Purpose and Goal: CNEP # 2045

  • Describe the characteristics of transfusion associated necrotizing enterocolitis.
  • Identify at least two strategies for the prevention of transfusion associated necrotizing enterocolitis.

None of the planners, faculty or content specialists has any conflict of interest or will be presenting any off-label product use. This presentation has no commercial support or sponsorship, nor is it co-sponsored.

Requirements for Successful Completion

  • Successfully complete the post-test.
  • Complete the evaluation form.

Date

  • December 2015 – December 2017

Learning Objectives

  • Describe the pathophysiology of transfusion associated necrotizing enterocolitis.
  • Describe the clinical presentation of transfusion associated necrotizing enterocolitis.
  • Identify at least two treatment strategies for the prevention of transfusion associated necrotizing enterocolitis.

Introduction

  • Necrotizing enterocolitis is a devastating disease.
  • It is a leading cause of prolonged hospitalization for premature infants in the United States.
  • There is growing evidence that necrotizing enterocolitis can be associated with packed red blood cell transfusions.
  • Necrotizing enterocolitis is also known as NEC.
  • Transfusion associated NEC is also known as TANEC.

Definition and Incidence

  • NEC is one of the most common gastrointestinal emergencies in the newborn infant.
  • It is characterized by ischemic necrosis of intestinal mucosa.
  • Ischemic necrosis is associated with:
    • Inflammation of the GI tract
    • Invasion of gas forming organisms
    • Dissection of gas into the portal venous system
     
  • NEC increases the risk of long term morbidity.
  • Early recognition and treatment improves outcomes.
  • The incidence of NEC is between 1–3/1000 births.
  • NEC occurs in 1-8% of all NICU admissions.

Premature Infants

  • 90% of NEC occurs in premature infants.
  • NEC is inversely related to age and weight.
  • NEC increases as gestational age decreases.
  • NEC also increases as birthweight decreases.
    • Birthweight 401–750 grams – 11.5%
    • Birthweight 751–1000 grams – 9%
    • Birthweight 1001–1250 grams – 6%
    • Birthweight 1251–1500 grams – 4%
     
  • The overall rate of mortality is as high as 80%.
  • Mortality is inversely related to gestational age.
  • Mortality is inversely related to birthweight.

Term Infants

  • The majority of infants with NEC are premature.
  • Approximately 13% of NEC occurs in term infants.
  • The majority of term infants who develop NEC will have a preexisting illness:
    • Congenital heart disease
    • Birth hypoxia
    • Seizures
    • Sepsis
    • Hypoglycemia
    • Severe IUGR
    • Polycythemia
    • Genetic disorders
     

Pathophysiology

  • The pathology of NEC is due to intestinal infarction.
  • NEC occurs mostly in the terminal ileum and colon.
  • The etiology and pathogenesis of NEC is unknown.
  • NEC is thought to be caused by multiple factors:
    • Prematurity
    • Microbial bowel overgrowth
    • Impaired mucosal defense
    • Circulatory instability of GI tract
    • Hypertonic medication use
    • Formula feeding
     
  • The premature GI tract and immune system are thought to predispose premature infants to NEC.
    • Immature mucosal barrier
    • Increased intestinal permeability
    • Increased bacterial penetration
    • Immature bowel motility
    • Immature bowel function
    • Immature local host defenses
    • Diminished concentrations of:
      • Secretory IgA
      • Mucosal enzymes
       
     

Clinical Presentation

  • Most infants who develop NEC are:
    • Healthy
    • Feeding well
    • Growing
     
  • The median age at onset is:
    • 3 days for <26 weeks gestation
    • 11 days for >31 weeks gestation
     
  • 25% of NEC presents later than 30 days.
  • Many infants present with nonspecific signs.
    • 20–30% present with bacterial sepsis.
     
  • The clinical presentation of NEC may involve:
  • Systemic signs
    • Apnea
    • Bradycardia
    • Respiratory distress
    • Lethargy
    • Poor feeding
    • Temperature instability
    • Hypotension
    • Shock
     
  • Abdominal signs
    • Gastric residuals
    • Bilious residuals
    • Distention
    • Tenderness
    • Discoloration
    • Vomiting
    • Diarrhea
    • Bloody stools
    • Rectal bleeding
     
  • The earliest sign may be changes in feeding tolerance.

Bell Staging Criteria

  • Bell staging is a common way to define NEC.
  • Stage I is suspected NEC.
    • Infants are mildly ill.
    • Nonspecific systemic signs
      • Apnea
      • Lethargy
      • Temperature instability
       
    • Abdominal signs are present:
      • Gastric residuals
      • Distention
      • Vomiting
      • Bloody stools
       
    • X-rays are normal or show dilation
     
  • Stage II is proven NEC.
    • Infants are mildly to moderately ill.
    • Nonspecific systemic signs:
      • Apnea
      • Lethargy
      • Temperature instability
      • Mild metabolic acidosis
      • Thrombocytopenia
       
    • Abdominal signs are present:
      • Gastric residuals
      • Distention
      • Vomiting
      • Bloody stools
      • Absent bowel sounds
      • Tenderness
      • Discoloration
       
    • X-rays show:
      • Dilation
      • Ileus
      • Pneumatosis
      • Ascites
       
     
  • Stage III is advanced NEC.
    • Infants are critically ill.
    • Nonspecific systemic signs:
      • Hypotension
      • Bradycardia
      • Severe apnea
      • Respiratory acidosis
      • Metabolic acidosis
      • Neutropenia
      • Disseminated coagulopathy
       
    • Abdominal signs are severe.
      • Distension
      • Marked tenderness
      • Perforation
      • Peritonitis
       
    • X-rays show:
      • Pneumatosis
      • Pneumoperitoneum
      • Portal venous system air
       
     

Diagnosis

  • Diagnosis is based on the presence of:
    • Abdominal distention
    • Bloody stools
    • Rectal bleeding
    • Pneumatosis
     
  • Dilated loops of bowel on X-ray
    • Consistent with ileus
    • Typical of early stages
     
  • Pneumatosis on X-ray
    • Hallmark of NEC
    • Looks like bubbles in small bowel wall
     
  • Pneumoperitneum on X-ray
    • Occurs when perforation is present
    • Indicative of intraperitoneal air
    • Often looks like a "football" sign
     
  • Sentinal loops on X-ray
    • Dilated loops that do not change
    • Dilated loops that remain fixed
    • Indicative of perforation
    • Indicative of necrosis
     
  • Portal venous system air
    • Predictive of poor outcome
    • Indicative of surgical intervention
     

Milk Feeding

  • Milk feeding is a consistent risk factor for NEC.
  • >90% of infants with NEC have received milk feeds.
  • Milk is thought to provide substrate for bacterial growth.
  • Trophic feeds have not been shown to reduce NEC.
  • Delayed feeds have not been shown to reduce NEC.

Human Milk

  • Human milk is more protective against NEC.
  • Human milk reduces the risk of NEC by:
    • Reducing intestinal inflammation
    • Reducing introduction of foreign antigens
    • Lowering gastric pH
    • Decreasing growth of pathogenic bacteria
    • Facilitating growth of nonpathogenic bacteria
    • Providing growth factors to repair intestinal mucosa
    • Improving intestinal motility to decrease stasis
    • Stimulating mucosal defense system
    • Providing immunoglobulins, cytokines, antioxidants
     

Transfusion Associated NEC

  • Red blood cell transfusions have been shown to be associated with an increased risk of NEC.
  • Several studies have reported this association.
    • NEC has occurred within 48 hours.
    • The incidence of TANEC is 20–35%.
    • Surgical intervention is more likely.
     
  • Infants with TANEC have a higher risk of mortality.
    • They have lower birthweights.
    • They have earlier gestational ages.
    • They have been more severely ill.
    • They develop NEC after 30 days.
     
  • TANEC is thought to occur because of:
    • Immunologic injury to the intestine
    • Vasoconstriction and thrombus formation
    • Intestinal injury due to impaired blood flow
     
  • Stored red blood cells are known to have:
    • Reduced ability to change shape
    • Increased adhesion properties
    • Increased aggregation properties
     

Treatment and Medical Management

  • Medical management should be initiated immediately whenever NEC is suspected.
  • Medical management consists of:
    • Supportive care
    • Antibiotics
    • Laboratory monitoring
    • Serial X-ray monitoring
     
  • Supportive care
    • NPO
    • Bowel rest
    • Decompression
    • Fluid management
    • Respiratory support
    • Cardiovascular support
     
  • Antibiotic therapy
    • Commonly a 10–14 day course
    • Antibiotic use based on local bacteria
    • Ampicillin, Gentamicin, Flagyl
    • Zosyn and Gentamicin
    • Vancomicin, Zosyn, Gentamicin
    • Meropenem
     
  • Laboratory monitoring
    • Every 12–24 hours until stable
    • CBC with differential
    • Platelet count
    • Basic metabolic panel
     
  • Serial X-ray monitoring
  • Every 6–12 hours until stable
    • Supine anterior-posterior
    • Left lateral decubitus
    • Cross table lateral
     

Treatment and Surgical Management

  • Surgical management is indicated when:
    • Bowel perforation occurs
    • Pneumoperitoneum is present
    • Signs of peritonitis are present
     
  • Surgical procedures include:
    • Surgical resection
    • Exploratory laparotomy
    • Peritoneal drain placement
     

Complications

  • Acute complications
    • Infection
      • Sepsis
      • Meningitis
      • Peritonitis
      • Abscess formation
       
     
  • Disseminated coagulopathy
  • Respiratory failure
  • Cardiovascular
    • Hypotension
    • Shock
     
  • Metabolic
    • Hypoglycemia
    • Metabolic acidosis
     
  • Late complications
    • Intestinal narrowing
      • Stricture formation
      • Adhesion formation
       
    • Short bowel syndrome
     

Prognosis and Outcomes

  • The earlier NEC is recognized and treated, the better the prognosis.
  • The overall survival rate is 70–80%.
  • Mortality rates
    • 601–750 grams – 42%
    • 751–1000 grams – 29%
    • 1001–1250 grams – 21%
    • 1251–1500 grams – 16%
     
  • Long-term outcome
    • No side effects – 50%
    • GI morbidity – 10%
     
  • Growth and development
    • Infants <1000 grams have significant delays.
    • NEC survivors have twice as many delays as infants at the same gestational age who did not have NEC.
    • Infants who required surgical intervention have poorer outcomes than infants who required medical management.
     

Prevention Strategies

  • Strategies are aimed at reducing risk factors.
  • The use of human milk is known to reduce risks.
    • Exclusive use is the most important strategy.
    • Fortified human milk use results in less NEC.
    • Donor human milk may be used as needed.
    • Formula fed infants have an increased risk.
      • Studies show 3 times more risk.
       
     
  • Feeding protocols can also be beneficial.
    • Cautious feeding advancement
    • Avoidance of hypertonic medications
    • Avoidance of hypertonic formulas
    • Prompt treatment of polycythemia
     
  • Timing of initiation of feeds
    • Optimal timing remains unknown.
    • There is no clear association with NEC.
     
  • Probiotics
    • Probiotics are live nonpathogenic bacteria.
    • Probiotics are thought to offer protection by:
      • Improving intestinal barrier function
      • Modulating the immune system
      • Suppressing growth of pathogens
       
    • The use of probiotics appears promising by:
      • Decreasing the severity of NEC
      • Decreasing overall mortality rates
      • Universal use is not yet recommended.
       
     
  • Immunoglobulins
    • Oral immunoglobulins may reduce NEC.
    • IgG and IgA may inhibit cytokine release.
     
  • Nutritional supplements
    • Arginine appears to offer protection.
    • Glutamine has not been shown to be effective.
    • Oligosaccharides are currently being studied.
     
  • Other recommended strategies
    • Avoidance of histamine 2 blockers
    • Avoidance of prolonged use of antibiotics
     

Strategies Specific to TANEC

 

  • Strategies are aimed at balancing hemodynamic stability and nutritional needs.
  • Preliminary evidence suggests a protective effect can be obtained by:
    • Exclusive use of human milk
    • Limiting blood draws to avoid anemia
    • Standardizing transfusion practices
    • Transfusing fresh single donor blood
    • Monitoring infants for subtle changes
    • Holding feedings during a transfusion
     
  • Infants may not be able to tolerate feedings while intestinal blood flow is impaired.
  • Optimal timing for withholding feeds is unclear.
    • Holding feedings before a transfusion
    • Holding feedings after a transfusion
    • More research is needed to guide practice.
     

 

Summary

 

  • NEC is a common GI emergency in newborn infants.
  • There is growing evidence that red blood cell transfusions can be associated with NEC.
  • Transfusion associated NEC is also known as TANEC.
  • TANEC occurs in 25–35% of all NEC cases.
  • Infants with TANEC are at higher risk of mortality.
  • NEC and TANEC are a leading cause of prolonged hospitalization.
    • The costs of prolonged hospitalization are exorbitant.
    • The prevention of NEC is a national health priority.
    • Early recognition and possible prevention can have a significant impact on the elimination of TANEC.
     

 

 

References

 

 

  1. Gephardt, S.M. 2012. Transfusion-Associated Necrotizing Enterocolitis. Advances in Neonatal Care, 12 (4), p. 232-236.
  2. Luton, A. 2013. Transfusion-Associated Necrotizing Enterocolitis: Translating Knowledge into Nursing Practice. Neonatal Network, 32 (3), p 167-174.
  3. Schanler, R.J. 2014. Clinical Features and Diagnosis of Necrotizing Enterocolitis in Newborns. Up-To-Date.
  4. Schanler, R.J. 2014. Pathology and Pathogenesis of Necrotizing Enterocolitis in Newborns. Up-To-Date.
  5. Schanler, R.J. 2014. Management of Necrotizing Enterocolitis in Newborns. Up-To-Date.
  6. Schanler, R.J. 2014. Prevention of Necrotizing Enterocolitis in Newborns. Up-To-Date.
  7. Parker, L.A., Neu, J., Torrazza, R.M., and Li, Y. 2013. Scientifically Based Strategies for Enteral Feeding in Premature Infants. NeoReviews, 14 (7), p. e350-e359.

 

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