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

• ClinicalTrials.gov Identifier: NCT01029353
• Recruitment Status: Completed
• First Posted: December 10, 2009
• Results First Posted: November 23, 2021
• Last Update Posted: November 23, 2021
• Sponsor: NICHD Neonatal Research Network
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center for Research Resources (NCRR)
• Information provided by (Responsible Party): NICHD Neonatal Research Network

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Infant, Newborn; Infant, Low Birth Weight; Infant, Small for Gestational Age; Infant, Premature; Enterocolitis, Necrotizing; Intestinal Perforation	Procedure: Laparotomy; Procedure: Drainage	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 529 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: January 2010
• Actual Primary Completion Date: August 2019
• Actual Study Completion Date: August 2019

Arms and Interventions

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 Name: 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 Name: Peritoneal drain

Outcome Measures

Primary Outcome Measures :

1. Death or Neurodevelopmental Impairment (NDI) [ Time Frame: at 18-22 months corrected age ]
   Death or NDI at 18-22 months corrected age

Secondary Outcome Measures :

1. Death [ Time Frame: by 18-22 months corrected age ]
   Death by 18-22 months corrected age
2. Survival With Neurodevelopmental Impairment (NDI) [ Time Frame: by 18-22 months corrected age ]
   NDI at 18-22 months corrected age (among survivors)
3. Death or Moderate to Severe Cerebral Palsy [ Time Frame: up to the follow-up visit completed within the 18-22 months corrected age window ]
   Death within 18-22 months corrected age or moderate to severe cerebral palsy at 18-22 months corrected age
4. Death or Bayley Cognitive Composite Score Less Than 85 [ Time Frame: up to the follow-up visit completed within the 18-22 months corrected age window ]
   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.
5. Death or Blindness [ Time Frame: up to the follow-up visit completed within the 18-22 months corrected age window ]
   Death within 18-22 months corrected age or blindness at 18-22 months corrected age
6. Death or Hearing Loss [ Time Frame: up to the follow-up visit completed within the 18-22 months corrected age window ]
   Death within 18-22 months corrected age or hearing loss at 18-22 months corrected age
7. Subsequent Laparotomy [ Time Frame: 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 ]
   Subsequent laparotomy after initial surgery
8. Any Intraoperative Complications During Any Surgery [ Time Frame: 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
9. Any Wound Dehiscence [ Time Frame: 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
10. Any Intra-abdominal Abscess [ Time Frame: 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
11. Any Intestinal Stricture [ Time Frame: 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
12. Any Late Onset Sepsis [ Time Frame: 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
13. Any Parenteral Nutrition (PN)-Associated Cholestasis [ Time Frame: 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
14. Any Severe IVH [ Time Frame: 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
15. Duration of Mechanical Ventilation [ Time Frame: 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
16. Duration of Parenteral Nutrition [ Time Frame: 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
17. Final Bowel Length [ Time Frame: 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
18. Time to Full Feeds [ Time Frame: 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
19. Length of Hospital Stay [ Time Frame: from randomization up to 1 year following birth ]
    Length of hospital stay while on study
20. Death or NDI Stratified by Pre-operative Diagnosis [ Time Frame: at 18-22 months corrected age ]
    Death or NDI at 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).
21. Death Stratified by Pre-operative Diagnosis [ Time Frame: by 18-22 months corrected age ]
    Death within 18-22 months corrected age. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).
22. Survival With Neurodevelopmental Impairment (NDI) Stratified by Pre-operative Diagnosis [ Time Frame: by 18-22 months corrected age ]
    NDI at 18-22 months corrected age (among survivors). Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).
23. Death or Moderate to Severe Cerebral Palsy Stratified by Pre-operative Diagnosis [ Time Frame: up to the follow-up visit completed within the 18-22 months corrected age window ]
    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).
24. Death or Bayley Cognitive Composite Score Less Than 85 Stratified by Pre-operative Diagnosis [ Time Frame: up to the follow-up visit completed within the 18-22 months corrected age window ]
    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.
25. Death or Blindness Stratified by Pre-operative Diagnosis [ Time Frame: up to the follow-up visit completed within the 18-22 months corrected age window ]
    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).
26. Death or Hearing Loss Stratified by Pre-operative Diagnosis [ Time Frame: up to the follow-up visit completed within the 18-22 months corrected age window ]
    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).
27. Subsequent Laparotomy Stratified by Pre-operative Diagnosis [ Time Frame: between randomization and Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Subsequent laparotomy after initial surgery. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).
28. Any Intraoperative Complications During Any Surgery Stratified by Pre-operative Diagnosis [ Time Frame: 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).
29. Any Wound Dehiscence Stratified by Pre-operative Diagnosis [ Time Frame: 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).
30. Any Intra-abdominal Abscess Stratified by Pre-operative Diagnosis [ Time Frame: 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).
31. Any Intestinal Stricture Stratified by Pre-operative Diagnosis [ Time Frame: 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).
32. Any Late Onset Sepsis Stratified by Pre-operative Diagnosis [ Time Frame: 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).
33. Any Parenteral Nutrition (PN)-Associated Cholestasis Stratified by Pre-operative Diagnosis [ Time Frame: 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).
34. Any Severe IVH Stratified by Pre-operative Diagnosis [ Time Frame: 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).
35. Duration of Mechanical Ventilation Stratified by Pre-operative Diagnosis [ Time Frame: 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).
36. Duration of Parenteral Nutrition Stratified by Pre-operative Diagnosis [ Time Frame: 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).
37. Final Bowel Length Stratified by Pre-operative Diagnosis [ Time Frame: 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).
38. Time to Full Feeds Stratified by Pre-operative Diagnosis [ Time Frame: 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).
39. Length of Hospital Stay Stratified by Pre-operative Diagnosis [ Time Frame: from randomization up to 1 year following birth ]
    Length of hospital stay while on study. Stratification variable is pre-operative diagnosis: Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP).

Eligibility Criteria

• Ages Eligible for Study: up to 8 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35233

United States, California

University of California - Los Angeles

Los Angeles, California, United States, 90025

Stanford University

Palo Alto, California, United States, 94304

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06504

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30303

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Massachusetts

Tufts Medical Center

Boston, Massachusetts, United States, 02111

United States, Michigan

Wayne State University

Detroit, Michigan, United States, 48201

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64108

United States, New Mexico

University of New Mexico

Albuquerque, New Mexico, United States, 87131

United States, New York

University of Rochester

Rochester, New York, United States, 14642

United States, North Carolina

RTI International

Durham, North Carolina, United States, 27705

Duke University

Durham, North Carolina, United States, 27710

United States, Ohio

Cincinnati Children's Medical Center

Cincinnati, Ohio, United States, 45267

Case Western Reserve University

Cleveland, Ohio, United States, 44106

Research Institute at Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Pennsylvania

Univeristy of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Rhode Island

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States, 02905

United States, Texas

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States, 75235

University of Texas Health Science Center at Houston

Houston, Texas, United States, 77030

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84108

Sponsors and Collaborators

NICHD Neonatal Research Network

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Abbot R. Laptook, MD; Brown University, Women & Infants Hospital of Rhode Island
• Principal Investigator: Michele C. Walsh, MD MS; Case Western Reserve University, Rainbow Babies and Children's Hospital
• Principal Investigator: C. Michael Cotten, MD; Duke University
• Principal Investigator: David Carlton, MD; Emory University
• Principal Investigator: Greg Sokol, MD; Indiana University
• Principal Investigator: Abhik Das, PhD; RTI International
• Principal Investigator: Krisa P. Van Meurs, MD; Stanford University
• Principal Investigator: Ivan D. Frantz III, MD; Tufts Medical Center
• Principal Investigator: Brenda Poindexter, MD, MS; Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Waldemar A. Carlo, MD; University of Alabama at Birmingham
• Principal Investigator: Edward F. Bell, MD; University of Iowa
• Principal Investigator: Kristi L. Watterberg, MD; University of New Mexico
• Principal Investigator: Myra Wyckoff, MD; University of Texas, Southwestern Medical Center at Dallas
• Principal Investigator: Kathleen A. Kennedy, MD MPH; The University of Texas Health Science Center, Houston
• Principal Investigator: Seetha Shankaran, MD; Wayne State University
• Principal Investigator: Richard A. Ehrenkranz, MD; Yale University
• Study Director: Martin K. Blakely, MD; Vanderbilt University Medical Center
• Principal Investigator: William Truog, MD; Children's Mercy Hospital Kansas City
• Principal Investigator: Barbara Schmidt, MD, MSc; Univeristy of Pennsylvania
• Principal Investigator: Carl D'Angio, MD; University of Rochester
• Principal Investigator: Uday Devaskar, MD; University of Carlifornia - Los Angeles
• Principal Investigator: Leif Nelin, MD; Research Institute at Nationwide Children's Hospital
• Principal Investigator: Brad Yoder, MD; University of Utah

  Study Documents (Full-Text)

Documents provided by NICHD Neonatal Research Network:

Study Protocol  [PDF] February 12, 2013

Statistical Analysis Plan  [PDF] August 23, 2019

More Information

Additional Information:

NICHD Neonatal Research Network 

• Responsible Party: NICHD Neonatal Research Network
• ClinicalTrials.gov Identifier: NCT01029353
• Other Study ID Numbers: NICHD-NRN-0039; 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 ); U10HD036790 ( 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 ); UL1RR025764 ( U.S. NIH Grant/Contract ); UL1RR025777 ( U.S. NIH Grant/Contract ); M01RR008084 ( U.S. NIH Grant/Contract ); UL1RR024979 ( U.S. NIH Grant/Contract ); U10HD068284 ( U.S. NIH Grant/Contract ); U10HD068278 ( U.S. NIH Grant/Contract ); U10HD068270 ( U.S. NIH Grant/Contract ); U10HD068263 ( U.S. NIH Grant/Contract ); U10HD068244 ( U.S. NIH Grant/Contract ); UG1HD087226 ( U.S. NIH Grant/Contract )
• First Posted: December 10, 2009
• Results First Posted: November 23, 2021
• Last Update Posted: November 23, 2021
• Last Verified: November 2021

Keywords provided by NICHD Neonatal Research Network:

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

Additional relevant MeSH terms:

Enterocolitis; Enterocolitis, Necrotizing; Intestinal Perforation; Birth Weight; Body Weight; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases