Dr. Gamal Samy Aly

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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

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• Evidence-Based Medicine

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

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• 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.

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• 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.

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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.

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• Step3Critical appraisal of the evidence through
  evaluation of the validity and applicability of
  the evidence or clinical guidelines.
• Step4Applying the Evidence to patients in
  practice ? through decision making
• Step 5Evaluation of the performance.

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Levels of Evidence and Grades of Recommendations
Grade of recommendation Level of evidence Intervention
A 1a Systematic review of randomized controlled trials
A 1b Individual randomized controlled trial
B 2a Systematic review of cohort studies
B 2b Individual cohort study
B 3a Systematic review of case-control studies
B 3b Individual case-control study
C 4 Case series
D 5 Expert opinion
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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

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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 gt 34 weeks.
• 2 days at term
• No clear association with gender, race, or
  socioeconomic status.

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Associated Contributing Factors

• Umbilical catheters
• Cyanotic heart disease
• Patent Ductus Arteriosus
• Indomethacin
• Asphyxia/Hypotension
• Antenatal cocaine exposure

• Polycythemia
• Hyperosmolarity
• Rate of feeding advance
• Formula feeding

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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

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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?

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Clinical Presentation

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

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Clinical Presentation

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

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• EBM in NEC
• (Questions and Answers)

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• 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.

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• 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.

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• Question
• Could abdominal ultrasonography affect the
  diagnosis of NEC?
• Conclusion Comment
• Abdominal_ultrasonography USG helps the
  diagnosis mainly through detection of

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• - 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.

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

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• 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.

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• 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).

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• 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.

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• 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.

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• 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).

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In the category of management

• Question
• Could breast milk protect against NEC more
  than artificial milk?

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• 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.

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

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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

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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

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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

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• 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 .

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• 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.

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

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• 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.

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• Question
• Could oral immunoglobulin protects against
  NEC?

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• 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.

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• Question
• Could oral argenine protect against NEC?

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Arginine supplementation prevents NEC in the
premature infant

• Randomized, double-blind,placebo-controlled
  (birth weight lt1250, 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
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• 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.

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

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• 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 .

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• Question
• Could platelet activating factor
  inhibitors protect against NEC?

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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?

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• 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.

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• Question
• Could oral epidermal growth factor protect
  against NEC?

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• 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.

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• 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 its
  association with NEC.

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• 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.

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What are Oral Probiotics?

• Beneficial bacteria that are introduced into
  the gut of premature infants prophylactically in
  an attempt to promote development of normal gut
  flora.

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• Question Could the use of Probiotics decrease
  the incidence of NEC?

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What are Oral Probiotics

• At birth the intestinal tract is sterile, but in
  normal situations, it quickly becomes colonized
  with favorable organisms, most often
  Lactobacillus and Bifidobacteria.
• In premature infants the intestine tends to get
  colonized with coliforms, enterococcus and
  bacteroides.

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Probiotics for preventing NEC

• Systematic review of 1393 VLBW infants treated
  with a variety of organisms
• Reduced risk of
• NEC (RR 036, 95 CI 020065)
• Death (RR 047, 030073)
• Achieved full feeds faster
• No difference in rates of sepsis
• Deschpande et al, Lancet 2007

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NEC Still a Major Challenge in Neonatology!!

• Up to 20-40 mortality.
• Morbidity includes
• Intestinal obstruction / stricture formation
• Malabsorption
• Short gut syndrome
• TPN dependence / cholestasis
• Poor neuro developmental outcome

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Thank You Dr.Gamal Samy