Necrotizing Enterocolitis

Richard J. Schanler, M.D.Schneider Children’s Hospital at North Shore, Manhasset, NY

and Albert Einstein College of Medicine, Bronx, NYschanler@nshs.edu

February 2010

Necrotizing Enterocolitis

Ischemic necrosis of the intestinal mucosa associated with inflammation, invasion of enteric gas forming organisms, and dissection of gas into the muscularis and portal venous system.

Epidemiology of NECEpidemiology of NEC The most common acquired GI emergency in The most common acquired GI emergency in

premature infantspremature infants IncidenceIncidence

1-3 cases/1000 live births 1-3 cases/1000 live births 1%-5% of NICU admissions1%-5% of NICU admissions Not changed in 20 years!Not changed in 20 years!

Mortality: 20% - 40% Mortality: 20% - 40% OccurrenceOccurrence

Most cases Most cases sporadic sporadic Age of onset:Age of onset:

1 day-3 months postnatal age (mean = 20 days)1 day-3 months postnatal age (mean = 20 days) 3-10 days after birth3-10 days after birth

Risk FactorsRisk Factors IschemiaIschemia

PDAPDA Perinatal asphyxiaPerinatal asphyxia PolycythemiaPolycythemia Umbilical cathetersUmbilical catheters Exchange transfusionExchange transfusion ShockShock AnemiaAnemia HypothermiaHypothermia Maternal cocaine Maternal cocaine

abuseabuse Maternal Maternal

preeclampsiapreeclampsia Congenital heart Congenital heart

diseasedisease Congenital GI Congenital GI

anomaliesanomalies

PrematurityPrematurity FeedingFeeding

Formula feedingsFormula feedings Rapid advancement Rapid advancement

feedingsfeedings Hypertonic formulaHypertonic formula

InfectionInfection InflammationInflammation Colonization Colonization EpidemicsEpidemics

0

1

2

3

4

5

6

7

8

23 24 25 26 27 28 29 30 31 32 33 34 35 36

%

Gestational age

Epidemiology: Risk Factors for NECEpidemiology: Risk Factors for NEC

NEC in Term vs. Preterm Infants In term infants there is a greater association

with: Congenital heart disease Congenital bowel anomalies PROM Neural tube defects Chorioamnionitis Low APGAR scores [Asphyxia] Exchange transfusions

Martinez-Tallo, et al: Biol Neonate 1997

Clinical Presentation of NEC in Clinical Presentation of NEC in Premature InfantsPremature Infants

Non-specific signs/symptomsNon-specific signs/symptoms Poor feeding, apnea, respiratory failure, Poor feeding, apnea, respiratory failure,

temperature instability, lethargy, hypotensiontemperature instability, lethargy, hypotension Abdominal signs/symptomsAbdominal signs/symptoms

Feeding intolerance Feeding intolerance Gastric residuals Gastric residuals Abdominal distention/tendernessAbdominal distention/tenderness Bilious emesisBilious emesis Occult or grossly bloody stoolsOccult or grossly bloody stools VomitingVomiting DiarrheaDiarrhea

Clinical Staging of NEC: Clinical Staging of NEC: Modified Bell’s CriteriaModified Bell’s Criteria

Stage I (A & B): Suspected NECStage I (A & B): Suspected NEC Lethargy, temperature instability, gastric residuals, abdominal Lethargy, temperature instability, gastric residuals, abdominal

distention, apnea, emesis, occult/gross blood in stools. distention, apnea, emesis, occult/gross blood in stools. X-rays:X-rays: normal or mild abdominal distention (ileus)normal or mild abdominal distention (ileus)

Stage II (A & B): Proven NECStage II (A & B): Proven NEC Abdominal distention & tenderness (mild-mod), absent bowel Abdominal distention & tenderness (mild-mod), absent bowel

sounds, mild metabolic acidosis, thrombocytopenia, abdominal sounds, mild metabolic acidosis, thrombocytopenia, abdominal wall cellulitis, palpable mass. wall cellulitis, palpable mass. X-rays:X-rays: Pneumatosis intestinalis, Pneumatosis intestinalis, intestinal dilation, ileus, ascites.intestinal dilation, ileus, ascites.

Stage III (A & B): Advanced NECStage III (A & B): Advanced NEC Impending bowel perforation, hypotension, severe apnea and Impending bowel perforation, hypotension, severe apnea and

bradycardia, peritonitis, marked abdominal distention and bradycardia, peritonitis, marked abdominal distention and tenderness, respiratory and metabolic acidosis, DIC, neutropenia. tenderness, respiratory and metabolic acidosis, DIC, neutropenia. X-rays:X-rays: pneumoperitoneum pneumoperitoneum

Bell 1978, Walsh 1986

Spontaneous Intestinal PerforationSpontaneous Intestinal Perforation SpontaneousSpontaneous Occurs earlyOccurs early Isolated Isolated Not NECNot NEC Not related to feedings Not related to feedings

except for possibly the lack of feedingsexcept for possibly the lack of feedings May be related to early dexamethasone and May be related to early dexamethasone and

possibly indomethacin*possibly indomethacin*

Stark NEJM 2001Stark NEJM 2001Gordon J Perinatol 1999Gordon J Perinatol 1999

Differential DiagnosisDifferential Diagnosis Sepsis with ileusSepsis with ileus Volvulus/malrotation Volvulus/malrotation Inspissated meconium syndromeInspissated meconium syndrome Intestinal atresiasIntestinal atresias Hirschsprung enterocolitisHirschsprung enterocolitis Severe gastroenteritisSevere gastroenteritis SIP (Spontaneous Intestinal Perforation)SIP (Spontaneous Intestinal Perforation)

IndocinIndocin SteroidsSteroids OtherOther

The Role of Infection and NECThe Role of Infection and NEC Bacterial colonization of intestinal tract important in Bacterial colonization of intestinal tract important in

the pathogenesis of NECthe pathogenesis of NEC Impaired host defense of the immature GI tract Impaired host defense of the immature GI tract

predisposes to bacterial overgrowthpredisposes to bacterial overgrowth Commensal vs pathogenic bacteriaCommensal vs pathogenic bacteria

Increased bacterial proliferation, inflammation, Increased bacterial proliferation, inflammation, and endotoxin release impairs mucosal barrier and endotoxin release impairs mucosal barrier function function

A variety of bacterial and viral pathogens have been A variety of bacterial and viral pathogens have been associated with NECassociated with NEC

Oral aminoglycoside prophylaxisOral aminoglycoside prophylaxis Risk vs benefitRisk vs benefit

Intestinal HomeostasisIntestinal Homeostasis

Jesse N, Neu J 2006

Bacteria and Immune Activation

Neish, et alScience, 2000

Enteral Feeding and NECEnteral Feeding and NEC The fetal GI tract is exposed to nutrients and growth The fetal GI tract is exposed to nutrients and growth

factors via swallowed amniotic fluidfactors via swallowed amniotic fluid Yet, NEC does not occur in-uteroYet, NEC does not occur in-utero

90% of infants with NEC have been fed milk 90% of infants with NEC have been fed milk enterallyenterally NOT a justification for postponement of feedings NOT a justification for postponement of feedings

in high-risk infantsin high-risk infants

Mechanism of Injury due to Enteral Mechanism of Injury due to Enteral FeedingsFeedings

Poor GI motility results in stasis and bacterial Poor GI motility results in stasis and bacterial overgrowthovergrowth

Feedings are substrate for bacterial proliferationFeedings are substrate for bacterial proliferation Fermentation of malabsorbed carbohydrates by Fermentation of malabsorbed carbohydrates by

enteric bacteriaenteric bacteria Increased intraluminal pressure [distention]Increased intraluminal pressure [distention] Decreased mucosal blood flowDecreased mucosal blood flow Short chain fatty acid products of fermentation, Short chain fatty acid products of fermentation,

toxic to enterocytestoxic to enterocytes

The Role of Inflammatory The Role of Inflammatory Mediators and NECMediators and NEC

Activation of the inflammatory cascade results in intestinal injury and bowel necrosis ……final common pathway in the pathogenesis of NEC

Elevated levels of inflammatory mediators associated with NEC TNF- IL-6 IL-1 NO INF- PAF [platelet activating factor]

o PAF critical inflammatory mediator in pathogenesis of NEC

o PAF mesenteric circulation NEC in rats o PAF action blocked by PAF-acetyhydrolase

Intestinal Ischemia and NECIntestinal Ischemia and NEC Intestinal ischemia and necrosis may result from Intestinal ischemia and necrosis may result from

severe hypoxemia severe hypoxemia Mediated by loss of nitric oxide (vasodilator) Mediated by loss of nitric oxide (vasodilator)

productionproduction Reperfusion that follows intestinal ischemia may Reperfusion that follows intestinal ischemia may

result in intestinal necrosisresult in intestinal necrosis The mesenteric circulation is vulnerable to The mesenteric circulation is vulnerable to

hemodynamic changes in preterm infants; impaired hemodynamic changes in preterm infants; impaired autoregulationautoregulation

Diving reflex not major role in NEC Diving reflex not major role in NEC Ischemia may be a predisposing factor for NEC, but it Ischemia may be a predisposing factor for NEC, but it

is not the sole cause of diseaseis not the sole cause of disease

Prematurity and the Risk of NECPrematurity and the Risk of NEC Immature mucosal barrierImmature mucosal barrier Decreased GI motilityDecreased GI motility Increased GI permeabilityIncreased GI permeability Altered intestinal floraAltered intestinal flora Immaturity of local host defensesImmaturity of local host defenses

Decreased secretory IgADecreased secretory IgA Deficiency of local factors lining intestinal lumenDeficiency of local factors lining intestinal lumen

Mucosal enzymes & GI hormones are suppressed or absentMucosal enzymes & GI hormones are suppressed or absent ProteasesProteases PepsinPepsin

Impaired autoregulation of the microcirculationImpaired autoregulation of the microcirculation Increased gastric pHIncreased gastric pH

H-2 Blocker Therapy and NEC NICHD Neonatal Network

Case Control study of Bell Stage II or greater

11,072 infants (BW 401-1500 gm)

7.1% developed NEC.

Antecedent H-2 blocker therapy associated with higher incidence of NEC (p < 0.001)

Guillet, R. et al, Pediatrics Jan. 2006

Susceptibility of Premature Infants to NEC

Hunter, Upperman, Ford, Camerini, Pediatr Res 2008; 63:117

Immaturity of the intestinal epithelial barrier and neonatal mucosal immune system predispose the premie to bacterial invasion which triggers sequence of NEC. Stimulation of pro-inflammatory cytokines compromises intestinal defenses. Imbalance between epithelial cell injury and repair leads to cycle of bacterial invasion, immune activation, uncontrolled inflammation, and gut barrier failure.

IgA, local factors

Increased gastric pH

Decreased motility

NICU flora

immune activationuncontrolled inflammation

gut barrier failure

Bacteria Feeding Hypoxia

PAF

NEC

Endotoxin

TNF

PGI2

NO

Acetylhydrolase

PAF Antagonists

TXB2, LTC 4

Complement, TNF

O2 Radical

PMN

Intestinal Ischemia

Human MilkIgA, Steroids

Steroids

Host DefenseIgAAntibioticsEnzymes

Caplan 1994

Prevention of NECPrevention of NEC Oral IgA-IgG Oral IgA-IgG (Eibl MM 1988)(Eibl MM 1988)

Enteral antibiotic prophylaxis Enteral antibiotic prophylaxis (Siu 1998)(Siu 1998)

Long-chain polyunsaturated fatty acids Long-chain polyunsaturated fatty acids (Carlson 1998)(Carlson 1998)

Antenatal steroids Antenatal steroids (Bauer 1984, Halac 1990)(Bauer 1984, Halac 1990)

Arginine and Glutamine supplementation Arginine and Glutamine supplementation (Amin HJ 2002)(Amin HJ 2002)

Gut priming/trophic feedsGut priming/trophic feeds (Berseth CL 2003)(Berseth CL 2003)

PAF antagonistsPAF antagonists (Caplan MS 1997)(Caplan MS 1997)

Oral probioticsOral probiotics (Hoyos AB 1999, Caplan MS 1999, Lin HC 2005)(Hoyos AB 1999, Caplan MS 1999, Lin HC 2005)

Epidermal growth factorEpidermal growth factor (Dvorak B 2002, Halpern MD 2003)(Dvorak B 2002, Halpern MD 2003)

ErythropoietinErythropoietin (Ledbetter DJ 2000, Kumral 2003)(Ledbetter DJ 2000, Kumral 2003)

BreastmilkBreastmilk

Prevention of NEC: BreastmilkPrevention of NEC: Breastmilk Bioactive factors… modulate inflammatory cascade….alter mucosal environmentBioactive factors… modulate inflammatory cascade….alter mucosal environment

Secretory IgASecretory IgA LactoferrinLactoferrin Cytokines (IL-10)Cytokines (IL-10) Enzymes (PAF-acetylhydrolase)Enzymes (PAF-acetylhydrolase) Growth factors (EGF)Growth factors (EGF) ErythropoeitinErythropoeitin HormonesHormones NucleotidesNucleotides OligosaccharidesOligosaccharides AntioxidantsAntioxidants GlutamineGlutamine Polyunsaturated fatty acidsPolyunsaturated fatty acids

Inhibits bacterial growth, possesses anti-inflammatory properties, accelerates Inhibits bacterial growth, possesses anti-inflammatory properties, accelerates mucosal repairmucosal repair

Formula-fed infants are 6-10 times more likely to develop NEC than breastfed Formula-fed infants are 6-10 times more likely to develop NEC than breastfed infantsinfants

NEC in Premature Infants (UK)

OR Formulas only vs Human Milk only all cases 2.5 (1.2;5.2), p<0.02; confirmed 6.5 (1.9;22), p<0.001

OR Formulas only vs Formulas as supplements to Mother’s Milk all cases 3.0 (1.5;5.7), p<0.005; confirmed 3.0 (1.4;6.5),

p<0.005Multi-center Not randomizedHuman Milk = Mother’s own milk and/or pasteurized donor milk Lucas & Cole, Lancet 1990;336:1519-23

Formulas Only (n=236) 24 (10.2%) 17 (7.2%)

Formulas plus Mother’s Milk (n=437) 16 (3.7%) 11 (2.5%)

Human Milk (n= 253) 11 (4.3%) 3 (1.2%)

In-Hospital Diet All Cases Confirmed Cases

Medical Management of NECMedical Management of NEC Initial work-up & Stabilization:Initial work-up & Stabilization:

Bowel rest (NPO), initiation of TPNBowel rest (NPO), initiation of TPN Broad-spectrum antibiotics for 10-14 daysBroad-spectrum antibiotics for 10-14 days

Include anaerobic coverage if perforation is suspectedInclude anaerobic coverage if perforation is suspected Decompression (large bore Anderson og tube)Decompression (large bore Anderson og tube) Serial abdominal X-rays Serial abdominal X-rays Surgical consultationSurgical consultation

Severe NEC:Severe NEC: Fluid resuscitation (isotonic fluid)Fluid resuscitation (isotonic fluid) Intubation/mechanical ventilationIntubation/mechanical ventilation Correct acid-base and electrolyte imbalanceCorrect acid-base and electrolyte imbalance Inotropic supportInotropic support Correct coagulation disorder (FFP, platelets, cryo)Correct coagulation disorder (FFP, platelets, cryo)

Laboratory evaluation:Laboratory evaluation: Blood gas, CBC, Lytes, BUN/CR, CRP, platelets, blood Blood gas, CBC, Lytes, BUN/CR, CRP, platelets, blood

cultureculture

Laboratory AbnormalitiesLaboratory Abnormalities Common abnormalities:Common abnormalities:

ThrombocytopeniaThrombocytopenia Correlates with disease progression and bowel necrosisCorrelates with disease progression and bowel necrosis

HyponatremiaHyponatremia Associated with bowel necrosis and bowel wall edemaAssociated with bowel necrosis and bowel wall edema

Metabolic acidosisMetabolic acidosis Associated with bowel necrosisAssociated with bowel necrosis

Early marker of NECEarly marker of NEC Elevated CRP Elevated CRP

Other abnormalitiesOther abnormalities Positive blood culture (30%)Positive blood culture (30%) Stool: occult blood, gross blood, stool reducing substances (+ Stool: occult blood, gross blood, stool reducing substances (+

breath H)breath H) Glucose instability (hypoglycemia or hyperglycemia)Glucose instability (hypoglycemia or hyperglycemia) Disseminated Intravascular CoagulationDisseminated Intravascular Coagulation Abnormal WBC (elevated or depressed)Abnormal WBC (elevated or depressed)

Severe neutropenia (37%)Severe neutropenia (37%)Pourcyrous et al. Pediatrics 2005

Surgical Management of NECSurgical Management of NEC NEC is the most common surgical emergency in newbornsNEC is the most common surgical emergency in newborns 27%-60% of patients with NEC will require surgical 27%-60% of patients with NEC will require surgical

interventionintervention 50% survival after surgery50% survival after surgery

Pneumonperitoneum is the only Pneumonperitoneum is the only absoluteabsolute indicationindication for for surgerysurgery

Relative indications:Relative indications: Tender abdominal mass, increasing abdominal Tender abdominal mass, increasing abdominal

distention and tenderness, abdominal wall erythemadistention and tenderness, abdominal wall erythema Clinical deterioration with progressive metabolic Clinical deterioration with progressive metabolic

acidosis, thrombocytopenia, leukopenia/leukocytosisacidosis, thrombocytopenia, leukopenia/leukocytosis Fixed bowel loop, portal venous gas on serial x-raysFixed bowel loop, portal venous gas on serial x-rays

Surgical Management of NECSurgical Management of NEC Exploratory laparotomy:

Resection of all necrotic bowel and exteriorization of all viable ends as stomas (standard surgical approach)

May have “second look” in 24-48 hr to reassess bowel viability

Peritoneal drain (PD) placement: Less operative stress, bedside procedure, local anesthesia,

small incision, less bleeding, ? “temporizing” measure until the patient is stable (an adjunct to laparotomy).

Subsequent laparotomy … once the patient is clinically stable

20%-70% of infants never required F/U laparotomy Overall survival rate with PD is comparable to infants treated

with exploratory laparotomy selection bias

Neonatal mortality similar after initial laparotomy or drain placement

Trend towards increased neurodevelopmental impairment with initial drain

Blakely et al., Pediatrics 2006;117:680-687

Surgical Management of NECSurgical Management of NEC

Re-feeding After NEC No known systematic studies. Problem: definition of NEC and

variability of severity of disease.

Re-feeding After NECRe-feeding After NEC Stage I: within 24-48 hours. Consider slightly

lower volume than prior to episode.

Stage II: 7-14 days. Consider slow progression, ie., Minimal enteral feedings.

Stage III: at least as long as stage II; Partially a surgical decision.

Late Complications of NECLate Complications of NEC Stricture (25%-35% of survivors) Short bowel syndrome (25%) Severe fluid and electrolyte losses through the ileostomy Malabsorption Enterocutaneous fistulas Abscess, wound dehiscence & infection Cholestasis, liver cirrhosis and liver failure Recurrent NEC (4%-6%) Postnatal Growth delay

Protein synthesis and metabolism may be re-directed from growth to tissue repair

Early feedings after NEC may enhance intestinal adaptation and decrease the frequency of growth delay

Neurodevelopmental delay Up to 50% of survivors of surgical NEC Increased CP, MDI<70, PDI<70, blindness, deafness

ParenteralParenteralAmino AcidsAmino Acids

ImmatureImmatureEnzymeEnzymeSystemsSystems

Toxic serum levelsToxic serum levelsor intermediatesor intermediates

Decrease in vagalDecrease in vagalstimulation, gastrin,stimulation, gastrin,

and glucagonand glucagon

Lack of enteral feedingsLack of enteral feedings

Other potentiallyOther potentiallytoxic drugs ortoxic drugs or

TPN componentsTPN components(e.g. Furosemide(e.g. Furosemide

Vitamins) Vitamins) SepsisSepsis

EndotoxemiaEndotoxemia

HepaticHepaticmembranemembranedysfunctiondysfunction

Essential fattyEssential fattyacid deficiencyacid deficiency

Specific aminoSpecific aminoacid deficiencyacid deficiency

Abnormal bileAbnormal bileacid productionacid production

Immaturity of bile secretionImmaturity of bile secretion

Premature birthPremature birth

BILE FLOWBILE FLOW Serum bilirubinSerum bilirubin Serum bile acidsSerum bile acids

Development of Cholestasis (PNAC)

PhytosterolsPhytosterols

GI surgeriesGI surgeries

Summary: Research Targets to Prevent NEC

Prevent mucosal breakdown Enteral nutrients, protein, certain amino acids,

butyrate, ?growth factors Stimulation of motility Stabilization of innate immunity Stabilization of microbial-intestinal interactions Control inflammatory response Non-invasive laboratory markers that show increased risk Specific genetic profile need to be identified Human milk!