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1.
Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial.
Costeloe, K, Hardy, P, Juszczak, E, Wilks, M, Millar, MR, ,
Lancet (London, England). 2016;(10019):649-660
Abstract
BACKGROUND Probiotics may reduce necrotising enterocolitis and late-onset sepsis after preterm birth. However, there has been concern about the rigour and generalisability of some trials and there is no agreement about whether or not they should be used routinely. We aimed to test the effectiveness of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late-onset sepsis, and death in preterm infants. METHODS In this multicentre, randomised controlled phase 3 study (the PiPS trial), we recruited infants born between 23 and 30 weeks' gestational age within 48 h of birth from 24 hospitals in southeast England. Infants were randomly assigned (1:1) to probiotic or placebo via a minimisation algorithm randomisation programme. The probiotic intervention was B breve BBG-001 suspended in dilute elemental infant formula given enterally in a daily dose of 8·2 to 9·2 log10 CFU; the placebo was dilute infant formula alone. Clinicians and families were masked to allocation. The primary outcomes were necrotising enterocolitis (Bell stage 2 or 3), blood culture positive sepsis more than 72 h after birth; and death before discharge from hospital. All primary analyses were by intention to treat. This trial is registered with ISRCTN, number 05511098 and EudraCT, number 2006-003445-17. FINDINGS Between July 1, 2010, and July 31, 2013, 1315 infants were recruited; of whom 654 were allocated to probiotic and 661 to placebo. Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group. Rates of the primary outcomes did not differ significantly between the probiotic and placebo groups. 61 infants (9%) in the probiotic group had necrotising enterocolitis compared with 66 (10%) in the placebo group (adjusted risk ratio 0·93 (95% CI 0·68-1·27); 73 (11%) infants in the probiotics group had sepsis compared with 77 (12%) in the placebo group (0·97 (0·73-1·29); and 54 (8%) deaths occurred before discharge home in the probiotic group compared with 56 (9%) in the placebo group (0·93 [0·67-1·30]). No probiotic-associated adverse events were reported. INTERPRETATION There is no evidence of benefit for this intervention in this population; this result does not support the routine use of B breve BBG-001 for prevention of necrotising enterocolitis and late-onset sepis in very preterm infants. FUNDING UK National Institute for Health Research Health Technology Assessment programme.
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2.
Inflammation-induced increases in plasma endocan levels are associated with endothelial dysfunction in humans in vivo.
Cox, LA, van Eijk, LT, Ramakers, BP, Dorresteijn, MJ, Gerretsen, J, Kox, M, Pickkers, P
Shock (Augusta, Ga.). 2015;(4):322-6
Abstract
Although endothelial dysfunction is central to the pathogenesis of sepsis, no specific and clinically applicable marker for endothelial dysfunction is currently available. Endocan, a proteoglycan excreted by endothelial cells in response to inflammatory cytokines, may serve as such a marker. Our objective was to investigate the kinetics of endocan and its relationship with inflammation-induced endothelial dysfunction during experimental human endotoxemia. Endothelial function was assessed in 17 healthy male volunteers before and 4 h after the administration of 2 ng/kg lipopolysaccharide (LPS) by determination of the vasodilatory response of forearm blood vessels to intra-arterial infusion of endothelium-dependent (acetylcholine) or endothelium-independent (nitroglycerin/sodium nitroprusside) vasodilators using venous occlusion plethysmography. Plasma levels of endocan, inflammatory cytokines, intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) were measured, and correlations with endothelial dysfunction were explored. Plasma levels of all measured cytokines, endocan, ICAM, and VCAM concentrations significantly increased after LPS administration. Furthermore, LPS administration resulted in a significantly blunted response to acetylcholine (mean ± SD increase in forearm blood flow [FBF] of 383% ± 320% before LPS vs. 173% ± 134% after LPS, P = 0.03), whereas the response to nitroglycerin/sodium nitroprusside was not affected (mean ± SD increase in FBF of 174% ± 120% before LPS vs. 110% ± 82% after LPS, P = 0.11). Furthermore, there was a significant correlation between the increase in plasma endocan levels and the attenuation of vasodilatory responses to acetylcholine (r = -0.48, P < 0.05). No correlation existed between plasma levels of ICAM or VCAM and the attenuation of the acetylcholine-induced vasodilatory response. Endocan levels are related to endothelial dysfunction in humans in vivo during systemic inflammation evoked by experimental endotoxemia. Therefore, this study suggests that endocan could be a novel marker of endothelial dysfunction in inflammatory conditions.
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3.
Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the intensive care unit.
Nejat, M, Pickering, JW, Walker, RJ, Westhuyzen, J, Shaw, GM, Frampton, CM, Endre, ZH
Critical care (London, England). 2010;(3):R85
Abstract
INTRODUCTION To evaluate the utility of urinary cystatin C (uCysC) as a diagnostic marker of acute kidney injury (AKI) and sepsis, and predictor of mortality in critically ill patients. METHODS This was a two-center, prospective AKI observational study and post hoc sepsis subgroup analysis of 444 general intensive care unit (ICU) patients. uCysC and plasma creatinine were measured at entry to the ICU. AKI was defined as a 50% or 0.3-mg/dL increase in plasma creatinine above baseline. Sepsis was defined clinically. Mortality data were collected up to 30 days. The diagnostic and predictive performances of uCysC were assessed from the area under the receiver operator characteristic curve (AUC) and the odds ratio (OR). Multivariate logistic regression was used to adjust for covariates. RESULTS Eighty-one (18%) patients had sepsis, 198 (45%) had AKI, and 64 (14%) died within 30 days. AUCs for diagnosis by using uCysC were as follows: sepsis, 0.80, (95% confidence interval (CI), 0.74 to 0.87); AKI, 0.70 (CI, 0.64 to 0.75); and death within 30 days, 0.64 (CI, 0.56 to 0.72). After adjustment for covariates, uCysC remained independently associated with sepsis, AKI, and mortality with odds ratios (CI) of 3.43 (2.46 to 4.78), 1.49 (1.14 to 1.95), and 1.60 (1.16 to 2.21), respectively. Concentrations of uCysC were significantly higher in the presence of sepsis (P < 0.0001) or AKI (P < 0.0001). No interaction was found between sepsis and AKI on the uCysC concentrations (P = 0.53). CONCLUSIONS Urinary cystatin C was independently associated with AKI, sepsis, and death within 30 days. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry ACTRN012606000032550.
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4.
Cerebral perfusion in sepsis-associated delirium.
Pfister, D, Siegemund, M, Dell-Kuster, S, Smielewski, P, Rüegg, S, Strebel, SP, Marsch, SC, Pargger, H, Steiner, LA
Critical care (London, England). 2008;(3):R63
Abstract
INTRODUCTION The pathophysiology of sepsis-associated delirium is not completely understood and the data on cerebral perfusion in sepsis are conflicting. We tested the hypothesis that cerebral perfusion and selected serum markers of inflammation and delirium differ in septic patients with and without sepsis-associated delirium. METHODS We investigated 23 adult patients with sepsis, severe sepsis, or septic shock with an extracranial focus of infection and no history of intracranial pathology. Patients were investigated after stabilisation within 48 hours after admission to the intensive care unit. Sepsis-associated delirium was diagnosed using the confusion assessment method for the intensive care unit. Mean arterial pressure (MAP), blood flow velocity (FV) in the middle cerebral artery using transcranial Doppler, and cerebral tissue oxygenation using near-infrared spectroscopy were monitored for 1 hour. An index of cerebrovascular autoregulation was calculated from MAP and FV data. C-reactive protein (CRP), interleukin-6 (IL-6), S-100beta, and cortisol were measured during each data acquisition. RESULTS Data from 16 patients, of whom 12 had sepsis-associated delirium, were analysed. There were no significant correlations or associations between MAP, cerebral blood FV, or tissue oxygenation and sepsis-associated delirium. However, we found a significant association between sepsis-associated delirium and disturbed autoregulation (P = 0.015). IL-6 did not differ between patients with and without sepsis-associated delirium, but we found a significant association between elevated CRP (P = 0.008), S-100beta (P = 0.029), and cortisol (P = 0.011) and sepsis-associated delirium. Elevated CRP was significantly correlated with disturbed autoregulation (Spearman rho = 0.62, P = 0.010). CONCLUSION In this small group of patients, cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium. However, the state of autoregulation differed between the two groups. This may be due to inflammation impeding cerebrovascular endothelial function. Further investigations defining the role of S-100beta and cortisol in the diagnosis of sepsis-associated delirium are warranted. TRIAL REGISTRATION ClinicalTrials.gov NCT00410111.
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5.
Effects of N-acetylcysteine on microalbuminuria and organ failure in acute severe sepsis: results of a pilot study.
Spapen, HD, Diltoer, MW, Nguyen, DN, Hendrickx, I, Huyghens, LP
Chest. 2005;(4):1413-9
Abstract
STUDY OBJECTIVE The level of microalbuminuria is thought to reflect the severity of inflammation-induced systemic vascular permeability and may have prognostic value with regard to organ dysfunction and survival. N-acetylcysteine (NAC) has been shown to decrease capillary leakage in experimental sepsis. The present study investigated the effect of early treatment with NAC on microalbuminuria and organ dysfunction in severe clinical sepsis. DESIGN Prospective, randomized, placebo-controlled study. SETTING A 24-bed multidisciplinary ICU in a university teaching hospital. PATIENTS Thirty-five patients included within 4 h of fulfilling consensus criteria of severe sepsis. INTERVENTIONS Patients were randomly assigned to receive either NAC (continuous infusion starting with 50 mg/kg/4 h followed by 100 mg/kg/24 h for 44 h; n = 18) or placebo (n = 17) in addition to standard therapy. MEASUREMENTS AND RESULTS Urine samples for measurement of microalbuminuria/creatinine ratio (MACR) were collected on inclusion and after 4 h, 24 h, and 48 h. Severity of illness and degree of organ failure were determined by using, respectively, the APACHE (acute physiology and chronic health evaluation) II score and the sequential organ failure assessment (SOFA) score. The MACR did not differ over time between the placebo- and the NAC-treated groups. SOFA scores were comparable between both treatment groups at baseline (6.2 +/- 3.9 vs 6.5 +/- 2.7, NAC vs placebo; p = 0.6) and increased during treatment in the NAC-treated patients but not in the placebo group (7.9 +/- 3.7 vs 5.9 +/- 2.5, p = 0.09 and 7.7 +/- 3.8 vs 5.1 +/- 2.1, p < 0.05; NAC vs placebo, respectively, at 24 h and at 48 h). The cardiovascular SOFA score progressively increased during NAC treatment, reaching higher values as compared to time-matched scores in the placebo group. CONCLUSIONS Early NAC administration does not influence the course of MACR in severe clinical sepsis, suggesting that NAC might not attenuate endothelial damage in this condition. NAC treatment even aggravated sepsis-induced organ failure, in particular cardiovascular failure.
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6.
Post-pyloric enteral nutrition in septic patients: effects on hepato-splanchnic hemodynamics and energy status.
Rokyta, R, Matejovic, M, Krouzecky, A, Senft, V, Trefil, L, Novak, I
Intensive care medicine. 2004;(4):714-7
Abstract
OBJECTIVE To evaluate the effects of post-pyloric enteral nutrition (EN) on hepato-splanchnic and systemic hemodynamics, metabolism and gastric mucosal energy balance in septic patients. DESIGN Prospective clinical study. SETTING Medical intensive care unit (ICU) in a university hospital. PATIENTS Ten hemodynamically stable, mechanically ventilated patients with severe sepsis. Eight patients required norepinephrine. INTERVENTION Low dose post-pyloric EN (Survimed, 40 ml bolus, 40 ml h(-1) continuously). MEASUREMENTS AND RESULTS Three data sets: F1 = baseline fasting, EN(120) = after 120 min of EN, F2=120 min after EN cessation. In addition to global hemodynamics and gastric mucosal PCO(2), we measured hepato-splanchnic blood flow (HSBF) using continuous primed indocyanine green dye infusion with hepatic venous sampling. The mean arterial pressure remained unchanged. During EN systemic vascular resistance decreased ( p<0.05), while cardiac index increased (p<0.001). Simultaneously, HSBF increased during EN and decreased again at F2 (1.54 [0.88; 1.66] l min(-1) m(-2 )at F1; 1.72 [1.18; 1.83] l min(-1) m(-2 )at EN and 1.38 [0.91; 1.63] l min(-1) m-(2 )at F2, p<0.001). Hepatic venous acid base status, lactate/pyruvate ratio and splanchnic lactate balance remained unchanged. There was also no change in splanchnic oxygen extraction ratio or in gastric mucosal to arterial PCO(2) difference. CONCLUSION The initiation of low dose post-pyloric EN in medical ICU patients with severe sepsis led to the parallel increase of systemic and hepato-splanchnic blood flow. Hepato-splanchnic energy metabolism, oxygen kinetics and gastric mucosal energy balance did not deteriorate during EN, suggesting that EN during sepsis may not be harmful even in patients requiring norepinephrine.
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7.
Effect of polymyxin B-immobilized fiber on bone resorption in patients with sepsis.
Nakamura, T, Kawagoe, Y, Matsuda, T, Koide, H
Intensive care medicine. 2004;(9):1838-41
Abstract
OBJECTIVE To analyze the effects of polymyxin B-immobilized fiber (PMX-F) on bone resorption in septic patients. DESIGN AND SETTING Observational prospective study in intensive care units of a general hospital. PATIENTS AND PARTICIPANTS 25 patients with severe sepsis and 20 healthy controls. MEASUREMENTS AND RESULTS Septic patients were randomly assigned to two groups: PMX-F treatment group (n=15) and conventional treatment group (n=10). Total pyridinium crosslink pyridinoline (PYD) and deoxypyridinoline (DPD) in urine were determined by modified high-performance liquid chromatography. Nitric oxide production was assessed by measuring the ratio of the nitric oxide breakdown products to urinary creatinine (NOx/Cr). Plasma endotoxin levels were determined by endospecy test. The blood albumin, ionized calcium, and parathyroid hormone were also measured. PMX-F treatment was performed twice separated by 24 h. Urinary NOx/Cr, PYD/Cr, and DPD/Cr were significantly increased in septic patients compared with those in healthy controls. Blood ionized calcium in septic patients was lower than in healthy controls, while parathyroid hormone levels in septic patients were higher than in healthy controls (P<0.01). PMX-F treatment reduced plasma endotoxin, urinary NOx/Cr, PYD/Cr, DPD/Cr, and serum parathyroid hormone levels and increased blood ionized calcium significantly; however, conventional treatment did not affect these levels. CONCLUSIONS Septic patients increased nitric oxide production and bone resorption, and PMX-F treatment is effective in reducing nitric oxide levels and bone resorption markers.
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8.
Enteral glutamine supplementation and morbidity in low birth weight infants.
Vaughn, P, Thomas, P, Clark, R, Neu, J
The Journal of pediatrics. 2003;(6):662-8
Abstract
OBJECTIVE To determine if glutamine-supplemented enteral nutrition decreased the incidence of nosocomial sepsis in neonates. METHODS In a multicenter (n = 20) clinical trial, we randomly allocated infants (n = 649) with birth weight between 500 and 1250 g, who were <7 days of age, and had no major anomalies to receive enteral glutamine supplementation (0.3 g/kg/day) or sterile water (placebo) for the first 28 days. The primary outcome variable was the number of infants who had blood culture-proven nosocomial sepsis between 7 days' and 36 weeks' postmenstrual age. RESULTS Infants were assigned to placebo (n = 335) or to glutamine supplementation (n = 314). Neonates assigned to glutamine were similar to those assigned placebo for demographic characteristics and nutritional support during the first week. There was no difference in the occurrence of culture-proven nosocomial sepsis (33.7% vs 30.9%) or suspected sepsis (51.6% vs 47.1%) between the placebo and glutamine groups; however, neonates treated with glutamine less often had gastrointestinal dysfunction (7.5% vs 2.5%, P <.01) and severe neurologic sequelae (15.1% vs 10.4%, P =.08). CONCLUSIONS At a dose of 0.3 g/kg/day, enteral glutamine does not appear to reduce nosocomial sepsis in premature neonates.