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Necrotizing Enterocolitis
Ira Adams-Chapman, M.D.
Assistant Professor in PediatricsMedical Director, Developmental Progress Clinic
Emory University School of MedicineDivision of Neonatology
NEC EpidemiologyIncidence
• NEC incidence up to 10% in VLBW overall– Up to 22% in selected centers
• Incidence inversely related to gestational age– Smaller infants also with higher morbidity and
mortality
• Rare in term infants– Usually associated with predisposing/underlying
disorders
• Remains a significant cause of morbidity and mortality in the VLBW population
• Overall mortality rate 15-30% • 20-40% require surgery
– With up to 50% mortality
• 20% of medically managed NEC patients develop strictures
• Concern regarding ND outcome of survivors– poor growth, CP, vision and hearing impairment, low
Bayley scores
NEC EpidemiologyMorbidity and Mortality
Pathophysiology of NECPrematurity
Feeding
Immaturity of intestine
Motility Circulatory Barrier Immune and digestion regulation function defense
NECAbnormal bacterial
colonizationHypoxic-ischemic
Injury?
• Prematurity and low BW most consistently documented risk factors– Risk inversely related to GA and BW
• 90% are premature
• 90% were feeding– Breastmilk reduces risk by 3 to 10-fold
NEC Epidemiology: Risk Factors
How Do We Feed Babies?
• Mature suck swallow develops at approximately 34 weeks gestation
• Suckling stimulates digestive enzymes and may enhance feeding tolerance
• Gavage feeds for the immature infants – no consensus on which regimen is best
• Monitor for tolerance – residuals, serial abdominal exams
Nutritional Goals
• Provide adequate calories for growth:
• 120 kcal/kg/day
• 15-30 gm/kg/day of weight gain
• Head circumference should increase 1 cm/week
• Linear growth is important
Advancing feeding volumes
The Big Questions:• How much?• How fast to increase?• Feeding frequency?• Continuous vs bolus?• Do feeding practices
impact the risk of NEC?
Advancing Feeding Volumes
• No clear consensus on best practice
• Judicious advancement with constant assessment of patient tolerance
• Typically, start with 20 ml/kg/day and then advance daily by 10 ml/kg/day
• Advantages to bolus vs continuous feeds
• Monitor for signs of NEC
Breastfeeding and Prematurity• Breastmilk is best!• Variable nutritional
content of breastmilk• Content changes over
time• Unsupplemented BM
may not meet all nutritional needs of the growing preemie
• Appears to confer some protection from risk of NEC
Minimal Enteral Nutrition
• Trophic feedings/Non-nutritive feedings are strongly advised
• Prevents atrophy of intestinal enzymes
• Associated with improved feeding tolerance
• May help prevent microinvasion of bacteria
• Animal models supports use of trophic feedings
Enteral Nutrition
• Start early!!!
• Benefits of colostrum
• Benefits of breastmilk
• Benefits of trophic feedings in the preterm
Pathophysiology of NECPrematurity
Feeding
Immaturity of intestine
Motility Circulatory Barrier Immune and digestion regulation function defense
NECAbnormal bacterial
colonizationHypoxic-ischemic
Injury?
Immature Intestinal Motility and Digestion
• Incompletely digested molecules can cause intestinal injury
• Delayed transit time can contribute to the problem
• Feeding can mature motility patterns while hypoxia can worsen it
Pathophysiology of NECPrematurity
Feeding
Immaturity of intestine
Motility Circulatory Barrier Immune and digestion regulation function defense
NECAbnormal bacterial
colonizationHypoxic-ischemic
Injury?
Immature Circulatory Regulation
• Hypoxia-ischemia unlikely to be inciting injury
• However, immature intestinal circulatory regulation could predispose to ischemic injury in response to feeding or abnormal bacteria
• Reduced endothelial nitric oxide may play a role
Pathophysiology of NECPrematurity
Feeding
Immaturity of intestine
Motility Circulatory Barrier Immune and digestion regulation function defense
NECAbnormal bacterial
colonizationHypoxic-ischemic
Injury?
Immature Intestinal Barrier Function• Intestinal barrier has structural and biochemical
component
• Structural barrier (tight junctions formed by 10 weeks).– Structural epithelial barrier regulates
absorption/secretion• Amniotic fluid matures these functions from 26 weeks to term
– Goblet cells produce mucins adding to structural barrier• Expression mimics adult pattern between 23 and 27 weeks
• Paneth cells important to biochemical barrier– Secrete antimicrobial peptides (defensins)
• Contribute to antimicrobial, inflammatory, & secretory defenses
• Paneth cells and defensin expression reduced in preterm infants
Immature Intestinal Barrier Function
Immature intestinal barrier function
Immature secretionand absorption
Immature mucinexpression by Goblet cells
Decreased Paneth cellnumber
Immature secretorydiarrhea
Inability to rid intestineof pathogens/toxins?
Increased intestinalpermeability
Enhanced bacterialadherence
Reduced defensinexpression
Reducedantimicrobial
activity?Reduced
proinflammatoryactivity?
Reducedsecretorydiarrhea?
Pathophysiology of NECPrematurity
Feeding
Immaturity of intestine
Motility Circulatory Barrier Immune and digestion regulation function defense
NECAbnormal bacterial
colonizationHypoxic-ischemic
Injury?
Immature Immune Defense• Many inflammatory mediators implicated in the
pathogenesis of NEC
• Inflammation key defense mechanism especially in microbe rich intestine– Inflammatory pathways also activate anti-apoptotic/
cytoprotective mediators
• But can cause harmful collateral damage– Barrier damage can cause opportunistic infection
• Excessive or hypoactive inflammation may play a role
Immature Immune Defense
Immature intestinal innate immunity
ExaggerationInflammation
Poor inflammatoryresponse
Increasedintestinal injury?
Intestinal barrierdamage?
Bacterialovergrowth?
Increasedapoptosis?
Opportunisticinfection?
VS.
Pathophysiology of NECPrematurity
Feeding
Immaturity of intestine
Motility Circulatory Barrier Immune and digestion regulation function defense
NECAbnormal bacterial
colonizationHypoxic-ischemic
Injury?
Abnormal Bacterial Colonization
• Commensal bacteria regulate genes important for barrier function, digestion and angiogenesis
• Commensals also inhibit inflammatory signalling
• NEC does not develop in sterile in utero environment
• Abnormal Clostridium colonization in VLBW has been implicated in NEC
Hooper LV, et al., Science, 2001Collier-Hyams LS, et al., Cell Mol Life Sci, 2005de la Cochietiere MF, Ped Res, 2004
Pathophysiology of NEC
• Etiology is unknown; multifactorial
• Contributing risk factors:– Ischemia– Feedings– Breast milk protective– Bacterial invasion– Immature mucosal immune system
Clinical Presentation
• Feeding intolerance and residuals• Abdominal distension• Visable loops of bowel• Hypoactive bowel sounds• Bloody stools• Tenderness• Systemic symptoms (↓BP, ↓PLT, ↓WBC, DIC,
RDS, acidosis)
NEC: Clinical PresentationBell’s Stages
I. Suspected diseaseMild systemic signs (apnea, bradycardia, temperature instability)Mild intestinal signs (abdominal distention, gastric residuals, bloody stools)Nonspecific or normal radiological signs
II. Definite diseaseMild to moderate systemic illnessAdditional intestinal signs (absent bowel sounds, abdominal tenderness)Specific radiologic signs (pneumatosis intestinalis or portal venous air)Laboratory changes (metabolic acidosis, thrombocytopenia)
III. Advanced diseaseSevere systemic illness (hypotension)Additional intestinal signs (marked abdominal distention, peritonitis)Severe radiologic signs (pneumoperitoneum)Additional laboratory changes (metabolic and respiratory acidosis, DIC)
Radiographic Findings in NEC
• Dilated loops of bowel
• Thickened loops of bowel
• Pneumatosis intestinalis
• Pneumoperitoneum
• Portal venous air
Normal Bowel Gas Pattern
Nonspecific but Abnormal Bowel Gas Pattern
Nonspecific but Abnormal Bowel Gas Pattern
Pneumatosis Intestinalis
Pneumoperitoneum
PneumoperitoneumCross Table Image
PneumoperitoneumLeft Lateral Decubitus View
PneumoperitoneumOutline of Falciform Ligament
NEC: Diagnosis and Management
I. Suspected diseaseMedical treatment
(Course determined by
clinical judgement)
Clinical concern for NEC
NPOLow-intermittent orogastric suction
Obtain culturesAntibiotics
Serial x-raysHematologic studies, blood chemistries
Support clinically as indicated
II. Definite diseaseMedical treatment 7-14d
III. Advanced diseaseIntensive cardiovascular and respiratory support
Consider surgical intervention
NEC: Diagnosis and Management
Surgical indicationsRadiologic signs:PneumoperitoneumPersistent fixed loopPortal venous airAscites
Laboratory signs:Severe thrombocytopeniaSevere neutropeniaSevere acidosis
Management of NEC
• Exploratory laparotomy
• Perintoneal drainage with Penrose
• Medical Management– Antibiotics– Vasopressors– Coagulopathy/DIC– Decompression
Management of NEC
• Lap vs drain??– Clinical trials in progress– Is one more appropriate depending on the
diagnosis?– Small percentage will ultimately require
surgery
Spontaneous Bowel Perforation
• Different disease than NEC
• Infants typically have never been fed
• Occurs within the 1st week of life
• Typically isolated perforation in small bowel
• Overall prognosis better than NEC
Short Bowel Syndrome
How short is too short????
• The answer keeps changing!!Present IC valve - >25 cm
Absent IC valve - >40 cm
• At risk for TPN induced cholestasis
• Malabsorption syndrome
• Bowel transplantation
Short Bowel Syndrome
• Bowel adaptation occurs after bowel resection• Characterized by epithelial hyperplasia• Mucosal atrophy occurs if unable to establish
enteral feedings• Monitor stool pH, fat absorption and volume and
consistency of output• Risk for bacterial overgrowth – esp if IC valve
removed
Short Bowel Syndrome
• Nutritional deficiency– Fat soluable vitamins (Vit A, D, E)– Minerals (Fe, Zn, Ca, Mg)
– Bowel lengthening procedure– Transplantation
Short Bowel Syndrome
• Incidence varies between sites
• Recent report of 15 centers across US reported rates from 0.1% to 1.6%
• Site specific outcomes
• Variable patient populations
Copyright ©2008 American Academy of Pediatrics
Cole, C. R. et al. Pediatrics 2008;122:e573-e582
FIGURE 2 Types of food consumed by ELBW infants at 18 to 22 months' corrected age (n = 2159)
Copyright ©2008 American Academy of Pediatrics
Cole, C. R. et al. Pediatrics 2008;122:e573-e582
FIGURE 1 Estimated time to in-hospital death for infants 401 to 1500 g birth weight
Why Does It Matter??
Everyone wants a
honey pot to take home!
Neurodevelopmental OutcomeAssociation with NEC
• Serious complication of prematurity
• Affects 10% of ELBW infants
• Often associated with severe SIRS
• Various cytokines are elevated in patients with NEC – TNF-α, PAF, IL-6, IL-8, NO
• Cytokine response has not been well correlated to disease severity
Neurodevelopmental OutcomeAssociation with NEC
• Recent evidence that the inflammatory response associated with NEC may be a mediator for brain injury
• NICHD outcome study showed 2-fold increased risk for abnormal motor outcome.
• Recent abstracts suggest increased incidence of abnormal CUS and mental delay
Neurodevelopmental OutcomeAssociation with NEC
• Recent review by Hintz, et al, Pediatrics
• Infants with surgical NEC were more likely to have growth impairment, MDI <70, PDI < 70 and overall neurodevelopmental impairment at 18-22 months AA, compared to infants with medically managed NEC or no NEC
ND Outcome and NEC
NEC: Potential Preventive Strategies•Common practiceHuman milk feedingsConservative feedingTrophic feeding
•Research ongoingAntenatal steroidsIgA supplementationArginine supplementationErythropoietinOral antibioticsProbiotics
Thank You!