Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis.

Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.

Semaphorin 3F signaling actively retains neutrophils at sites of inflammation.

Neutrophilic inflammation is central to disease pathogenesis, for example, in chronic obstructive pulmonary disease, yet the mechanisms that retain neutrophils within tissues remain poorly understood. With emerging evidence that axon guidance factors can regulate myeloid recruitment and that neutrophils can regulate expression of a class 3 semaphorin, SEMA3F, we investigated the role of SEMA3F in inflammatory cell retention within inflamed tissues. We observed that neutrophils upregulate SEMA3F in response to proinflammatory mediators and following neutrophil recruitment to the inflamed lung. In both zebrafish tail injury and murine acute lung injury models of neutrophilic inflammation, overexpression of SEMA3F delayed inflammation resolution with slower neutrophil migratory speeds and retention of neutrophils within the tissues. Conversely, constitutive loss of sema3f accelerated egress of neutrophils from the tail injury site in fish, whereas neutrophil-specific deletion of Sema3f in mice resulted in more rapid neutrophil transit through the airways, and significantly reduced time to resolution of the neutrophilic response. Study of filamentous-actin (F-actin) subsequently showed that SEMA3F-mediated retention is associated with F-actin disassembly. In conclusion, SEMA3F signaling actively regulates neutrophil retention within the injured tissues with consequences for neutrophil clearance and inflammation resolution.

Impact of an Advanced Pharmacy Practice Experience Student-Run "Meds 2 Beds" and Discharge Counseling Program on Quality of Care.

Purpose: As health care progresses toward pay for performance reimbursement models and focus is placed on the patient as a consumer, health care systems must adapt by initiating new programs and services. This institution responded by implementing a "Meds 2 Beds" program integrating clinical services with dispensing and medication delivery during transitions of care. This study evaluates outcomes relevant to patients, health care providers, pharmacists, and administrators. Methods: This observational chart review evaluated the effectiveness of a "Meds 2 Beds" program from May 1, 2014, through December 1, 2015. Patients who participated in this program were matched 1:1 with controls who did not. The primary outcome was 30-day hospital readmission. Secondary outcomes included 30-day emergency department (ED) visits, patient satisfaction, and financial impact. Results: In this sample, 185 "Meds 2 Beds" patients were matched to 185 controls. Thirty day readmission occurred in 16 (8.7%) "Meds 2 Beds" cases and 19 (10.3%) controls (P = .71). Rates of 30-day ED visits were nonsignificantly reduced in cases (22 [11.9%] vs 33 [18.1%]; odds ratio = 0.62, P = .11) and occurred significantly later (11 vs 7 days, P = .03). Conclusions: This study showcases a creative medication delivery and discharge counseling program. The program provides financial benefit to the institution creating a direct revenue stream from prescription dispensing while highlighting a potential for reduced readmissions and ED visits (although a statistically significant difference was not demonstrated in this analysis). A similar model can be adopted by other health care institutions to improve the quality of patient care.

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of NEC. However, slow feed advancement may delay establishment of full enteral feeding and be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine the effect of slow rates of enteral feed advancement on the incidence of NEC, mortality, and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 7), MEDLINE via PubMed (1966 to August 2015), EMBASE (1980 to August 2015), and CINAHL (1982 to August 2015). We also searched clinical trials databases, conference proceedings, previous reviews, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of slow (up to 24 mL/kg/day) versus faster rates of advancement of enteral feed volumes upon the incidence of NEC in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment effects in the individual trials and reported the risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference for continuous data, with respective 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses. MAIN RESULTS: We identified nine randomised controlled trials in which 949 infants participated. Most participants were stable preterm infants with birth weights between 1000 and 1500 g. Fewer participants were extremely preterm, extremely low birth weight, or growth-restricted. The trials typically defined slow advancement as daily increments of 15 to 24 mL/kg and faster advancement as 30 to 40 mL/kg. Meta-analyses did not show statistically significant effects on the risk of NEC (typical RR 1.02, 95% CI 0.64 to 1.62; typical RD -0.00, 95% CI -0.03 to 0.03) or all-cause mortality (typical RR 1.18, 95% CI 0.90 to 1.53; typical RD 0.03, 95% CI -0.02 to 0.08). Slow feeds advancement delayed the establishment of full enteral nutrition by one to five days and increased the risk of invasive infection (typical RR 1.46, 95% CI 1.03 to 2.06; typical RD 0.07, 95% CI 0.01 to 0.13; number needed to treat for an additional harmful outcome 14, 95% CI 8 to 100). AUTHORS' CONCLUSIONS: The available trial data suggest that advancing enteral feed volumes at daily increments of 30 to 40 mL/kg (compared to 15 to 24 mL/kg) does not increase the risk of NEC or death in VLBW infants. Advancing the volume of enteral feeds at slow rates results in several days of delay in establishing full enteral feeds and increases the risk of invasive infection. The applicability of these findings to extremely preterm, extremely low birth weight, or growth-restricted infants is limited. Further randomised controlled trials in these populations may be warranted to resolve this uncertainty.

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: The introduction of enteral feeds for very preterm (less than 32 weeks' gestation) or very low birth weight (VLBW; less than 1500 g) infants is often delayed for several days or longer after birth due to concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. OBJECTIVES: To determine the effect of delayed introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 8), MEDLINE (1966 to September 2014), EMBASE (1980 to September 2014), CINAHL (1982 to September 2014), conference proceedings and previous reviews. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days after birth) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment effects in the individual trials and reported the risk ratio (RR) and risk difference for dichotomous data and mean difference for continuous data, with respective 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses. MAIN RESULTS: We identified nine randomised controlled trials in which 1106 infants participated. Few participants were extremely preterm (less 28 weeks' gestation) or extremely low birth weight (less than 1000 g). The trials defined delayed introduction of progressive enteral feeds as later than four to seven days after birth and early introduction as four days or less after birth. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical RR 0.93, 95% CI 0.64 to 1.34; 8 trials; 1092 infants) or all-cause mortality (typical RR 1.18, 95% CI 0.75 to 1.88; 7 trials; 967 infants). Four of the trials restricted participation to growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Planned subgroup analyses of these trials found no statistically significant effects on the risk of NEC or all-cause mortality. Infants who had delayed introduction of enteral feeds took longer to establish full enteral feeding (reported median differences two to four days). AUTHORS' CONCLUSIONS: The evidence available from randomised controlled trials suggested that delaying the introduction of progressive enteral feeds beyond four days after birth did not reduce the risk of developing NEC in very preterm or VLBW infants, including growth-restricted infants. Delaying the introduction of progressive enteral feeds resulted in a few days' delay in establishing full enteral feeds but the clinical importance of this effect was unclear. The applicability of these findings to extremely preterm or extremely low birth weight was uncertain. Further randomised controlled trials in this population may be warranted.

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of necrotising enterocolitis. However, slow feed advancement may delay establishment of full enteral feeding and be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine the effect of slow rates of enteral feed advancement on the incidence of necrotising enterocolitis, mortality, and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group Specialised Register. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 8), MEDLINE, EMBASE, and CINAHL (to September 2014), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of slow (up to 24 ml/kg per day) versus faster rates of advancement of enteral feed volumes upon the incidence of necrotising enterocolitis in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment effects in the individual trials and reported the risk ratio and risk difference for dichotomous data and mean difference for continuous data, with respective 95% confidence intervals. We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses. MAIN RESULTS: We identified six randomised controlled trials in which a total of 618 infants participated. Most participants were stable preterm infants of birth weight between 1000 g and 1500 g. Few participants were extremely preterm, extremely low birth weight, or growth-restricted. The trials typically defined slow advancement as daily increments of 15 ml/kg to 20 ml/kg and faster advancement as 30 ml/kg to 35 ml/kg. Meta-analyses did not detect statistically significant effects on the risk of necrotising enterocolitis (typical risk ratio (RR) 0.96, 95% confidence interval (CI) 0.55 to 1.70) or all-cause mortality (typical RR 1.57, 95% CI 0.92 to 2.70). Infants who had slow advancement took significantly longer to regain birth weight (reported median differences 2 to 6 days) and to establish full enteral feeding (1 to 5 days). AUTHORS' CONCLUSIONS: The available trial data suggest that advancing enteral feed volumes at daily increments of 30 ml/kg to 35 ml/kg does not increase the risk of necrotising enterocolitis in very preterm or VLBW infants. Advancing the volume of enteral feeds at slow rates resulted in several days delay in regaining birth weight and establishing full enteral feeds. The applicability of these findings to extremely preterm, extremely low birth weight, or growth-restricted infants is limited. Further randomised controlled trials in these populations may be warranted to resolve this uncertainty.

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: The introduction of enteral feeds for very preterm (< 32 weeks) or very low birth weight (< 1500 g) infants is often delayed for several days or longer after birth due to concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. OBJECTIVES: To determine the effect of delayed introduction of progressive enteral feeds on the incidence of necrotising enterocolitis, mortality and other morbidities in very preterm or very low birth weight infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 3), MEDLINE (1966 to April 2013), EMBASE (1980 to April 2013), CINAHL (1982 to April 2013), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days after birth) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or very low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: We identified seven randomised controlled trials in which a total of 964 infants participated. Few participants were extremely preterm (< 28 weeks) or extremely low birth weight (< 1000 g). The trials defined delayed introduction as later than five to seven days after birth and early introduction as less than four days after birth. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical risk ratio (RR) 0.92 (95% confidence interval (CI) 0.64 to 1.34) or all-cause mortality (typical RR 1.26 (95% CI 0.78 to 2.01)). Three of the trials restricted participation to growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Planned subgroup analyses of these trials did not find any statistically significant effects on the risk of NEC or all-cause mortality. Infants who had delayed introduction of enteral feeds took longer to establish full enteral feeding (reported median difference two to four days). AUTHORS' CONCLUSIONS: The evidence available from randomised controlled trials suggests that delaying the introduction of progressive enteral feeds beyond four days after birth does not affect the risk of developing NEC in very preterm or very low birth weight infants, including growth-restricted infants. Delaying the introduction of progressive enteral feeds results in a few days delay in establishing full enteral feeds but the clinical importance of this effect is unclear. The applicability of these findings to extremely preterm or extremely low birth weight is uncertain. Further randomised controlled trials in this population may be warranted.

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants.

BACKGROUND: The introduction of enteral feeds for very preterm (< 32 weeks) or very low birth weight (< 1500 grams) infants is often delayed due to concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis. However, prolonged enteral fasting may diminish the functional adaptation of the immature gastrointestinal tract and extend the need for parenteral nutrition with its attendant infectious and metabolic risks. Trophic feeding, giving infants very small volumes of milk to promote intestinal maturation, may enhance feeding tolerance and decrease the time taken to reach full enteral feeding independently of parenteral nutrition. OBJECTIVES: To determine the effect of early trophic feeding versus enteral fasting on feed tolerance, growth and development, and the incidence of neonatal morbidity (including necrotising enterocolitis and invasive infection) and mortality in very preterm or VLBW infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12), MEDLINE, EMBASE and CINAHL (1980 until December 2012), conference proceedings and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effects of early trophic feeding (milk volumes up to 24 ml/kg/day introduced before 96 hours postnatal age and continued until at least one week after birth) versus a comparable period of enteral fasting in very preterm or very low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two authors and synthesis of data using risk ratio, risk difference and mean difference. MAIN RESULTS: Nine trials in which a total of 754 very preterm or very low birth weight infants participated were eligible for inclusion. Few participants were extremely preterm (< 28 weeks) or extremely low birth weight (< 1000 grams) or growth restricted. These trials did not provide any evidence that early trophic feeding affected feed tolerance or growth rates. Meta-analysis did not detect a statistically significant effect on the incidence of necrotising enterocolitis: typical risk ratio 1.07 (95% confidence interval 0.67 to 1.70); risk difference 0.01 (-0.03 to 0.05). AUTHORS' CONCLUSIONS: The available trial data do not provide evidence of important beneficial or harmful effects of early trophic feeding for very preterm or very low birth weight infants. The applicability of these findings to extremely preterm, extremely low birth weight or growth restricted infants is limited. Further randomised controlled trials would be needed to determine how trophic feeding compared with enteral fasting affects important outcomes in this population.

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens that include slowly advancing enteral feed volumes reduce the risk of necrotising enterocolitis. However, slow feed advancement may delay establishment of full enteral feeding and be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine the effect of slow rates of enteral feed advancement on the incidence of necrotising enterocolitis, mortality and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12), MEDLINE, EMBASE and CINAHL (to December 2012), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of slow (up to 24 ml/kg/day) versus faster rates of advancement of enteral feed volumes upon the incidence of necrotising enterocolitis in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed using the standard methods of the Cochrane Neonatal Review Group. MAIN RESULTS: We identified five randomised controlled trials in which a total of 588 infants participated. Few participants were extremely preterm, extremely low birth weight or growth restricted. The trials defined slow advancement as daily increments of 15 to 20 ml/kg and faster advancement as 30 to 35 ml/kg. Meta-analyses did not detect statistically significant effects on the risk of necrotising enterocolitis (typical risk ratio (RR) 0.97, 95% confidence interval (CI) 0.54 to 1.74) or all-cause mortality (RR 1.41, 95% CI 0.81 to 2.74). Infants who had slow advancement took significantly longer to regain birth weight (reported median differences two to six days) and to establish full enteral feeding (two to five days). AUTHORS' CONCLUSIONS: The available trial data suggest that advancing enteral feed volumes at slow rather than faster rates does not reduce the risk of necrotising enterocolitis in very preterm or VLBW infants. Advancing the volume of enteral feeds at slow rates results in several days delay in regaining birth weight and establishing full enteral feeds but the long term clinical importance of these effects is unclear. The applicability of these findings to extremely preterm, extremely low birth weight or growth restricted infants is limited. Further randomised controlled trials in these populations may be warranted to resolve this uncertainty.

Association of plasminogen activator inhibitor-type 1 (-675 4G/5G) polymorphism with pre-eclampsia: systematic review.

BACKGROUND AND AIMS: Excessive generation of plasminogen activator inhibitor-type 1 (PAI-1) is implicated in the pathogenesis of pre-eclampsia and related conditions. The PAI-1 (-675 4G/5G) promoter polymorphism (rs1799889) affects transcriptional activity and is a putative genetic risk factor for pre-eclampsia. The aim of this study was identify, appraise and synthesise the available evidence for the association of the PAI-1 (-675 4G/5G) polymorphism with pre-eclampsia. METHODS: Systematic review and random effects meta-analysis of genetic association studies. RESULTS: We found 12 eligible genetic association studies in which a total of 1511 women with pre-eclampsia, eclampsia or HELLP syndrome and 3492 controls participated. The studies were generally small (median number of cases 102, range 24 to 403) and underpowered to detect plausible association sizes. Meta-analysis of all of the studies detected statistically significant gene-disease associations in the recessive [pooled odds ratio 1.28 (95% confidence interval 1.09, 1.50); population attributable risk 7.7%] and dominant [pooled odds ratio 1.21 (95% confidence interval 1.01, 1.44); population attributable risk 13.7%] models. We did not find evidence of statistical heterogeneity, funnel plot asymmetry or small study bias. CONCLUSIONS: These data suggest that the fibrinolytic pathway regulated by the PAI-1 gene may contribute to the pathogenesis of pre-eclampsia and related conditions. This association, if confirmed in larger genetic association studies, may inform research efforts to develop novel interventions or help to prioritise therapeutic targets that merit evaluation in randomised clinical trials.

Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge.

BACKGROUND: Preterm infants are often growth-restricted at hospital discharge. Feeding infants after hospital discharge with nutrient-enriched formula rather than standard term formula might facilitate "catch-up" growth and improve development. OBJECTIVES: To determine the effect of feeding nutrient-enriched formula compared with standard term formula on growth and development for preterm infants following hospital discharge. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2011, Issue 4), MEDLINE, EMBASE, and CINAHL (to September 2011), conference proceedings and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared the effect of feeding preterm infants following hospital discharge with nutrient-enriched formula (post-discharge formula or preterm formula) compared with standard term formula. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: We found 15 eligible trials in which a total of 1128 preterm infants participated. The trials were of variable methodological quality with lack of allocation concealment and incomplete follow-up in some trials being the major potential sources of bias. The trials (N = 10) that compared feeding infants with "post-discharge formula" (energy density about 74 kcal/100 ml) versus standard term formula (about 67 kcal/100 ml) did not find consistent evidence of effects on growth parameters up to 12 to 18 months corrected age. The trials (N = 5) that compared feeding with "preterm formula" (about 80 kcal/100 ml) versus term formula found some evidence of higher rates of growth through infancy: weighted mean differences at 12 to 18 months corrected age about 500 g in weight, 5 to10 mm in length, and 5 mm in head circumference. Few trials assessed neurodevelopmental outcomes and these did not detect any statistically significant differences in developmental indices at 18 months corrected age. There are not yet any data on growth or development through later childhood. AUTHORS' CONCLUSIONS: Current recommendations to prescribe "post-discharge formula" for preterm infants following hospital discharge are not supported by the available evidence. Some limited evidence exists that feeding preterm infants following hospital discharge with "preterm formula" (which is generally only available for in-hospital use) may increase growth rates up to 18 months corrected age.

Pathogenesis and prevention of necrotizing enterocolitis.

PURPOSE OF REVIEW: Necrotizing enterocolitis (NEC) remains the most common serious acquired gastrointestinal disorder affecting preterm infants. Here we review recent advances in our understanding of the pathogenesis of this multifactorial condition and consider the implications for practice and research. RECENT FINDINGS: NEC is an important cause of mortality and serious morbidity in preterm infants. The risk is inversely proportional to gestational age and weight at birth. Fetal growth restriction and compromise may be additional specific risk factors. NEC, particularly severe NEC requiring surgical intervention and NEC with invasive infection, is associated with acute morbidity and mortality and adverse neurodevelopmental outcomes. The principal modifiable postnatal risk factors for NEC in preterm infants relate to enteral feeding practices including formula milk feeding, early and rapid advancement of enteral feed volumes, and exposure to H2-receptor antagonists. SUMMARY: Our understanding of the pathogenesis of this condition remains incomplete. With the exception of feeding with human milk, only limited evidence is currently available to support interventions to prevent NEC. Promising strategies that merit further evaluation in randomized controlled trials include the use of prebiotics and probiotics and the avoidance of exposure to H2-receptor antagonists.

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: The major modifiable risk factors for necrotising enterocolitis (NEC) in very low birth weight (VLBW) infants relate to enteral feeding practices. Observational studies suggest that conservative feeding regimens that include slowly advancing enteral feed volumes reduce the risk of NEC. However, slow feed advancement may delay establishment of full enteral feeding and so be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine the effect of slow rates of enteral feed advancement on the incidence of NEC, mortality and other morbidities in VLBW infants. SEARCH STRATEGY: We used the standard search strategy of the Cochrane Neonatal Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 4), MEDLINE (1966 to December 2010), EMBASE (1980 to December 2010), CINAHL (1982 to December 2010), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of slow (up to 24 ml/kg/day) versus faster rates of advancement of enteral feed volumes upon the incidence of NEC in VLBW infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis was performed in accordance with the standard methods of the Cochrane Neonatal Review Group. MAIN RESULTS: We identified four randomised controlled trials in which a total of 496 infants participated. Few participants were extremely low birth weight or growth restricted. The trials defined slow advancement as daily increments of 15 to 20 ml/kg and faster advancement as 30 to 35 ml/kg. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical relative risk 0.91, 95% confidence interval 0.47 to 1.75) or all cause mortality (typical relative risk 1.43, 95% confidence interval 0.78 to 2.61). Infants who had slow rates of feed volume advancement took significantly longer to regain birth weight [reported median difference 2 to 6 days] and to establish full enteral feeding [reported median difference 2 to 5 days]. AUTHORS' CONCLUSIONS: Current data do not provide evidence that slow advancement of enteral feed volumes reduces the risk of NEC in VLBW infants. Increasing the volume of enteral feeds at slow rather than faster rates results in several days delay in regaining birth weight and establishing full enteral feeds but the long term clinical importance of these effects is unclear. Further randomised controlled trials are needed to determine how the rate of daily increment in enteral feed volumes affects clinical outcomes in VLBW infants.

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.

BACKGROUND: The introduction of progressive enteral feeds for very low birth weight (VLBW) infants is often delayed for several days or longer after birth due to concern that earlier introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. OBJECTIVES: To determine the effect of delayed introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in VLBW infants. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 4), MEDLINE (1966 to December 2010), EMBASE (1980 to December 2010), CINAHL (1982 to December 2010), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days' postnatal age) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in VLBW infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed in accordance with the standard methods of the Cochrane Neonatal Review Group. MAIN RESULTS: We identified five randomised controlled trials (RCT) in which a total of 600 infants participated. The trials defined delayed introduction as later than five to seven days after birth and early introduction as less than four days after birth. Two of the trials, in which a total of 488 infants participated, only recruited growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Meta-analyses did not detect statistically significant effects on the risk of NEC [typical relative risk 0.89, 95% confidence interval (CI) 0.58 to 1.37] or all cause mortality (typical relative risk 0.93, 95% CI 0.53 to 1.64). Infants who had delayed introduction of enteral feeds took significantly longer to establish full enteral feeding (reported median difference three days). AUTHORS' CONCLUSIONS: Current trial data do not provide evidence that delayed introduction of progressive enteral feeds reduces the risk of NEC in VLBW infants. Delaying the introducing of progressive enteral feeds results in several days delay in establishing full enteral feeds but the clinical importance of this effect is unclear. Further RCTs are needed to give more precise estimates of the effect of delaying the introduction of enteral feeds on clinical outcomes in VLBW infants.