necrotizing enterocolitis gadassi noa md. mph.. nec - incidence 1%-8% of all nicu ’ s admissions ...

NECROTIZING ENTEROCOLITISGadassi Noa MD. MPH.

NEC - Incidence

1%-8% of all NICU’s admissions Mortality rate 10%-50% Mainly affects preterm infants (90%) ~ 10% in term infants Incidence increases as gestational and birth

weight decrease No gender, seasonal, socioeconomic

association

NEC - onset of disease

Endemic versus epidemic appearance Median days of onset at term: 2 days Median age at onset < 26 weeks: 23 days

Pathophysiology Prematurity Formula Feeding Bacterial colonization Intestinal Ischemia

Prematurity 90% of cases occur in preterm infants 10% of babies < 1500 gr The more preterm, the higher the risk The specific reason is not well undcerstood Immature gut:

Decreased mucus production Decreases gastrointestinal hormones Inappropriate cellular and humoral immune response to intestinal

pathogens (IgA, Neutrophil function, Macrophage activation, cytokine production and function)

Different blood flow autoregulation Decreased motility Bacterial colonization

Cytokines and immune receptors on enterocytes

Enteral feeding 90%-95% of NEC cases were exposed to

enteral feeding Feeding the preterm infant:

* When to start?* Rate? Cycling bolus vs continuous?* Volume?* Type of feeding? Formula?* Osmolarity?

Factors in Breast Milk that may Influence Pathophysiology of NEC

Neonatal antigen specific antibodies - IgA, IgG, IgM

Leukocytes Oligosacharides Polyunsaturated fatty

acids Lactoferrin Glutamine Arginine

Platelet activating factor acetylhydrolase

Epidermal growth factor

IL-10 Erythropoietin

Copyright ©2006 American Academy of PediatricsJesse, N. et al. Neoreviews 2006;7:e143-e150

An interrelationship between lack of enteral feeding and intestinal integrity

Bacterial colonization / infection

The fetus has sterile intestinal invironment Commensal microflora (bacterial cells within the

intestine) vs. pathogenic bacteria Nutrition impact on colonization pattern:

Breastfeeding – Lactobacilli and BifidobacteriumFormula-fed – Enterobcteriaceae

Effect of composition of intestinal flora on intestinal homeostsis and epithelial development

Bacteremia occurs in ~ 20%-30% cases of NEC(gram+, gram-, anaerobes, viruses..)

Hypoxia-ischemia

Term neonates – conditions that compromise the intestinal blood flow: Polycytemia Birth asphyxia Exchange transfusion Congenital heart disease IUGR with reverse diastolic flow in the umbilical

artery

Hypoxia-ischemia Preterm neonates:

Prone to hypotension events Prone to hemodynamic stress: active PDA, PDA

Tx, umbilical catheters Imbalanced intestinal perfusion

Impaired intestinal circulatory autoregulation Immature intestinal vasomotor tone Coagulation necrosis

Hypothetical series of events leading NEC – Imbalance between Mucosal Injury and Host Defense

RISK FACTORS OF NEC

Prematurity Perinatal asphyxia Hypothermia Shock Hypoxia PDA Cyanotic heart

disease

Polycythemia Thrombocytosis Anemia Exchange transfusion GI anomalies Non breast formula Hypertonic formula Too much formula -

too fast

NEC - PATHOLOGY Anatomic injury:

Mainly in terminal ileum and ascending colon.

Pathology:Mucosal and sub-mucosal edemaIntestinal wall hemorrhagesLocal ischemia, coagulation necrosisInflammatory cellular responseBacterial growth

NEC pathology (cont.)

NEC - Signs and symptomsGastrointestinal

Feeding intolerance Abdominal

distention/tenderness Gastric aspirates Bilious vomiting Bloody stools Abdominal mass Abdominal wall

erythema

NEC - Signs and symptomsSystemic Lethargy Apnea/respiratory distress Temperature instability “Not right” Acidosis (metabolic/respiratory) Glucose instability Poor perfusion DIC

Diagnosis : Clinical

Serial abdominal examinations: Progressive abdominal tenderness Muscular guarding Abdominal wall erythema Abdominal mass

Diagnosis - Laboratory evaluation Leukocytosis, leukopenia, neutropenia Thrombocytopenia Electrolyte imbalance Hypo-hyperglycemia Metabolic Acidosis Hypoxia, hypercapnia

Diagnosis - Radiologic hallmarks Abnormal air pattern Abdominal fluid (ascites), wall edema Fixed dilated loop Pneumatosis intestinalis Portal vein air Pneumoperitoneum

Generalized bowel distention

Fixed dilated loop

Pneumatosis intestinalis

Pneumatosis Intestinalis

Pneumatosis Intestinlis(70%-80% of confirmed cases of NEC)

Portal venous gas

Free intraperitoneal air

NEC - Differential Diagnosis Dysmotility of prematurity Septic ileus Bowel obstruction / volvulus / malrotation Gastroenteritis Anal fissure Milk protein sensitivity enterocolitis

Clinical staging of Necrotizing Enterocolitis by Bell’s criteria

Modified Bell´s Staging Criteria for Necrotizing Enterocolitis (NEC)

StageSystemic signsAbdominal signsRadiographic signsTreatment

IASuspected

Temperature instability, apnea, bradycardia, lethargy

Gastric retention, abdominal distention, emesis, heme-positive stool

Normal or intestinal dilation, mild ileusNPO, antibiotics x 3 days

IBSuspected

Same as aboveGrossly bloody stoolSame as aboveSame as IA

IIADefinite, mildly ill

Same as aboveSame as above, plus absent bowel sounds with or without abdominal tenderness

Intestinal dilation, ileus, pneumatosis intestinalis

NPO, antibiotics x 7 to 10 days

IIBDefinite, moderately ill

Same as above, plus mild metabolic acidosis and thrombocytopenia

Same as above, plus absent bowel sounds, definite tenderness, with or without abdominal cellulitis or right lower quadrant mass

Same as IIA, plus ascitesNPO, antibiotics x 14 days

IIIAAdvanced, severely ill, intact bowel

Same as IIB, plus hypotension, bradycardia, severe apnea, combined respiratory and metabolic acidosis,DIC, and neutropenia

Same as above, plus signs of peritonitis, marked tenderness, and abdominal distention

Same as IIA, plus ascitesNPO, antibiotics x 14 days, fluid resuscitation, inotropic support, ventilator therapy, paracentesis

IIIBAdvanced, severely ill, perforated bowel

Same as IIIASame as IIIASame as above, plus pneumoperitoneumSame as IIA, plus surgery

Modified Bell’s criteria

NEC - TREATMENT No enteral feeding (NPO) I.V. fluids (TPN) + blood products Abdominal decompression I.V. antibiotic Abdominal X-ray follow-up Respiratory supportive treatment Surgery? Peritoneal drainage?

NEC - Surgery Abdominal decompression Resection of necrotic bowel Diversion of the proximal intestine towards

abdominal wall (ileostomy, jejunostomy, colostomy)

“Second look” Re-anastemosis after healing Peritoneal drainage

INDICATIONS FOR OPERATION

Absolute indicationsPneumoperitoneum

Relative indicationsClinical deterioration:Metabolic acidosisVentilatory failureOliguria, hypovolemiaThrombocytopenialeukopenia, leukocytosis

Relative indications:Portal airErythema-abdominal wallAbdominal massFixed dialeted loop

Nonindications:Severe GI hemorrhageAbdominal tendernessIntesital obstructionGasless abdomen+ascites

Peritoneal Drainage vs Laparotomy Metanalysis 2010:

5 prospective trials At least 25 patients in each arm PD is associated with 55% excess mortality

compared with LAP. PD patients were 0.78 weeks younger

Sola JE et al. Peritoneal drainage versus laparotomy for necrotizing enterocolitis and intestinal perforation: a meta-analysis. J Surg Res. 2010 June 1;161(1): 95-100

Peritoneal Drainage vs Laparotomy Cochrane 2011:

2 RCT – No differences: Mortality within 28 days of procedure (approx 30%) Mortality by 90 days (approx 35-40%) Number of infants needing TPN for more than 90

days Nearly 50% of the infants with PD could avoid

laparotomy Retain full feeding was quicker after laparotomy

(1 trial)

Complications of NEC

Intestinal strictures (39%)/fistula/abscess Recurrent NEC (6%) Jejunostomy, ileostomy, colostomy Malabsorption TPN complications Cholestasis Short-gut syndrome Extraintestinal: sepsis, BPD, neurodevelopmental

delay, growth retardation

Sites of absorption and secretion along the GIT

Neurodevelopmental and growth outcomes of ELBW infants after NEC

BW < 1000 g, Multicenter retrospective analysis Surgical NEC versus medically managed NEC Neurodevelopment and growth at 18-22 months

124 SurgNEC, 121 MedNEC SurgNEC more likely to receive diagnosis of cPVL,

CLD (treated with postnatal steroids) Growth < 10 percentile at 18-22 months significantly

more likely among SurgNEC SurgNEC is a significant risk factor for Bayley

MDI<70 and PDI<70

Hintz et al. Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants After Necrotizing Enterocolitis. Pediatrics 2005;115:696–703

Neurodevelopment outcome:NEC vs No NEC Metaanalysis of 11 nonrandomized trials Survivors of stage II or higher NEC are at risk for long-term

neurodevelopmental impairment (OR 1.82), especially if they require surgery for the illness (OR 1.99)

Schulzke SM et al. Neurodevelopmental Outcomes of Very Low-Birth-Weight Infants With Necrotizing EnterocolitisA Systematic Review of Observational Studies Arch Pediatr Adolesc Med. 2007;161(6):583-590

Neurodevelopment outcome

Rees CM et al. Neurodevelopmental outcome of neonates with medically ans surgery treated necrotizing enterocolitis . Arch Dis Child Fetal Neonatal Ed. 2007; 92:193-198

Long Term Costs Compares the long term healthcare costs

beyond the initial hospitalization period until 36 months.

Compared medical and surgical NEC survivors (316) with that of matched controls (2909) without a diagnosis of NEC during birth hospitalization

Ganapathy et al. Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid. BMC Pediatrics 2013, 13:127

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Prevention of NEC Good hygiene Trophic feeding Human milk Antenatal steroids Probiotics Acidification?

Glutamine?Arginine?

•Ofek Shlomai et al. Probiotics for Preterm Neonates: What Will It Take to Change Clinical Practice? Neonatology 2014;105:64–70•Neena Modi. Probiotics and Necrotising Enterocolitis: The Devil (as Always) Is in the Detail. Neonatology 2014;105:71–73

Probiotics

Copyright ©2006 American Academy of Pediatrics

Jesse, N. et al. Neoreviews 2006;7:e143-e150

Toll-like receptor (TLR) ligands and signaling are crucial for the intestinal surface to protect and repair itself in the face of infectious or inflammatory insult

Copyright ©2006 American Academy of Pediatrics

Jesse, N. et al. Neoreviews 2006;7:e143-e150

Results of the loss of epithelial integrity due to changes in barrier function

Hypothetical Events in the Pathophysiology of NEC

Modified Bell Staging Criteria for NEC

Onset

Age

• Preterm infants (90%) > Term infants (10%).

• Term infants develop NEC much earlier than preterm.

Laparotomy versus peritoneal drainage for necrotizing entercolitis and perforation

Moss et al. NEJM, May 2006

Multicenter randomized trial< 1500 g, < 34 wks

Outcome measures:Survival at 90 days postoperativelyDependence on TPN 90 days postoperatively and length of hospital stay

Lapaotomy vs. peritoneal drainage in NEC, < 1500 g, Moss et al. NEJM, May 2006

238 assessed for eligibility

117 randomly assigned to treatment

63 declined to participate58 for other reasons

62 laparotomy 55 peritoneal drainage

No lost to follow-upNo discontinuation of intervention

238 assessed for eligibility 238 assessed for eligibility

63 declined to participate58 for other reasons

238 assessed for eligibility

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

55 peritoneal drainage

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

238 assessed for eligibility

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

63 declined to participate58 for other reasons

238 assessed for eligibility

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

62 laparotomy 55 peritoneal drainage

117 randomly assigned to treatment

62 laparotomy

238 assessed for eligibility

55 peritoneal drainage

117 randomly assigned to treatment

62 laparotomy

63 declined to participate58 for other reasons

238 assessed for eligibility

55 peritoneal drainage

117 randomly assigned to treatment

62 laparotomy

Moss et al. NEJM, May 2006

Results: PD LAP P

Deaths (at 90 days post-op) 19/55 (34.5%) 22/62 (35.5%) 0.92

TPN dependence 17/36 (47.5%) 16/40 (40%) 0.53

Hospital stay (days) 126±58 116±56 0.43

Subgroup analyses–

Extensive pneumatosis intestinalis, gestational age <25 wks, acidosis: No significant advantage of either treatment in any group.

Copyright ©2006 American Academy of Pediatrics Jesse, N. et al. Neoreviews 2006;7:e143-e150

One approach to minimal enteral nutrition in very preterm infants (<=1,000 g)

Trophic Feeding

Algorithm for surgical treatment of NEC