-
1.
ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions 1.
Berrington, JE, McGuire, W, Embleton, ND
Biochemistry and cell biology = Biochimie et biologie cellulaire. 2021;(1):1-6
Abstract
Results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32 weeks gestation) reduces late-onset sepsis (LOS) and necrotising enterocolitis (NEC). The Enteral Lactoferrin in Neonates (ELFIN) study, performed in the UK, aimed to further address this issue with a well powered double-blind placebo controlled trial of >2200 preterm infants. The results from ELFIN did not demonstrate a reduction in LOS or NEC, or several other clinically important measures. Of the 1093 infants, 316 (29%) in the intervention group developed late-onset sepsis versus 334 (31%) of 1089 in the control group, with an adjusted risk ratio of 0.95 (95% CI = 0.86-1.04; p = 0.233). Reasons for the differences in ELFIN trial results and other studies may include population differences, the routine use of antifungal prophylaxis in the UK, timing of administration of the lactoferrin in relation to disease onset, or specific properties of the lactoferrin used in the different trials. The UK National Institutes for Health Research funded "Mechanisms Affecting the Guts of Preterm Infants in Enteral feeding trials" (MAGPIE) study is further exploring the use of lactoferrin, and the results should be available soon.
-
2.
Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis.
De Winter, S, van Hest, R, Dreesen, E, Annaert, P, Wauters, J, Meersseman, W, Van den Eede, N, Desmet, S, Verelst, S, Vanbrabant, P, et al
European journal of drug metabolism and pharmacokinetics. 2021;(5):653-663
Abstract
BACKGROUND There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable. OBJECTIVE The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV. METHODS Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling. RESULTS A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V1) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V1, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained. CONCLUSION The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance. TRIAL REGISTRATION ClinicalTrials.gov ID: NCT02365272.
-
3.
Oropharyngeal Administration of Mother's Milk Prior to Gavage Feeding in Preterm Infants: A Pilot Randomized Control Trial.
Abd-Elgawad, M, Eldegla, H, Khashaba, M, Nasef, N
JPEN. Journal of parenteral and enteral nutrition. 2020;(1):92-104
Abstract
BACKGROUND Oropharyngeal administration of mother's colostrum in early days has an immunoprotective effect in preterm infants. OBJECTIVES Our aim was to study the effect of oropharyngeal administration of mother's milk (OPAMM) on decreasing the incidence of nosocomial sepsis. METHODS In a pilot prospective randomized study on preterm (<32 weeks gestation and 1500 g weight) infants, we compared OPAMM practice (applying 0.2 mL of mother's colostrum or milk prior to gavage feeding until full oral feeding is reached) with regular gavage feeding. The primary outcome was incidence of culture-proven nosocomial sepsis. Secondary outcomes included bacterial colonization of the gastrointestinal tract, feeding intolerance, time to reach full feeding, incidence of necrotizing enterocolitis, ventilator-associated pneumonia, duration of respiratory support, incidence of bronchopulmonary dysplasia (BPD), length of hospital stay, and neonatal mortality. RESULTS The outcomes of 200 neonates (100 in each group) were analyzed. OPAMM practice did not significantly reduce the incidence of culture proven nosocomial sepsis (8% vs 13%, P = 0.35). Infants in the OPAMM group had a significantly lower growth of Klebsiella species in the oropharyngeal pouch, borderline lower incidence of ventilator-associated pneumonia, shorter duration of oxygen therapy, less episodes of feeding intolerance, reached full feeding earlier, and had a shorter length of hospital stay. OPAMM practice did not affect the incidence of necrotizing enterocolitis, BPD, or neonatal mortality. CONCLUSION OPAMM prior to gavage feeding does not reduce the incidence of nosocomial sepsis but had beneficial effects on early achievement of feeding, and early hospital discharge in preterm very low-birth-weight infants.
-
4.
[Transcutaneous electrical acupoint stimulation for early enteral nutrition tolerance in patients with sepsis of gastrointestinal dysfunction: a multi-center randomized controlled trial].
Liu, H, Zhu, J, Ni, HB, Hu, XX
Zhongguo zhen jiu = Chinese acupuncture & moxibustion. 2020;(3):229-33
Abstract
OBJECTIVE To compare the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) combined with conventional western medicine and western medicine alone on early enteral nutrition tolerance in patients with sepsis. METHODS Forty-nine patients with sepsis were randomly divided into an observation group (24 cases) and a control group (25 cases). The control group was treated with conventional western medicine, including limited fluid resuscitation, anti-infection and maintenance of hemodynamics, and enteral nutrition was provided when the hemodynamics became stable and the dosage of vasoactive drugs was reduced. The observation group, on the basis of the treatment of the control group, was treated with TEAS at Tianshu (ST 25), Shangjuxu (ST 37), Jiexi (ST 41), Diji (SP 8), Zusanli (ST 36), Zhongwan (CV 12) and Daheng (SP 15) when the enteral nutrition was provided (dilatational wave, 2 Hz/10 Hz, twice a day, 30 min each time), and the TEAS stopped when enteral nutrition was normal. The antral motility index (MI) was evaluated by ultrasonography on the first, third and fifth day into treatment in the two groups, and the duration from providing enteral nutrition to normal enteral nutrition was recorded. The acute gastrointestinal injury (AGI) classification, admission time of intensive care unit (ICU) and hospitalization time were compared. RESULTS The antral MI on the third and fifth day into treatment in the observation group was significantly higher than that in the control group (P<0.05). The duration from providing enteral nutrition to normal enteral nutrition was (5.08±0.65) days in the observation group, which was shorter than (5.56±0.65) days in the control group (P<0.05). The improvement of AGI classification after treatment in the observation group was significantly superior to the control group (P<0.05). The hospitalization time in the observation group was shorter than that in the control group (P<0.05). CONCLUSION TEAS combined with conventional western medicine treatment could significantly promote gastrointestinal peristalsis, improve the early intestinal nutrition tolerance in patients with sepsis, so as to shorten the time of reaching the standard of enteral nutrition and hospitalization time, which is better than conventional western medicine treatment alone.
-
5.
Dysbiosis in early sepsis can be modulated by a multispecies probiotic: a randomised controlled pilot trial.
Stadlbauer, V, Horvath, A, Komarova, I, Schmerboeck, B, Feldbacher, N, Klymiuk, I, Durdevic, M, Rainer, F, Blesl, A, Stiegler, P, et al
Beneficial microbes. 2019;(3):265-278
Abstract
The gut is hypothesised to play an important role in the development and progression of sepsis. It is however unknown whether the gut microbiome and the gut barrier function is already altered early in sepsis development and whether it is possible to modulate the microbiome in early sepsis. Therefore, a randomised, double blind, placebo-controlled pilot study to examine the alterations of the microbiome and the gut barrier in early sepsis and the influence of a concomitant probiotic intervention on dysbiosis at this early stage of the disease was conducted. Patients with early sepsis, defined as fulfilling the sepsis definition from the 2012 Surviving Sepsis Campaign guidelines but without signs of organ failure, received multispecies probiotic (Winclove 607 based on Omnibiotic® 10 AAD) for 28 days. Gut microbiome composition, function, gut barrier and bacterial translocation were studied. Patients with early sepsis had a significantly lower structural and functional alpha diversity, clustered differently and showed structural alterations on all taxonomic levels. Gut permeability was unaltered but endotoxin, endotoxin binding proteins and peptidoglycans were elevated in early sepsis patients compared to controls. Probiotic intervention successfully increased probiotic strains in stool and led to an improvement of functional diversity. Microbiome composition and function are altered in early sepsis. Probiotic intervention successfully modulates the microbiome and is therefore a promising tool for early intervention in sepsis.
-
6.
Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial.
,
Lancet (London, England). 2019;(10170):423-433
Abstract
BACKGROUND Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. METHODS In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. FINDINGS We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86-1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. INTERPRETATION Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. FUNDING UK National Institute for Health Research Health Technology Assessment programme (10/57/49).
-
7.
Electroacupuncture Improves Intestinal Dysfunction in Septic Patients: A Randomised Controlled Trial.
Meng, JB, Jiao, YN, Zhang, G, Xu, XJ, Ji, CL, Hu, MH, Lai, ZZ, Zhang, M
BioMed research international. 2018;:8293594
Abstract
OBJECTIVE To investigate the effects of electroacupuncture (EA) at "Zusanli" (ST36) and "Shangjuxu"(ST37) on reducing inflammatory reaction and improving intestinal dysfunction in patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi. METHODS A total of 71 patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi were randomly assigned to control group (n=36) and treatment group (n=35). Patients in control group were given conventional therapies including fluid resuscitation, anti-infection, vasoactive agents, mechanical ventilation, supply of enteral nutrition, and glutamine as soon as possible. In addition to conventional therapies, patients in treatment group underwent 20 minutes of EA at ST36-ST37 twice a day for five days. At baseline, day 1, day 3, and day 7 after treatment, the plasma levels of procalcitonin (PCT), tumor necrosis factor-α (TNF-α), intestinal fatty acid-binding proteins (I-FABP), D-lactate, citrulline, and TCM quantitative score of intestinal dysfunction were measured and recorded, respectively. And days on mechanical ventilation (MV), length of stay in intensive care unit (ICU), and 28d mortality were recorded. RESULTS During treatment, the plasma levels of PCT, TNF-α, I-FABP, D-lactate, and TCM quantitative score of intestinal dysfunction were declining in both groups, while the treatment group showed a significant decline (P<0.05). Plasma levels of citrulline were increasing in both groups, while the treatment group showed a significant increase (P<0.05). However, there were no significant differences in the days on MV, length of stay in ICU, and 28d mortality between two groups (P>0.05). CONCLUSIONS EA at ST36-ST37 can reduce inflammatory reaction and has protective effects on intestinal function in patients with sepsis-induced intestinal dysfunction with syndrome of obstruction of the bowels Qi. TRIAL REGISTRATION This trial was registered at http://www.chictr.org.cn/(ChiCTR-IOR-17010910).
-
8.
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
-
-
Free full text
-
Abstract
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.
-
9.
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.
-
10.
[Influence of simvastatin treatment on Toll-like receptor 4 in monocytes of peripheral blood in patients with sepsis and severe sepsis].
Shao, H, Wang, C, Zhu, W, Huang, X, Guo, Z, Zhang, H, Qin, B
Zhonghua wei zhong bing ji jiu yi xue. 2016;(2):159-63
Abstract
OBJECTIVE To investigate the influence of simvastatin treatment on Toll-like receptor 4 (TLR4) in monocytes of peripheral blood in patients with sepsis and severe sepsis and its significance. METHODS A prospective randomized controlled trial was conducted. 106 patients with sepsis and 92 patients with severe sepsis admitted to Department of Critical Care Medicine of Henan Provincial People's Hospital from August 2013 to June 2015 were enrolled. These two groups of patients were randomized into conventional treatment group and simvastatin group. All patients received treatment according to the 2012 International Sepsis Treatment Guidelines, including anti-infection drugs, nutritional support, and palliative treatment, and the patients with severe sepsis were given early goal-directed therapy (EGDT). The patients in simvastatin group received simvastatin 40 mg daily orally for at least 15 days. The peripheral blood was collected and the monocytes were isolated at 1, 5, 10, 15 days after intensive care unit (ICU) admission. TLR4 expression on the surface of TLR4/CD14(+) double positive monocytes was determined by flow cytometry, and adverse reaction was observed during treatment. RESULTS TLR4 expression on the surface of monocytes showed a tendency of decreasing with prolongation of simvastatin treatment in the simvastatin group in patients with sepsis (n = 59) or severe sepsis (n = 54). However, in patients with sepsis, TLR4 level was significantly decreased from 10 days in simvastatin group as compared with that of conventional therapy group (n = 47), and it was decreased up to 15 days [mean fluorescence intensity (MFI): 21 (19, 28) vs. 27 (25, 33) at 10 days, Z = 2.198, P = 0.021; 16 (15, 21) vs. 26 (23, 34) at 15 days, Z = 4.611, P = 0.002]. In patients with severe sepsis, there was no significant difference in TLR4 level at different time points between simvastatin group and conventional treatment group (n = 38) [MFI: 55 (52, 63) vs. 56 (48, 65) at 1 day, Z = 0.313, P = 0.692; 47 (42, 56) vs. 49 (41, 58) at 5 days, Z = 0.827, P = 0.533; 40 (35, 42) vs. 42 (37, 45) at 10 days, Z = 1.012, P = 0.301; 33 (30, 38) vs. 38 (35, 41) at 15 days, Z = 0.539, P = 0.571]. No adverse reaction related with simvastatin was found during treatment in patients with sepsis or severe sepsis. CONCLUSIONS Statins could significantly down-regulate the TLR4 expression on peripheral blood monocytes in septic patients, while it showed no significant influence on TLR4 expression in patients with severe sepsis. A different effect of statins on TLR4 expression and the downstream inflammation process in sepsis and severe sepsis patients might partially explain the discrepancy in previous reports about the therapeutic effect of statins therapy in sepsis and severe sepsis patients.