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

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


Feeding





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


Feeding





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


Feeding





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?


Feeding





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.


Feeding





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


• 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


• Nutritional deficiency– Fat soluable vitamins (Vit A, D, E)– Minerals (Fe, Zn, Ca, Mg)

– Bowel lengthening procedure– Transplantation


• 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


• 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


• 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!

Documents

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