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

• ClinicalTrials.gov Identifier: NCT06048614
• Recruitment Status: Recruiting
• First Posted: September 21, 2023
• Last Update Posted: March 12, 2024
• Sponsor: KK Women's and Children's Hospital
• Collaborators: Singapore General Hospital; Genome Institute of Singapore; Translational Immunology Institute; Duke-NUS Graduate Medical School
• Information provided by (Responsible Party): Thowfique Kadavukarayil Ibrahim, KK Women's and Children's Hospital

Study Description

Brief Summary:

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

1. 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.

2. The other aims of this study are to test whether the intervention is

   1. Effective treatment for MOP
   2. Reduce the duration of ICU stay
   3. Reduce the rate of necrotizing enterocolitis, sepsis, Total Parenteral Nutrition (TPN) days and number of intravenous catheter days
3. 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.

Condition or disease	Intervention/treatment	Phase
Meconium Obstruction of Prematurity	Procedure: Saline Enema (SE); Drug: Glycerin Suppository	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 95 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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)
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: January 2, 2024
• Estimated Primary Completion Date: July 31, 2026
• Estimated Study Completion Date: December 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intervention Arm (Saline Enema Arm); 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); 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
Active Comparator: Control Arm (Glycerin Suppository Arm); 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Time to reach full enteral feeds in days [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]

   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.

Secondary Outcome Measures :

1. Rate of treatment failure [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Treatment failure is defined as the need to use additional treatment measures, apart from the study intervention to resolve MOP in the study cohort.
2. Rate of (a) Culture positive sepsis (b) Necrotising enterocolitis. [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]

   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.

3. Duration in days of (a) ICU stay (b) Total parenteral nutrition (c) PICC days. [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]

   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.

4. Overall cost of care calculated in SGD at the time of discharge [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]

   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.

Other Outcome Measures:

1. Identification and quantification of bacteria from meconium/stool samples by DNA sequencing and analysis of top 50 bacteria Genus [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Bacteria are identified from meconium/stools samples, collected at birth and weekly interval till discharge or 36 weeks of gestation
2. To measure the serum level of IL 6 in pg/ml [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]

   Use Olink Target 48 platform to measure

   Rationale:

   To explore the relationship between gut microbiome and gut-brain axis

3. To measure the serum level of neurotransmitters noradrenaline in pg/L [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Use Norepinephrine ELISA Kit from abcam to measure
4. Measure serum levels of dopamine in arbitrary units (peak area of analyte divided by peak area of an internal standard) [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Use Norepinephrine ELISA Kit from abcam to measure
5. Measure serum levels of serotonin in arbitrary units (peak area of analyte divided by peak area of an internal standard) [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Use Norepinephrine ELISA Kit from abcam to measure
6. Measure serum levels of GABA in arbitrary units (peak area of analyte divided by peak area of an internal standard) [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Use Norepinephrine ELISA Kit from abcam to measure
7. Measure level of Propionate in µM [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Use Short Chain Fatty Acid Panel to measure
8. Measure level of Butyrate in µM [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Use Short Chain Fatty Acid Panel to measure
9. Measure level of Acetate in µM [ Time Frame: Before 36 weeks of corrected age of discharge of the infant ]
   Use Short Chain Fatty Acid Panel to measure

Eligibility Criteria

• Ages Eligible for Study: 1 Day to 36 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Criteria A: For infant presenting with early onset of MOP

  1. Birth weight 500 - 1250 gram
  2. ≥ 23 weeks gestation
  3. No BO for 48 hours
  4. BO present but with a small amount or stain of meconium
  5. Feeds intolerance or abdominal X-ray showing dilated loops of bowel

• Criteria B: For infant presenting with Late onset of MOP

  1. Birth weight 500 - 1250 gram
  2. ≥ 23 weeks gestation
  3. 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:

1. Neuromuscular disorder
2. Moderate or severe asphyxia
3. 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
4. Without parental consent
5. Aggravated medical instability
6. Single mothers < 21 years

Contacts and Locations

Contacts

Contact: Seow Ching Li, Biomedical; 63948005 ext 8005; li.seow.ching@kkh.com.sg

Contact: Kathy Liaw, Biomedical; 63948939 ext 8939; kathy.liaw.c.s@singhealth.com.sg

Locations

Singapore

KK Women's and Children Hospital; Recruiting

Singapore, Singapore, 229899

Contact: Seow Ching Li li.seow.ching@kkh.com.sg

Contact: Wen Yi Wan wan.wen.yi@kkh.com.sg

Principal Investigator: Thowfique Ibrahim

Sponsors and Collaborators

KK Women's and Children's Hospital

Singapore General Hospital

Genome Institute of Singapore

Translational Immunology Institute

Duke-NUS Graduate Medical School

Investigators

• Principal Investigator: Thowfique Ibrahim, FRCPCH, FAMS; Singhealth Duke-NUS Medical School, NUS and LKC Medical School

More Information

Publications:

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Chathas MK, Paton JB, Fisher DE. Percutaneous central venous catheterization. Three years' experience in a neonatal intensive care unit. Am J Dis Child. 1990 Nov;144(11):1246-50. doi: 10.1001/archpedi.1990.02150350078030.

Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR, Fanaroff AA, Lemons JA, Donovan EF, Oh W, Stevenson DK, Ehrenkranz RA, Papile LA, Verter J, Wright LL. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr. 1996 Jul;129(1):63-71. doi: 10.1016/s0022-3476(96)70191-9.

Shim SY, Kim HS, Kim DH, Kim EK, Son DW, Kim BI, Choi JH. Induction of early meconium evacuation promotes feeding tolerance in very low birth weight infants. Neonatology. 2007;92(1):67-72. doi: 10.1159/000100804. Epub 2007 Mar 14.

Krasna IH, Rosenfeld D, Salerno P. Is it necrotizing enterocolitis, microcolon of prematurity, or delayed meconium plug? A dilemma in the tiny premature infant. J Pediatr Surg. 1996 Jun;31(6):855-8. doi: 10.1016/s0022-3468(96)90153-0.

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Kim YJ, Kim EK, Kim ES, Kim HS, Choi JH, Cheon JE, Kim WS, Kim IO, Park KW. Recognition, diagnosis and treatment of meconium obstruction in extremely low birth weight infants. Neonatology. 2012;101(3):172-8. doi: 10.1159/000330850. Epub 2011 Oct 22.

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• Responsible Party: Thowfique Kadavukarayil Ibrahim, Senior Consultant(Assistant Professor), KK Women's and Children's Hospital
• ClinicalTrials.gov Identifier: NCT06048614
• Other Study ID Numbers: 2023/2270
• First Posted: September 21, 2023
• Last Update Posted: March 12, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Meconium Ileus; Intestinal Obstruction; Cystic Fibrosis; Premature Birth; Fetal Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Pancreatic Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Glycerol; Cryoprotective Agents; Protective Agents; Physiological Effects of Drugs