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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