Necrotizing Enterocolitis Ira Adams-Chapman, M.D. Assistant Professor in Pediatrics Medical Director, Developmental Progress Clinic Emory University School of Medicine Division of Neonatology

NEC Epidemiology Incidence 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 Epidemiology Morbidity and Mortality

Pathophysiology of NEC Prematurity Feeding Immaturity of intestine Motility Circulatory Barrier Immune and digestion regulation function defense NEC Abnormal bacterial colonization Hypoxic-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 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 NEC Prematurity Feeding Immaturity of intestine Motility Circulatory Barrier Immune and digestion regulation function defense NEC Abnormal bacterial colonization Hypoxic-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 NEC Prematurity Feeding Immaturity of intestine Motility Circulatory Barrier Immune and digestion regulation function defense NEC Abnormal bacterial colonization Hypoxic-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 NEC Prematurity Feeding Immaturity of intestine Motility Circulatory Barrier Immune and digestion regulation function defense NEC Abnormal bacterial colonization Hypoxic-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 secretion and absorption Immature mucin expression by Goblet cells Decreased Paneth cell number Immature secretory diarrhea Inability to rid intestine of pathogens/toxins? Increased intestinal permeability Enhanced bacterial adherence Reduced defensin expression Reduced antimicrobial activity? Reduced proinflammatory activity? Reduced secretory diarrhea?

Pathophysiology of NEC Prematurity Feeding Immaturity of intestine Motility Circulatory Barrier Immune and digestion regulation function defense NEC Abnormal bacterial colonization Hypoxic-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 Exaggeration Inflammation Poor inflammatory response Increased intestinal injury? Intestinal barrier damage? Bacterial overgrowth? Increased apoptosis? Opportunistic infection? VS.

Pathophysiology of NEC Prematurity Feeding Immaturity of intestine Motility Circulatory Barrier Immune and digestion regulation function defense NEC Abnormal bacterial colonization Hypoxic-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, 2001 Collier-Hyams LS, et al., Cell Mol Life Sci, 2005 de 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 Presentation Bell’s Stages I. Suspected disease Mild systemic signs (apnea, bradycardia, temperature instability) Mild intestinal signs (abdominal distention, gastric residuals, bloody stools) Nonspecific or normal radiological signs II. Definite disease Mild to moderate systemic illness Additional intestinal signs (absent bowel sounds, abdominal tenderness) Specific radiologic signs (pneumatosis intestinalis or portal venous air) Laboratory changes (metabolic acidosis, thrombocytopenia) III. Advanced disease Severe 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

Pneumatosis Intestinalis

Pneumoperitoneum

Pneumoperitoneum Cross Table Image

Pneumoperitoneum Left Lateral Decubitus View

Pneumoperitoneum Outline of Falciform Ligament

NEC: Diagnosis and Management I. Suspected disease Medical treatment (Course determined by clinical judgement ) Clinical concern for NEC NPO Low-intermittent orogastric suction Obtain cultures Antibiotics Serial x-rays Hematologic studies, blood chemistries Support clinically as indicated II. Definite disease Medical treatment 7-14d III. Advanced disease Intensive cardiovascular and respiratory support Consider surgical intervention

NEC: Diagnosis and Management Surgical indications Radiologic signs: Pneumoperitoneum Persistent fixed loop Portal venous air Ascites Laboratory signs: Severe thrombocytopenia Severe neutropenia Severe 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 1 st 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 Outcome Association 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 Outcome Association 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 Outcome Association 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 months AA, compared to infants with medically managed NEC or no NEC

ND Outcome and NEC

NEC: Potential Preventive Strategies Common practice Human milk feedings Conservative feeding Trophic feeding Research ongoing Antenatal steroids IgA supplementation Arginine supplementation Erythropoietin Oral antibiotics Probiotics

Thank You!