Laparotomy vs. Drainage for Infants With Necrotizing Enterocolitis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

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

Intervention / Treatment
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* Procedure: Laparotomy
* Procedure: Drainage


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 8 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NICHD Neonatal Research Network, Very Low Birth Weight (VLBW), Extremely Low Birth Weight (ELBW), Prematurity, Laparotomy, Drainage, Isolated intestinal perforation, Focal intestinal perforation