Things we do that cause gut disease in neonates

How to prevent gut disease in neonatesPhillip GordonTulaneTopics we will coverNEC (overview)Term NECPreterm NECNEC associated with transfusionsNEC associated with cows milk intoleranceCatastrophic NEC

Spontaneous Intestinal Perforations

NEC is increasing

The data suggests that nationally, current trends in prematurity and neonatal care have resulted in increased NEC incidence in lower level units. This situation calls for more proactive regional NICUs who can provide support and education to surrounding units. What is NEC?

Its not just inflammation, its hemorrhagic necrosis

The reason that this distinction is important is that the neonatal bowel is utilizing the innate immune system to modulate inflammation rather than adaptive immunity (which kicks in weeks to months later as we introduce food)NormalNECIt is the innate immune system in combination with external factors that creates a permissive situation for NECHemorrhagic necrosis is a common end point that allows us to give an umbrella diagnosis of NEC, but infants with widely variable presentation and severity of disease all have the same pathology i.e. its not a very useful differentiator

There are variable combinations of factors and triggers that each distinctly increase the risk of progression to NEC

Large cohort analyses have allowed recognition of distinct NEC subgroups, based on their etiologic risk factors, and have been key to new strategies for NEC prevention

Term NECHypoxia / IschemiaFeeding a colonized gutAn immature and naive gutThe Classic NEC TriadReview of term NEC risk factorsNEC risk factors with prematurityTerm NECPreterm NECAn immature and naive gutFeeding a colonized gutHypoxia / IschemiaBacterial OvergrowthThe Key differences are:The principle mechanistic difference between term and preterm NEC is that one is triggered by hypoxic-ischemic pre-events, the other by bacterial overgrowth that the bowel cannot contain or tolerate.

However, the circumstances in which NEC evolves is quite different in the two populations and thus understanding the co-morbidities and evolution of NEC in each distinct disease process can help us understand the rationale behind prevention strategies.

How do clinical databases see NEC?These are the Diagnostic Categories currently available in the Pediatrix Database:

Rule out NECSuspected NECMedical NECSurgical NEC

Which of these are truly NEC? Clinically, NEC is diagnosed in any child with bowel pneumatosis on x-ray

This is the distribution of NEC and SIP by gestational age. Most NEC is preterm NEC.

< 80 mL/kg/dayIrregular stoolingIntermittent aspiratesLoopyFormulaPreterm NEC Pathogenesis (1) Feeding Intolerance of Prematurity / Ileus

80-120 mL/kg/dayNot stoolingIleusStacking AspiratesFormulaPneumatosis (x-ray)Preterm NEC Pathogenesis (2)Pneumatosis / NECCan we cut the incidence of (preterm) NEC in half today?A Standardized Feeding Protocol

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Christensen, Gordon, Besner , 2010

Human MilkWhat is different about term NEC?They are fed at full feeds almost immediately

They have intact G.I. motility (more or less)

They are able to feed P.O.

Parents have more input into the childs feedingPerinatal factors associated with term NEC

Lambert , et al., 2007

Other = perinatal hypoxia / ischemia, sepsis or respiratory distress

Out of 5877 infants > 36 weeks, 30 had NEC diagnosed by pneumatosis All infants but one were rapidly advanced with formula (that infant was fed breast milk fortified with human milk fortifier thus had the potential for bacterial overgrowth)The were 4 common NEC preconditions:

1- cong. heart disease (incidence = 1.5%) 2- shock/sepsis (incidence = 50%) 3- hypoxia/ischemia (incidence = 9%) 4- polycythemia(incidence = 13%)

These variables were significantly higher in the NEC cohort than controlsFeature M/MD (sd, rg, %)Age (days) when NEC was diagnosed15 12; (12; 146)Location of patient when NEC developedHome=2, NICU=28Transferred to children's hospital for surgical management8 (27%)Surgery for NEC7 (23%)Bowel perforation and resection5 (17%)Total bowel necrosis diagnosed2 (7%)Survival (%)26/30 (87%)Length of hospital stay (days) all 30 patientsb (32; 2244)Length of hospital stay (days) 26 survivors(37; 7145)Outcomes for Ischemic NEC

Lambert , et al., 2007Preventing term NECTerm NEC has preconditions that place patients at risk. Exclusive feeding of human milk may reduce risk, but this population is rarer and more challenging to capture for standardized feeding protocols (especially in non-tertiary NICUs) and thus may not be as amenable to prevention when compared to preterm NEC. A high index of suspicion for a co-morbid, perinatal risk factors should prompt a controlled feeding advance (50 ml/kg/day on day 1 -> 100 ml/kg/day on day 2 -> 150 ml/kg/day on day 3) to facilitate observation during the period of greatest risk

Transfusion Associated NEC is a subset of Preterm NECn = 11n = 40n = 6n = 3n = 3Gestation age (weeks)Birth weight (grams)Transfusion associated NECNEC not associated with transfusionPneumatosis associated with IVIGVolume 8, Issue 2

What are the co-travelers with transfusion-associated NEC?Incidence is decreased in infants receiving breast milkIncidence is decreased in infants whose feedings are held during the time of transfusion

Incidence is increased in infants with lowest HCTsIncidence is increased in infants on exclusive formula feedsIncidence is increased in infants who have had a previous transfusion

There is no relation to the age of the pRBCs at time of transfusion

Cows Milk Allergy versus NECWe have known for some time that infants with cows milk allergy can present with pneumatosis. More recently, we have seen case studies and case series demonstrating premature infants with multiple episodes of pneumatosis that finally resolve with elemental formula and that are highlighted by eosinophilia in the stool and/or blood which also resolve with elemental formula. These infants have a milder form of NEC that is precipitated principally by relatively early onset of milk allergy (usually not before 4 weeks of life).Gordon et al. J. Perinatol, 2008Infants who have NEC with eosinophilia are less likely to dieEosinophilsN LivedN Died< 5(76.8%)1821 (78%)514 (22%)5 -10 (13.8%)328 (81%)77 (19%)>10 (9.4%)223 (85.2%)45 (16.8%)Patients extracted from the Pediatrix database of preterm neonates (< 36 weeks with a diagnosis of medical or surgical NEC from 1997-2009 and also had a reported CBC on the day of diagnosis)Catastrophic NEC

Catastrophic NECThis is the NEC subgroup we know the least aboutNEC (n = 7099)LivedDiedDied < 7 daysDied > 7 daysPERINATAL VARIABLESMedian10-90thMedian10-90thp valueMedian10-90thMedian10-90thp valueMaternal Age26(19-36)26(18-36)NS26(18-36)26(18-36)0.3Gestational30(25-35)26(24-32)0.00126(24-32)25(23-31)0.01Birth weight1.32(0.72-2.5)0.82(0.55-1.6)0.0010.86(0.6-1.7)0.74(0.5-1.4)0.001APGAR 1 min7(2-8)5(1-8)0.0015(1-8)5(1-8)NSAPGAR 5 min8(6-9)7(4-9)NS8(5-9)7(4-9)0.001Age at diagnosis15(4-40)18(7-42)0.0118(7-40)19(7-47)NSPatients extracted from the Pediatrix database of preterm neonates (< 36 weeks with a diagnosis of medical or surgical NEC from 1997-2009 for whom discharge data was available)There is a trend towards lymphocytosis at presentation in catastrophic NECNECLivedDiedp valueDied < 7 daysDied > 7 daysp valueCBC data (n)55691494Avg of WBC11 (4.9-20.7)11.2 (4.3-25.9)0.00110.5 (3.9-25)12.1 (4.9-27.2)0.004Avg of Hgb12.8 (9.9-16.9)12.1 (9.3-15)0.00111.8 (9-14.9)12.5 (9.9-15.2)0.004Avg of Hct37.4 (29-49)35.6 (27.6-44.4)0.00135.1 (27.1-44.2)36.2 (29.2-44.7)0.001Avg of Plat288 (117-506)178 (56-409.3)0.001198 (59-422)150 (54-375)0.001Avg of Seg35 (13-61)31 (8.5-59)0.00129 (7-56)36.3 (12-65.5)0.001Avg of Band8 (1-29)13 (2.55-33)0.00113 (3-32)12 (2-33.45)NSAvg of Lymph37 (16-59.3)34.8 (13.5-62.2)NS37.8 (14.5-65)29 (11-57.35)0.001We dont yet know what causes catastrophic NEC but, if I had to guessThese would be the etiologies highest on my list of possibilities:

Viral-triggered NEC (Rotavirus, Adenovirus, Norwalk virus, etc.).Some may be coincident with transfusion, therefore some may actually be transfusion-associated NECSome may be a combination: emerging cows milk allergy, viral challenge and/or transfusion associated, in other words, these sub-group designations are not mutually exclusive

The only new potentially preventative measure here is the possible viral aspect, because infants who are part of a NEC cluster need to be quarantined to prevent further spread.

Spontaneous Intestinal PerforationsSIP presents as a single or a few isolated perforations most commonly in the ileum of distal jejunum in infants < 1000 grams birth weight. The average day of life 0f presentation is 7 days and the clinical finding is pneumoperitoneum in most cases.Spontaneous Intestinal Perforations

NormalNECSIPSIP is not NEC. The simplest evidence for this is the histology. NEC has mucosal necrosis, SIP doesnt. SIP has focal muscularis necrosis, NEC doesnt. Even in cases of SIP that are occult and the perforation has gone undiagnosed for days to weeks, this histopathology remains remarkably consistent (with only minimal total tissue necrosis at the peforation margins.Risk factors associated with SIPExtreme prematurity / low birth weight (< 100o grams)Early postnatal steroids (dexamethasone or hydrocortisone)Early postnatal indomethacin (in the first 4 days of life)The combination of early steroids and early indomethacinEarly postnatal ibuprofenPrenatal indomethacin, given shortly before delivery of an extremely premature infant (for tocolysis)SGA infants who are also premature.High endogenous cortisol levels in the first days of lifeCandida chorioamnionitisSummary of surgical outcomes data for SIP & NECSIP preferentially treated by drain is associated with increased cPVL and likely increased neurodevelopmental insult (NDI) compared to age matched controlsSurgical NEC has a higher mortality than SIP and has a greater risk of NDI when compared to SIP cohorts and controls, but all available data suffers from SIP contamination in currently published NEC cohorts.It is probable that NDI associated with NEC and SIP could be improved by choosing primary laparotomy rather than drain.It is imperative that future outcome studies differentiate SIP from NEC in the primary disease cohorts

SIP and NEC are preventable diseasesNo early steroids or NSAIDsUse feeding guidelines, initiate feeding advances earlyPromote breast milk feeding at every opportunityUse glycerin as appropriateMinimize blood draws and transfusions (draw retics with HCTs)Wash your hands between babiesPay attention to aspirates that stack, ignore those that dont, ignore all colors but dark green.Dont over wean the respiratory support or the isolette temp while advancing feedsQuarantine infants with NEC to minimize the chance of NEC clusters (contact precautions).

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