Continuous Versus Intermittent Bolus Feeding in Very Preterm Infants – Effect on Respiratory Morbidity

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Brief Title

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

Official Title

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

Brief Summary

      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.

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


Primary Outcome

Incidence of BPD

Secondary Outcome

 Invasive Ventilatory requirements


Chronic Lung Disease of Prematurity


Method of feeding; continuous feeding OR bolus feeding

Study Arms / Comparison Groups

 Continuous feeding (CF)
Description:  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.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

December 3, 2019

Completion Date

December 2022

Primary Completion Date

June 2022

Eligibility Criteria

        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




1 Day - 3 Days

Accepts Healthy Volunteers



Agnihotri Biswas, MRCPCH, +65 67725075, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

National University Hospital, Singapore

Study Sponsor

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

Verification Date

May 2019