Shripada Rao

A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy – are we there yet?

BackgroundThe objective of this study was to systematically review randomized trials assessing therapeutic hypothermia as a treatment for term neonates with hypoxic ischemic encephalopathy.MethodsThe Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL databases, reference lists of identified studies, and proceedings of the Pediatric Academic Societies were searched in July 2006. Randomized trials assessing the effect of therapeutic hypothermia by either selective head cooling or whole body cooling in term neonates were eligible for inclusion in the meta-analysis. The primary outcome was death or neurodevelopmental disability at ≥ 18 months.ResultsFive trials involving 552 neonates were included in the analysis. Cooling techniques and the definition and severity of neurodevelopmental disability differed between studies. Overall, there is evidence of a significant effect of therapeutic hypothermia on the primary composite outcome of death or disability (RR: 0.78, 95% CI: 0.66, 0.92, NNT: 8, 95% CI: 5, 20) as well as on the single outcomes of mortality (RR: 0.75, 95% CI: 0.59, 0.96) and neurodevelopmental disability at 18 to 22 months (RR: 0.72, 95% CI: 0.53, 0.98). Adverse effects include benign sinus bradycardia (RR: 7.42, 95% CI: 2.52, 21.87) and thrombocytopenia (RR: 1.47, 95% CI: 1.07, 2.03, NNH: 8) without deleterious consequences.ConclusionIn general, therapeutic hypothermia seems to have a beneficial effect on the outcome of term neonates with moderate to severe hypoxic ischemic encephalopathy. Despite the methodological differences between trials, wide confidence intervals, and the lack of follow-up data beyond the second year of life, the consistency of the results is encouraging. Further research is necessary to minimize the uncertainty regarding efficacy and safety of any specific technique of cooling for any specific population.

Evidence-based guidelines for use of probiotics in preterm neonates

BackgroundCurrent evidence indicates that probiotic supplementation significantly reduces all-cause mortality and definite necrotising enterocolitis without significant adverse effects in preterm neonates. As the debate about the pros and cons of routine probiotic supplementation continues, many institutions are satisfied with the current evidence and wish to use probiotics routinely. Because of the lack of detail on many practical aspects of probiotic supplementation, clinician-friendly guidelines are urgently needed to optimise use of probiotics in preterm neonates.AimTo develop evidence-based guidelines for probiotic supplementation in preterm neonates.MethodsTo develop core guidelines on use of probiotics, including strain selection, dose and duration of supplementation, we primarily used the data from our recent updated systematic review of randomised controlled trials. For equally important issues including strain identification, monitoring for adverse effects, product format, storage and transport, and regulatory hurdles, a comprehensive literature search, covering the period 1966-2010 without restriction on the study design, was conducted, using the databases PubMed and EMBASE, and the proceedings of scientific conferences; these data were used in our updated systematic review.ResultsIn this review, we present guidelines, including level of evidence, for the practical aspects (for example, strain selection, dose, duration, clinical and laboratory surveillance) of probiotic supplementation, and for dealing with non-clinical but important issues (for example, regulatory requirements, product format). Evidence was inadequate in some areas, and these should be a target for further research.ConclusionWe hope that these evidence-based guidelines will help to optimise the use of probiotics in preterm neonates. Continued research is essential to provide answers to the current gaps in knowledge about probiotics.

Prebiotic Supplementation in Full-term Neonates: A Systematic Review of Randomized Controlled Trials

OBJECTIVE To systematically review randomized controlled trials evaluating the efficacy and safety of prebiotic supplementation in full-term neonates. DATA SOURCES Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and CINAHL databases and proceedings of relevant conferences. STUDY SELECTION Eleven of 24 identified trials (n = 1459) were eligible for inclusion. Intervention Trials comparing formula milk supplemented with or without prebiotics, commenced at or before age 28 days and continued for 2 weeks or longer. MAIN OUTCOME MEASURES Stool colony counts (bifidobacteria, lactobacilli, and pathogens), pH, consistency, frequency, anthropometry, and symptoms of intolerance. RESULTS Six trials reported significant increases and 2 reported a trend toward increases in bifidobacteria counts after supplementation. Meta-analysis estimated significant reduction in stool pH in infants who received prebiotic supplementation (weighted mean difference, -0.65; 95% confidence interval, -0.76 to -0.54; 6 trials). Infants who receive a supplement had slightly better weight gain than did controls (weighted mean difference, 1.07 g; 95% confidence interval, 0.14-1.99; 4 trials) with softer and frequent stools similar to breastfed infants. All but 1 trial reported that prebiotic supplementation was well tolerated. In that trial, diarrhea (18% vs 4%; P = .008), irritability (16% vs 4%; P = .03), and eczema (18% vs 7%; P = .046) were reported more frequently by parents of infants who received prebiotic supplements. CONCLUSIONS Prebiotic-supplemented formula is well tolerated by full-term infants. It increases stool colony counts of bifidobacteria and lactobacilli and results in stools similar to those of breastfed neonates without affecting weight gain. Larger trials with long-term follow-up are needed to determine whether these short-term benefits are sustained.

Prebiotic supplementation in preterm neonates: Updated systematic review and meta-analysis of randomised controlled trials

BACKGROUND & AIMS Regular administration of prebiotic oligosaccharides promote beneficial gut flora in infants. We aimed to systematically review randomized controlled trials evaluating the safety and efficacy of prebiotic oligosaccharide supplementation in preterm infants ≤ 37 weeks of gestation. METHODS Available studies from Medline, Embase, comparing formula milk supplemented with or without prebiotics, reporting on safety and the incidence of necrotising enterocolitis (NEC), late onset sepsis, feed tolerance, physical growth and various stool characteristics were eligible. RESULTS 7 trials (n = 417) were included. Five trials (n = 345) reported on the incidence of NEC, 3 trials (n = 295) reported on the incidence of late onset sepsis. Meta-analysis revealed a pooled RR (95% CI) of 1.24 (0.56-2.72) for NEC, 0.81 (0.57-1.15), p 0.23 for the risk of late onset sepsis. 3 individual trials (n = 295) did not observe any improvement in time to enteral feeds post intervention. Meta-analysis indicated a statistically significant difference in the growth of bifidobacteria in the oligosaccharide group with a weighted mean difference of 0.53 (95% CI: 0.33, 0.73) *10(6) colonies/g, p < 0.00001. A reduction in stool viscosity and pH was also observed. None of the trials reported life threatening adverse effects. CONCLUSIONS Supplementation with prebiotic oligosaccharides was safe and did not result in decreased incidence of NEC, late onset sepsis and time to full enteral feeds but resulted in a significantly higher growth of beneficial microbes.

Prebiotic supplementation of formula in preterm neonates: a systematic review and meta-analysis of randomised controlled trials

BACKGROUND & AIMS Review the efficacy and safety of prebiotic oligosaccharide supplementation of formula in reducing the incidence of NEC and sepsis; study its effect on growth, gut colonisation and stool characteristics in preterm neonates < or =37 weeks. METHODS The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL databases and proceedings of relevant conferences were searched. Only randomised control trials using prebiotic supplemented vs unsupplemented formula milk commenced within 28 days of life and continued for > or =2 weeks were included in the review. RESULTS Only one trial reported that NEC did not occur in any of the enrolled neonates. Others did not report on NEC or sepsis. All trials reported anthropometric parameters. Meta-analysis showed no significant effect on weight gain between the two groups. The two trials reporting on stool flora showed a statistically significant increase in bifidobacterial counts in the prebiotic supplemented group (Weighted mean difference (WMD)=0.53; 95% CI: 0.33, 0.73) logCFU/g of stool. CONCLUSION Prebiotic supplemented formula increased stool colony counts of bifidobacteria and lactobacilli in preterm neonates without adversely affecting weight gain.

Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-analysis.

CONTEXT: Late-onset sepsis (LOS) is a major cause of mortality and morbidity in preterm infants. Despite various preventive measures, its incidence continues to remain high, hence the urgent need for additional approaches. One such potential strategy is supplementation with probiotics. The updated Cochrane Review (2014) did not find benefits of probiotics in reducing the risk of LOS in preterm infants (19 studies, N = 5338). Currently there are >30 randomized controlled trials (RCTs) of probiotics in preterm infants that have reported on LOS. OBJECTIVES: To conduct a systematic review including all relevant RCTs. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and E-abstracts from the Pediatric Academic Society meetings and other pediatric and neonatal conference proceedings were searched in June and August 2015. STUDY SELECTION: RCTs comparing probiotics versus placebo/no probiotic were included. DATA EXTRACTION: Relevant data were extracted independently by 3 reviewers. RESULTS: Pooled results from 37 RCTs (N = 9416) using fixed effects model meta analysis showed that probiotics significantly decreased the risk of LOS (675/4852 [13.9%] vs 744/4564 [16.3%]; relative risk, 0.86; 95% confidence interval, 0.78–0.94; P = .0007; I2 = 35%; number needed to treat, 44). The results were significant even after excluding studies with high risk of bias. CONCLUSIONS: Probiotic supplementation reduces the risk of LOS in preterm infants.

Probiotics for Preterm Neonates: What Will It Take to Change Clinical Practice?

Necrotizing enterocolitis (NEC) is a major cause of mortality (25%) and morbidity including recurrent sepsis, dependence on parenteral nutrition, need for surgery, and survival with short bowel syndrome in preterm very low birth weight infants. Mortality (45-100%) and morbidity including the risk of long-term neurodevelopmental impairment are higher in extremely preterm infants needing surgery for NEC. Systematic reviews of randomized controlled trials (RCT) indicate that probiotics significantly reduce the risk of NEC (RR 0.39; 95% CI 0.29-0.52; p < 0.00001) and all-cause mortality (RR 0.52; 95% CI 0.40-0.69; p < 0.00001) while facilitating enteral feeds in preterm infants. At present, data from 25 RCT (∼5,000 neonates) and reports on routine use (∼3,000 neonates) indicates that significant adverse effects of probiotics are rare. Despite the robust evidence, there is still reluctance in incorporating routine probiotic prophylaxis in clinical practice. If the goal is to have zero tolerance for NEC, then probiotic prophylaxis must be adopted as soon as possible. Current gaps in knowledge can be addressed by continued research while providing routine probiotic supplementation. We believe that the concept of evidence-based practice of medicine has been stretched too far in this case. Trial sequential analysis has already shown that the evidence for probiotic supplementation was conclusive after 10 trials. Results of the ongoing trials are unlikely to change the conclusions of the systematic reviews significantly. Currently we are at trial number 25; how many more trials do we need? What will it take to change clinical practice?

Role of Probiotics in Short Bowel Syndrome in Infants and Children—A Systematic Review

Short bowel syndrome (SBS) is a cause of significant morbidity and mortality in children. Probiotics, due to their beneficial effects on the gastrointestinal tract (e.g., improving gut barrier function, motility, facilitation of intestinal adaptation and decreasing pathogen load and inflammation) may have a therapeutic role in the management of SBS. To conduct a systematic review of the current evidence for the effects of probiotic supplementation in children with SBS, the standard Cochrane methodology for systematic reviews was used. The databases, Pubmed, Embase, ACTR, CENTRAL, and the international trial registry, and reference lists of articles were searched for randomised (RCT) or quasi-randomised controlled trials reporting on the use of probiotics in SBS. Our search revealed no RCTs on the use of probiotics in children with SBS. We found one small cross-over RCT (placebo controlled crossover clinical trial), one case control study and nine case reports on the use of probiotics in children with SBS. In the crossover RCT, there was no consistent effect on intestinal permeability (primary outcome) after supplementation with Lactobacillus rhamnosus (LGG) in nine children with SBS. The case control study (four cases: four controls) reported a trend for increase in height and weight velocity and improvement in non-clinical outcomes, such as gut flora, lymphocyte count and serum prealbumin. Five of the nine case reports showed that children (n = 12) with SBS were benefited (e.g., cessation of diarrhoea, improved faecal flora, weight gain and weaning from parenteral nutrition) by probiotic supplementation. The remaining four reported on the adverse effects, such as Lactobacillus sepsis (n = 3) and D-lactic acidosis (n = 2). There is insufficient evidence on the effects of probiotics in children with SBS. The safety and efficacy of probiotic supplementation in this high-risk cohort needs to be evaluated in large definitive trials.

Antibiotic-impregnated catheters for the prevention of CSF shunt infections: A systematic review and meta-analysis

Abstract Context. CSF infections are a serious complication of CSF shunts and external ventricular drains (EVDs). Antibiotic-impregnated catheters (AIC) have been tried in order to minimise the risk of such infections. Objectives. To conduct a systematic review and a meta-analysis comparing AICs versus non-AICs used as ventriculo-peritoneal (VP) shunts or external ventricular drains (EVDs) in the neonatal population. The secondary aim was to include data from a paediatric and adult population if insufficient information was available from neonatal studies. Data sources. PubMed (March 2011), EMBASE (March 2011), CENTRAL (1980–March 2011), and CINAHL (March 2011) were searched. Study selection. Both randomised controlled trials (RCTs) and observational studies were included. Results. Only three observational studies reported on the use of AI-VP shunt catheters in the neonatal population. Meta-analysis found a statistically significant difference favouring AI shunts (RR: 0.37; CI: 0.16, 0.86; p = 0.02). Twelve studies (one RCT, 11 observational; n = 3284) compared AI versus non-AI VP shunts in a paediatric and adult population. The RCT showed a trend towards benefit using the AICs (RR: 0.38; 95% CI: 0.11, 1.30; p = 0.12). A meta-analysis of the 11 observational studies showed a significant benefit in the AI group (RR: 0.37; CI: 0.23, 0.60; p = 0.0001; n = 3149). Similar benefits were noted for AI-EVDs in RCTs (RR: 0.19; 95% CI: 0.05, 0.64; p = 0.01; n = 472, two studies) and observational studies (RR: 0.31; 95 CI: 0.13, 0.74; p = 0.009; n = 2415, five studies). Conclusions. A meta-analysis of mainly observational studies suggests that AICs may be an effective way of reducing the incidence of shunt and EVD infections. Well-designed multi-centre RCTs are urgently needed.

Benefits of probiotics on enteral nutrition in preterm neonates: a systematic review

INTRODUCTION The optimization of enteral nutrition is a priority in preterm neonates worldwide. Probiotics are known to improve gut maturity and function in preterm neonates. To our knowledge, previous systematic reviews have not adequately assessed the effects of probiotic supplementation on enteral nutrition in preterm neonates. OBJECTIVE We assessed the evidence on effects of probiotics on enteral nutrition in preterm neonates. DESIGN A systematic review of randomized controlled trials (RCTs) of probiotic supplementation in preterm (gestation <37 wk) or low-birth-weight (birth weight <2500 g) neonates was conducted. With the use of the Cochrane Neonatal Review Group strategy, we searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Cumulative Index of Nursing and Allied Health Literature databases and proceedings of Pediatric Academic Society meetings in April 2014. RESULTS A total of 25 RCTs (n = 5895) were included in the review. A meta-analysis (random-effects model) of data from 19 of 25 trials (n = 4527) estimated that the time to full enteral feeds was shorter in the probiotic group (mean difference: -1.54 d; 95% CI: -2.75, -0.32 d; P < 0.00001, I(2) = 93%). Other benefits included fewer episodes of feed intolerance, better weight gain and growth velocity, decreased transition time from orogastric to breast feeds, and increased postprandial mesenteric flow. There were no adverse effects of probiotic supplementation. CONCLUSIONS Probiotics reduced the time to full enteral feeds in preterm neonates. Additional research is necessary to assess the optimal dose, duration, and probiotic strain or strains used specifically for facilitating enteral nutrition in this population.