hypothesis that sepsis upregulates the gene expression of the newly described ubiquitin ligases, MuRF1 and atrogin-1/MAFbx. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. In some experiments, rats were treated with the glucocorticoid receptor antagonist RU 38486 before induction of sepsis. At various time points after induction of sepsis, mRNA levels for MuRF1 and atrogin-1/MAFbx were determined in extensor digitorum longus muscles by real-time PCR. Sepsis resulted in a 10-16-fold increase in gene expression of the ubiquitin ligases studied here. These changes were much greater than those observed previously for another ubiquitin ligase, E3alpha, in muscle during sepsis. Treatment of rats with RU 38486 prevented the sepsis-induced increase in mRNA levels for MuRF1 and atrogin-1/MAFbx, suggesting that glucocorticoids participate in the upregulation of these genes in muscle during sepsis. The present results lend further support to the concept that the ubiquitin-proteasome pathway plays an important role in sepsis-induced muscle proteolysis and suggest that multiple ubiquitin ligases may participate in the development of muscle wasting during sepsis.

Animals↗
PubMed2001

Late immunoneutralization of procalcitonin arrests the progression of lethal porcine sepsis.

BACKGROUND: Procalcitonin (ProCT) is becoming increasingly recognized as a mediator as well as a marker of sepsis. Serum ProCT concentrations rise soon after induction of sepsis and remain elevated over a prolonged period of time. In contrast, many pro-inflammatory cytokines, e.g., tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), rise and decline early in the course of sepsis. Researchers have improved survival in animal models of sepsis by prophylactically blocking IL-1beta and TNF-alpha with immunotherapy, but therapeutic treatment has been less successful in clinical trials. We hypothesized that the sustained elevation of ProCT in the serum would allow for effective therapeutic immunoneutralization of this peptide late in the course of sepsis. METHODS: Lethal polymicrobial sepsis was induced in 10 castrated, male Yorkshire pigs by intraabdominal spillage of cecal contents (1 gm/kg) and intraabdominal instillation of 2 x 10(11) cfu of a toxigenic strain of E. coli (O18:K1:H7). The treated group (n = 5) received an intravenous infusion of purified rabbit antiserum to the aminoterminus of porcine ProCT. The control group (n = 5) received nonreactive, purified rabbit IgG. The purified antiserum was infused to all animals 3 h after the induction of sepsis, at which time very severe physiologic dysfunction was manifest, and many of the animals appeared to be preterminal. Physiologic and metabolic parameters were measured until death or for 15 h after induction of sepsis, at which time all surviving animals were euthanized. RESULTS: Therapeutic immunoneutralization of serum ProCT improved most measured physiologic and metabolic parameters in septic pigs. Specifically, there was a significant increase in mean arterial pressure, urine output and cardiac index in all animals treated with ProCT antibody. Serum creatinine was significantly lower in treated animals. Although acidosis was not as severe in treated animals, as indicated by higher pH values and lower lactate concentrations, these results did not achieve statistical significance. Significantly, 11 h after the induction of sepsis there was 100% mortality in the control group while only one animal in the treated group expired. CONCLUSION: The prolonged elevation of ProCT concentrations in sepsis allows neutralization of this peptide to be effective during the course of this disorder. These findings suggest that immunoneutralization of ProCT may be a useful treatment in clinical situations where sepsis is already fully established.

Animals↗
PubMed2000

Procalcitonin release patterns in a baboon model of trauma and sepsis: relationship to cytokines and neopterin.

OBJECTIVES: Procalcitonin (PCT) has been described as an early, discriminating marker of bacteria-associated sepsis in patients. However, little is known of its source and actions, in part because no appropriate animal models have been available. We tested the hypothesis that plasma PCT increases during various pathophysiological conditions, such as hemorrhagic shock and sepsis, which differ with regard to the degree of associated endotoxemia. We further hypothesized that in sepsis, PCT would be significantly different in survivors vs. nonsurvivors. DESIGN: Prospective, blinded analysis of previously collected plasma of experimental animals. SETTING: Independent nonprofit research laboratory in a trauma hospital and a contract research institute. SUBJECTS: A total of 22 male baboons (17.5-31 kg). INTERVENTIONS: Hemorrhagic-traumatic shock was induced by hemorrhage for up to 3 hrs, reperfusion with shed blood and infusion of cobra venom factor (n = 7). By using a similar experimental setup, severe hyperdynamic sepsis was induced (n = 15) by intravenous infusion of live Escherichia coli (2 x 10(9) colony-forming units/kg) over 2 hrs, followed by antibiotic therapy (gentamicin 4 mg/kg twice a day). MEASUREMENTS AND MAIN RESULTS: Plasma PCT at baseline was barely detectable, but levels increased significantly (p < .05) to 2+/-1.8 pg/mL 2 hrs after the start of reperfusion in the shock group, and to 987+/-230 pg/mL at 4 hrs after E. coli in the sepsis group. Levels were maximal between 6 and 32 hrs and had returned nearly to baseline levels at 72 hrs. Interleukin-6 levels paralleled the course of PCT measurements, whereas a significant increase in neopterin was seen at 24 hrs. PCT levels were approximately three times higher in the sepsis group than in the shock group, corresponding to endotoxin levels (at the end of hemorrhage, 286+/-144 pg/mL vs. 3576+/-979 pg/mL at the end of E. coli infusion; p = .003). PCT levels were significantly different at 24 hrs between survivors (2360+/-620 pg/mL) and nonsurvivors (4776+/-563 pg/mL) in the sepsis group (p = .032), as were interleukin-6 (1562+/-267 vs. 4903+/-608 pg/mL; p = .01) and neopterin/creatinine ratio (0.400+/-0.038 vs. 0.508+/-0.037; p = .032). CONCLUSIONS: PCT is detectable in the baboon as in humans, both in hemorrhagic shock and sepsis. PCT levels are significantly higher in sepsis than in hemorrhage, a finding that is probably related to the differences in endotoxin. The baboon can be used for the study of PCT kinetics in both models; PCT kinetics are clearly different from other markers of sepsis, either IL-6 or neopterin, in both models. There are significant differences between survivors and nonsurvivors in the sepsis model.

Animals↗
PubMed2005

Cloxacillin versus vancomycin for presumed late-onset sepsis in the Neonatal Intensive Care Unit and the impact upon outcome of coagulase negative staphylococcal bacteremia: a retrospective cohort study.

BACKGROUND: Coagulase negative staphylococcus (CONS) is the main cause of late-onset sepsis in Neonatal Intensive Care Units (NICU). Although CONS rarely causes fulminant sepsis, vancomycin is frequently used as empiric therapy. Indiscriminate use of vancomycin has been linked to the emergence of vancomycin resistant organisms. The objective of this study was to compare duration of CONS sepsis and mortality before and after implementation of a policy of selective vancomycin use and compare use of vancomycin between the 2 time periods. METHODS: A retrospective study was conducted of infants > or =4 days old, experiencing signs of sepsis with a first positive blood culture for CONS, during two 12-month periods. Late-onset sepsis was treated empirically with vancomycin and gentamicin during period 1, and cloxacillin and gentamicin during period 2. The confidence interval method was used to assess non-inferiority of the outcomes between the two study groups. RESULTS: There were 45 episodes of CONS sepsis during period 1 and 37 during period 2. Duration of sepsis was similar between periods (hazard ratio of 1.00, 95%CI: 0.64, 1.57). One death during period 2 was possibly related to CONS sepsis versus none in period 1. Vancomycin was used in 97.8% of episodes in period 1 versus 81.1% of episodes in period 2. CONCLUSION: Although we failed to show non-inferiority of duration of sepsis in the cloxacillin and gentamicin group compared to the vancomycin and gentamicin group, duration of sepsis was clinically similar. Restricting vancomycin for confirmed cases of CONS sepsis resistant to oxacillin appears effective and safe, and significantly reduces vancomycin use in the NICU.

Anti-Bacterial Agents↗
PubMed1993

Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome.

OBJECTIVE: To determine whether plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and lipopolysaccharide are detectable in patients when they first present with the sepsis syndrome and to determine whether levels correlate with patient survival. DESIGN: Prospective study comparing patients with the sepsis syndrome, critically ill patients without sepsis, and normal healthy volunteers. SETTING: Tertiary care hospital affiliated with a medical school. PATIENTS: The study included 97 consecutive patients on a medical service who met the criteria for the sepsis syndrome; 20 critically ill patients without sepsis who were in the medical intensive care unit; and 20 healthy volunteers who served as comparison groups. MEASUREMENTS: Plasma tumor necrosis factor-alpha, IL-1 beta, interleukin-6, and endotoxin (lipopolysaccharide) levels were measured when a patient was first identified as having the sepsis syndrome. Survival was defined as being alive 30 days after the sepsis syndrome was diagnosed. RESULTS: Fifty-four percent of patients with the sepsis syndrome had detectable levels of TNF-alpha (median, 26 pg/mL; range, nondetectable to 1000 pg/mL); 37% had detectable levels of IL-1 (median, 20 pg/mL; range, nondetectable to 2850 pg/mL); 80% had detectable levels of IL-6 (median, 415 pg/mL; range, nondetectable to 2380 pg/mL); and 89% had detectable levels of lipopolysaccharide (median, 2.6; range, nondetectable to 12.5 endotoxin units [EU]/mL). In all cases levels were higher than those in critically ill patients without sepsis and normal healthy controls (P < 0.001 for all comparisons). Plasma levels of TNF-alpha, IL-1 beta, IL-6, and lipopolysaccharide were detectable in patients regardless of culture status. The IL-6 level was 69% (95% CI, 30% to 108%) higher in patients who died compared with those who survived. The scores for the individual levels of TNF-alpha, IL-1 beta, IL-6, and lipopolysaccharide were summed to arrive at a total lipopolysaccharide-cytokine score, and mortality increased with lipopolysaccharide-cytokine score (P < 0.001). CONCLUSIONS: Patients with the sepsis syndrome have detectable levels of circulating TNF-alpha, IL-1, IL-6, and lipopolysaccharide independent of culture-documented infection. Lipopolysaccharide and cytokines may play a pathogenic role in sepsis, and the combination of several elevated factors may be important in determining patient survival.

Adolescent↗
PubMed1981

Hepatocellular dysfunction in early sepsis despite increased hepatic blood flow.

Although it is known that hepatic failure occurs in late sepsis, it is not known whether there are alterations in hepatocellular function in early sepsis when hyperdynamic circulation exists in conjunction with hyperglycemia and hyperinsulinemia. To study this, indocyanine green (ICG) clearance and serum levels of hepatic enzymes were measured during early and late sepsis. Sepsis in rats was produced by cecal ligation and puncture (CLP). Ten hours following CLP (early sepsis) total hepatic blood flow (THBF) as measured by hydrogen polarography increased from 23.9 +/- 1.1 to 30.6 +/- 1.4 (ml/min/100 gm). ICG (5 mg/kg body weight--BW) was given intravenously and sequential blood samples taken to determine ICG clearance. ICG half-times (T/2) were 4.99 +/- 0.15 and 6.57 +/- 0.51 minutes for sham-operated and early sepsis rats, respectively (mean +/- S.E., P less than 0.01). SGOT and SGPT levels (IU/ml) increased from 38.1 +/- 0.6 to 69.8 +/- 2.6 and 9.9 +/- 0.4 to 25.6 +/- 1.5, respectively (P less than 0.001). Thus the T/2 of ICG as well as serum levels of liver enzymes increased significantly during early sepsis. Eight additional rats underwent CLP and were tested 16 hours later (late sepsis). THBF in late sepsis decreased to 15.5 +/- 0.5 ml/min/100 gm. ICG T/2 at that time was 8.2 +/- 0.48 min and SGOT and SGPT level were 132 +/- 14.5 and 42 +/- 3.4, respectively (P less than 0.001). These results indicate that heptocellular dysfunction occurs even in the early period of sepsis when THBF is increased. Progressive dysfunction occurs in late sepsis concomitant with a decrease in THBF.

Alanine Transaminase↗
PubMed1993

Epidemiology, pathophysiology and clinical presentation of gram-negative sepsis.

OBJECTIVE: To review the epidemiology and pathophysiology of gram-negative sepsis and the new consensus terminology describing the clinical signs of sepsis. DATA SOURCES: Review of the medical literature and compiled data from animal and clinical trials. PARTICIPANTS: Members of the Society of Critical Care Medicine, American College of Chest Physicians and American Association of Critical-Care Nurses with expertise on the subject of sepsis and its complications. RESULTS: Preconference and general sessions were offered at the National Teaching Institutes of the American Association of Critical-Care Nurses, with the goal of clarifying the epidemiology, risk factors and pathophysiology of gram-negative sepsis. In addition, current terminology and new (1992) consensus terminology describing the clinical signs of sepsis were presented. Special emphasis was placed on the role of the healthcare provider in the prevention and recognition of sepsis and the role of the septic mediators in the septic cascade. CONCLUSIONS: If the incidence of sepsis is to be reduced, the healthcare provider must be aware of the risk factors for sepsis and methods of reducing nosocomial infections. A thorough understanding of the role of mediators and consensus terminology used to describe sepsis, severe sepsis, septic shock and multiple organ dysfunction syndrome is necessary to recognize early or progressive signs of sepsis and to initiate state-of-the-art therapy.

Adult↗
PubMed2026

Potential mitochondria-associated pathogenic genes in sepsis: a multi-omics Mendelian randomization study.

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of sepsis. However, human genetic evidence linking mitochondria-related genes to sepsis susceptibility remains limited. This study aimed to identify mitochondria-related genes associated with sepsis risk using a multi-omics Mendelian randomization framework. METHODS: Summary-data-based Mendelian randomization (SMR) was applied using sepsis genome-wide association study (GWAS) summary statistics from the UK Biobank and FinnGen databases. Expression, methylation, single-cell, and protein quantitative trait loci (QTLs) were used as genetic instruments. Colocalization analyses were conducted to evaluate whether SMR associations were driven by shared genetic variants. Expression of prioritized candidate genes was further examined in clinical septic samples, and correlations with disease severity (SOFA scores) were assessed. RESULTS: SMR analysis prioritized 13 mitochondria-related genes associated with sepsis risk. Immune cell-specific eQTL analysis suggested that genetically predicted SURF1 expression in memory B cells and na&#xef;ve T cells was associated with sepsis risk. Differential expression of 12 candidate genes was confirmed in septic patients by qPCR, and PPOX expression showed a negative correlation with SOFA scores. Integration of mQTL and eQTL data supported a regulatory relationship between methylation at cg06661924 and AK4 expression. Increased genetically predicted AK4 expression was associated with higher sepsis risk (OR&#xa0;=&#xa0;1.21, 95% CI 1.02-1.42). Protein-level analysis identified DUT as a potential sepsis-associated candidate, with consistent evidence across streptococcal and pneumococcal septicemia subtypes. Subtype analyses also suggested heterogeneous genetic signals across different sepsis subtypes. CONCLUSION: This study prioritized several mitochondria-related genes associated with sepsis susceptibility based on human genetic evidence. These findings provide candidate targets for further mechanistic and translational investigation.

Humans↗