Saline Enema Administration in Meconium Obstruction of Prematurity and Impact on the Resolution, Feeds, Microbiome, and Gut-brain Axis.

Study Overview
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Brief Summary
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The goal of this clinical trial is to study the effect of twice-daily saline enema (SE) in the treatment obstruction of prematurity (MOP) in infants with the birth weight ≤1.25kg. The main questions, the trial aims to answer are To validate the finding of our pilot study which had shown that twice-daily SE reduces the time to reach full enteral feeds in premature infant as compared to premature infant treated with Glycerine Suppository (GS), in a larger cohort. Infant with MOP fails to pass meconium in the first 48 hours of life and develop symptoms and signs like abdominal distension and feed intolerance. The other aims of this study are to test whether the intervention is Effective treatment for MOP Reduce the duration of ICU stay Reduce the rate of necrotizing enterocolitis, sepsis, Total Parenteral Nutrition (TPN) days and number of intravenous catheter days The study also wants to explore the impact of this intervention on the gut microbiome, gut-brain interaction and immune response of the new-born.

Detailed Description
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Very low birth weight infants (VLBW ≤ 1.5 kg) constitute more than 60% of bed occupancy in level III neonatal units. They face the risk of 10-50% long-term disability, and their initial healthcare cost ranges from S$50,000 to 1 million, an important healthcare issue. The incidence of meconium obstruction of prematurity (MOP) is 20-30% in extremely low birth weight (ELBW ≤ 1 kg) infants. The intervention based on the current standard of care increase the risk of laparotomy necrotizing enterocolitis, intestinal perforation, and neurodevelopmental risks posed by general anaesthesia. Our published pilot RCT demonstrated that saline enema (SE) is an effective, feasible, and safe intervention to reduce the time to reach full enteral feeds and is a potentially effective treatment for MOP in ELBW (< 1 kg) infants. Our primary hypothesis is that Infants with Twice-daily high-volume SE (20-40 ml/kg/day) intervention will result in reduced time to reach full enteral feeds compared to infants treated with conventional management with Glycerin suppository (GS) in (≤1.25kg) infants with MOP. Our exploratory hypothesis is that SE will have a protective effect on the gut microbiome, inflammatory and immune response in preterm infants. Ninety-five infants born over three years in KK Hospital (KKH) and Singapore General Hospital (SGH) will be enrolled and randomized at 48 hours or later to receive SE or GS. The standardized protocol will be used for the accreditation and administration of SE. Primary, secondary, and exploratory outcomes data, including treatment failure data, will be recorded. Infants will be followed up to 36 weeks of gestation or discharge, whichever is earlier. Maternal and infant characteristics, inflammatory and immune response, and safety outcome data will be collected. If the findings of our pilot trial are confirmed, the protocol can become the standard of care in preterm infants with MOP. Additionally, significant healthcare cost savings will be realized alongside an improved understanding of the Microbiome, immune and inflammatory response pertaining to the gut.

Official Title
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The Administration of Saline Enema Versus Glycerin Suppository as a Treatment Intervention for Meconium Obstruction of Prematurity (MOP) and to Study the Impact on the Resolution of MOP, Time to Reach Full Enteral Feeds, Gut Microbiome, and Gut-brain Axis, a Randomised Control Trial.

Conditions
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Meconium Obstruction of Prematurity

Intervention / Treatment
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* Procedure: Saline Enema (SE)
* Drug: Glycerin Suppository


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Criteria A: For infant presenting with early onset of MOP Birth weight 500 - 1250 gram ≥ 23 weeks gestation No BO for 48 hours BO present but with a small amount or stain of meconium Feeds intolerance or abdominal X-ray showing dilated loops of bowel Criteria B: For infant presenting with Late onset of MOP Birth weight 500 - 1250 gram ≥ 23 weeks gestation Infants who passed meconium initially and develop evidence of meconium obstruction at a later age (feed intolerance or vomiting and abnormal abdominal X-ray with or without abdominal distension) Exclusion Criteria: Infants that: Neuromuscular disorder Moderate or severe asphyxia Inability to start enteral feeding, which continued for 3 consecutive days before 2 weeks of post-natal age for reasons unrelated to meconium inspissation or its complication Without parental consent Aggravated medical instability Single mothers < 21 years

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 36 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: The treatment group will receive SE with normal saline (20-40 ml/kg/per SE) 2 times a day at 48 to 72 hrs of age at the earliest. The infant with medical instability procedure will be deferred until the infant is medically fit and intervention is continued until the infant reaches full feeds, defined as 110 ml/kg/day or yellow stools whichever is earlier. SE will be recommenced if the infant does not open bowel for 2 days before reaching full feeds. In ≤ 750 grams infant, paediatric surgeons would perform the first catheterisation with 6F catheter, insertion length will be limited to 8 cm, and saline is infused with the aid of gravity. Syringe flushing is allowed if gravity force fail to drive saline to the intestine.Two ultrasound abdominal examination will be performed and first scan will coincide with first SE in 500-750 grams infants.Failure to resolve the MOP with SE will be designated as treatment failure and managed with contrast enema or Laparotomy by paediatric surgeons.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Arm (Saline Enema Arm)<br>After randomisation, infant who allocated with intervention group will proceed with SE with normal saline (20-40ml/kg twice daily) earliest at 48 to 72 hours of age. Then continue until 2 days of yellow stools/ 110ml/kg/day of oral feeds; whichever is earlier. SE are recommended if baby do not do bowel opening (BO) for 2 days before reaching full feeds | Procedure: Saline Enema (SE)<br>* infant who allocated with intervention group will proceed with SE with normal saline (20-40ml/kg twice daily) at 48 hours of age. Then continue until 2 days of yellow stools/ 110ml/kg/day of oral feeds; whichever is earlier. SE are recommended if baby do not do bowel opening (BO) for 2 days before reaching full feeds Failure to resolve the MOP with SE will be designated as treatment failure and managed with contrast enema or Laparotomy by paediatric surgeons, following a formal referral.GS is not allowed in intervention arm<br>|
| Active Comparator: Control Arm (Glycerin Suppository Arm)<br>Infants randomized to GS received the standard management protocol for meconium retention in the unit. GS (2,000 mg, a quarter unit, four doses 12 h apart) were administered to infants earliest at 48 hour to 72 hours of birth, with subsequent once-daily GS being administered at the discretion of the managing team. Infants who were diagnosed with meconium obstruction later in the first 2 weeks of life were also treated with glycerin suppositories for 48 hrs, with subsequent once-daily GS being administered at the discretion of the managing team. Infants who failed to respond to glycerin suppositories were referred to the surgical team by the managing team The subsequent management of meconium retention was at the surgeon's discretion and included continued GS by the surgical team, contrast enema or surgical interventions performed in escalating order as mentioned. | Drug: Glycerin Suppository<br>* Infants randomized to GS received the standard management protocol for meconium retention in the unit. GS (2,000 mg, a quarter unit, four doses 12 h apart) were administered to infants earliest at 48 hour to 72 hours of birth, with subsequent once-daily GS being administered at the discretion of the managing team. Infants who were diagnosed with meconium obstruction later in the first 2 weeks of life were also treated with glycerin suppositories for 48 hrs, with subsequent once-daily GS being administered at the discretion of the managing team. Infants who failed to respond to glycerin suppositories were referred to the surgical team by the managing team The subsequent management of meconium retention was at the surgeon's discretion and included continued GS by the surgical team, contrast enema or surgical interventions performed in escalating order as mentioned.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach full enteral feeds in days | Time to reach full enteral feeds is measured from birth to the time infant reaches full oral milk feeds. Full oral milk feed is defined as milk volume of 110ml/kg/day. The total parenteral nutrition is discontinued when infant reaches milk feed volume of 110ml/kg/day. Rationale: SE loosens the thick and sticky meconium by saline absorption and triggers effective and strong peristaltic contractions, thereby leading to the evacuation of meconium from the gut. The evacuation of meconium leads to the resolution of the gut obstruction, thereby enhancing feed tolerance in premature infants with meconium obstruction of prematurity. | Before 36 weeks of corrected age of discharge of the infant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of treatment failure | Treatment failure is defined as the need to use additional treatment measures, apart from the study intervention to resolve MOP in the study cohort. | Before 36 weeks of corrected age of discharge of the infant | 
| Rate of (a) Culture positive sepsis (b) Necrotising enterocolitis. | Rationale: If twice daily SE leads to the shortening of time to reach full enteral feeds, resolution of MOP, and promote friendly bacteria microbiome, then it has the potential to reduce NICU stay, risk of necrotising enterocolitis, risk of sepsis, duration of total parenteral nutrition, duration of PICC and overall cost of care. | Before 36 weeks of corrected age of discharge of the infant | 
| Duration in days of (a) ICU stay (b) Total parenteral nutrition (c) PICC days. | Rationale: If twice daily SE leads to the shortening of time to reach full enteral feeds, resolution of MOP, and promote friendly bacteria microbiome, then it has the potential to reduce NICU stay, risk of necrotising enterocolitis, risk of sepsis, duration of total parenteral nutrition, duration of PICC and overall cost of care. | Before 36 weeks of corrected age of discharge of the infant | 
| Overall cost of care calculated in SGD at the time of discharge | Rationale: If twice daily SE leads to the shortening of time to reach full enteral feeds, resolution of MOP, and promote friendly bacteria microbiome, then it has the potential to reduce NICU stay, risk of necrotising enterocolitis, risk of sepsis, duration of total parenteral nutrition, duration of PICC and overall cost of care. | Before 36 weeks of corrected age of discharge of the infant |