scholarly journals Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial)

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Serife Kurul ◽  
H. Rob Taal ◽  
Robert B. Flint ◽  
Jan Mazela ◽  
Irwin K. M. Reiss ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Late Onset ◽  
Medical Center ◽  
Optimal Dose ◽  
Dose Finding ◽  
Preterm Neonates ◽  
Optimal Dosage ◽  
Open Label ◽  
Main Trial ◽  
Late Onset Sepsis

Abstract Background Late onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies. Methods The PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics. Discussion The study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals. Trial registration Clinicaltrials.gov, NCT04152980, Registered November 6th, 2019

scholarly journals Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Şerife Kurul ◽  
Sinno H. P. Simons ◽  
Christian R. B. Ramakers ◽  
Yolanda B. De Rijke ◽  
René F. Kornelisse ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Gestational Age ◽  
Neonatal Sepsis ◽  
Late Onset ◽  
Medical Center ◽  
Inotropic Support ◽  
Inflammatory Biomarkers ◽  
Preterm Neonates ◽  
Sepsis Severity ◽  
Suspected Sepsis

Abstract Background Sepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis. Methods The study was conducted at the Erasmus University Medical Center–Sophia Children’s Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia). Results A total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64–3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70–5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68–2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support. Conclusions Our findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.

scholarly journals Is Lactoferrin More Effective in Reducing Late-Onset Sepsis in Preterm Neonates Fed Formula Than in Those Receiving Mother's Own Milk? Secondary Analyses of Two Multicenter Randomized Controlled Trials

2019 ◽  
Vol 36 (S 02) ◽  
pp. S120-S125 ◽  
Author(s):  
Paolo Manzoni ◽  
Maria Angela Militello ◽  
Stefano Rizzollo ◽  
Elena Tavella ◽  
Alessandro Messina ◽  
...  
Keyword(s):  
Relative Risk ◽  
Preterm Infants ◽  
Late Onset ◽  
Preterm Neonates ◽  
Antimicrobial Protein ◽  
Donor Milk ◽  
Randomized Controlled ◽  
Late Onset Sepsis ◽  
Post Hoc ◽  
Mother’S Own Milk

Background Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain. Aim To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk. Study Design This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM. Results (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18–0.64; p < 0.0008). Among no-MM infants, LOS occurred in 7/35 (20.0%) randomized to placebo and in 2/54 (3.7%) randomized to BLF (RR: 0.19; RRR: 0.81; 95% CI for RR: 0.16–0.96; p = 0.026). In multivariable logistic regression analysis, there was no interaction between BLF treatment effect and type of feeding (p = 0.628). (B) In 1,891 infants not exclusively fed MM in our RCT of BLF and in the ELFIN RCT, BLF reduced the RR of LOS by 18% (RR: 0.82; 95% CI: 0.71–0.96; p = 0.01). Conclusion Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS.

Prolonged empiric antibiotics and time to full enteral feed in preterm infants less than 29 weeks of gestational age

2021 ◽  
pp. 1-5
Author(s):  
M.R. Alturk ◽  
H. Salama ◽  
H. Al Rifai ◽  
M. Al Qubaisi ◽  
S. Alobaidly
Keyword(s):  
Parenteral Nutrition ◽  
Preterm Infants ◽  
Antibiotic Treatment ◽  
Gestational Age ◽  
Late Onset ◽  
Blood Cultures ◽  
Hospital Death ◽  
Late Onset Sepsis ◽  
Empiric Antibiotic ◽  
Antibiotic Courses

BACKGROUND: Early empiric antibiotic exposure appears to negatively influence feeding tolerance in preterm infants. However, the effect of prolonged antibiotic treatment is unknown. The objective of this study was to investigate whether prolonged antibiotics impact the time to full enteral feed in infants less than 29 weeks of gestational age with negative blood cultures. METHODS: Retrospective data for infants less than 29 weeks gestation age were retrieved from the PEARL-Peristat perinatal registry in Qatar. Exclusion criteria were major congenital anomalies, conditions requiring surgery in the first 10 days of life, positive blood cultures in the first 48 hours of life, and death within the first week of life. Antibiotic courses were categorized as prolonged if continued more than 48 hours. The primary outcome was the duration of total parenteral nutrition. RESULTS: Of 199 study infants, 185 (92.9%) underwent antibiotic treatment for >  48 hours despite negative blood cultures. The median duration of parenteral nutrition was not significantly different between the prolonged and short antibiotic groups (25 and 22 days, respectively; p = 0.139). Infants with prolonged antibiotic courses experienced non-significantly higher levels of necrotizing enterocolitis (7.1% and 18.4%, respectively), bronchopulmonary dysplasia (28.6% and 45.4%, respectively), and retinopathy of prematurity (14.3% and 38.4%, respectively). There were no differences in the late-onset sepsis rate (78.6% and 82.1%, respectively) and the in-hospital death rate (7.1% and 7.6%, respectively). CONCLUSIONS: Prolonged antibiotic treatment in infants less than 29 weeks gestation with negative blood cultures has no significant impact on the time to full enteral feed.

ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions

2020 ◽  
Author(s):  
Janet Elizabeth Berrington ◽  
William McGuire ◽  
NIcholas David Embleton
Keyword(s):  
United Kingdom ◽  
Preterm Infants ◽  
Late Onset ◽  
Disease Onset ◽  
Intervention Group ◽  
Control Group ◽  
Bovine Lactoferrin ◽  
The United Kingdom ◽  
Late Onset Sepsis ◽  
The Uk

Previous studies suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32 weeks gestation) may reduce late onset sepsis (LOS) and necrotising enterocolitis (NEC), but have been underpowered. The Enteral Lactoferrin in Neonates (ELFIN) study, performed in the United Kingdom (UK), aimed to further address this issue with a well powered double blinded placebo controlled trial of >2200 preterm infants. ELFIN did not demonstrate a reduction in LOS or NEC, or several other clinically important measures. 316 (29%) of 1093 infants 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 antifungals in the UK, timing of administration of the lactoferrin in relation to disease onset, or specific properties of the lactoferrin used in different trials. Further exploration is being undertaken in the UK NIHR funded Mechanisms Affecting the Guts of Preterm Infants in Enteral feeding trials (MAGPIE) study, for which results should be available soon.

Ohio Statewide Quality-Improvement Collaborative to Reduce Late-Onset Sepsis in Preterm Infants

PEDIATRICS ◽  
2011 ◽  
Vol 127 (3) ◽  
pp. 427-435 ◽  
Author(s):  
H. C. Kaplan ◽  
C. Lannon ◽  
M. C. Walsh ◽  
E. F. Donovan ◽  
Keyword(s):  
Quality Improvement ◽  
Preterm Infants ◽  
Late Onset ◽  
Quality Improvement Collaborative ◽  
Late Onset Sepsis

scholarly journals Probiotics to prevent necrotising enterocolitis and nosocomial infection in very low birth weight preterm infants

2017 ◽  
Vol 117 (7) ◽  
pp. 994-1000 ◽  
Author(s):  
J. Uberos ◽  
E. Aguilera-Rodríguez ◽  
A. Jerez-Calero ◽  
M. Molina-Oya ◽  
A. Molina-Carballo ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Very Low Birth Weight ◽  
Late Onset ◽  
Necrotising Enterocolitis ◽  
Stage Ii ◽  
Preterm Neonates ◽  
Probiotic Supplementation ◽  
Late Onset Sepsis ◽  
Reduced Risk

AbstractThe aim of the study was to determine whether routine probiotic supplementation (RPS) with Lactobacillus rhamnosus GG (LGG) or Lactobacillus acidophilus +Lactobacillus bifidum is associated with reduced risk of necrotising enterocolitis (NEC)≥Stage II in preterm neonates born at ≤32 weeks’ gestation. We conducted a retrospective cohort study on the effect of probiotic supplementation in very low birth weight infants in our neonatal unit by comparing two periods: before and after supplementation. The incidence of NEC≥Stage II, late-onset sepsis and all-cause mortality was compared for an equal period ‘before’ (Period I) and ‘after’ (Period II) RPS with LGG or L. acidophillus+L. bifidum. Multivariate logistic regression analysis was conducted to adjust for relevant confounders. The study population was composed of 261 neonates (Period I v. II: 134 v. 127) with comparable gestation duration and birth weights. In <32 weeks, we observed a significant reduction in NEC≥Stage II (11·3 v. 4·8 %), late-onset sepsis (16 v. 10·5 %) and mortality (19·4 v. 2·3 %). The benefits in neonates aged ≤27 weeks did not reach statistical significance. RPS with LGG or L. acidophillus+L. bifidum is associated with a reduced risk of NEC≥Stage II, late-onset sepsis and mortality in preterm neonates born at ≤32 weeks’ gestation.

scholarly journals Cause of preterm birth and late-onset sepsis in very preterm infants: the EPIPAGE-2 cohort study

2021 ◽  
Author(s):  
Mathilde Letouzey ◽  
◽  
Laurence Foix-L’Hélias ◽  
Héloïse Torchin ◽  
Ayoub Mitha ◽  
...  
Keyword(s):  
Cohort Study ◽  
Preterm Birth ◽  
Preterm Infants ◽  
Late Onset ◽  
Very Preterm Infants ◽  
Very Preterm ◽  
Late Onset Sepsis
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