Survival In Severe Sepsis Research Articles

Loss-of-function/gain-of-function polymorphisms of the ATP sensitive P2X7R influence sepsis, septic shock, pneumonia, and survival outcomes.

Extracellular ATP (eATP) released from damaged cells activates the P2X7 receptor (P2X7R) ion channel on the surface of surrounding cells, resulting in calcium influx, potassium efflux and inflammasome activation. Inherited changes in the P2X7R gene (P2RX7) influence eATP induced responses. Single nucleotide polymorphisms (SNPs) of P2RX7 influence both function and signaling of the receptor, that in addition to ion flux includes pathogen control and immunity. Subjects (n = 105) were admitted to the ICU at the University Hospital Ulm, Germany between June 2018 and August 2019. Of these, subjects with a diagnosis of sepsis (n = 75), were also diagnosed with septic shock (n = 24), and/or pneumonia (n = 42). Subjects with pneumonia (n = 43) included those without sepsis (n = 1), sepsis without shock (n = 29) and pneumonia with septic shock (n = 13). Out of the 75 sepsis/septic shock patients, 33 patients were not diagnosed with pneumonia. Controls (n = 30) were recruited to the study from trauma patients and surgical patients without sepsis, septic shock, or pneumonia. SNP frequencies were determined for 16 P2RX7 SNPs known to affect P2X7R function, and association studies were performed between frequencies of these SNPs in sepsis, septic shock, and pneumonia compared to controls. The loss-of-function (LOF) SNP rs17525809 (T253C) was found more frequently in patients with septic shock, and non-septic trauma patients when compared to sepsis. The LOF SNP rs2230911 (C1096G) was found to be more frequent in patients with sepsis and septic shock than in non-septic trauma patients. The frequencies of these SNPs were even higher in sepsis and septic patients with pneumonia. The current study also confirmed a previous study by our group that showed a five SNP combination that included the GOF SNPs rs208294 (C489T) and rs2230912 (Q460R) that was designated #21211 was associated with increased odds of survival in severe sepsis. The results found an association between expression of LOF P2RX7 SNPs and presentation to the ICU with sepsis, and septic shock compared to control ICU patients. Furthermore, frequencies of LOF SNPs were found to be higher in sepsis patients with pneumonia compared to those without pneumonia. In addition, a five SNP GOF combination was associated with increased odds of survival in severe sepsis. These results suggest that P2RX7 is required to control infection in pneumonia and that inheritance of LOF variants increases the risk of sepsis when associated with pneumonia. This study confirms that P2RX7 genotyping in pneumonia may identify patients at risk of developing sepsis. The study also identifies P2X7R as a target in sepsis associated with an excessive immune response in subjects with GOF SNP combinations.

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

A nanotrap improves survival in severe sepsis by attenuating hyperinflammation

Targeting single mediators has failed to reduce the mortality of sepsis. We developed a telodendrimer (TD) nanotrap (NT) to capture various biomolecules via multivalent, hybrid and synergistic interactions. Here, we report that the immobilization of TD-NTs in size-exclusive hydrogel resins simultaneously adsorbs septic molecules, e.g. lipopolysaccharides (LPS), cytokines and damage- or pathogen-associated molecular patterns (DAMPs/PAMPs) from blood with high efficiency (92–99%). Distinct surface charges displayed on the majority of pro-inflammatory cytokines (negative) and anti-inflammatory cytokines (positive) allow for the selective capture via TD NTs with different charge moieties. The efficacy of NT therapies in murine sepsis is both time-dependent and charge-dependent. The combination of the optimized NT therapy with a moderate antibiotic treatment results in a 100% survival in severe septic mice by controlling both infection and hyperinflammation, whereas survival are only 50–60% with the individual therapies. Cytokine analysis, inflammatory gene activation and tissue histopathology strongly support the survival benefits of treatments.

Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-κB Pathway.

Organ dysfunction caused by sepsis is life-threatening and results in high mortality. Therapeutic options for sepsis are limited. Pathogenic factors are considered as components of environmental pressure that modify DNA methylation patterns thereby enhancing disease progression. Here, we found that sepsis patients exhibited higher levels of genomic DNA methylation patterns and hypermethylated genes associated with the NF-kB signaling pathway. Therefore, we hypothesized that a DNA methyl transferase inhibitor, Decitabine, may mitigate inflammation and improve survival by inhibiting the NF-κB signaling pathway. To test the hypothesis, mice challenged with caecal ligation and puncture (CLP) were subcutaneously injected with Decitabine solution (0.5, 1, and 1.5 mg/kg) 2 h following operation. Our results indicated that Decitabine reduces DNA methyltransferases (DNMTs), attenuates NF-κB activation, downregulates inflammatory cytokine levels, and inhibits the progression of sepsis. Thus, DNA methylation may be indispensable for sepsis and serve as a predicting factor. The use of Decitabine could represent a novel strategy in the treatment of sepsis.

Progression in optimal sepsis care: the sooner, the better?

After the landmark study of Rivers et al . (1) proposed the concept of the “golden hour” in the management of severe sepsis and septic shock, early goal-directed therapy (EGDT) became the practice in emergency departments (EDs). EGDT includes the early detection of sepsis, early obtainment of blood culture and administration of broad spectrum antibiotics, risk stratification using lactate measurement and fluid challenge for hypotensive patients, and hemodynamic optimization guided by pre-determined targets for preload (central venous pressure), afterload (mean arterial pressure), and finding a balance between oxygen delivery and oxygen consumption reflected by central venous oxygen saturation. However, three recent large studies, ProCESS (Protocolized Care for Early Septic Shock), ARISE (Australasian Resuscitation in Sepsis Evaluation), and ProMISe (Protocolized Management in Sepsis) have challenged the benefits of this approach to improving survival in severe sepsis (2). Although there have been concerns about protocolized therapy, recent guidelines still recommend the prompt identification of sepsis and treatment with broad-spectrum antibiotic agents and intravenous fluids (3). However, considerable controversy exists over how rapidly sepsis must be treated.

Timing to antibiotic therapy in septic oncologic patients presenting without hypotension.

Sepsis accounts for only 2% of the hospitalizations worldwide but more than 17% of total in-hospital mortality. Inappropriate antimicrobial selection and delays in appropriate therapy have been associated with reduced survival in severe sepsis and septic shock. No studies to date have exclusively targeted septic oncologic patients without hypotension. This study was a retrospective chart review of 100 adult cancer patients presenting to the emergency department with sepsis without hypotension. We investigated the effect of time to appropriate antibiotics on in-hospital mortality and hospital length of stay. It was hypothesized that increased time to antibiotic administration would worsen patient outcomes including in-hospital mortality and length of stay. Each 1-h delay in administration of appropriate antibiotic therapy increased the odds of in-hospital mortality by 16% (adjusted OR 1.16. 95% CI 1.04-1.34, p=0.04). Time to appropriate antibiotics had no effect on hospital length of stay. Time to appropriate antibiotics and in-hospital mortality were associated in this population of adult oncologic patients with sepsis without hypotension. Clinicians in the emergency department should strive to ensure the timely administration of a complete and appropriate empiric antibiotic regimen in septic patients with active cancer even in the absence of hypotension.

Sepsis Patients with First and Second-Hit Infections Show Different Outcomes Depending on the Causative Organism.

Objective: With improving rates of initial survival in severe sepsis, second-hit infections that occur following resolution of the primary insult carry an increasing burden of morbidity. However, despite the clinical relevance of these infections, no data are available on differential outcomes in patients with first and second-hit infections depending on the nature of the causative organism. This study aims to explore any differences in these subgroups.Design: In a retrospective, observational cohort study, the United Kingdom Intensive Care National Audit & Research Centre (ICNARC) database was used to explore the outcomes of patient with first-hit infections leading to sepsis, and sepsis patients with second-hit infections grouped according to the Gram status of the causative organism.Setting: General critical care units in England, Wales, and Northern Ireland participating in the ICNARC programme between 1 January, 2007 and 30 June, 2012.Patients: Patient groups analyzed included 2119 patients with and 1319 patients without sepsis who developed an intensive care unit acquired infection in blood. Subgroups included patients with trauma, emergency neurosurgery, elective surgery, and cardiogenic shock.Measurements and main results: Gram-negative organisms were associated with poorer outcomes in first-hit infections. The 90-day mortality of patients who developed a Gram-negative infection was 43.6% following elective surgery and 27.9% following trauma. This compared with a mortality of 25.6 and 20.6%, respectively, in Gram-positive infections. Unexpectedly, an inverse relationship between Gram status and mortality was observed in second-hit infections. Patients with an initial diagnosis of sepsis who developed secondary infections caused by Gram-negative organisms had a 90-day mortality of 40.4%, compared with 43.6% in Gram-positive infections.Conclusions: Our study identifies a fundamental difference in patient outcomes between first-hit and second-hit bacterial infections, which may be due to genetic, microbiological, immunological, and environmental factors. This finding has direct implications for risk stratification and defines future research priorities.

Serum lipid profile, cytokine production, and clinical outcome in patients with severe sepsis

PurposeThe purpose of the study is to evaluate the prevalence and clinical significance of hypolipidemia and the relationship to cytokine concentrations and outcomes in septic patients. Materials and methodsA prospective study was undertaken including 50 patients with severe sepsis due to community-acquired infections. Serum concentrations of total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein as well as tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL-8, IL-10, and transforming growth factor (TGF) β1 were determined on admission and days 3 and 10 during hospitalization. ResultsOf the 50 patients enrolled, 28 survived, whereas 22 died during their hospital stay. Sepsis survivors had significantly higher HDL-C concentrations than nonsurvivors, whereas all patients with HDL-C values greater than 25 mg/dL survived. Baseline levels of TGF-β1 were significantly higher in survivors. High-density lipoprotein levels correlated inversely with TNF-α, IL-6, and IL-10 concentrations and positively with baseline TGF-β1 levels. Independent risk factors of mortality were IL-10 levels on day 3, whereas HDL-C concentration on admission was related to survival. ConclusionsLow cholesterol and lipoprotein concentrations are detected in septic patients, especially in individuals with poor outcome. High-density lipoprotein cholesterol concentration seems to be an early independent predictive marker of survival in severe sepsis.

Therapeutic plasma exchange as rescue therapy in severe sepsis and septic shock: retrospective observational single-centre study of 23 patients

BackgroundSeveral case series and small randomized controlled trials suggest that therapeutic plasma exchange (TPE) improves coagulation, hemodynamics and possibly survival in severe sepsis. However, the exact role of TPE in modern sepsis therapy remains unclear.MethodsWe performed a retrospective observational single-centre study on the use of TPE as rescue therapy in 23 consecutive patients with severe sepsis or septic shock from 2005 to 2012. Main surrogate markers of multiple organ failure (MOF) before, during and after TPE as well as survival rates are reported.ResultsAt baseline, mean SOFA score was 13 (standard deviation [SD] 4) and median number of failed organ-systems was 5 (interquartile range [IQR] 4–5). TPEs were performed 3 days (IQR 2–10) after symptom onset and 1 day (IQR 0–8) after ICU admission. The median total exchange volume was 3750 ml (IQR 2500–6000), which corresponded to a mean of 1.5 times (SD 0.9) the individual plasma volume. Fresh frozen plasma was used in all but one treatments as replacement fluid. Net fluid balance decreased significantly within 12 hrs following the first TPE procedure by a median of 720 mL (p = 0.002), irrespective of outcome. Reductions of norepinephrine dose and improvement in cardiac index were observed in individual survivors, but this was not significant for the overall cohort (p = 0.574). Platelet counts decreased irrespective of outcome between days 0 and 2 (p < 0.003), and increased thereafter in many survivors. There was a non-significant trend towards younger age and higher procalcitonin levels among survivors. Nine out of 23 TPE treated patients (39%) survived until ICU discharge (among them 3 patients with baseline SOFA scores of 15, 17, and 20).ConclusionsOur data suggest that some patients with severe sepsis and septic shock may experience hemodynamic stabilisation by early TPE therapy.

Effects of intermittent high-volume hemofiltration in the treatment of patients with severe sepsis and septic shock

To investigate the effects of intermittent high-volume hemofiltration (IHVHF) on 28-day survival in severe sepsis and septic shock patients. A retrospective cohort study was conducted. Basic data, IHVHF treatment modality and related information during IHVHF treatment of patients with severe sepsis or septic shock receiving IHVHF because of acute renal failure or multiple organ failure (MOF) were collected. Cox proportional hazard model was used to analyze the risk factors of the patients' 28-day mortality after IHVHF treatment. Totally 44 patients were enrolled, the patients were divided into the high dose group (≥70 ml×kg(-1)×h(-1), n=17) and the low dose group (<70 ml×kg(-1)×h(-1), n=27) according to the mean dose of IHVHF performed. Except for the significant differences of body mass index between the high dose group and the low dose group (20.7±3.2 kg/m(2) vs. 25.3±3.0 kg/m(2), P<0.01), there were no significant differences in basic data and IHVHF treatment method. In 44 patients 17 died within 28 days. The observed 28-day mortality of patients were significantly lower than the predicted mortality [38.6% vs. (61.8±21.9)%, P<0.01]. The mortality rate was significantly lower in the high dose group than in the low dose group [11.8% (2/17) vs. 55.6% (15/27), P=0.004]. Multivariable Cox proportional hazard model analysis showed that the high the sequential organ failure assessment (SOFA) score before IHVHF was associated with increased risk of 28-day mortality [relative risk (RR)=1.279, 95% confidence interval (95%CI)1.127 - 1.452, P<0.001], and high dose IHVHF (RR=0.149, 95%CI 0.032 - 0.694, P=0.015), total hours of IHVHF (RR=0.981, 95%CI 0.966 - 0.997, P=0.016) were associated with decreased risk of 28-day mortality. For patients with severe sepsis and septic shock and complicated by acute renal failure or MOF, high dose IHVHF (≥ 70 ml×kg(-1)×h(-1)) was a protective factor against 28-day mortality for these patients, and prolongation of IHVHF treatment could decrease 28-day mortality.

Central Venous Oxygen Saturation Under Non-Protocolized Resuscitation Is Not Related to Survival in Severe Sepsis or Septic Shock

Protocolized hemodynamic resuscitation in severe sepsis or septic shock is not universally applied in all emergency departments and general hospital wards around the world. It is unknown whether ScvO2 levels are associated with the clinical outcome of severe sepsis or septic shock under nonprotocolized resuscitation. In this prospective study, we enrolled 124 noncirrhotic patients who were admitted to intensive care units for severe sepsis or septic shock. The average Acute Physiology and Chronic Health Evaluation II score was 25.3 (SD, 7.6). According to ScvO2 levels after initial resuscitation before intensive care unit admission, patients were divided into high (ScvO2 ≥ 70%, n = 63) and low (ScvO2 < 70%, n = 61) ScvO2 groups. Compared with high ScvO2 groups, low ScvO2 groups showed no significant differences in 28-day mortality (25.4% vs. 24.6%; P = 0.943) or hospital mortality (30.2% vs. 31.1%; P = 0.794). Multivariate logistic regression models showed that low mean arterial pressure (hazard ratio, 0.967; 95% confidence interval, 0.940-0.994; P = 0.019) and high central venous pressure (hazard ratio, 1.150; 95% confidence interval, 1.057-1.251; P = 0.001) after initial resuscitation were associated with higher 28-day mortality. On the contrary, ScvO2 levels after resuscitation were not related to 28-day or hospital mortality. In conclusion, our results showed that mean arterial pressure and central venous pressure were still the most important hemodynamic variables in initial hemodynamic resuscitation. Low postresuscitation ScvO2 was not associated with a worse outcome. It is possible that ScvO2 less than 70% might not necessarily be associated with tissue hypoxia, and critical ScvO2 levels require to be determined by further studies.

Fluid Balance, Interferon-Gamma, Interleukin- 12 and Tumor Necrosis as predictive factors of Survival in Severe Sepsis

Background: The cardiovascular derangements of severe sepsis in human include arteriolar, venular dilation, capillary leak, and immunomodulatory response. Intravascular volume replacement during resuscitation most frequently converts the circulation to a high-out put hypotensive state. We hypothesized that patients with severe sepsis had any predicting factors to survive than those who do not.Design and Method: Randomized Clinical Trials were conducted of 110 patients suffered from severe sepsis in ICU/HCU. Admission APACHE II, SOFA scores, IFN- , IL-12, TNF-á, and fluid balance were computed from the extracted data. Patients allowed to severe sepsis treatment according with the International Consensus Committee. Summary estimates using both the Mantel-Haenszel test and precision based approaches were computed for statistical analysis.Result: Of 110 patients ranged in age from 46 to 71 years with a mean (± SE) age of 63.45 ± 3.97 years. The mean admission APACHE II score was 25.96 ± 3.65; and the day 1 SOFA score was 9.57 ± 1.24. Twenty one patients did not survive, Non-survival had higher mean APACHE II than survivals (29.85 vs 20.46), respectively (p &lt; 0.01). Higher first day IFN- , IL-12, TNF-á, and SOFA scores (p&lt; 0.01). Whereas 26 patients who achieved a negative fluid balance of &gt; 500 mL on &gt; of the first 3 days of treatment survived (RR 5.0; 95% CI : 2.3 to 10.7, p &lt; 0.0001).Conclusion: These results suggest that at least 1 day of negative fluid balance (&lt;-500mL), IFN- , IL-12, and TNF-á may be a good independent predictors of survival in patients with severe sepsis. These findings suggest the hypothesis that four independent predictors of severe sepsis portend a good prognosis for a larger prospective study (Sains Medika, 4(1):13-22).

Free hemoglobin concentration in severe sepsis: methods of measurement and prediction of outcome

IntroductionHemolysis can be induced in sepsis via various mechanisms, its pathophysiological importance has been demonstrated in experimental sepsis. However, no data on free hemoglobin concentrations in human sepsis are available. In the present study we measured free hemoglobin in patients with severe sepsis as well as in postoperative patients using four methods. It was our aim to determine the potential value of free hemoglobin as a biomarker for diagnosis and outcome of severe sepsis in critical illness.MethodsPlasma concentration of free hemoglobin was determined in patients with severe sepsis (n = 161) and postoperative patients (n = 136) on day 1 of diagnosis and surgery. For the measurement of free hemoglobin, an enzyme linked immunosorbent assay and three spectrophotometric algorithms were used. Moreover, SAPS II- and SOFA scores as well as procalcitonin concentration and outcome were determined. Kaplan-Meier analysis was performed and odds ratios were determined after classification of free hemoglobin concentrations in a high and low concentration group according to the median. For statistical evaluation the Mann-Whitney test and logistic regression analysis were used.ResultsIn non-survivors of severe sepsis, free hemoglobin concentration was twice the concentration compared to survivors. Thirty-day survival of patients, as evidenced by Kaplan-Meier analysis, was markedly lower in patients with high free hemoglobin concentration than in patients with low free hemoglobin concentration. Best discrimination of outcome was achieved with the spectrophotometric method of Harboe (51.3% vs. 86.4% survival, p < 0.001; odds ratio 6.1). Multivariate analysis including free hemoglobin, age, SAPS II- and SOFA-score and procalcitonin demonstrated that free hemoglobin, as determined by all 4 methods, was the best and an independent predictor for death in severe sepsis (p = 0.022 to p < 0.001). Free hemoglobin concentrations were not significantly different in postoperative and septic patients in three of four assays. Thus, free hemoglobin can not be used to diagnose severe sepsis in critical illness.ConclusionsFree hemoglobin is an important new predictor of survival in severe sepsis.

Comparison of Thrombelastometry with Simplified Acute Physiology Score II and Sequential Organ Failure Assessment Scores for the Prediction of 30-Day Survival

Disseminated intravascular coagulation contributes to mortality of sepsis. The study was performed to investigate thromboelastometry as a potential predictor of 30-day survival in severe sepsis and to compare thromboelastometry to Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) scores. Ninety-eight patients with severe sepsis were included in the cohort study. Thromboelastometry clotting time, clot formation time (CFT), maximum clot firmness (MCF), and α angle as well as SAPS II and SOFA scores were determined at the day of diagnosis. Thromboelastometry variables differed in survivors and nonsurvivors. Mean CFT was prolonged (276 ± 194 vs. 194 ± 109 s, P = 0.021; mean ± SD), and both MCF (52.7 ± 12.1 mm vs. 57.3 ± 11.5 mm, P = 0.042) and α angle (53.4 ± 12.8 degrees vs. 58.9 ± 11.8 degrees, P = 0.028) were reduced in nonsurvivors. Clotting time and SAPS II and SOFA scores were not different. Thromboelastometry values were classified as normal and pathological, respectively, using the median of the variables as the cutoff. Thromboelastometry values were normal if CFT was less than 185 s, MCF was greater than 55 mm, and α was greater than 57.5 degrees. Thirty-day survival was 85.7% when all thromboelastometry variables were normal, but 58.7% when at least one variable was pathological (P = 0.005). Multivariate analysis revealed that the absence or presence of at least one pathological thromboelastometry variable allows for better prediction of 30-day survival in severe sepsis than the SAPS II and SOFA scores (P = 0.01; odds ratio, 4.1), respectively, emphasizing the importance of the coagulation system in sepsis.

Aquaporin 5 Gene Promoter −1364A/C Polymorphism Associated with 30-day Survival in Severe Sepsis

Because the aquaporin (AQP) 5 promoter -1364A/C polymorphism is associated with altered AQP5 expression, this association could have an impact on key mechanisms in sepsis, such as cell migration, activity of the rennin-angiotensin- aldosterone system (RAAS), and water transport across biologic membranes. Therefore, we tested the hypothesis that the AQP5 promoter -1364A/C polymorphism is associated with increased 30-day survival in severe sepsis. In a prospective study, adults with severe sepsis (N = 154) were genotyped for the AQP5 promoter -1364A/C polymorphism. The clinical endpoint was 30-day survival. Kaplan-Meier plots and multivariate proportional hazard analyses were used to evaluate the relationship between genotypes and clinical outcomes. Thirty-day survival was significantly associated with AQP5 -1364A/C genotypes (P = 0.001). Survival rates were 57% for AA genotypes (n = 90) but 83% for combined AC/CC genotypes (56 vs. 8, respectively). Multivariate proportional hazard analysis including sex, age, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment score, body mass index, necessity for continuous hemofiltration/dialysis, concentrations of plasma angiotensin II, serum aldosterone, C-reactive protein, and interleukin 6 as covariates revealed the AQP5 -1364A/C polymorphism as a strong and independent prognostic factor for 30-day survival. In this analysis, homozygous AA subjects were at high risk for death within 30 days (hazard ratio, 3.59; 95% CI, 1.47-8.80; P = 0.005) compared with AC/CC genotypes. The C-allele of the AQP5 -1364A/C polymorphism is associated with increased 30-day survival in patients with severe sepsis. This finding suggests the importance of variations in expression of AQP5 channels in severe sepsis.

An age-related decrease in factor V Leiden frequency among Polish subjects

Factor V Leiden (G1691A FV mutation) is a widely acknowledged risk factor of deep vein thrombosis, including pulmonary embolism as the most serious complication. However, its high prevalence of ~5%in the Caucasian population might be related to an unknown evolutionary advantage. It might exert a beneficial effect on the carrier, e.g. protecting women from excessive bleeding during labour or allowing increased survival in severe sepsis or with other inflammatory diseases. The aim of our study was to verify or contradict the hypothesis of a favourable association between the A allele (A1691) and longevity in the Polish population. For this purpose, the G1691A mutation was analyzed by PCR-RFLP in 1016 Poles: 400 neonates (187 female and 312 male), 184 healthy adults (129 female and 55 male), and 432 long-lived individuals (age ≥95 years: 343 women and 89 men). Frequencies of G1691A carriers and the A1691 allele in long-lived individuals (0.2% and 0.1%, respectively) were significantly lower than in neonates (4.2% and 2.2%, respectively) and adults (3.3% and 1.6%). The frequency of the G1691A factor V Leiden mutation decreased with age, which indicates a shorter survival time among A1691 allele carriers in the Polish population.

Hydrogen Sulfide Improves Neutrophil Migration and Survival in Sepsis via K+ATPChannel Activation

Recovering the neutrophil migration to the infectious focus improves survival in severe sepsis. Recently, we demonstrated that the cystathionine gamma-lyase (CSE)/hydrogen sulfide (H(2)S) pathway increased neutrophil recruitment to inflammatory focus during sterile inflammation. To evaluate if H(2)S administration increases neutrophil migration to infectious focus and survival of mice. Sepsis was induced by cecal ligation and puncture (CLP). The pretreatments of mice with H(2)S donors (NaHS or Lawesson's reagent) improved leukocyte rolling/adhesion in the mesenteric microcirculation as well as neutrophil migration. Consequently, bacteremia levels were reduced, hypotension and lung lesions were prevented, and the survival rate increased from approximately 13% to approximately 80%. Even when treatment was delayed (6 h after CLP), a highly significant reduction in mortality compared with untreated mice was observed. Moreover, H(2)S pretreatment prevented the down-regulation of CXCR2 and l-selectin and the up-regulation of CD11b and G protein-coupled receptor kinase 2 in neutrophils during sepsis. H(2)S also prevented the reduction of intercellular adhesion molecule-1 expression in the endothelium of the mesenteric microcirculation in severe sepsis. Confirming the critical role of H(2)S on sepsis outcome, pretreatment with dl-propargylglycine (a CSE inhibitor) inhibited neutrophil migration to the infectious focus, enhanced lung lesions, and induced high mortality in mice subjected to nonsevere sepsis (from 0 to approximately 80%). The beneficial effects of H(2)S were blocked by glibenclamide (a ATP-dependent K(+) channel blocker). These results showed that H(2)S restores neutrophil migration to the infectious focus and improves survival outcome in severe sepsis by an ATP-dependent K(+) channel-dependent mechanism.

Systolic and diastolic function and survival in severe sepsis and septic shock: clinical, echocardiographic, biochemical correlation

The exact mechanisms causing cardiac dysfunction in sepsis are still in major part obscure or controversial.

Early Introduction of Peritoneal Dialysis May Improve Survival in Severe Sepsis

Acute renal failure is a serious complication of sepsis and is associated with a very high mortality. Recent evidence suggests that proinflammatory cytokines (interleukins 1 and 6 and tumor necrosis factor alpha) released into the circulation in response to sepsis can be removed from the blood via hemofiltration and appear in the dialysate in times of peritoneal dialysis as well. An infant who developed acute renal failure in full-blown sepsis is presented. Peritoneal dialysis was initiated on the fourth day after admission. Changes in clinical and laboratory parameters were monitored. Urine output (1.13 mL/kg per hour) began to improve on the sixth day after admission (second day after the introduction of peritoneal dialysis); normalization of serum creatinine level was achieved on the 30th day after admission. Parallel with the serum creatinine level (255 micromol/L on day 5 after admission vs 208 micromol/L by day 9 after admission, fifth day of PD), serum procalcitonin, C-reactive protein, and lactate dehydrogenase levels decreased dramatically (procalcitonin >500 vs 261 microg/L; C-reactive protein, 203 vs 25.9 mg/L; and lactate dehydrogenase, 3092 vs 1744 U/L on days 5 and 9 after admission, respectively). Considering that there are no guidelines defined for the management of acute renal failure with accompanying sepsis in children, authors point out that peritoneal dialysis is an easy-to-perform and effective renal replacement modality in low body weight, critically ill patients. Early initiation of peritoneal dialysis does not only improve fluid and electrolyte imbalance but also may significantly reduce the destructive effect of systemic cytokine storm in sepsis and contribute to a more favorable outcome, even in cases of critical cardiovascular and hemostaseological status.

Insulin-like Growth Factor-1 Improves Survival in Sepsis via Enhanced Hepatic Bacterial Clearance

Both insulin-like growth factor (IGF)-1 and bacterial clearance by Kupffer cells are significantly reduced in severe sepsis. Kupffer cell apoptosis is triggered by tumor necrosis factor (TNF)-alpha and activation of the PI-3 kinase pathway prevents TNF-induced Kupffer cell death. We evaluated if the marked decline in IGF-1 is related to bacterial clearance in sepsis. Sepsis was induced in C57BL/6 mice by intratracheal inoculation with Pseudomonas aeruginosa (strain PA103). Some mice received IGF-1 24 mg/kg either before infection or 12 hours after infection. In vitro studies were performed using the clonal Kupffer cell line KC13-2. Sepsis resulted in decreased levels of IGF-1. In vitro studies with KC13-2 cells demonstrated that IGF-1 protected Kupffer cells against TNF-alpha-induced apoptosis by activating the PI-3 kinase pathway and stabilizing the inhibitor of apoptosis protein, XIAP. In the animal model, pretreatment with IGF-1 decreased hepatic TNF-alpha and IL-6, improved hepatic bacterial clearance as demonstrated by real-time polymerase chain reaction with primers specific for P. aeruginosa, and improved survival in severe sepsis. Moreover, we rescued mice from severe sepsis by IGF-1 treatment 12 hours after infection. These studies show that the decline in IGF-1 levels in sepsis is related to bacterial clearance and that replacement of IGF-1 in a murine model of sepsis improves overall survival.