Virtual elimination of necrotising enterocolitis for 5 years – reasons?
Introduction
A standardised feeding regimen was adopted in 1997 for guiding enteral feeding of neonates <32 weeks’ gestation during clinical trials (18 months each) involving erythromycin as a prokinetic and carboxymethylcellulose as a laxative as well as for a period of 2 years without any trials [1], [2], [3]. The feeding regimen prospectively defined readiness for commencing, guidelines for upgrading, and indications for stopping/restarting enteral feeds (3). Most aspects of this regimen (e.g., daily maximum milk increments and total volume) were not significantly different from current practices except for the specific policy of not commencing/ceasing enteral feeds in presence of hemodynamic instability associated with patent ductus arteriosus (PDA) requiring indomethacin, and/or sepsis (3). A total of 298 neonates <32 weeks’ gestation (including 78 <28 week) were enterally fed during the 5 year period. Their demographic characteristics, median (interquartile) age at starting feeds and days to reach full enteral feeds of 150 ml/kg/day were not significantly different between the study and control groups during both the trials and overall remained comparable during the entire period of 5 years (Table 1, Table 2). Except for a single case definite NEC (⩾Stage II) was virtually eliminated from the nursery during these 5 years. This was in contrast to six deaths from NEC per year for 5 years prior to adopting the standardised feeding regimen (4). The time to reach full feeds was also reduced by over 54% (including for neonates <28 weeks gestation) during these 5 years compared with a historical cohort with comparable demographic characteristics (3). The significant results most probably reflect the continued benefits of a standardised feeding regimen (increased awareness leading to early detection and management of signs of “feed intolerance”) [3], [5]. However contribution by our specific policy in relation to PDA and/or sepsis cannot be ruled out given the currently accepted risk factors and pathogenesis of NEC. We review the complex interplay between immaturity, enteral feeds, intestinal bacterial colonisation and a hypoxia-compromised gut mucosa that may occur specifically in preterm neonates with hemodynamic instability due to PDA and/or sepsis. We also emphasise the need for clinical trials in this area in the light of current variations in feeding practices (6), our results over 5 years, and our feeding practices in presence of these high-risk factors.
Section snippets
Discussion
The incidence and mortality related to necrotising enterocolitis (NEC) has not changed despite the recent advances in neonatology. Although prematurity is the singlemost important high-risk factor for NEC, it is generally agreed that an interplay between prematurity, enteral feeds, intestinal bacterial colonisation and a hypoxia-compromised gut mucosa is necessary to reach a threshold before gut mucosal integrity is broken leading to bowel necrosis [7], [8]. The notion that enteral feeds per se
PDA and indomethacin
In the absence of a simple bedside diagnostic test, an assumption of compromised gut integrity may be safe in the presence of a haemodynamically significant PDA which is known to be associated with diastolic steal of gut flow. Treatment with indomethacin is known to transiently decrease the superior mesenteric flow and blunt the physiological postprandial mesenteric hyperaemia in neonates [11], [12]. A haemodynamically significant PDA per se is also known to be associated with systemic
Sepsis
There is increasing evidence that nosocomial infections are caused by translocation of enteric organisms (14). Endotoxemia and sepsis impair mesenteric perfusion and cause organ dysfunction and exacerbations of polymicrobial bacteremia due to intestinal mucosal leakage (15). As early as the first day of life, infected neonates have been shown to have splanchnic hyperaemia indicating the role of systemic inflammatory response (16). The acute phase of systemic sepsis is often characterised by
PAF, PAF-AH and breast milk
Despite the multiple factors that may initiate it, the subsequent pathology of NEC is similar in all cases (8). Inflammatory mediators, particularly platelet-activating factor (PAF) are currently considered to play a vital role in this final common pathway leading to NEC [8], [20]. PAF has potent proinflammatory actions and prolonged effects despite the short half-life due to release of secondary mediators like leukotriene C4, TNF∝, noradrenaline, prostaglandins and oxygen free radicals [21],
Enteral feeding, autoregulation of gut flow/oxygenation and sepsis
Consequences of carbohydrate malabsorption (bacterial proliferation and formation of short chain fatty acids, CO2, and H2), alteration of intestinal bacterial flora and mesenteric flow are the possible mechanisms by which enteral feeding may be involved in the pathogenesis of NEC (7). Physiological postprandial intestinal hyperaemia is essential for meeting the increased oxygen demand by gut after enteral feeding (12). Whether or not the gut can meet the increased demand for oxygen in presence
References (51)
The epidemiology and pathogenesis of necrotising enterocolitis
Semin. Neonatol.
(1997)- et al.
Aggressive nutrition of the very low birth weight infant
Clin. Perinatol.
(2002) - et al.
Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less
J. Paediatr.
(1996) - et al.
Sepsis and indomethacin failure in premature infants with symptomatic patent ductus arteriosus
Lancet
(1987) - et al.
The role of inflammatory mediators in necrotising enterocolitis
Semin. Neonatol.
(1997) - et al.
Sequential release of leukotriens and norepinephrine in rat bowel after platelet activating factor
Gastroenterology
(1988) - et al.
Role of platelet activating factor and tumour necrosis factor alpha in neonatal necrotising enterocolitis
J. Paediatr.
(1990) - et al.
Breast milk and neonatal necrotising enterocolitis
Lancet
(1990) - et al.
Presence of platelet activating factor acetylhydrolase in milk
J. Lipid Res.
(1993) - et al.
Endogenous bacterial toxins are required for the injurious action of platelet activating factor in rats
Gastroenterology
(1995)
Necrotising enterocolitis-perinatal approach to prevention, early diagnosis and management
Semin. Neonatol.
Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial
J. Pediatr.
Modulation of the gastrointestinal tract of infants by human milk. Interfaces and interactions. An evolutionary perspective
J. Nutr.
Can prophylactic oral erythromycin reduce time to full enteral feeds in preterm neonates?
IJCP
Benefits of a standardised feeding regimen during a clinical trial in preterm neonates
IJCP
Comparison of clinical characteristics and high-risk factors in Australian aboriginal and non-aboriginal neonates with necrotising enterocolitis
IJCP
The “inclusion benefit” in clinical trials
J. Pediatr.
Role of platelet-activating factor in the pathophysiology of necrotising enterocolitis
Acta Paediatr. Suppl.
Early aggressive nutrition in preterm infants
Semin. Neonatol.
Effect of indomethacin on superior mesenteric artery blood flow velocity in preterm infants
J. Pediatr.
Doppler assessment of human neonatal gut blood flow velocities: postnatal adaptation and response to feeds
J. Paediatr. Gastroenterol. Nutr.
Effect of patency of the ductus arteriosus on blood pressure in very preterm infants
Arch. Dis. Child
Bacterial translocation and its surgical implications
G. Chir.
Cited by (20)
Necrotizing Enterocolitis
2021, Clinics in PerinatologyCitation Excerpt :In 2017, a meta-analysis of 9 observational studies (N = 4755 infants) found a 67% reduction in the odds of NEC (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.17–0.65) among infants weighing less than 1500 g when standardized feeding protocols were implemented.67 The details of the feeding protocols seem to be less important than reducing variation in clinical management among clinicians.68,75 Based on this evidence, implementation of a standardized feeding protocol, such as American Society for Parenteral and Enteral Nutrition76 or the California Perinatal Quality Collaborative71,77 guidelines, should be strongly considered because these may decrease the incidence of NEC, or decrease days of parenteral nutrition, without adverse effects.
Reducing Incidence of Necrotizing Enterocolitis
2017, Clinics in PerinatologyCitation Excerpt :Delayed cord clamping is a feasible, safe, and no cost intervention at the time of delivery.11 Several investigators have demonstrated a reduction in NEC incidence with implementation of standardized feeding guidelines in their NICUs despite variability in the specifics of the guidelines (Fig. 2).14–18 These guidelines have generally incorporated an early minimal enteral nutrition phase during which 10 mL/kg/d to 20 mL/kg/d of enteral nutrition have been given without increase, followed by daily advancement based on continued tolerance.
Qualitative Description of Neonatal Expert Perspectives About Necrotizing Enterocolitis Risk
2014, Newborn and Infant Nursing ReviewsCitation Excerpt :Risk for NEC was reduced even further when ibuprofen was administered orally compared with indomethacin across six studies (n = 166), with reduced risk of 55% (95% CI 0.23–0.82). Additionally, several feeding guidelines recommend withholding feeds during indomethacin treatment for PDA.21,35 Based on this evidence, a recent clinical practice guideline recommends using ibuprofen instead of indomethacin to medically close a PDA.36
Common complications of dysregulated inflammation in the neonate
2013, Newborn and Infant Nursing ReviewsCitation Excerpt :Broadly effective across the NEC subsets, preferential feeding of human milk according to a systematic, unit-standardized approach that is responsive to periods at high risk for injury (such as during transfusion) has potential to reduce NEC. Neonatal intensive units with the lowest incidence of the disease have high rates of human milk use and generally have a standardized approach to feeding, transfusion and patent ductus arteriosus management.68–72 When mother's milk is unavailable, donor milk is an appropriate species-specific alternative.73,74
Hale’s Medications and Mothers’ Milk<sup>TM</sup>: 2019 A Manual of Lactational Pharmacology
2018, : 2019 A Manual of Lactational Pharmacology