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
Interventional
Primary Outcome
Incidence of BPD
Secondary Outcome
Invasive Ventilatory requirements
Condition
Chronic Lung Disease of Prematurity
Intervention
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.
Publications
* 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
Other
Estimated Enrollment
150
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
Gender
All
Ages
N/A - 3 Days
Accepts Healthy Volunteers
No
Contacts
Agnihotri Biswas, MRCPCH, +65 67725075, [email protected]
Location Countries
Malaysia
Location Countries
Malaysia
Administrative Informations
NCT ID
NCT03961139
Organization ID
2018/00773
Responsible Party
Sponsor
Study Sponsor
National University Hospital, Singapore
Study Sponsor
Agnihotri Biswas, MRCPCH, Principal Investigator, Senior Consultant Neonatologist, NUH Singapore
Verification Date
May 2019