Dr. Gamal Samy Aly Professor of Pediatrics & Neonatology Ain Shams University ,Cairo, Egypt President of the Egyptia

1. Evidence Based Medicine In Necrotizing Enterocolitis Dr. Gamal Samy Aly Professor of Pediatrics & Neonatology Ain Shams University ,Cairo, Egypt President of the Egyptian Society for Neonatal Care

2. Evidence-Based Medicine We are now in the era of Evidence-Based Medicine (Halliday, 1999)

3. Definition: EBM means the proper use of current best evidence in making decisions about the care of individual patients. Evidence-Based Pediatrics is the practice of health care based on the best available evidence that we are doing more good than harm.

4. EBM is the integration of best research evidence with clinical expertise and patients values. Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough . It is a life long self-directed and problem-based learning process.

5. There are an average of 19 new articles appearing in pediatric journals every day, so, it is very difficult for practicing pediatricians to keep up to date (James, 2000). EBM allows data from clinical trials to be synthesized into easily readable systematic reviews.

6. Practicing EBM: Comprises 5 steps • Step 1: Formulating answerable Clinical Question through giving time to generate questions to foster self learning. • Step 2: Searching for the best evidence to answer the question through acquiring and identifying the best information and clinically relevant resources.

7. Step3:Critical appraisal of the evidence through evaluation of the validity and applicability of the evidence or clinical guidelines. • Step4:Applying the Evidence to patients in practice  through decision making • Step 5:Evaluation of the performance.

8. Levels of Evidence and Grades of Recommendations

9. Necrotizing Enterocolitis (NEC) The most common intestinal emergency encountered in the NICU. Incidence is up to 10% of all NICU admissions. Only definitive risk factors are prematurity and enteral alimentation but other features include: Bowel ischemia and/or reperfusion Inflammatory response Infectious agents

10. Necrotizing Enterocolitis Age of onset is inversely related to birth weight and gestational age. Up to 20 days at less than 30 weeks Up to 14 days at 31-33 weeks 5 days at > 34 weeks. 2 days at term No clear association with gender, race, or socioeconomic status.

11. Umbilical catheters Cyanotic heart disease Patent Ductus Arteriosus Indomethacin Asphyxia/Hypotension Antenatal cocaine exposure Polycythemia Hyperosmolarity Rate of feeding advance Formula feeding Associated Contributing Factors

12. Pathophysiology No single theory that satisfactorily explains the etiology. The general accepted sequence is: Initial ischemic or toxic mucosal damage Bacterial proliferation Invasion of damaged mucosa by bacteria Transmural necrosis or gangrene Perforation of bowel wall and peritonitis

13. NEC and IUGR: Why? Pathogenesis of NEC requires enteral feeding gut ischaemia bacterial infection Abnormal gut blood flow recognised in IUGR Ischaemic damage or reperfusion injury?

14. Clinical Presentation A) Insidious Presentation Feeding intolerance, increasing residuals Abdominal distension Emesis, may be bilious Occult blood in stool Lethargy, apnea

15. Clinical Presentation B) Sudden Presentation Grossly bloody stools Glucose instability Abdominal distension Peritonitis Poor perfusion, shock Death

16. EBM in NEC (Questions and Answers)

17. Question: Could stool pattern help in the diagnosis of NEC? • Conclusion & Comment: Presence of blood in the stool (macroscopic or microscopic then changed to macroscopic) increases the possibility of NEC diagnosis.

18. 0ccult (microscopic) blood has no significance correlation with NEC • NEC may be associated with more frequent and seedy stool; this information needs more studies for confirmation.

19. Question: Could abdominal ultrasonography affect the diagnosis of NEC? • Conclusion & Comment: Abdominal_ultrasonography [USG] helps the diagnosis mainly through detection of :

20. - Portal vein gas [PVG] which usually missed by routine plain X. R. while easily detected by USG, its presence is highly indicative of NEC. - Absence of PVG does not exclude NEC. - No single imaging test is sensitive and specific for the diagnosis.

21. Conclusion: Colour doppler US is more accurate than abdominal X ray in early detection of bowel necrosis in NEC.

22. Question:Could computerized tomography (CT) affect the diagnosis of NEC? • Conclusion and Comment: • It can help in detection of bowel necrosis, obstruction, PVG, dilated loops and ascitis. No evidence available for its routine use or any superior effect above plain abdominal X-R or USG.

23. C.T study can help early and safe diagnosis of NEC especially after application of the new technique (by detecting the C.T. attenuation coefficient of urine after oral administration of contrast material).

24. Question: Could culture studies (from blood, stool, duodenal aspirate and peritoneal aspirate) affect the diagnosis of NEC? • Conclusion and Comment: • Culture studies (from blood, stool, duodenal aspirate and peritoneal aspirate) correlates poorly with NEC diagnosis because no specific organism associated with NEC.

25. Question:Could detection of Plasma intestinal fatty acid binding protein (IFABP) be considered as early biochemical marker helping the diagnosis of NEC? • Conclusion and Comment: IFABP levels evaluation considered as useful biochemical marker for intestinal ischemia particularly in the early reversible phase.

26. Question: could measurement of Glutamine (GLN) and Argenine (ARG) amino acids affect the diagnosis of NEC? • Conclusion and Comment: • Infants who have NEC have selective amino acid deficiencies including reduced levels of Glutamine (GLN) and Argenine (ARG).

27. In the category of management: • Question: Could breast milk protect against NEC more than artificial milk?

28. Conclusion and Comment: • There is an excellent evidence that human breast milk decreases the incidence of NEC and its morbidity and mortality. • No evidence of full, complete protection of breast milk against NEC. • The protective effect of breast milk against NEC is more in the preterm babies.

29. Question: • Could feeding pattern (delayed rather than early, slow rather than rapid and no feeding rather than trophic feeding protect against NEC?

30. Cochrane review Early vs Late feeding 72 babies in 2 studies Early feeders had Fewer days parenteral nutrition Fewer investigations for sepsis No difference in NEC Weight gain

31. Cochrane reviewRapid vs Slow increase 369 babies in 3 studies Rapid: 20 to 35 ml/kg/day Slow: 10 to 20 ml/kg/day Rapid group: Reached full enteral feeds and regained birth weight faster No difference in NEC rate or length of stay

32. Cochrane review Minimal Enteral Nutrition 380 babies in 8 studies 12 to 24 ml/kg/day for 5 to 10 days MEN group Faster to full enteral feeds Shorter length of stay No difference in NEC

33. Conclusion and Comment: • Delayed feeding has no evidence to have NEC protective effect. • Slow feeding has no evidence to have NEC protective effect. • Early trophic feeding with breast milk or half strength formula is highly accepted .

34. Conclusion and Comment: • Rapid advancement is more injurious than slow one (its relation to NEC occurrence is still unproved but the available studies can not absolutely exclude this ). • Ideal rate of feeding advancement is still unclear.

35. Question: Could antenatal corticosteroid protect against NEC in preterm 34w gestation or less.

36. Comments and Conclusion: • Excellent evidence for a protective effect of antenatal steroids given to preterms 34w or less against NEC. • A single course of antenatal steroids is a rare example of a treatment that yields both a health benefit and a cost saving. • The protection effect is more with intact membranes but still present also with PROM.

37. Question: Could oral immunoglobulin protects against NEC?

38. Conclusion and comment: • According to the recent Cochrane database multi systematic review and the recent multi centers RCT, the evidence does not support the administration of oral immunoglobulin for the prevention of NEC.

39. Question: Could oral argenine protect against NEC?

40. Arginine supplementation prevents NEC in the premature infant • Randomized, double-blind,placebo-controlled (birth weight <1250, gestation 32 wks) • Arginine supplementation (1.5mmol/kg/day) in premature infants reduces the incidence of all stages of NEC Amin et al J Pediatrics 2002

41. Comments and conclusion: • Oral arginine supplement can be used to decrease incidence of all NEC Stages in high risk infants. • Cost studies should be done before its routine practical use.

42. Question: Could enteral antibiotics (esp. the use of vancomycin and gentamicin) protect against NEC?

43. Comments and conclusion: • Although there are some studies indicate that oral antibiotics can decrease the incidence of NEC. [Especially the use of vancomycin and Gentamycin]. • It is recommended not to use enteral antibiotic prophylactic routinely in the NICUS, only for selected high risk cases for short period .

44. Question: Could platelet activating factor inhibitors protect against NEC?

45. Pro inflammatory mediators are increased in NEC • Platelet-activating factor is elevated before the development of any clinical or radiographic evidence of NEC • Other leukotrienes are also involved: TNF- , IL-6, IL-10, and IL-1

46. Conclusion and comments: • No enouph evidence to support the protective effect of platelet activating factor inhibitors against NEC, although, some studies support and prove its protective effect. • rH PAFI can be used in prevention of NEC for specific high risk infants but its routine prophylactic use need further RCT.

47. Question: Could oral epidermal growth factor protect against NEC?

48. Conclusion and comments: • No evidence available in the human being up till now to prove its protective effect against NEC. • Epidermal growth factor still one of the promising lines of both prevention and treatment of NEC in the future. Its benefits proved in the rate model as its level decreases in NEC babies but its receptors are present unchanged giving more chance for its possible effective use.

49. Question: Could oral indomethacin increase the incidence of NEC? • Conclusion and comment : • The use of indomethacin as antenatal tocolytic agent should be used with caution as the available data up till now do not exclude it’s association with NEC.

50. Question: Could erythropoietin decrease the incidence of NEC? Comments and conclusion: • Recombinant erythropoietin could protect against NEC in VLBW infants. • Erythropoietin receptors present in the neonatal intestinal villous enterocytes.