The prevention and management of necrotizing enterocolitis

Current Paediatrics (2003) 13, 184 --189

c 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0957-5839(03)00025 -3

The prevention and management of necrotizing enterocolitis Robert C. Coombs Consultant Neonatologist, Jessop Wing, Tree Root Walk, Sheff|eld S10 2SF, UK

KEYWORDS necrotizing enterocolitis; epidermal growth factor; erythropoietin; arginine; Doppler ultrasound; platelet activating factor

Summary Necrotizing enterocolitis remains a devastating illness and there is some evidence that mortality fromit isincreasing. Although there has been little change in the management of established necrotizing enterocolitis, studies based on known risk factors are leading to possible preventive strategies. Several of these are based on the knowledge that breast milk is partially protective. Nutritional approaches may involve arginine, erythropoietin and epidermal growth factor supplementation.Other strategies may include manipulating the bacterial milieu of the bowel and influencing the inflammatory cascade.

c 2003 Elsevier Science Ltd. All rights reserved.

PRACTICE POINTS *

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Necrotizing enterocolitis remains a major cause of neonatal morbidity and mortality, with around100 deaths per year in England and Wales The resultant increased length of hospital stay is signif|cant and expensive There is now an increased understanding of why breast milk may be protective Potential benef|ts can be gained from epidermal growth factor, erythropoietin and arginine supplementation There is new evidence on bacterial colonization of the gut Debate over the optimal surgical management for the condition is, however, ongoing

INTRODUCTION Although necrotizing enterocolitis (NEC) remains a devastating condition, there do appear to be new approaches that may well impact on its prevalence, severity and management. Many of these advances seem to have occurred in response to the question, ‘why is breast milk protective’? Correspondence to: RCC.Tel.: +44 (0)144 226 8387; E-mail: r.c.coombs@sheff|eld.ac.uk

PREVALENCE AND COST Data on prevalence are diff|cult to obtain, primarily because of a variation in the classif|cation of ‘mild’ cases (stage 1 of the Bell classif|cation). Between October 1993 and October 1994, the British Paediatric Surveillance Unit (for England, Wales, Scotland and Ireland) survey of NEC found 185 cases of def|nite NEC grade 2 (intramural/portal gas or diagnosis conf|rmed at laparotomy or post mortem), with 115 suspected to be grade 1, thus giving an incidence of conf|rmed NEC as 0.23 cases per 1000 live births. Interestingly, of the 300 cases, 35% had a birthweight of more than 1500, and 46% were over 29 weeks gestation -- a relatively mature population. The mortality in this survey was 65 (22%). Forty-nine percent of conf|rmed cases received surgical management (British Paediatric Surveillance Unit 11th Annual Report 1996 --1997). A further breakdown of the data would have been useful in trying to assess whether the pattern of infants affected by NEC is changing. In the UK EPICure Study of 4004 births at 20 --25 weeks gestation over a 10 -month period in 1995, 811 were admitted for intensive care; 497 died before discharge, of whom17 had a primary cause of death as NEC. This probably accounts for about 25% of all infants dying with NEC. The data in Table 1, obtained from the Off|ce of National Statistics, show the number of NEC ICD code 777.5 deaths in England and Wales for the years 1996 --2000. In the USA, mortality rate between 1990 and 1992 was 12.3 per 100 000 live births, similar to that of the UK. Interestingly, it may be that

NECROTIZING ENTEROCOLITIS

185

Table 1 Deaths from necrotizing enterocolitis (NEC) 1996 --2000,England and Wales Births (England and Wales) Year

Number

1996

649 485

1997

643 095

1998

635 901

1999

621872

2000

604 441

Neonatal deaths NEC (ICD9) 777.5 ‘main’or‘other’condition Male Main Other Main Other Main Other Main Other Main Other

28 11 30 14 33 26 33 21 31 19

Neonatal total

Postneonatal deaths NEC (ICD9) 777.5 ‘underlying condition’

Infant total

Rate per 100 000 live births

Female 14 11 23 8 22 12 22 20 29 13

64

6

70

10.8

75

2

77

11.9

93

9

101

15.9

96

11

107

17.2

92

8

100

16.5

ICD9,International Classif|cation of Diseases,9th edn.Data from the Off|ce of National Statistics.

the rates in both the USA and the UK are increasing as more immature infants survive. We usually think of NEC as a disease of the preterm or growth-retarded infant, with an increasing incidence with increasing prematurity. In most series, however, about 10% of cases are term infants. Bolisetty and Lui, in a large Australian study,1 reviewed all term infants presenting over a 6.5-year period. Of these,19 (66%) had an underlying congenital disease: 10 cardiac, 5 endocrine and 4 other conditions. Although the association with cardiac disease is not surprising, we should be vigilant towards NEC in the term infant without a known risk who has a normal cardiac status. Bernstein et al.,2 in a large series of 19 759 infants weighing less than 1500 g (the Vermont Oxford Network), conf|rmed the association between intrauterine growth retardation (growth below the 10th centile) and NEC, with an odds ratio of 1.27. In this study and the current Cochrane Review, antenatal steroids were not protective, an effect that had been seen in the early Cochrane Reviews. There are also new data on the cost of NEC. Bisquera et al.,3 reviewed all 866 infants weighing less than 1500 g who were admitted to two hospitals in Texas, USA. Eighty-six developed stage 2 or 3 NEC, of whom 43% underwent surgery. The cases were matched with two controls, infants with NEC having a 70% chance of survival. Infants with medical NEC will stay in hospital for an additional 22 days (at a cost of $73 700), whereas if they develop surgical NEC and survive, they will stay an additional 2 months (with a cost of $186 200). Including the cost incurred by the non-survivors, the extra cost of NEC was calculated to be about $6.5 million, or $216 000 per survivor.

ERYTHROPOIETIN Breast milk contains a large quantity of erythropoietin, in an amount not dissimilar to that used to treat anaemia of prematurity. Erythropoietin receptors are present on the preterm enterocyte, and rat enterocytes exposed to erythropoietin migrate more quickly, this being a marker of improved mucosal integrity. Erythropoietin also appears to be resistant to digestion and, when added to formula feeds, can be used to stimulate erythropoesis.4 In a retrospective non-randomized study of 483 infants of birthweight 500 --1250 g either given or not given erythropoietin at the discretion of the consultant, the incidence of NEC in the group receiving erythropoietin to stimulate the marrow was 12 out of 260, compared with 24 out of 223 in those who did not receive it. The erythropoietin group seemed not surprisingly to be a more ‘sick’ group with more respiratory distress syndrome, ventilator use, surfactant treatment and patent ductus arteriosus.5

ARGININE Endothelial nitric oxide, a potent local vasodilator, may be important in maintaining mucosal integrity. The inhibition of nitric oxide synthetase (NOS) has been shown to potentiate the severity of NEC-like lesions in experimental models; conversely, enhanced NOS activity may be protective. Arginine is the amino acid with the richest source of nitrogen and is a precursor for the formation of glutamine and glutamate, nitric oxide being synthesized from arginine by NOS. Several studies have shown that infants developing NEC

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have lower serum levels of arginine than infants who do not.6 Amin et al. have studied the effect of arginine supplementation.7 In a randomized study, infants of 32 weeks gestation or less were supplemented for the f|rst 4 weeks of life with 1.5 mmol per kg (261mg/kg) arginine per day, either in their parenteral nutrition regimen or, when their daily oral intake reached 40% of their total intake, into their milk. Five out of 75 infants (6.7%) in the arginine-supplemented group developed NEC (all Bell stage 2), compared with 21 out of 77 (27.35%) in the control group (13 being Bell stage 2). The median age at which they developed NEC was also later in the supplemented group, at 20 versus 10 days. Even in the supplemented group, the levels of arginine at the time of diagnosis of NEC were lower than those seen in the non-affected infants. The authors suggested that this might reflect an increased metabolic demand for arginine in an effort to maintain gastrointestinal blood flow.

EPIDERMAL GROWTH FACTOR Epidermal growth factor (EGF), a heat-stable 53 amino acid peptide, is present in large amounts in amniotic fluid and breast milk. It has a marked trophic effect on the gastrointestinal tract, with enhanced proliferation and differentiation of the epithelial cells. Sullivan et al. demonstrated in an 8 -month-old infant with nectrotising enteritis that intravenous EGF improved the crypt cell proliferative activity and recovery of the surface epithelium.8 Its action appears to occur through binding to a specif|c receptor, EGF-R. In knockout mice, the inactivation of EGF-R results in a haemorrhagic enterocolitis similar to NEC.EGF is also produced in the salivary glands, and Helmrath et al.9 have recently shown that the salivary EGF levels are signif|cantly lower in infants with NEC than in age-matched controls. In a neonatal rat model of NEC in which the ischaemic insult is derived from asphyxia and cold stress, Dvorak et al.10 supplemented an artif|cial rat milk substitute with EGF. Although the control pups fed ad libitum from their mother, grew normally and did not develop NEC, those fed the milk substitute did not grow. The addition of 500 ng/ml EGF to the rat milk substitute reduced the severity score for NEC by 50%.

BACTERIAL COLONIZATION PREBIOTICS AND PROBIOTICS NEC is not seen in utero and is unusual in the infant who has not been enterally fed, suggesting that both bacterial colonization of the gut and luminal contents are important. Lucas, and recently Schanler et al.,11 have reported the protective effect of breast milk.

CURRENT PAEDIATRICS

Two recent studies have looked at upper gastrointestinal colonization in preterm infants. In a unit in which they gastrically gravity-fed their infants 4 -hourly, Mehall12 looked at the colonization rate of their nasogastric tubes, which were used for a week at a time. Following removal of the tube, its distal (intraoesophageal) end was discarded and the outside of the tube that had not been in the infant was cleaned with isopropyl alcohol. The tubes were then cut into 2 cm lengths and repeatedly washed to suspend any bacteria that might have been resident within the lumen of the tube.One hundred and twenty-f|ve tubes from 50 infants (mean gestational age 28.5 weeks, mean birthweight 1387 g) were studied. Colonization was def|ned as a score of over 1000 colony-forming units of bacteria, excluding Staphylococcus epidermidis and Streptococci. Of the 125 tubes, 71 were colonized with a mean of three different colony types per tube. Infants receiving histamine H2 -antagonists were more likely to be colonized: 41 out of 48 tubes compared with 32 out of 66. Nineteen infants were fed breast milk; 39 out of 49 of their weekly tubes were colonized and no infant was intolerant of feeding, whereas 32 of the 76 tubes from formula-fed infants were colonized and, for 24 of those weeks, the infants showed evidence of feed intolerance. Ten infants (three of those fed breast milk and seven fed formula) had tubes colonized with Gram-negative rods. None of the three breast-fed infants developed NEC, whereas all seven formula-fed infants did. Four babies underwent laparotomy, the same organism being isolated from the peritoneal cavity and nasogastric tube.The infants with colonized tubes also gained weight at a slower rate: 94.2 g/week compared with 178.9 g/ week. In Leeds, Hoy et al.13 looked at duodenal colonization on 422 occasions in 122 infants of median gestation 28 weeks and birthweight1100 g. At the time of nasogastric placement, the tube was passed into the duodenum and its position conf|rmed by the withdrawal of non-acid bile. A volume of 0.1ml duodenal juice was then taken for culture prior to withdrawal of the new tube into the stomach. Overall, 25% of intubations were sterile, the number decreasing with postnatal age from 68.8% at less than 3 days to 20% after 1 week. One-third (158/422) contained Gram-positive organisms, one-third (150/422) had Gram-negative organisms, often mixed with Gram-positive organisms, and six out of 422 samples grew only yeasts. Of great interest was that, by using molecular typing, the authors were able to demonstrate considerable crosscolonization between infants on the unit, with marked temporal clustering; an organism would appear in the unit, colonize many infants and then be replaced by another. In this study, 20 infants had 23 episodes of NEC, for which there were preceding duodenal samples

NECROTIZING ENTEROCOLITIS

for 13. Seven grew Enterobacteriaceae: in two, the strains were indistinguishable, and in four the same enteribacteriaceae were found in other infants who did not develop NEC. Only four infants were fed exclusively on their mother’s milk, and there was no relationship between the amount of mother’s milk and colonization. Antibiotic usage was similar between those who were colonized with Gram-negative bacilli and those who were not. These two studies highlight the fact that the upper gastrointestinal tract is not sterile; indeed, in this population it is highly colonized, usually with one organism predominating. Gewolb et al. have demonstrated a paucity of bacterial species in the stools of infants weighing less than 1000 g, antibiotics and formula feeds being associated with lower counts.14 This is a very different picture from that seen in the term infant, in whom a rich mixture of organisms is found. Several groups have attempted to change the colonization pattern of the preterm gut by the use of probiotics. Kitajima et al. randomized infants to feeds supplemented with 0.5 109 live Bif|dobacterium breve daily for 28 days.15 These infants had decreased aspirated gas and an improved weight gain. Of the group, 73% were colonized (stool culture) by 2 weeks, although, interestingly, 12% of the controls were also colonized, demonstrating the ease with which organisms can pass between infants. There were no adverse effects. In Colombia, Hoyos16 supplemented all 1237 admissions to her neonatal unit with a daily dose of 250 106 live Lactobacillus acidophilus and 250 106 Bif|dobacterium infantis until discharge. In comparison to the previous year’s admissions of 1282 who did not receive the supplementation, the numbers of babies with NEC fell from 85 to 34. There were 14 fatalities from NEC, compared with 35 the previous year. No complications attributable to this supplementation were noted. Another way to influence gut colonization may be through prebiotics. One of the reasons breastmilk-fed infants have a more diverse flora, with Bif|dobacteria predominating, may be the presence of neutral oligosaccharides. These appear to resist absorption in the small bowel and facilitate the growth of Bif|dobacterium; i.e. they act as prebiotics. In a population of neonates initially fed on breast milk, Boehm et al.17 randomized infants changing to formula to either a conventional formula or one containing a 10 g/l mixture of galacto- and fructo-oligosaccharides. The supplemented infants, although already colonized with Bif|dobacteria, signif|cantly increased their stool colony count. The stools were softer and more frequent in the supplemented group. There was no difference in weight gain nor were there any unwarranted effects.

187

SPLANCHNIC BLOOD FLOW VELOCITIES Interest in splanchnic Doppler flow was partly triggered by the observations of the association between absent or reversed end-diastolic flow in the umbilical artery and the development of NEC. Although Doppler ultrasound has proved to be a useful tool for measuring blood flow velocity in the superior mesenteric artery and celiac axis, it has not proved to be an easy tool for the longterm monitoring of splanchnic perfusion. Robel-Tillig et al.18 provide further data on the outcome of fetuses with abnormal velocity ratios (pulsatility index).They studied124 infants with a birthweight of below 1500 g for whom they had antenatal Doppler ultrasound data, dividing them into two groups: those with normal and those with abnormal Doppler scans. Postnatally, all 42 infants with abnormal antenatal pulsatility indices were growth retarded, to a mean 4th percentile. Thirty-eight (88%) developed abdominal symptoms, compared with 20% of the control group with normal antenatal Doppler readings. No infants developed NEC, although f|ve required surgical intervention such as a temporary ileostomy (not often seen in the UK). Although the early postnatal Doppler velocities demonstrated lower systolic and diastolic velocities on day 1, the only signif|cant difference by day 5 was a slight increase in pulsatility index in the growth-retarded group. It is interesting to speculate why postnatal Doppler ultrasound has not been more informative. Does the fasting velocity reflect the mucosal response to bacterial colonization or an adverse luminal environment?

ENTERAL ANTIBIOTICS AND IMMUNOGLOBULIN The Cochrane Library has recently reviewed these two areas.19,20 There have been f|ve eligible trials of enteral antibiotics involving 456 infants, four early studies using gentamicin or kananycin, the latest employing vancomycin started on day 2 for 7 days.21 Overall, there was a reduction in the incidence of NEC (RR 0.47, 95% CI 0.28 -0.78) and NEC deaths (RR 0.32, 95% CI 0.10 -- 0.96) but not overall deaths (RR 0.67, 95% CI 0.34--1.32). Siu et al.21 found no evidence of vancomycin resistance, but the stool flora did change in their study, favouring Gram-negative organisms and yeasts. There is however, still concern about possible resistance with the widespread use of oral antibiotics. There have been three eligible trials of enteral immunoglobulin in 2095 infants using predominantly IgG. There was no reduction during the study period in the incidence of NEC (RR 0.84, 95% CI, 0.57--1.25) or in NEC-related deaths (RR1.1, 95% CI, 0.47--2.59). Breast milk contains primarily IgA, however, but only one study

188

CURRENT PAEDIATRICS

used a preparation including IgA, this study showing a possible benef|t. There are no studies of IgA supplementation on its own.

PLATELETACTIVATING FACTOR Many models of NEC propose that there is a f|nal common pathway linking the proposed risk factors with the development of ischaemic necrosis.One of the proposed mediators is platelet activation factor (PAF), one member of a family of phospholipids synthesized by many cell types, including enterocytes. It usually acts at a local level and has a short half-life. Breast milk contains PAF acetylhydrolase, a PAF degrading enzyme. Ewer22 has studied the effect of endogenous PAF in a neonatal pig model of NEC. Following parenteral administration, there was a profound fall in mesenteric blood flow, with a resultant haemorrhagic necrosis. Similar effects are found with induced ischaemia and endotoxaemia, and the response can be modif|ed by the prophylactic administration of the PAF receptor antagonist WEB2170.

SURGICAL MANAGEMENT The criteria for surgery and the choice of procedure for NEC vary greatly between units.Over the past 20 years, the option of percutaneous peritoneal drainage as opposed to primary laparotomy has become more widespread for intestinal perforation, especially in infants weighing less than 1000 g. The long-term benef|t of this approach is not, however, clear. It is undoubtedly a more straightforward procedure than laparotomy, although not without its own risks (Fig.1). Moss et al.23 in a review of published studies of the management of perforated NEC, pointed out that there was a signif|cant variation in survival between units irrespective of surgical method -- percutaneous peritoneal drainage or laparotomy. Units tended to use percutaneous peritoneal drainage for smaller babies, reserving laparotomy for the larger ones: mean birthweight 931g versus 1615 g. Correction for the effect of birthweight revealed no benef|t in terms of survival for either treatment option. A prospective randomized study has now been set up to try and address this issue. The Necrotising EnterocolitisTrial, co-ordinated by the, Department of Paediatric Surgery, Institute of Child Health, London, will randomize infants weighing less than 1000 g with perforated NEC to either primary peritoneal drainage, with the possibility of a delayed laparotomy after 12 h in the face of continued deterioration, or primary laparotomy. Another issue relates to where surgery should be performed. There is an increasing body of data suggesting that transfer of the sick infant with NEC either to

Figure 1 Intestinal perforation secondary to percutaneous peritoneal drainage

another hospital or out of the neonatal unit to theatre may not be in the baby’s best interest, hypothermia and the diff|culty of observation and intervention being the main concerns. Several units have now described their practice of operating on very low birthweight infant with NEC on the neonatal unit, thus avoiding the risks associated with transfer.24

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10. Dvorak B, Halpern M D, Holubec H et al. Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Am J Physiol Gastrointest Liver Physiol 2002; 282: G156--G164. 11. Schanler R J, Shulman R J, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics 1999; 103: 1150--1157. 12. Mehall J R, Kite C A, Saltzman D A, Wallett T, Jackson R J, Smith S D. Prospective study of the incidence and complications of bacterial contamination of enteral feeding in neonates. J Pediatr Surg 2002; 37: 1177--1182. 13. Hoy C M, Wood C M, Hawkey P M, Puntis J W. Duodenal microflora in very-low-birth-weight neonates and relation to necrotizing enterocolitis. J Clin Microbiol 2000; 38: 4539--4547. 14. Gewolb I H, Schwalbe S R, Taciak V L, Harrison T S, Panigrahi P. Stool microflora in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed 1999; 80: F167--F173. 15. Kitajima H, Sunida Y, Tanaka R, Yuki N, Takayama H, Fujimura M. Early administration of Bif|dobacterium breve to preterm infants: randomised control trial. Arch Dis Child 1997; 76: F101--F107. 16. Hoyos A B. Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bif|dobacterium infantis to neonates in an intensive care unit. Int J Infect Dis 1999; 3: 197--202. 17. Boehm G, Lidestri M, Casetta P et al. Supplementation of a bovine milk formula with an oligosaccharide mixture increases counts of

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faecal bifidobacteria in preterm infants. Arch Dis Child Fetal Neonatal Ed 2002; 86: F178--F181. Robel-Tillig E, Vogtmann C, Bennek J. Prenatal hemodynamic disturbances -- pathophysiological background of intestinal motility disturbances in small for gestational age infants. Eur J Pediatr Surg 2002; 12: 175--179. Bury R G, Tudehope D. Enteral antibiotics for preventing necrotizing enterocolitis in low birthweight or preterm infants (Cochrane Review). In: The Cochrane Library, Issue 1, 2001. Oxford: Update Software. Foster J, Cole M. Oral immunoglobulin for preventing necrotizing enterocolitis in preterm and low birth-weight neonates (Cochrane Review). In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software. Siu Y K, Ng P C, Fung S C et al. Double blind, randomised, placebo controlled study of oral vancomycin in prevention of necrotising enterocolitis in preterm, very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 1998; 79: F105--F109. Ewer A K. Role of platelet-activating factor in the pathophysiology of necrotizing enterocolitis. Acta Paediatr 2002; 91(Suppl.): 2--5. Moss R L, Dimmitt R A, Henry M C, Geraghty N, Efron B. A metaanalysis of peritoneal drainage versus laparotomy for perforated necrotizing enterocolitis. J Pediatr Surg 2001; 36: 1210--1213. Anveden-Hertzberg L, Gauderer M W. Surgery is safe in very low birthweight infants with necrotizing enterocolitis. Acta Paediatr 2000; 89: 242--245.