Necrotizing enterocolitis
- Definitions
- Epidemiology
- Risk Factors
- Pathogenesis
- Pathophysiology
- Clinical Presentation
- Diagnosis
- Management
- Prognosis
- Prevention
Definitions
Necrotizing Enterocolitis: an acquired neonatal acute intestinal necrosis of unknown etiology NEC is neither a uniform nor a well-defined disease entity
Definitions
Isolated spontaneous intestinal perforation
(SIP): ill-defined clinical syndrome of undetermined cause resembling NEC with less systemic involvement and a less severe clinical course. It may present a variant of classical NEC
The National Institute of Child Health and Human Development Neonatal Network (NICHD): intestinal perforation without evidence of pneumatosis since
Definitions
Acquired neonatal intestinal diseases (ANIDs)
Wider umbrella includes different pathologies affecting
gastrointestinal tract in preterm and term infants. Some
which do lead to the common final pathology of NEC and
some which do not.
Includes:
- NEC
- SIP
- Viral enteritis of infancy
- Cow’s milk protein allergy
Epidemiology
Incidence: 0.3-2.4 / 1000 live births
- 2-5 % of all NICU admissions
- 5-10 % of VLBW infants
Over 90 % of cases occur in preterm babies
About 10 % occur in term newborns:
essentially limited to those that have some underlying illness or condition requiring NICU admission
Epidemiology
Sporadic or epidemic clusters
Sex, race, geography, climate, season: No role
- Male VLBW infants are at greater risk of death
- Black infants: increased risk of NEC, and its associated mortality
Risk Factors: Prematurity
Prematurity is the single greatest risk factor
The risk is inversely related to birth weight and gestational age
Risk Factors: Genetics
Familial:
There are report a consanguineous Jewish Ashkenazi family in which three of four children died within a few weeks after birth from severe enterocolitis
Also a Lebanese consanguineous family where three term sibs presented with severe early and lethal enterocolitis, all with delayed meconium passage
a multicenter retrospective study of 450 twin pairs born at < or =32 weeks of gestation, showed that intraventricular hemorrhage,
necrotizing enterocolitis, and bronchopulmonary dysplasia are familial in origin
Risk Factors: G-6-PD deficiency
G6PD deficiency was significantly higher (27.8%) in infants with NEC compared with the 5.3% prevalence
among NICU admissions (odds ratio = 6.9; 95% confidence interval = 2 to 23.5)
G6PD deficiency also was found to be a marker for more severe NEC
G6PD deficiency should be considered a risk factor for NEC
Risk Factors: Cocaine
Maternal cocaine abuse increases the risk by 2.5 folds (95% CI = 1.17 to 5.32, P = 0.02)
Risk Factors: Indomethacin
Indomethacin for Tocolysis: Metaanalysis 2007
Recent exposure (within 48 hours of delivery) to antenatal indomethacin was associated with
necrotizing enterocolitis (OR, 2.2; 95% CI; 1.1-4.2).
Risk Factors: Indomethacin
Indomethacin in Early Life:
Associated with SIP3
Prolonged versus Short Course of Indomethacinfor the treatment of PDA in preterm infants: Systematic Review
- The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course.
- Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants
Risk Factors: Dexamethasone
Combined use of indomethacin and dexamethasone increases the risk of SIP in VLBW neonates
Risk Factors: H2-blockers
Antecedent H2-blocker use was associated with an increased incidence of
NEC (OR 1.71, 95% CI 1.34-2.19, P < .0001)
Risk Factors: Co-amoxiclav
Co-amoxiclav should be avoided in women at risk of preterm delivery because of the increased risk of neonatal necrotizing enterocolitis (RR 4.60, 95% CI 1.98 to 10.72)
Risk Factors: Acyclovir
Term baby, developed NEC after receiving prophylactic acyclovir.
Mother had herpes genitalis and pROM at 32 wks of GA, treated with acyclovir until vaginal delivery
Acyclovir treatment in uteroand after birth is discussed as a possible cause of necrotizing enterocolitis in the infant.
Risk Factors: Kayexalate
Necrotizing enterocolitis in a 850 gram infant receiving sorbitol-free sodium polystyrene sulfonate
Their case report shows that Kayexalateper se, and not necessarily suspended in sorbitol, can lead to
gastrointestinal tract complications and NEC in preterm infants.
Risk Factors: UAC
UAC cause a decrease in mesenteric blood flow
Therefore, their use in hemodynamically unstable neonates or in those with gastrointestinal disease should be very carefully Considered
High vs. low UAC: necrotising enterokolitis are not more frequent with high compared to low catheters
Preprandial SMA BFV and postprandial SMA BFV responses to minimal enteral feedings were not affected by the presence of a UAC
Risk Factors: UVC
Compared long-term (up to 28 days) and short-term (7-10 days) use of umbilical venous catheters in premature infants with birth weights of less than 1251 grams
There were no differences in time to full feedings or to regain birth weight or in the incidence of necrotizing enterocolitis or death
Risk Factors: PDA
No association between significant PDA and NEC
The age at starting feed and full enteral feed was significantly delayed in infants with significant PDA
Risk Factors: in Term babies
Limited to those that have some underlying illness or condition requiring NICU admission.2
- Congenital Heart Disease
- Intrauterine growth restriction
- Polycythemia
- Hypoxic-ischemic events
Risk Factors: Exchange transfusion
There is no evidence of long-term benefit from partial exchange in polycythaemic infants
The incidence of gastrointestinal injury is increased NEC (RR 8.68; 95% CI 1.06 to 71.1)
Pathophysiology
Hypoxic-Ischemic insult
Enteral Feeding
Microbiologic Flora
Cytokines and Inflammatory Mediators
Hypoxic-ischemic insult
Hypoxia-Reoxygenation.
Ischemia-Reperfusion.
Intramural microcirculation.
Balance between Endothelin-1 and Nitric Oxide.26
Enteral feeding
Formula vs. Donor Breast Milk
Formula is associated with higher risk of NEC
Enteral feeding
Disadvantages of Formula:
Higher osmolality ±
Lack of immunoprotective factors
Lack of growth factors
Altering intestinal flora
Microbiome and Infection
- Microbiome and Infection
- Several organisms have been accused, but non has been proven to be causative:
- Enterobacteriaceae
- Enterobacter sakazakii
- Coagulase-negative staphylococci: SIP
- Closrtidium perfringens
- Candida species: SIP
- Cytomegalovirus
- Torovirus
- HIV
- Mucormycosis
Cytokines and Inflammatory Mediators
Platelet Activating Factor (PAF)
Tumor Necrosis Factor (TNF)
High-mobility group box 1 protein (HMGB 1)
Interferon-gamma (INF-gamma)
Interleukins (ILs)
Matrix metalloproteinases (MMPs)
Clinical presentation
Onset varies with gestational age
- VLBW 14 – 20 days
- Term first week
Course of the disease
- Fulminant presentation
- Slow, paroxysmal presentation
Clinical presentation
Systemic signs:
- Respiratory distress, apnea, bradycardia
- Lethargy, irritability
- Temp. instability
- Poor feeding
- Hypotension
- Acidosis
- Oligurea
- Bleeding diathesis
Clinical presentation
Abdominal (enteric) signs:
- Distension
- Tenderness
- Gastric aspirate, vomiting
- Ileus
- Abdominal wall erythema, induration
- Ascites
- Abdominal mass
- Bloody stool
Diagnosis
A high index of suspicionis required Sometimes cannot be differentiated from sepsis
Diagnosis, laboratory studies
No lab test is specific for NEC
The most common triad(!):
- Thrombocytopenia
- Persistent metabolic acidosis
- Severe refractory hyponatremia
↑ WBC, ↓ WBC, ↓ PMN
Hyperkalemia
Stool: reducing substances, occult blood
Diagnosis, radiologic studies
Abdominal X-ray:
- Abnormal gas pattern, ileus
- Bowel wall edema
- Pneumatosis intestinalis
- Fixed position loop
- Intrahepaticportal venous gas (in the absence of UVC)
- Pneumoperitonium, left lateral decubitus or cross-table lateral views
Diagnosis, radiologic studies
Pneumatosis intestinalis.
Very obvious case.
Tremendous amount of air in bowel walls
Diagnosis, radiologic studies
Pneumatosis intestinalis. Note the air visible in
the bowel wall. The air dissects the bowel wall
giving it a double lined appearance (ie., ailroad
tracks without the ties)
Diagnosis, radiologic studies
Abdominal ultrasound:
Thick-walled loops of bowel with hypomotility.
Intraperitoneal fluid is often present
Intramural gas can be identified in early-stage NEC
In the presence of pneumatosis intestinalis, gas is identified in the portal venous irculation within the liver
Color Doppler US is more accurate than abdominal radiography in depicting bowel necrosis in NEC
Diagnosis, radiologic studies
Abdominal Doppler ultrasound:
neonates with high resistance patterns of blood flow velocity in the superior mesenteric artery on the first day of life are at increased risk of developing necrotizing enterocolitis
Modified Bell’s Staging Criteria
Stage I : Suspected NEC
Clinical signs and symptoms
No diagnostic radiograph
Modified Bell’s Staging Criteria
Stage II : Definite (confirmed) NEC
A.Mild NEC
- Sign & symptoms, absent B/S, gross blood in stool
- AXR: ileus, focal areas of pneumatosis intestinalis
- A.Moderate NEC
- Systemically ill
- AXR: extensive pneumatosis intestinalis, early ascites, possible intrahepatic portal venous gas
Modified Bell’s Staging Criteria
A: Severe NEC without perforation
- Critically ill
- Abdominal wall induration, extensive erythema
- AXR: prominent ascites, paucity of bowel gas, persistent fixed loop
B: Severe NEC with perforation
Differential diagnosis
Systemic infection: sepsis, pneumonia
Surgical abdominal catastrophes
Infectious enterocolitis
Allergic collitis
Feeding intolerance
Management
The main principle of management of confirmed NEC is to treat it as an acute abdomen with impending or septic peritonitis
Isolation: cohort isolation in case of epidemic clusters
Management, medical
Basic NEC protocol: for all stages
NPO
- NGT with low pressure suction
- Close monitoring of vital signs & abdominal girth
- Remove UAC and UVC
- Septic workup: blood, urine, and stool cultures
- LP and CSF culture: controversial
- Antibiotics: ampicillin + gentamicin or cefotaxime
- add Metronidazole or clindamycin if peritonitis or
- perforation is suspected
Management, medical
Basic NEC protocol …..continued
- Monitor for GI bleeding
- Fluid balance: maintain urine output 1-3 ml/kg/hr
- Lab.: CBC, PLT, electrolytes q 8-12 hrs
- PT, PTT, as indicated CR
- Radiology: serial AXR q 6-8 hrs in the first 2-3 days
- Family support
Management, medical
Stage I
Basic NEC protocol
If all cultures are negative, the infant improved clinically, and AXR is normal, antibiotics can be stopped after 2-3 days and feeding can be resumed.
Management, medical
Stage II
Basic NEC protocol
- NPO for 14 days
- TPN, 90-110 kcal/kg/day
- Antibiotics for 14 days
- Respiratory support
- ± Inotropic support
- Surgical consultation
Management, medical
Stage III
- As stage II
- Inotropic support
- Treat anemia, thrombocytopenia, coagulopathy
- Surgical intervention
Management, surgical
Early Surgical Consultation
Indications for surgery:
- Perforation: 20-30 % of cases
- 12-48 hrs after onset
- Full-thickness necrosis
- Deterioration despite aggressive medical treatment
Management, surgical
Surgical Approach:
Exploratory laparotomy
Peritoneal drainage
Management, surgical
Exploratory laparotomy:
The most commonly used approach
Intestinal resection with enterostomy
Primary anastomosis
Management, surgical
Peritoneal drainage:
More conservative approach, Started in 1977
Insertion of a peritoneal drainelocal anaesthesia
Initially, used for very sick premature babies, with weight ≤ 1000 g
Now, it is used more commonly with larger and more stable babies
It is used as a definite treatment in some centers
Management, surgical
Laparoscopy:
use of laparoscopy on day 30 of life in the treatment of a VLBW infant (900 g)
with perforated NEC
Needlescopic diagnosis is feasible and appears to be safe, even in
critically ill micropremmies less than 1000 g. The technique can provide useful information for surgical decision-making and allows for precise placement of a microlaparotomy incision over the site of perforation, thus minimizing the trauma from open surgery in this special group of patients
Prognosis and Outcome
NEC with perforation: mortality 20-40 %
Recurrent NEC : rare complication, 4%
Subacute or intermittent symptoms of bowel obstruction: strictures, 10-35 %
Short-gut syndrome: FTT, high mortality
The type of operation (peritoneal drain vs. laparotomy) performed for erforated NEC does not influence survival or other clinically important early outcomes in preterm infants
Neurodevelopmental Outcome
Preterm infants who develop NEC are at a significantly higher risk for developing neurodevelopmental disability
Neurodevelopmental Outcome
NEC is associated with significantly worse neurodevelopmental outcome than prematurity alone.
Presence of advanced NEC and need for surgery increase the risk of neurological impairment
Survivors of stage II or higher NEC are at risk for long-term neurodevelopmental impairment, especially if they require surgery for the illness
Prevention
- Breast milk
- Antenatal Steroid therapy
- Oral immunoglobulins
- Oral antibiotics
- Probiotics (Lactobacillus, Bifidobacterium)
- Feeding strategies
- Oral PAF antagonists
- Glutamine
- Arginine
- Polyunsaturated fatty acids (PUFA)
- Lactoferin
- Pentoxifylline
Prevention: breast milk
Formula vs. Donor Breast Milk:
Breast milk is associated with lower risk of NEC slower growth in the early postnatal period ¨
Prevention: Antenatal steroids
Antenatal corticosteroids for women at risk of preterm birth: Systematic Review
Decreased risk of NEC
RR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants
Prevention: Oral imunoglobulin
The evidence does not support the administration of oral immunoglobulin for the prevention of NEC. There are no randomised controlled trials of oral IgA alone for the prevention of NEC
Prevention: Probiotics
Probiotics might reduce the risk of necrotising enterocolitis in preterm neonates with less than 33 weeks' gestation (relative risk 0.36, 95% CI 0.20-0.65) the short-term and long-term safety of probiotics needs to be assessed in large trials Unanswered questions include the dose, duration, and type of probioticagents (species, strain, single or combined, live or killed) used for supplementation
Prevention: Feeding strategie
Probiotics might reduce the risk of necrotising enterocolitis in preterm neonates with less than 33 weeks' gestation (relative risk 0.36, 95% CI 0.20-0.65)
the short-term and long-term safety of probiotics needs to be assessed in large trials
Unanswered questions include the dose, duration, and type of probioticagents (species, strain, single or combined, live or killed) used for supplementation
Prevention: Glutamine
The available data from good quality randomised controlled trials suggest that glutamine supplementation does not confer clinically significant benefits for preterm infants
The narrow confidence intervals for the effect size estimates suggest that a further trial of this intervention is not a research priority
Prevention: Arginine
The data are insufficient at present to support a practice recommendation. A multicentre randomized controlled study of arginine supplementation in preterm neonates is needed, focusing on the incidence of NEC, particularly the more severe stages (2 or 3)