Necrotizing Enterocolitis: 21st Century Applications

Necrotizing Enterocolitis21st Century Applications

Dr. David Mendez

Miami Childrens Hospital

Kidz Medical Serivces

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NEC - 21st Century

I have received no financial support for this presentation, but have liberally borrowed thoughts

and ideas from people smarter than me

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OUTLINE

1. Epidemiology

2. Etiology and Risk Factors

3. Pathophysiology

4. Pathology

5. Clinical Characteristics

6. Diagnosis

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7. Management

8. Prevention

9. Old Ideas

10. New Ideas

11. The Future

OUTLINE

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EPIDEMIOLOGY

All The Follwing Are True

Term Babies Get NEC - Approx 5% of All NEC

Developed Countries Have a Higher NEC Rate

NEC Can Happen Any Time NEC Rates Have Not Changed NEC Clusters are Real NEC Hits Females and Males Equally

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EPIDEMIOLOGY

NEC Is Often Seen as an Indicator of Survival and Medical Progress

The More Skilled the NICU Is at Keeping Babies Alive, the More Higher the Rate of NEC

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Most NICU’s Have a NEC Rate Of 6-7% for their VLBW Population

Mortality Rates Vary Between 12-30%

Fatality Rates are Relatively Higher in Infants Requiring Surgical vs. Medical Management

EPIDEMIOLOGY

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3 POPULATIONS OF NEC

Pre-term, Early Onset, Non-fed

Pre-term, Fed, Later Onset

Term

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PRE-TERM, EARLY ONSET, NON-FED

Often appears in 1st few days of life

“Spontaneous intestinal perforation”

Have not been fed

Associated with indomethacin use

Associated with glucocorticoid exposure

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Occurs in the first week of birthAssociated risk factors are present

1. Maternal drug exposure (cocaine)

2. Intestinal anomalies

3. Congenital heart disease

4. Perinatal stressors

5. IUGR

6. Hyperviscosity

TERM NEONATES

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Prematurity- most important risk factor

VLBW at highest risk

10% of all babies < 28 weeks

5% of all babies 28-32 weeks

Exposure to enteral feeds

Usually after the 1st week of life

PRE-TERM, FED, LATER ONSET

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Umbilical lines – not causally associatedTPN via UAC/UVC – does not increase risk of NEC

Low Apgar scores – not associated Presence of a PDA – not causally associated

Antenatal steroids – unclearPDA surgery and antenatal steroids-increase

OTHER POSSIBLE RISK FACTORS

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Clinical Parameters Alone Cannot Adequately Predict the Outcome In

NEC

MOSS ET.AL JOURNAL OF PERINATOLOGY(2008) 28, 665-674DOL:10.1038/JP2008.119

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AS IT STANDS...

NEC has a multifactorial cause; combining a genetic predisposition, intestinal immaturity, abnormal microbial colonization, abnormalities in microvascular tone and a highly immunoreactive intestinal mucosa leading to bacterial overgrowth, inflammation and ischemia of the bowel

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INTESTINAL IMMATURITY

Motility

Digestion

Absorbtion

Immune defense

Barrier function

Circulatory regulation

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After delivery the intestine undergo microbial colonization

This results in modification of the cells immune response

Fetal cell lines have an increased TLR4 response vs adult cell line

Excessive TLR4 have been associated with extensive and inappropriate inflammatory response

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Gastric secretions are limited in pre-term babies

Linked to increased risk of NEC

Use of H2 blockers may further increase risk

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PREMATURITY

Feeding

Circulatory Regulation

Barrier Function

Immune Defenses

Motility andDigestion

NECAbnormal microbial colonizati

on

Genetic predispositio

n

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INTESTINAL MOTILITY AND DIGESTION

Motility develops in 2nd trimester, matures in 3rd

Decreased and poorly organized motility can delay clearance, lead to bacterial overgrowth

Decreased digestion from protease immaturity and increased ph impair this 1st line of defense against toxins and pathogens

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CIRCULATORY REGULATION

Coagulation necrosis is the hallmark pathologic finding in NEC

Attempts to explain this by cardiac outputre-distribution after a period of asphyxia, theso called “diving reflex”

Does not appear be causal to the developmentof NEC

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CIRCULATORY REGULATION

Basal vascular resistance after birth

Nitric Oxide

Myogenic Response

Endothelin ( Et-1)

Anything that disrupts the balance can result in Intestinal Ischemia

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INTESTINAL BARRIER AND FUNCTION

Barrier prevents invasion of microbes and resultant systemic inflammatory disease

Preterms have higher intestinal permeability, the so-called “leaky gut”

Components include:1.Tight junction2.Peristalsis3.Mucus coat containing secretory IgA

Breast Milk Contains IgA

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IMMUNE DEFENSES

Antimicrobial peptides called defensins and cathelicidins produced by intestinal cells

Attack wide range of microbes

This in combination with iga effective barrier

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IMMUNE DEFENSES

Factors include TLR4, TLR9, PAF, TNF, Interleukins

Anti-inflammatoryfactors

Pro-inflammatoryfactors

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Relates to polymorphisms in toll-like receptors (TLRs)

TLRs appear to play a role in cell migration, proliferaton and

inflammatory response within the intestine

Two work in tandem TLR4 and TLR9

GENETIC PREDISPOSITION

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ABNORMAL BACTERIAL COLONIZATION

Normal colonization is a natural barrier to pathogenic flora

In pre-term babies that process is delayed and impaired

Pathogenic bacterial overgrowth invades the intestine and spreads systemically

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MICROBIOLOGIC FLORA AND INFECTION Several organisms have been accused,

but none has been proven to be causative:

� Enterobacteriaceae� Enterobacter sakazakii� Coagulase-negative staphylococci: SIP� Closrtidium perfringens� Candida species: SIP� Cytomegalovirus� Torovirus� HIV� Mucormycosis

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Since most NEC occurs > week after birth, abnormal colonization has been thought a risk factor for NEC

In the laboratory germ free intestines in lab animals don’t get NEC!

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A decrease in diveristy of microbes

Presence of unusual microbial species(Often found in hospitals)

An excessive inflammatory response inpre-term intestinal cells to normal and pathogenic flora


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The excessive immature inflammatory response associated with abnormal intestinal microbiota in considered a likely basis for the

pathogenesis of NEC

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ENTERAL FEEDINGS

Microbe colonization then followed by enteral feeds needed for NEC

Too much enteral feeds or too late enteral feeds appears to increase NEC risk

Breast milk fed babies at lower risk, but can still develop NEC

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Tolerated better

Helps intestinal mucosa mature faster

Presence of glutamate, nucleotides and growth factors

Presence of inhibitors of proinflammatory cytokines such as PAF-AH

ENTERAL FEEDINGSBreast Milk

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ENTERAL FEEDINGS

When to start

How much to give

How quickly to advance

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Study by Leaf et.al. Pediatrics 2012

Early group- 24-48hr after birth

Late group- 120-144 hrs after birth

Ave GA 31 weeks

Smallest babies 11ml/kg/day

Biggest babies 16ml/kg/day

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Study by Leaf et.al. Pediatrics 2012

No difference in the incidence of NEC

18% vs 15%

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Study by Money & Richardson(unpublished findings, 2010)

Incidence of NEC with no feeding guidelines – 9%

Incidence of NEC after feeding guidelines established – 2%

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TROPHIC FEEDS

No standard definition

Range from 1.5 ml/kg/day to 24 ml/kg/day

No standard time line for trophic feeds

No standard based on spec. birth weight/GA

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FULL ENTERAL FEEDS

Can vary from 150 ml/kg/day to 180 ml/kg/day

No standard how quickly to get there

No standard based on BW/GA

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CLINICAL PRESENTATION

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Pneumatosis intestinalis. Very obvious case. Tremendous amount of air in bowel walls

Reference:

Radiology Cases In NeonatologyCopyright 1996, Loren Yamamoto

DIAGNOSIS, RADIOLOGIC STUDIES

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Pneumatosis intestinalis.Note the air visible in the bowel wall. The air dissects the bowel wall giving it a double lined appearance(i.e., railroad tracks without the ties)

Reference:

Radiology Cases In NeonatologyCopyright 1996, Loren Yamamoto


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Pneumatosis intestinalis


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Supine AXR, The bowel is mildly dilated with gas, mainly on the left side. The bubbly pattern of gas seen mainly in the right

lower quadrant represents intramural gas.30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with pathologic

correlation. RadioGraphics 2007; 27:285-305.


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Free intraperitoneal gas is present anteriorly (arrows)

30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with pathologic correlation. RadioGraphics 2007; 27:285-305.


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NEC with perforation

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Left lateral decubitus radiograph shows free airReference: Necrotizing Enterocolitis, emidicine.com, Beverly P Wood,

MD, MS, PhD


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Closeup of intestine of infant showing necrosis and pneumatosis intestinalis.

Autopsy

PATHOLOGY

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30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with pathologic correlation. RadioGraphics 2007; 27:285-305.

Postmortem photograph of bowel involved with severe NEC. The arrows indicate areas of the bowel wall where there has been so much necrosis and sloughing of the mucosa, submucosa, and muscularis that only the

serosa is intact.

PATHOLOGY

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ENTEROCOLITIS NECROTIZANTENecrosis y “burbujas” (neumatosis en serosa)

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NEC induced by an intravenous injection of PAF in a rat model

PATHOLOGY

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BELL’S STAGING FOR NEC

Dr. Martin Bell in 1978 devloped criteria based on radiologic and clinical findings

Dr. Robert Kleigman in 1979 & 1986 helped to modify bells staging

Modified bells staging current standard for NEC

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Stage IA

Suspected

Stage IIA

Definite, mildly ill

Stage IIIA

Advanced, severely ill intact bowel

Stage IB

Suspected

Stage IIB

Definite, moderate ill

Stage IIIB

Advanced, severely ill perforated bowel

BELL’S STAGING FOR NEC

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MODIFIED BELL’S STAGING FOR NEC

Temperature instability, apnea,bradycardia, lethargy

Gastric retention, abdominal distension, emesis, heme + stool

Stage IA Clinical Findings

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Normal or intestinal dilatation

Mild ileus

Stage IA Radiographic Findings

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Temperature instability, apnea,bradycardia, lethargy

Gastric retention, abdominal distension, emesis, heme + stool

Stage IB Clinical Findings

Only difference – grossly bloody stools


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Normal or intestinal dilatation

Mild ileus

Stage IB Radiographic Findings

Same as Stage IA


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Temp. instability, apnea, bradycardia, lethargy

Gastric retention, abd. distension, heme + stoolor grossly blood stool

In addition

Absent bowel sounds, +/- abdominal tenderness

Stage IIA Clinical Findings


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Intestinal dilatation, ileus


Stage IIA Radiographic Findings


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Temp.Instability, apnea, bradycardia, lethargy

Gastric retention, abd. Distension, heme + stool or grossly blood stool

Absent bowel sounds, abdominal tenderness

In addition

Mild met. acidosis, thrombocytopenia,+/- abdominal cellulitis , +/- RLQ mass

Stage IIB Clinical Findings


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In addition

Asicites

Stage IIB Radiographic Findings


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All of IIB plus:

Hypotension, bradycardia, severe apnea, combined resp. and metabloic acidosis, DIC and neutropenia

Signs of peritonitis, marked tenderness, abdominal distension

Stage IIIA Clinical Findings


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Ascites

Stage IIIA Radiographic Findings


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All of IIB plus:

Hypotension, bradycardia, severe apnea, combined resp. and metabloic acidosis, DIC and neutropenia

Signs of peritonitis, marked tenderness, abdominal distension

Stage IIIB Clinical Findings(Same as IIIA)


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Ascites

In addition

Pneumoperitoneum

Stage IIIB Radiologic Findings(Same as IIIA)


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“Acquired Neonatal Intestinal Disease”

(ANID)

DIFFERENTIAL DIAGNOSIS

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*J AM Coli Surg. 2002 Dec; 195(6):796-803.Spontaneous localized intestinal perforation in very-low-birth weight infants: a distinct clinical entity different from necrotizing enterocolitis

SPONTANEOUS INTESTINAL PERFORATION

Isolated perforation of newborn

Typically at terminal ileum

Separate clinical entity from NEC*

Differentiation is important as there are managment considerations

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EPIDEMIOLOGY

Commonly found in VLBW, ELBW

Risk ~ 2-3% in VLBW, 5% in ELBW

Median gestational age 25-27 weeks

Median BW 670-973g

More frequent in male infants

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*Maternal factors in extremely low birth weight infants who develop spontaneous intestinal perforation.Ragouilliaux CJ; Keeney SE; Hawkins HK; Rowen JL Pediatrics 2007.@Focal small bowel perforation: an adverse effect of early postnatal dexamethasone therapy in extremely low birthweight

infants.Gordon PV; Young ML; Marshal DD; J Perinatol. 2001 Apr-May;21(3)New insights into spontaneous intestinal perforation using a national data setAttridge JT; Clark R; Gordon PV J Perinatol. 2006 Nov;26(11):667-70. Epub 2006 Oct 5.

1. Prematurity2. Antenatal3. Severe placental chorioamnionitis*4. ? Glucocorticoids/NSAIDS5. Postnatal6. Early postnatal glucocorticoids@7. ? Indocid

RISK FACTORS

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Single isolated perforation Typically in terminal ileum, but also

reported in jejunum, colon Focal hemorrhagic necrosis with well

defined margins seen (in contrast to ischemic, coagulative necrosis in NEC)

Bowel proximal and distal to perforation normal

PATHOLOGY AND PATHOGENESIS

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SIP NECFirst week of life, median age 7(0-15)

Abdominal distention, bluish discoloration (groin, scrotum)Hypotension

Pneumoperitoneum, gasless abdomen

Associated sepsis due to CONS, fungemia

Leukocytosis, raised ALP, bilirubin, decreased patelet, hct

After first week, median age 15

Abdominal distentionAbdominal erythemaCrepitus, induration

Pneumatosis intestinalis, portal venous gas, transient thickening of intestinal wall, fixed dilated SB loops, pneumoperitoneum

CLINICAL PRESENTATION

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Septicemia with ileus

Neonatal pseudomembranous colitis

Meconium plug/fetal peritonitis

Viral enteritis

Milk protein allergy

DIFFERENTIAL DIAGNOSIS (cont.)

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MANAGEMENT AND WORK UP

NPO

GI Decompression

IVF

KUB

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Laboratory studies- definite

CBC with PLT, blood C/S, electrolytesblood gas

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Laboratory studies - probably

Urine, stool c/s crp, pt/ptt

Spinal tap, full DIC work up, abdominal U/S, LFT’s are not standard but can be considered

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Surgical vs Medical

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SURGICAL MANAGEMENT

Laparotomy vs Peritoneal Drainage

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Peritoneal Drainage vs Laparotomy for NEC and Intestinal Perforation: A Meta-

Analysis

SURGICAL MANAGEMENT

Dr. Juan E Sola, Et.al Jour. of Surgical Research 161, 95-100 (2010)

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PD vs LAP

PD used as alternative to lap, even definitive therapy

Sola reviewed all comparative studies from2000-2008

Of the 12 studies done during this time 5 were selected for analysis ( 3 were prospective, 2were RCT)

273 babies received PD vs 250 babies for LAP

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PD vs LAP

Mortality for the PD group 35-54% Mortality for the LAP group 15-43%

The combined estimate of all studies noted a 55% increase in mortality with the PD group

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PD vs LAP

PD patients were on average younger (by .78 weeks) and smaller ( by 67 grams)

Of the 3 trials that were prospective, non-randomized trials , PD associated with an 89% increase in mortality

Of these babies they were 1.16 wks younger and 100 grams lighter

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PD vs LAP

Hypothesis that PD is superior to LAP was based on retrospective data

Results of studies by Rees et.al went as far to recommend early LAP and questioned the safety of PD in patients with perforated NEC and SIP

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PD vs LAP

There are limitations to meta-analysis papers

Survival data is subject to the design flaws ofeach individual study

There were differences in inclusion data

(i.e. BW < 1000gm vs < 1500gm )

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PD vs LAP

An editorial by pierro et.al echoed the opinion that PD may not have a role in the surgical treatment of NEC

In 2012, a cochcrane search noted that only 2 RCTs met eligibilily criteria and no significant difference in PD vs LAP were noted

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PD vs LAP

At present, Eunice Kennedy Shriver National Institute of Child Health and

Human Development (NICHD)

Is recruiting participants in the following study:

Laparotomy vs. Drainage for infants with necrotizing enterocolitis (NEST)

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PREVENTION

At present, there is no clinical approach to prevent the occurance of NEC in any

Neonatal Unit in the world

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PREBIOTICS AND PROBIOTICS

In theory, by pre-populating the small intestine with appropriate non-pathogenic flora( prebiotic) or by altering a possibly pathogenic flora (probiotic) we lower the

incidence of NEC

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PREVENTION

CW WOODS et.al, Journal of Perinatology (2012) 32, 150-152

Development of NEC in preterm infants receiving thickened feeds of ‘simplythick’

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PREBIOTICS

A nondigestible food ingredient that benefits the host by selectively stimulates

the favorable growth and/or activity of one or more indigenous probiotic bacteria

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PREBIOTICS

Oligosaccharides Indigestible Selectively enhances proliferation of

probiotic bacteria Especially bifodbacteria species

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PREBIOTICS

Examples of oligosaccarides

� Inulin

� Fructo-oligosaccarides

� Galacto-oligosaccarides

� Soybean oligosaccarides

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PREBIOTICS

Human milk contains over 100 specific types of oligosaccarides that appear to bind to specific organisms and actively provide host defense

Studies note that presence of human milk promotes gut colonization of a more bifidogenic flora

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PROBIOTICS

An oral supplement or a food product that contains a sufficient number of viable

microorganisms to alter the microflora of the host and has potential health benefits

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PROBIOTICS

1960’s and 70’s artificial colonization of infants in nurseries by less pathogenic strains of s.aureus was shown to prevent colonization by more pathogenic strains

In 1994-95 hoyos administered probiotics to all newborns admitted to the NICU in columbia and noted a drop in the incidence of NEC from 6.6% to 2.9%

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PROBIOTICS

1999- 2003 lin et.al. In a double-blind control trial of 367 infants < 1500 gms received breast milk with and w/o probiotics when enterally fed, clinically stable and > 7 days of life

Demonstrated a reduction of NEC from 5.3% in the controls vs 1.1% in the probiotic-fed babies

As of 2011 there are 9 published trials that favor the use of probiotics to reduce the risk of NEC

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PROBIOTIC

Lactobacillus acidophilus

Bifidobacterium infantis

Bifidobacterium bifidis

Streptococcus thermophilus

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PROBIOTICS

The published studies differed significantly in the types of probiotics used

Dosing of the probiotics differed Some studies used a combination of

probiotics and those studies appeared to be more effective

Studies also used different strains of the same probiotic

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PROBIOTICS

The studies didn’t stratify patients based on formula vs breast milk feeds

There are studies that did not demonstrate a difference in the incidence of NEC

In two of the studies, the NEC rate was 15-16% well above the usual incidence rate ( 6-7%)

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PROBIOTICS

Tarnow-mordi, et.al in pediatrics, 2009

“All infants who meet eligibility criteria,those parents should be offered

probiotics.”

“ Knowing what we know now, do we have a right to deny parents that option?”

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PROBIOTICS

Lack of available, quality-controlled, highly reliable product- most are over the counterfood additives

By FDA guidelines they are “gras”

The one most widely available probiotics “lactobacillus gg” when evaluated in amulti-center randomized trial, failed to showa difference

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A relatively new concept that implicates a causal association between the use of PRBC

transfusions and the onset of NEC

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Transfusion associated NEC(TANEC)

Transfusion related acute gut injury(TRAGI)

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TRANSFUSIONS AND NEC

Case report in 2004 of the association of an intrauterine transfusions and NEC

Initial reports from 2005- 2006 saw a temporal association between PRBC transfusions and NEC

Compared to NEC unrelated to transfusions these cases tended to be more severe, most requiring surgery and a higher mortality

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Harsono et al in 2011 reported that PRBC transfusions were protective against late onset NEC in VLBW infants

HARSONO M, TALATI A, DHANIREDDY R, ELABIAD MT. ARE PACKED RED BLOODCELL TRANSFUSIONS PROTECTIVE AGAINST LATE ONSET NECROTIZING ENTEROCOLITIS IN THE VERY LOW BIRTH WEIGHT INFANTS? E-PAS; 2011;509

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CHRISTENSEN RD, ET.AL TRANSFUSION, 2010; 50 1106-1112

In 2010, christensen et.al studied cases where baies with NEC confirmed by laparotomy and diagnosis was confirmedby the surgeon and pathologist

They then did a three-part study1. NEC within 48 hrs of a PRBC

transfusion

2. A case-control study of transfusion HX

3. Age of the blood transfused & feeding HX

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TRANSFUSIONS AND NECChirstensens study found the

following: The odds of tanec increased in babies who got PRBC

The age of the blood was not different

Neonates who developed tanec had been givn large volumes of milk in the 24 hours before and during transfusions. Furthermore, those given a boving milk product developed NEC 2x as many as those given human milk

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TRANSFUSIONS AND NECChirstensens study found the

following: The babies that got NEC:

Lower bw

Earlier gestation

Later onset

Than babies who did not get NEC

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TRANSFUSIONS AND NECMeta-analysis of Tanec in 2012

MOHAMED A, SHAH PS, P ; PEDIATRICS 2012; 129;529

Exposure to transfusions increase risk of NEC

Babies were younger by GA, smaller, most likely ventilated and with the presence of a PDA

Mortality was higher for this group vs non–tanec

In this meta-analysis the role of feeding was not able to be anaylzed for significance

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OLD IDEAS

Delay, delay, delay enteral feeds

Rapid feeding of babies

Formula vs human milk

Thickeners of breast milk

Aggressive and random transfusion practices

Antibiotics always, a lot, for a long time

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NEW IDEAS

Initiate early, trophic feeds (10-30ml/kg/day) within the 1st week of life

Advance to full feeds over 13-16 days

Human milk whenever possible

Consider pasteurized donor breast milk

Hold feeds before and during transfusions

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NEW IDEAS

Evaluate NICU-specific NEC rate as benchmark

Standardized feeding practices

Standardize transfusion practices

Participation in a registry (i.e. tragi registry)

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A baby is born premature We have screened the genetic code for the

balance of pro-inflammatory vs anti-inflammatory cytokine

We are aware of the normal microbicrobial flora for this baby in our population

The use of prebiotic and probiotic supplements are given to properly adjust the flora

Breast milk is given at a specified time, amount and advancement rate

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We continue to monitor the intestinal microflora for changes in composition and biodiversity

Aware of the genetic predispostion for an inflammatory reaction- we adjust the iga levels as well as the various tlr, interleukins, paf, tnf by increasing or decreasingthere signal to keep the balance between the two forces

While holding feeds for transfusions we monitor the nitric oxide receptors and endothelin levels and make sure they are balanced to prevent ischemia to the intestinal wall

Our mesenteric circulation in continually monitored to detect decreases in flow

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Having thus eliminated NEC and thus the need for surgical intervention, pediatric surgeons and neonatologists achieve a harmony of medical and surgical sprituality that transcends medicine and becomes the beacon of light that causes all branches of medicine to unite

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Health & Medicine

Necrotizing Enterocolitis: 21st Century Applications