Continuous Versus Intermittent Bolus Feeding in Very Preterm Infants - Effect on Respiratory Morbidity (CONFER)

January 14, 2020 updated by: National University Hospital, Singapore

Continuous Versus Intermittent Bolus Feeding in Very Preterm Infants - Effects on Respiratory Morbidity: A Multicentre Randomised Controlled Clinical Trial

Chronic Lung Disease (CLD) of Prematurity is a common yet challenging co-morbidity affecting extremely premature newborns. Multifactorial influences leading to this co-morbidity is known and targeted in various research studies. Gastroesophageal reflux (GER) is common among the same cohort of patients. The investigators hypothesize that recurrent milk reflux into the airways of the premature babies worsen the inflammation of premature lungs and is a major contributor of CLD.

The investigators hypothesize that Continuous feeding (CF) minimises GER and micro-aspiration, thereby reducing the incidence and severity of CLD in high-risk infants.

Our aim is to compare the effect of intermittent bolus versus continuous intra-gastric feeding on the incidence and severity of CLD in very low birth weight infants ≤ 1250 grams.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

The pathogenesis of bronchopulmonary dysplasia (BPD) is complex and multifactorial. As a result of premature birth, developmental arrest during a critical period of fetal lung development compounded by mechanical, oxidative and other injuries sustained during neonatal respiratory care forms the basis of pathogenesis. BPD affects up to 50% of infants with birth weight less than 1000 g. Between 2000 and 2009, despite advancement of neonatal care, annual BPD rates reported by Vermont Oxford Network among very low birth weight infants varied from 26.2% to 30.4% without any decline. Severely affected infants often require prolonged ventilation, high oxygen use, alternative airway and several potent medications over the first few months to years of their lives. High mortality rates, neurodevelopmental delay, respiratory morbidity and growth failure are associated with BPD.

Treatment of severe BPD with or without pulmonary hypertension is challenging. Prolonging the pregnancy in the face of premature labour, treating perinatal infections, augmenting pulmonary maturity with corticosteroids, judicious oxygen use, lung protective ventilation and optimizing nutrition to promote growth are important and well established measures to prevent or modify the progress of the chronic lung disease.

It is common to find infants with BPD also having significant symptoms of reflux. Gastroesophageal reflux (GER) is a well-known co-morbidity among preterms and ex-preterms on chronic ventilation, many of whom go on to require surgical fundoplication to stop the reflux thus preventing further lung damage. Some have reported dramatic respiratory improvement after resolution of GER. In the early days of a preterm baby with respiratory distress, GER is common and silent. Among infants, diagnosis of pathologic GER from a benign one is difficult. Many neonatal intensive care units (NICUs) would investigate for GER only when faced with moderate to severe BPD to achieve better respiratory symptom control. However GER has not been studied well as a factor precipitating the development of BPD among VLBW neonates. This is the focus of the study.

Aspiration of gastric contents into the lung is a widespread phenomenon in mechanically ventilated preterm infants. In animal models of gastric aspiration, gastric particulates altered the pulmonary mechanics, increased pulmonary inflammatory cells, released pro-inflammatory mediators, and inactivated surfactant. Development of bacterial pneumonia is a well-recognized complication following aspiration of gastric contents. The investigators hypothesize that repeated aspirations would aggravate and accelerate an inflammatory response in the lung finally leading on to BPD. In addition oxygen mediated damage and mechanical ventilation potentiate lung injury due to aspiration. Logically, if GER and aspiration could be minimized, it could decrease the incidence and severity of BPD.

Certain positioning of the baby, small volume of feed increment, keeping a close watch on feed tolerance are practical ways of improving feeding tolerance and reducing GER. The intermittent bolus intra-gastric feeding method is commonly used to feed premature babies. Other alternatives are continuous intra-gastric (feed volume is slowly infused in the stomach over couple of hours through the nasogastric tube) and continuous transpyloric feeding (feeding tube passes beyond the stomach to the duodenum and feed volume is slowly infused over hours). Transpyloric continuous feeding as compared to intermittent gastric bolus feeding, has been found to significantly reduce ventilatory support requirements in extremely low birth weight (ELBW) infants, possibly via its effect of minimising GER. In this study, none of the babies who received transpyloric feeding developed significant BPD and in addition babies with significant BPD improved after switching to transpyloric method. Transpyloric feeding tubes however are challenging to insert, and intestinal perforation is an uncommon but significant adverse effect. This feeding method is also not physiological as it bypasses the stomach. It remains to be seen if continuous gastric feeds, which is easily administered and safer, would yield some of the advantages of continuous transpyloric feeds over intermittent gastric feeding.

A Cochrane review in 2011 of continuous intra-gastric versus intermittent bolus intra-gastric feeding for premature infants found conflicting results, and was unable to make recommendations regarding the benefits and risks of these feeding methods. Clinical outcomes of interest from these trials were related to growth, feeding tolerance and gastrointestinal complications. The Cochrane review importantly found no significant difference in somatic growth and incidence of necrotising enterocolitis (NEC) between either feeding methods. Another Cochrane review in 2014 did not identify any randomised trial that evaluated the effects of continuous versus intermittent bolus intragastric tube feeding on gastro-oesophageal reflux disease in preterm and low birth weight infants and opined that well-designed and adequately powered trials are needed in this field. There were no studies comparing the effect of the above feeding methods on respiratory outcomes either.

Trial objectives

Aim: To compare the effect of intermittent bolus versus continuous intra-gastric feeding on the incidence and severity of BPD in very low birth weight infants (≤ 1250 grams).

Hypothesis: Continuous feeding (CF) minimises silent GER and micro-aspiration, thereby reducing the incidence and severity of bronchopulmonary dysplasia (BPD) in high-risk infants when compared to intermittent bolus feeding (BF).

Statistical considerations

Sample size calculation: based on 2015 data from the Singapore National Very-Low-Birth-Weight (VLBW) Infant Network for infants ≤ 1250 grams, mortality rate was 12.9% and BPD rate (defined as any oxygen supplementation or any respiratory support at 36 weeks post-conceptional age) was 29.4%. Thus the composite primary outcome rate was 42.3%. For a primary outcome rate reduction from 45% to 22.5%, with a type 1 error rate of 5% and a power of 80%, a sample size of 68 infants in each arm is required, giving a total sample size of 136 infants.

Study Type

Interventional

Enrollment (Anticipated)

150

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 day to 3 days (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Infants with a birth weight <1250g and a gestational age of between 24+0 - 33+6 weeks

Exclusion Criteria:

  1. Major congenital malformation
  2. Chromosomal abnormality
  3. 10-minute Apgar score of =3
  4. Not expected to survive beyond 72 hours of age
  5. Bilateral grade 4 intraventricular haemorrhage (IVH)
  6. Did not consent / Consent not available

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Continuous feeding (CF)

Infants fed through a naso or orogastric tube in a continuous fashion using syringe pump. Each feed cycle is of 4 hours (3 hrs continuous feeding and 1 hour rest). 6 feed cycles in a day.

Feed volume increment per day is as per departmental protocol and same as comparator arm.
Other: Method of feeding; continuous feeding OR bolus feeding

CF: Infants fed through a naso or orogastric tube in a continuous fashion using syringe pump. Each feed cycle is of 4 hours (3 hrs continuous feeding and 1 hour rest). 6 feed cycles in a day.

BF: Infants fed through a naso or orogastric tube in a gravity dependent bolus feeding every 2-3 hours. Each feed would take approximately 10 minutes.
Active Comparator: Bolus feeding (BF)

Infants fed through a naso or orogastric tube in a gravity dependent bolus feeding every 2-3 hours. Each feed would take approximately 10 minutes.

Feed volume increment per day is as per departmental protocol and same as experimental arm.
Other: Method of feeding; continuous feeding OR bolus feeding

CF: Infants fed through a naso or orogastric tube in a continuous fashion using syringe pump. Each feed cycle is of 4 hours (3 hrs continuous feeding and 1 hour rest). 6 feed cycles in a day.

BF: Infants fed through a naso or orogastric tube in a gravity dependent bolus feeding every 2-3 hours. Each feed would take approximately 10 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of BPD
Time Frame: occurring before 36 weeks post menstrual age or 28 days of life
BPD as defined by 2001 NICHD criteria
occurring before 36 weeks post menstrual age or 28 days of life
Incidence of Death
Time Frame: occurring before 36 weeks post menstrual age or 28 days of life
Death occurring before 36 weeks post menstrual age or 28 days of life
occurring before 36 weeks post menstrual age or 28 days of life

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Invasive Ventilatory requirements
Time Frame: 36 weeks post menstrual age or 28 days of life
Days on invasive ventilation
36 weeks post menstrual age or 28 days of life
Any Ventilatory requirements
Time Frame: 36 weeks post menstrual age or 28 days of life
Days on any ventilatory (invasive or non invasive) support
36 weeks post menstrual age or 28 days of life
Supplemental Oxygen support
Time Frame: 36 weeks post menstrual age or 28 days of life
Days on supplemental oxygen
36 weeks post menstrual age or 28 days of life
Feed tolerance
Time Frame: 36 weeks post menstrual age or 28 days of life
Time (days) from randomization to achievement of full feeds (defined as 150ml/Kg/Day)
36 weeks post menstrual age or 28 days of life
Weight outcomes
Time Frame: birth, 36 weeks and 40 weeks post menstrual age
Z-scores for weight (grams)
birth, 36 weeks and 40 weeks post menstrual age
Length outcomes
Time Frame: birth, 36 weeks and 40 weeks post menstrual age
Z-scores for length (cm)
birth, 36 weeks and 40 weeks post menstrual age
Head Growth outcomes
Time Frame: birth, 36 weeks and 40 weeks post menstrual age
Z-scores for head circumference (cm)
birth, 36 weeks and 40 weeks post menstrual age

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National University Hospital, Singapore

Investigators

  • Principal Investigator: Agnihotri Biswas, MRCPCH, Senior Consultant Neonatologist, NUH Singapore

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 3, 2019

Primary Completion (Anticipated)

June 1, 2022

Study Completion (Anticipated)

December 1, 2022

Study Registration Dates

First Submitted

May 15, 2019

First Submitted That Met QC Criteria

May 21, 2019

First Posted (Actual)

May 23, 2019

Study Record Updates

Last Update Posted (Actual)

January 18, 2020

Last Update Submitted That Met QC Criteria

January 14, 2020

Last Verified

May 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2018/00773

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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