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

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.

Study Overview

• Status: Completed
• Conditions: Enterocolitis, Necrotizing; Intestinal Perforation; Infant, Small for Gestational Age; Infant, Premature; Infant, Low Birth Weight; Infant, Newborn
• Intervention / Treatment: Procedure: Laparotomy; Procedure: Drainage

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 529
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90025
      • University of California - Los Angeles
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale University
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Columbus, Ohio, United States, 43205
      • Research Institute at Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univeristy of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Randomized Trial: Laparotomy; Under general anesthesia in the NICU or operating room, a laparotomy will be performed following standard procedures.	Procedure: Laparotomy; 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.
Active Comparator: Randomized Trial: Peritoneal drain placement; Place a one-fourth inch Penrose drain in the lower abdomen with local anesthesia and sedation.	Procedure: Drainage; Initial drainage will involve placing a Penrose drain in the abdomen.; Other Names: Peritoneal drain
Active Comparator: Preference Cohort: Laparotomy; Under general anesthesia in the NICU or operating room, a laparotomy will be performed following standard procedures.	Procedure: Laparotomy; 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.
Active Comparator: Preference Cohort: Peritoneal drain placement; Place a one-fourth inch Penrose drain in the lower abdomen with local anesthesia and sedation.	Procedure: Drainage; Initial drainage will involve placing a Penrose drain in the abdomen.; Other Names: Peritoneal drain

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death or Neurodevelopmental Impairment (NDI)	Death or NDI at 18-22 months corrected age	at 18-22 months corrected age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Death by 18-22 months corrected age	by 18-22 months corrected age
Survival With Neurodevelopmental Impairment (NDI)	NDI at 18-22 months corrected age (among survivors)	by 18-22 months corrected age
Death or Moderate to Severe Cerebral Palsy	Death within 18-22 months corrected age or moderate to severe cerebral palsy at 18-22 months corrected age	up to the follow-up visit completed within the 18-22 months corrected age window
Death or Bayley Cognitive Composite Score Less Than 85	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.	up to the follow-up visit completed within the 18-22 months corrected age window
Death or Blindness	Death within 18-22 months corrected age or blindness at 18-22 months corrected age	up to the follow-up visit completed within the 18-22 months corrected age window
Death or Hearing Loss	Death within 18-22 months corrected age or hearing loss at 18-22 months corrected age	up to the follow-up visit completed within the 18-22 months corrected age window
Subsequent Laparotomy	Subsequent laparotomy after initial surgery	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
Any Intraoperative Complications During Any Surgery	Any intraoperative complications during any surgery	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	Any wound dehiscence during any surgery	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	Any intra-abdominal abscess during any surgery	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	Any intestinal stricture during any surgery	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	Any late onset sepsis after randomization	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	Any Parenteral nutrition (PN)-associated cholestasis during any surgery	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	Any severe IVH ater randomization	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	Duration of mechanical ventilation while on study	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	Duration of parenteral nutrition while on study	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	Final bowel length after last surgery	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	Time to full feeds while on study	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	Length of hospital stay while on study	from randomization up to 1 year following birth
Death or NDI Stratified by Pre-operative Diagnosis	Death or NDI at 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).	at 18-22 months corrected age
Death Stratified by Pre-operative Diagnosis	Death within 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).	by 18-22 months corrected age
Survival With Neurodevelopmental Impairment (NDI) Stratified by Pre-operative Diagnosis	NDI at 18-22 months corrected age (among survivors). Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).	by 18-22 months corrected age
Death or Moderate to Severe Cerebral Palsy Stratified by Pre-operative Diagnosis	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).	up to the follow-up visit completed within the 18-22 months corrected age window
Death or Bayley Cognitive Composite Score Less Than 85 Stratified by Pre-operative Diagnosis	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.	up to the follow-up visit completed within the 18-22 months corrected age window
Death or Blindness Stratified by Pre-operative Diagnosis	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).	up to the follow-up visit completed within the 18-22 months corrected age window
Death or Hearing Loss Stratified by Pre-operative Diagnosis	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).	up to the follow-up visit completed within the 18-22 months corrected age window
Subsequent Laparotomy Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	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 Stratified by Pre-operative Diagnosis	Length of hospital stay while on study. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).	from randomization up to 1 year following birth

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Carl D'Angio, MD, University of Rochester; Principal Investigator: Brenda Poindexter, MD, MS, Children's Hospital Medical Center, Cincinnati; Study Director: Martin K. Blakely, MD, Vanderbilt University Medical Center; Principal Investigator: Barbara Schmidt, MD, MSc, Univeristy of Pennsylvania; Principal Investigator: Uday Devaskar, MD, University of Carlifornia - Los Angeles; Principal Investigator: Brad Yoder, MD, University of Utah

Publications and helpful links

Helpful Links

• NICHD Neonatal Research Network

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2010
• Primary Completion (Actual): August 1, 2019
• Study Completion (Actual): August 1, 2019

Study Registration Dates

• First Submitted: December 9, 2009
• First Submitted That Met QC Criteria: December 9, 2009
• First Posted (Estimate): December 10, 2009

Study Record Updates

• Last Update Posted (Actual): November 23, 2021
• Last Update Submitted That Met QC Criteria: November 19, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Drainage; Prematurity; Laparotomy; NICHD Neonatal Research Network; Very Low Birth Weight (VLBW); Extremely Low Birth Weight (ELBW); Isolated intestinal perforation; Focal intestinal perforation
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Body Weight; Gastroenteritis; Intestinal Diseases; Birth Weight; Enterocolitis; Enterocolitis, Necrotizing; Intestinal Perforation
• Other Study ID Numbers: NICHD-NRN-0039; UG1HD087226 (U.S. NIH Grant/Contract); U10HD036790 (U.S. NIH Grant/Contract); U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027871 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD040492 (U.S. NIH Grant/Contract); U10HD040689 (U.S. NIH Grant/Contract); U10HD053089 (U.S. NIH Grant/Contract); U10HD053109 (U.S. NIH Grant/Contract); U10HD053119 (U.S. NIH Grant/Contract); U10HD053124 (U.S. NIH Grant/Contract); UL1RR024139 (U.S. NIH Grant/Contract); UL1RR025744 (U.S. NIH Grant/Contract); UL1RR024979 (U.S. NIH Grant/Contract); M01RR008084 (U.S. NIH Grant/Contract); U10HD068244 (U.S. NIH Grant/Contract); U10HD068263 (U.S. NIH Grant/Contract); U10HD068270 (U.S. NIH Grant/Contract); U10HD068278 (U.S. NIH Grant/Contract); U10HD068284 (U.S. NIH Grant/Contract); UL1RR025764 (U.S. NIH Grant/Contract); UL1RR025777 (U.S. NIH Grant/Contract)