Sanjay Patole

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.

Is surgical ligation of patent ductus arteriosus necessary? The Western Australian experience of conservative management

Background: Surgical ligation of patent ductus arteriosus (PDA) is widely practised in preterm infants despite no clear evidence that this improves outcomes. Geographical isolation meant that ductal ligation was not an option in King Edward Memorial Hospital until recently. Objective: A retrospective data analysis to test the hypothesis that outcomes of infants with persistent PDA were no worse than those of infants with no significant duct or a duct that closed after medical treatment. Patients and Methods: A total of 252 infants (gestation ⩽28 weeks) born between 1 January 2000 and 30 June 2002 were divided into three groups: group 1, no significant PDA (n  =  154); group 2, significant PDA which closed after medical treatment (n  =  65); group 3, significant PDA remaining patent after medical treatment (n  =  33). A significant PDA was defined by a left atrium to aortic root ratio of >1.4 or a ductal diameter >1.5 mm with a left to right shunt. Results: Twenty four (10%) infants died at median (interquartile range) 15.5 (9–35) days. After adjustment for gestational age, relative to group 1, the infants from group 3 were at a 4.02 times increased risk of death (95% confidence interval 1.12 to 14.51). There was no significant difference between groups in the incidence of chronic lung disease, chronic lung disease or death, necrotising enterocolitis, intraventricular haemorrhage, duration of oxygen, or hospital stay. Conclusion: Mortality was higher in infants with a persistent PDA, but other morbidities were not significantly different. A randomised trial is needed to determine whether surgical ligation will reduce mortality in such infants.

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.

Pentoxifylline Reduces the Incidence and Severity of Necrotizing Enterocolitis in a Neonatal Rat Model

Necrotizing enterocolitis (NEC) is a potentially fatal illness in premature neonates. Tumor necrosis factor alpha (TNF-α) has been shown to play a central role in the inflammatory cascade leading to the development of NEC. Published evidence points to a significant role of pentoxifylline in inhibition of TNF-α and in reducing mucosal injury and improving healing in ischemia-reperfusion experiments. Our aim was to investigate the effect of pentoxifylline on the incidence of NEC in a neonatal rat model. Newborn Sprague-Dawley rat pups originating from eight separate litters were delivered by cesarean section at 21.5 d and were formula fed from birth by orogastric gavage. The rat pups were randomized to receive either intraperitoneal pentoxifylline (15 mg/kg/dose) or placebo, given every 8 h beginning at 24 h of age, in a blinded fashion. Experimental NEC was induced by exposure to hypoxia for 60 s followed by cold stress at 4°C for 10 min. The animals were euthanized at development of NEC or at 96 h and intestinal tissue was processed and examined for histologic changes of NEC. The incidence of NEC was significantly lower in the pentoxifylline group [pentoxifylline 5/38 versus placebo 15/36; p = 0.008, odds ratio (OR) = 0.21 95% confidence interval (CI) 0.07–0.67]. Among the pups developing NEC, significantly fewer rat pups treated with pentoxifylline had severe (≥3) intestinal injury scores [pentoxifylline 1/5 versus placebo 10/15; p = 0.031, OR 0.06, 95% CI 0.01–0.79]. We conclude that intraperitoneal administration of pentoxifylline significantly reduced the incidence and severity of NEC in our experimental animal model.

Strategies for prevention of feed intolerance in preterm neonates: a systematic review.

Postnatal growth restriction and failure to thrive have been recently identified as a major issue in preterm, especially extremely-low-birth-weight neonates. An increased length of time to reach full enteral feedings is also significantly associated with a poorer mental outcome in preterm neonates at 24 months corrected age. Optimization of enteral nutrition without increasing the risk of necrotizing enterocolitis (NEC) has thus become a priority in preterm neonates. A range of feeding strategies currently exists for preventing/minimizing feed intolerance in preterm neonates reflecting the dilemma surrounding the definition and significance of signs of feed intolerance due to ileus of prematurity and the fear of NEC. The results of a systematic review of current strategies for preventing/minimizing feed intolerance in preterm neonates are discussed. The need for clinical research in the area of signs of feed intolerance is emphasized to develop a scientific basis to feeding strategies. Only large pragmatic trials based on such strategies will reveal whether the benefits (improved growth and long term neurodevelopmental outcomes) of aggressive enteral nutrition can outweigh the risks of a potentially devastating illness like NEC, and of prolonged parenteral nutrition in preterm neonates.

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.

Neonatal outcome of gastroschisis and exomphalos: A 10-year review

Objective: To study neonatal outcomes associated with gastroschisis and exomphalos in a regional neonatal unit.

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.