Laparotomy vs. Drainage for Infants With Necrotizing Enterocolitis (NEST)

A Multi-center Randomized Trial of Laparotomy vs. Drainage as the Initial Surgical Therapy for ELBW Infants With Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP): Outcomes at 18-22 Months Adjusted Age

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Research Resources (NCRR)

This study will compare the effectiveness of two surgical procedures -laparotomy versus drainage - commonly used to treat necrotizing enterocolitis (NEC) or isolated intestinal perforations (IP) in extremely low birth weight infants (≤1,000 g). Infants diagnosed with NEC or IP requiring surgical intervention, will be recruited. Subjects will be randomized to receive either a laparotomy or peritoneal drainage. Primary outcome is impairment-free survival at 18-22 months corrected age.

Necrotizing enterocolitis (NEC) is a condition, generally affecting premature infants, in which the intestines become ischemic (lack oxygen and/or blood flow). NEC occurs in up to 5-15% of extremely low birth weight (ELBW) infants. Isolated or focal intestinal perforation (IP) is a less common condition, affecting an estimated 4% of ELBWs, in which a hole develops in the intestines leaking fluid into the abdominal cavity. Outcome for infants with NEC and/or IP is poor: 49% die and half of the surviving infants are neurodevelopmentally impaired. Surgical options for NEC and IP include two possible procedures: peritoneal drainage, in which a tube is placed in the abdominal cavity through a small incision for fluid to drain out; or laparotomy, in which an incision is made in the abdomen and necrotic intestine is removed. Drainage may be followed by a laparotomy. The Neonatal Research Network's observational study of 156 ELBW infants with NEC or IP (Pediatrics. 2006 Apr; 117(4): e680-7) showed comparable outcomes for the two procedures before hospital discharge, but suggested an advantage of laparotomy over drainage at 18-22 months corrected age with lower rates of death or neurodevelopmental impairment. However, the infants that underwent laparotomy were more mature; infants with drains were smaller and more premature. We hypothesize that initial laparotomy may improve an infant's long-term neurodevelopmental outcome, potentially by reducing the maximum severity or duration of inflammation. This study included a randomized controlled trial to compare the effectiveness of laparotomy versus drainage for treating NEC or IP in extremely low birth weight infants. Target enrollment is 300 infants diagnosed with NEC or IP for randomization to receive initially either a laparotomy or drainage. Subsequent laparotomies may be performed on infants in either group, if their condition continues to deteriorate. Surviving infants will return for a follow-up assessment at 18-22 months corrected age. This study also attempted to use a comprehensive cohort design that would have added additional information beyond the conventional randomized trial component. The cohort component included trial data among eligible, non-randomized infants with NEC/IP, who consented for the non-randomized cohort, would be collected and analyzed as a secondary specific aim. This additional cohort was called the preference cohort.

Infant, Newborn, Infant, Low Birth Weight, Infant, Small for Gestational Age, Infant, Premature, Enterocolitis, Necrotizing, Intestinal Perforation

NICHD Neonatal Research Network, Very Low Birth Weight (VLBW), Extremely Low Birth Weight (ELBW), Prematurity, Laparotomy, Drainage, Isolated intestinal perforation, Focal intestinal perforation

Under general anesthesia in the NICU or operating room, a laparotomy will be performed following standard procedures.

Under general anesthesia in the NICU or operating room, a laparotomy will be performed following standard procedures.

Initial laparotomy will be performed. Standard procedures will be used, including inspection of the bowel with removal of diseased areas, creation of stoma(s), and other procedures deemed indicated by the surgeon.

Death within 18-22 months corrected age or moderate to severe cerebral palsy at 18-22 months corrected age

Death within 18-22 months corrected age or Bayley cognitive composite score less than 85 at 18-22 months corrected age. Higher values of the Bayley cognitive composite score is better than lower values. Normal values are greater than or equal to 85. A moderate value is in the 70-84 range, and a severe value is <70.

between initial surgery and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Death or NDI at 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

Death within 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

NDI at 18-22 months corrected age (among survivors). Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

Death within 18-22 months corrected age or moderate to severe cerebral palsy at 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

Death within 18-22 months corrected age or Bayley cognitive composite score less than 85 at 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP). Higher values of the Bayley cognitive composite score is better than lower values. Normal values are greater than or equal to 85. A moderate value is in the 70-84 range, and a severe value is <70.

Death within 18-22 months corrected age or blindness at 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

Death within 18-22 months corrected age or hearing loss at 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

Subsequent laparotomy after initial surgery. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Any intraoperative complications during any surgery. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Any wound dehiscence during any surgery. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Any intra-abdominal abscess during any surgery. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Any intestinal stricture during any surgery. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Any late onset sepsis after randomization. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Any Parenteral nutrition (PN)-associated cholestasis during any surgery. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Any severe IVH ater randomization. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Duration of mechanical ventilation while on study. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Duration of parenteral nutrition while on study. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Final bowel length after last surgery. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Time to full feeds while on study. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

Length of hospital stay while on study. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

Inclusion Criteria: Infants born at ≤1,000 g birth weight Infant is ≤8 0/7 weeks of age at the time of eligibility assessment Pediatric surgeon decision to perform surgery for suspected NEC or IP Subject is at a center able to perform both laparotomy and drainage Exclusion Criteria: Major anomaly that influences likelihood of developing primary outcome or affects surgical treatment considerations Congenital infection Prior laparotomy or peritoneal drain placement Prior NEC or IP Infant for whom full support is not being provided Follow-up unlikely