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

Meconium Obstruction of Prematurity Clinical Trial

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06048614
• Other study ID #: 2023/2270
• Status: Recruiting
• Phase: N/A
• Start date: January 2, 2024
• Est. completion date: December 2026

Study information

• Verified date: March 2024
• Source: KK Women's and Children's Hospital
• Contact: Seow Ching Li, Biomedical
• Phone: 63948005
• Email: li.seow.ching[@]kkh.com.sg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 95
• Est. completion date: December 2026
• Est. primary completion date: July 31, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Day to 36 Weeks

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Intestinal Obstruction
• Meconium Ileus
• Meconium Obstruction of Prematurity
• Premature Birth

Intervention

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

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.

Locations

Country	Name	City	State
Singapore	KK Women's and Children Hospital	Singapore

Sponsors (5)

Lead Sponsor	Collaborator
KK Women's and Children's Hospital	Duke-NUS Graduate Medical School, Genome Institute of Singapore, Singapore General Hospital, Translational Immunology Institute

Country where clinical trial is conducted

Singapore, 

References & Publications (21)

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Garza-Cox S, Keeney SE, Angel CA, Thompson LL, Swischuk LE. Meconium obstruction in the very low birth weight premature infant. Pediatrics. 2004 Jul;114(1):285-90. doi: 10.1542/peds.114.1.285. — View Citation

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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. — View Citation

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Nakaoka T, Nishimoto S, Tsukazaki Y, Santo K, Higashio A, Kamiyama M, Uehara S, Yoneda A, Tanaka Y, Ichiba H. Ultrasound-guided hydrostatic enema for meconium obstruction in extremely low birth weight infants: a preliminary report. Pediatr Surg Int. 2017 Sep;33(9):1019-1022. doi: 10.1007/s00383-017-4129-9. Epub 2017 Jul 25. — View Citation

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Saenz de Pipaon Marcos M, Teresa Montes Bueno M, Sanjose B, Gil M, Parada I, Amo P. Randomized controlled trial of prophylactic rectal stimulation and enemas on stooling patterns in extremely low birth weight infants. J Perinatol. 2013 Nov;33(11):858-60. doi: 10.1038/jp.2013.86. Epub 2013 Aug 1. — View Citation

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* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Identification and quantification of bacteria from meconium/stool samples by DNA sequencing and analysis of top 50 bacteria Genus	Bacteria are identified from meconium/stools samples, collected at birth and weekly interval till discharge or 36 weeks of gestation	Before 36 weeks of corrected age of discharge of the infant
Other	To measure the serum level of IL 6 in pg/ml	Use Olink Target 48 platform to measure; Rationale: To explore the relationship between gut microbiome and gut-brain axis	Before 36 weeks of corrected age of discharge of the infant
Other	To measure the serum level of neurotransmitters noradrenaline in pg/L	Use Norepinephrine ELISA Kit from abcam to measure	Before 36 weeks of corrected age of discharge of the infant
Other	Measure serum levels of dopamine in arbitrary units (peak area of analyte divided by peak area of an internal standard)	Use Norepinephrine ELISA Kit from abcam to measure	Before 36 weeks of corrected age of discharge of the infant
Other	Measure serum levels of serotonin in arbitrary units (peak area of analyte divided by peak area of an internal standard)	Use Norepinephrine ELISA Kit from abcam to measure	Before 36 weeks of corrected age of discharge of the infant
Other	Measure serum levels of GABA in arbitrary units (peak area of analyte divided by peak area of an internal standard)	Use Norepinephrine ELISA Kit from abcam to measure	Before 36 weeks of corrected age of discharge of the infant
Other	Measure level of Propionate in µM	Use Short Chain Fatty Acid Panel to measure	Before 36 weeks of corrected age of discharge of the infant
Other	Measure level of Butyrate in µM	Use Short Chain Fatty Acid Panel to measure	Before 36 weeks of corrected age of discharge of the infant
Other	Measure level of Acetate in µM	Use Short Chain Fatty Acid Panel to measure	Before 36 weeks of corrected age of discharge of the infant
Primary	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	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
Secondary	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
Secondary	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
Secondary	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