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Stool Short-Chain Fatty Acids in Critically Ill Patients with Sepsis.
Valdés-Duque, BE, Giraldo-Giraldo, NA, Jaillier-Ramírez, AM, Giraldo-Villa, A, Acevedo-Castaño, I, Yepes-Molina, MA, Barbosa-Barbosa, J, Barrera-Causil, CJ, Agudelo-Ochoa, GM
Journal of the American College of Nutrition. 2020;(8):706-712
Abstract
Objective: To determine the concentration of stool short-chain fatty acids (SCFAs) in critically ill patients with sepsis and to compare the results between the critically ill patient and the control group.Methods: This descriptive, multicenter, observational study was conducted in five health institutions. Over a 6-month study period, critically ill patients with sepsis who were admitted to the intensive care unit (ICU) and met the inclusion criteria were enrolled, and a control, paired by age and sex, was recruited for each patient. A spontaneous stool sample was collected from each participant and a gas chromatograph coupled to a mass spectrometer (Agilent 7890/MSD 5975 C) was used to measure the concentrations SCFAs.Results: The final sample included 44 patients and 45 controls. There were no differences in the age and sex distributions between the groups (p > 0.05). According to body mass index (BMI), undernutrition was more prevalent among critically ill patients, and BMI in control subjects was most frequently classified as overweight (p = 0.024). Propionic acid, acetic acid, butyric acid, and isobutyric acid concentrations were significantly lower in the critically ill patient group than in the control group (p = 0.000). No association with outcome variables (complications, ICU stay, and discharge condition) was found in the patients, and patients diagnosed with infection on ICU admission showed significant decreases in butyric and isobutyric acid concentrations with respect to other diagnostic criteria (p < 0.05).Conclusions: The results confirm significantly lower concentrations of stool SCFAs in critically ill patients with sepsis than in control subjects. Due to its role in intestinal integrity, barrier function, and anti-inflammatory effect, maintaining the concentration of SCFAs may be important in the ICU care protocols of the critical patient.
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Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.
Lindsell, CJ, McGlothlin, A, Nwosu, S, Rice, TW, Hall, A, Bernard, GR, Busse, LW, Ely, EW, Fowler, AA, Gaieski, DF, et al
Trials. 2019;(1):670
Abstract
BACKGROUND Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018.
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Application of dynamic pulse pressure and vasopressor tools for predicting outcomes in patients with sepsis in intensive care units.
Fang, WF, Huang, CH, Chen, YM, Hung, KY, Chang, YC, Lin, CY, Fang, YT, Chang, YT, Chen, HC, Huang, KT, et al
Journal of critical care. 2019;:156-162
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PURPOSE We aimed to determine whether the combination of dynamic pulse pressure and vasopressor (DPV) use is applicable for mortality risk stratification in patients with severe sepsis. We proposed the use of the DPV tool and compared it with traditional sepsis severity indices. MATERIALS AND METHODS All adult patients who met the sepsis criteria of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) between August 2013 and January 2017 were eligible for the study. Patients who expired within 3 days of admission to the intensive care unit (ICU) were excluded. The primary outcomes were 7-day and 28-day mortality. RESULTS The study participants included 757 consecutive adult patients. A subpopulation of 155 patients underwent immune profiling assays on days 1, 3, and 7 of ICU admission. The DPV tool had a better performance for predicting 7-day mortality (area under curve, AUC: 0.70), followed by the Sequential Organ Failure Assessment (SOFA) (AUC: 0.64), the plus pulse pressure (AUC: 0.64). For predicting 28-day mortality, the DPV tool was not inferior to the SOFA (AUC: 0.61), DPV tool (AUC: 0.59). CONCLUSIONS The DPV tool can be applied for 7-day and 28-day mortality risk prediction in patients with sepsis.
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A Population-Based Cohort Study on the Drug-Specific Effect of Statins on Sepsis Outcome.
Lee, CC, Lee, MG, Hsu, TC, Porta, L, Chang, SS, Yo, CH, Tsai, KC, Lee, M
Chest. 2018;(4):805-815
Abstract
BACKGROUND Whether statin treatment, proved by recent experimental studies to have an antimicrobial activity, exerts a drug- or a class-specific effect in sepsis remains unknown. METHODS Short-term mortality in patients with sepsis was analyzed using data from the National Health Insurance Research Database. Use of statins was defined as the cumulative use of a specific statin (atorvastatin, simvastatin, or rosuvastatin) for > 30 days prior to the index sepsis admission. We determined the association between statin and sepsis outcome by multivariate-adjusted Cox models and propensity score (PS)-matched analysis, using a 1:1:1 PS matching technique. RESULTS A total of 52,737 patients with sepsis fulfilled the inclusion criteria, of which 1,855 were prescribed atorvastatin, 916 were prescribed simvastatin, and 732 were prescribed rosuvastatin. Compared with nonusers, simvastatin (hazard ratio [HR], 0.72; 95% CI, 0.58-0.90) and atorvastatin (HR, 0.78; 95% CI, 0.68-0.90) were associated with an improved 30-day survival, whereas rosuvastatin was not (HR, 0.87; 95% CI, 0.73-1.04). Using rosuvastatin as the reference, atorvastatin (HR, 0.79; 95% CI, 0.64-0.99) and simvastatin (HR, 0.77; 95% CI, 0.59-0.99) had superior effectiveness in preventing mortality. CONCLUSIONS Compatible with in vitro experimental findings, our results suggest that the drug-specific effect of statins on sepsis is not correlated to their lipid-lowering potency.
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Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis: A Randomized Clinical Trial.
Kawazoe, Y, Miyamoto, K, Morimoto, T, Yamamoto, T, Fuke, A, Hashimoto, A, Koami, H, Beppu, S, Katayama, Y, Itoh, M, et al
JAMA. 2017;(13):1321-1328
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IMPORTANCE Dexmedetomidine provides sedation for patients undergoing ventilation; however, its effects on mortality and ventilator-free days have not been well studied among patients with sepsis. OBJECTIVES To examine whether a sedation strategy with dexmedetomidine can improve clinical outcomes in patients with sepsis undergoing ventilation. DESIGN, SETTING, AND PARTICIPANTS Open-label, multicenter randomized clinical trial conducted at 8 intensive care units in Japan from February 2013 until January 2016 among 201 consecutive adult patients with sepsis requiring mechanical ventilation for at least 24 hours. INTERVENTIONS Patients were randomized to receive either sedation with dexmedetomidine (n = 100) or sedation without dexmedetomidine (control group; n = 101). Other agents used in both groups were fentanyl, propofol, and midazolam. MAIN OUTCOMES AND MEASURES The co-primary outcomes were mortality and ventilator-free days (over a 28-day duration). Sequential Organ Failure Assessment score (days 1, 2, 4, 6, 8), sedation control, occurrence of delirium and coma, intensive care unit stay duration, renal function, inflammation, and nutrition state were assessed as secondary outcomes. RESULTS Of the 203 screened patients, 201 were randomized. The mean age was 69 years (SD, 14 years); 63% were male. Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group (19 patients [22.8%] vs 28 patients [30.8%]; hazard ratio, 0.69; 95% CI, 0.38-1.22; P = .20). Ventilator-free days over 28 days were not significantly different between groups (dexmedetomidine group: median, 20 [interquartile range, 5-24] days; control group: median, 18 [interquartile range, 0.5-23] days; P = .20). The dexmedetomidine group had a significantly higher rate of well-controlled sedation during mechanical ventilation (range, 17%-58% vs 20%-39%; P = .01); other outcomes were not significantly different between groups. Adverse events occurred in 8 (8%) and 3 (3%) patients in the dexmedetomidine and control groups, respectively. CONCLUSIONS AND RELEVANCE Among patients requiring mechanical ventilation, the use of dexmedetomidine compared with no dexmedetomidine did not result in statistically significant improvement in mortality or ventilator-free days. However, the study may have been underpowered for mortality, and additional research may be needed to evaluate this further. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01760967.
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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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High Single-dose Vancomycin Loading Is Not Associated With Increased Nephrotoxicity in Emergency Department Sepsis Patients.
Rosini, JM, Davis, JJ, Muenzer, J, Levine, BJ, Papas, MA, Comer, D, Arnold, R
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2016;(6):744-6
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OBJECTIVE Vancomycin loading doses are recommended; however, the risk of nephrotoxicity with these doses is unknown. The primary objective of this study was to compare nephrotoxicity in emergency department (ED) sepsis patients who received vancomycin at high doses (>20 mg/kg) versus lower doses (≤20 mg/kg). METHODS A retrospective cohort study was performed in three academic EDs. Inclusion criteria were age ≥ 18 years, intravenous vancomycin order, and hospital admission. Exclusion criteria were no documented weight, hemodialysis-dependent, and inadequate serum creatinine (SCr) values for the measured outcome. Analyses compared the incidence of nephrotoxicity for patients who received vancomycin at high dose (>20 mg/kg) versus low dose (≤20 mg/kg). RESULTS A total of 2,131 consecutive patients prescribed vancomycin over 6 months were identified. Of these, 1,330 patients had three SCr values assessed for the primary outcome. High-dose initial vancomycin was associated with a significantly lower rate of nephrotoxicity (5.8% vs. 11.1%). After age, sex, and initial SCr were adjusted for, the risk of high-dose vancomycin compared to low-dose was decreased for the development of nephrotoxicity (relative risk = 0.60; 95% confidence interval = 0.44 to 0.82). CONCLUSION Initial dosing of vancomycin > 20 mg/kg was not associated with an increased rate of nephrotoxicity compared with lower doses. Findings from this study support compliance with initial weight-based vancomycin loading doses.
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One-year outcomes of rosuvastatin versus placebo in sepsis-associated acute respiratory distress syndrome: prospective follow-up of SAILS randomised trial.
Dinglas, VD, Hopkins, RO, Wozniak, AW, Hough, CL, Morris, PE, Jackson, JC, Mendez-Tellez, PA, Bienvenu, OJ, Ely, EW, Colantuoni, E, et al
Thorax. 2016;(5):401-10
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BACKGROUND Prior randomised trials have evaluated statins in patients with sepsis and acute respiratory distress syndrome (ARDS), but there has been no comprehensive evaluation of long-term effects, despite potential neuromuscular and mental health adverse effects of these drugs. AIM: To evaluate the effect of rosuvastatin versus placebo on survival, physical function and performance, and mental health outcomes in patients with sepsis-associated ARDS. METHODS Prospective follow-up evaluation of the ARDS Clinical Trials Network Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo in 568 mechanically ventilated patients with sepsis-associated ARDS, with blinded 6-month outcome assessment performed in the 272 eligible survivors for age-adjusted and sex-adjusted 36-Item Short Form Health Survey (SF-36) physical function and mental health domains, and in 84 eligible survivors for the 6 min walk test, along with secondary outcomes evaluations of survival, and additional patient-reported and performance-based measures at 6-month and 12-month follow-up. RESULTS Over 1-year follow-up, there was no significant difference in cumulative survival in the rosuvastatin versus placebo groups (58% vs 61%; p=0.377), with survivors demonstrating substantial impairments in physical function and mental health. Rosuvastatin versus placebo had no effect (mean treatment effect (95% CI)) on SF-36 physical function (0 (-7 to 8), p=0.939) or mental health (-6 (-12 to 1) p=0.085) domains, 6 min walk distance (per cent predicted: 2 (-9 to 14), p=0.679) or the vast majority of secondary outcomes. CONCLUSIONS Over 1-year follow-up, patients with sepsis-associated ARDS had high cumulative mortality, with survivors commonly experiencing impairments in physical functioning and performance, and mental health. Randomisation to rosuvastatin had no effect on these outcomes. TRIAL REGISTRATION NUMBER NCT00979121 and NCT00719446.
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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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Early enteral immunonutrition vs. parenteral nutrition in critically ill patients without severe sepsis: a randomized clinical trial.
Radrizzani, D, Bertolini, G, Facchini, R, Simini, B, Bruzzone, P, Zanforlin, G, Tognoni, G, Iapichino, G
Intensive care medicine. 2006;(8):1191-8
Abstract
OBJECTIVES We compared early parenteral nutrition (PN) and early enteral immunonutrition (iEN) in critically ill patients, distinguishing those with and without severe sepsis or septic shock (SS) on admission to intensive care units (ICUs). DESIGN AND SETTING Multicenter, randomized, unblinded clinical trial in 33 Italian general ICUs. PATIENTS AND PARTICIPANTS The study included 326 patients, 287 of whom did not have SS on ICU admission. Eligibility criteria excluded the two tails in the spectrum of critical conditions, i.e., patients either too well or too ill. Of the patients recruited 160 were randomized to iEN (142 without SS) and 166 to PN (145 without SS). INTERVENTIONS Patients were randomized to two arms: early iEN or early PN. MEASUREMENTS AND RESULTS Primary endpoint was 28-day mortality for all patients and the occurrence of SS during ICU stay for patients admitted without such condition. While 28-day mortality did not differ between iEN and PN (15.6% vs. 15.1%), patients without SS who received iEN had fewer episodes of severe sepsis or septic shock (4.9% vs. 13.1%). ICU length of stay was 4 days shorter in patients given iEN. CONCLUSIONS Compared to parenteral nutrition iEN appears to be beneficial in critical patients without severe sepsis or septic shock. Parenteral nutrition in these patients should be abandoned, at least when enteral nutrition can be administered, even at an initial low caloric content.