Re-feeding gastric residuals in extremely preterm infants

MANUSCRIPT CITATION

Salas AA, Cuna A, Bhat R, Mcgwin G, Carlo WA, Ambalavanan N. A randomised trial of re-feeding gastric residuals in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2015;100(3):F224-8. PMID 25552280

REVIEWED BY

Mikael Norman
MD, PhD, professor
Department of Neonatal Medicine, H1:02
Karolinska Institute & University Hospital

TYPE OF INVESTIGATION

Treatment

QUESTION

Does re-feeding of gastric residual volumes reduce the time needed to achieve full enteral feeding in preterm infants?

METHODS

  • Design: Randomized controlled trial
  • Allocation: Concealed
  • Blinding: The intervention was not masked
  • Follow-up period: 120 days or discharge (whichever occurred first)
  • Setting: NICUs of the University of Alabama at Birmingham Hospital and the Children’s of Alabama Hospital.
  • Patients: Inclusion criteria: infants with gestational age between 230 and 287 weeks receiving minimal enteral nutrition (defined as enteral feeding volume of <24 mL/kg/day) and intravenous fluids during the first week after birth. Definitions and procedures: Enteral feeding in preterm infants were generally administered as intermittent bolus gavage feedings every 3 h. Enteral nutrition with either expressed human milk (preferred) from the mother or high-protein full-strength preterm formula (24 cal/oz) was initiated within the first days after birth at a rate of <24 mL/kg/day for 3–5 days. Donor human milk was not offered as an alternative to mother’s milk. Feeding advancement was done by 20 mL/kg/day increments until the total volume reached ≥120 mL/kg/day. If human milk was the source of enteral nutrition, human milk fortifier was added once the enteral feeding volume reached 100–120 mL/kg/day. Gastric residual volumes were checked with a syringe prior to each feeding and with the infant in the supine position.
  • Exclusion criteria: infants with major congenital/chromosomal anomalies and those considered to have a low likelihood of survival.
  • Intervention: In the presence of gastric residual volumes more than 1/3 of previous feeding or >2 mL, and if the clinician’s decision was to continue enteral feeding – infants were randomized into one of two treatment groups, where gastric residual volumes were either re-fed (Re-feeding group) or discarded followed by feeding of fresh human milk or formula (Fresh-feeding group). Only gastric residual volumes containing blood on visual inspection by bedside nurses were not re-fed. Small gastric residual volumes (<1/3 of previous feeding volume or <2 mL) were managed according to clinician preference (usually re-fed). If an infant in the Re-feeding group had large gastric residual volumes for three consecutive feedings, the gastric residual volume before the fourth feeding was discarded and fresh milk/formula was given. The amount of gastric residual volume did not influence the amount of feed given at the next feeding in that the amount re-fed was included as part of the next feed’s volume.
  • Outcomes:
    • Primary outcome: The primary efficacy end point was time to achieve full enteral feeding (defined as ≥120 mL/kg/day) for two consecutive days
    • Secondary outcomes: a diagnosis of spontaneous intestinal perforation (SIP), of medical or surgical NEC and/or death. Secondary end points also included number of days receiving total parenteral nutrition (TPN), time to regain birth weight (days), number of episodes of feeding intolerance (defined as interruption of enteral feeding for >12 h) for bloody gastric residual volumes or abnormal abdominal examination, and duration of hospital stay in days.
  • Analysis and Sample Size: A sample size of 72 patients (36 patients in each group) was sufficient to detect a 2-day difference in the number of days to achieve full enteral feeding with an SD of 3 days, level of significance of 0.05 and power of 80%. Loss to follow-up for analysis of the primary efficacy end point was not anticipated. Both primary efficacy and safety end points were analyzed by intention to treat regardless of initiation of the intervention or compliance. Development of SIP or NEC during the period of minimal enteral nutrition or feeding advancement was an indication to discontinue the assigned intervention.
  • Patient follow-up: 59/72 (82%) included in analysis. Before achieving full enteral feeding, three infants were diagnosed with SIP and four with medical NEC in the Re-feeding group. Three of the four infants with medical NEC had Stage I NEC (suspect NEC) without pneumatosis intestinalis. None progressed to surgical NEC. In the Fresh-feeding group, two infants died (one due to pulmonary interstitial emphysema and another due to septic shock) and four infants developed SIP.

MAIN RESULTS:

  Re-feeding group (n=36) Fresh-feeding group (n=36)  p-value
Birth weight, g 790±168 788±240 0.96
Gestational age, weeks (median, IQR) 26 (25-27) 26 (25-27) 0.97
SGA (%) 4/36 (11) 5/36 (14) 0.72
Male sex (%) 17/36 (47) 16/36 (44) 0.81
Age at first enteral feed, days (median, IQR) 2 (1-3) 3 (2-4) 0.25
Primary and secondary efficacy end points in participants who did not develop a primary safety end point before achieving full enteral feeding (mean and SD)
  Re-feeding group (n=29) Fresh-feeding group (n=30)  p-value
Time to full enteral feeding, days 10.0 (3.2) 11.3 (3.2) 0.11
Time on TPN, days 6.9 (3.1) 7.2 (3.8) 0.70
Time to regain birth weight, days 14.9 (6.5) 14.5 (6.4) 0.83
Feeding intolerance (interruption > 12h) 10/29 (34%) 13/39 (43%) 0.49
Length of stay, days 92 (43) 94 (48) 0.87

The composite safety end point of spontaneous intestinal perforation, surgical necrotizing enterocolitis, or death occurred in 6 of 36 infants (17%) in the Re-feeding group versus 10 of 36 infants (28%) in the Fresh feeding group ( p=0.26).

CONCLUSION:

The authors conclude that re-feeding gastric residual volumes in extremely preterm infants does not reduce time to achieve full enteral feeding. They suggest that refeeding might be as safe as fresh feeding, but further research is needed, due to lack of sufficient statistical power in this study for safety analysis.

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COMMENTARY:

Salas et al tackle a common clinical question: what should you do when a significant volume of gastric content is aspirated before feeding an extremely preterm infant? The presence of gastric residuals, especially if they are large, could be an early sign of NEC and may call for caution on re-feeding. On the other hand, discarding gastric residuals may impair digestion and delay establishment of full enteral feeds. There is no evidence from clinical trials to support either approach, especially in the high-risk (for both NEC and undernutrition) group of extremely preterm infants.

Although the study by Salas et al is to be congratulated for its attempt to resolve an important every-day clinical question, the most important drawback is that conclusions – regarding both efficacy and safety – unfortunately suffer from some limitations. For the primary question “Does re-feeding of gastric residual volumes reduce the time needed to achieve full enteral feeding in preterm infants?”, the authors conclude that the answer is no. However, although intention to treat analysis was intended, the primary efficacy end point was only possible to assess in 59 infants, as the estimated sample size (n=72) was not reached. Therefore, there are two possibilities: Either the study may have been under-powered (p=0.11 for a group difference in primary outcome); or, the results rightly disprove the hypothesis for an effect size of 2 days difference or more to achieve full feeds. The authors could have helped the readers understand better whether this desired group difference was based either on some pilot data, or it was a consensual view of what would be the Minimal Clinically Significant Difference.

In addition, and as pointed out by the authors, numbers were too small to draw any firm conclusions about safety. Information on the volumes of gastric residuals in the two treatment arms was also lacking. Such information would help interpretation. Finally, donor milk1 was not offered, possibly contributing to quite high rates reported of intestinal perforation, surgical necrotizing enterocolitis, or death.

So what should the clinician do with gastric residuals in extremely preterm infants? Previous studies in ELBW infants (< 1000g) have demonstrated that disregarding of gastric residuals up to 2-3 ml (even if they were greenish) did not increase the risk for NEC.2 Other than that, there seems to be very little evidence. Given the findings by Salas et al, this reviewer agrees with the conclusion that re-feeding gastric residual volumes in extremely preterm infants does not seem to reduce time to achieve full enteral feeding, and is likely to be safe.

In this context, what is recommended on when and how feeds should be started in preterm infants? The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) suggest that minimal enteral nutrition be initiated within the first 2 days of life and advanced by 30 mL/kg/d in infants ≥1000g.3 A recent systematic review of studies in VLBW infants (1000-1500g) came to a similar conclusion: advancing enteral feed volumes at daily increments of 30 ml/kg to 35 ml/kg did not increase the risk of NEC. On the contrary, advancing the volume of enteral feeds at slower rates resulted in several days delay in regaining birth weight and establishing full enteral feeds.4 For the group of ELBW infants below 1000 g BW, recommendations are more scarce, most likely reflecting the lack of solid evidence. In Sweden, minimal enteral feeding with breastmilk is – right or wrong – initiated within hours after birth, also in extremely preterm infants.

REFERENCES

  1. Arslanoglu S, Corpeleijn W, Moro G, et al. Donor human milk for preterm infants: current evidence and research directions. Journal of pediatric gastroenterology and nutrition 2013;57:535-42.
  2. Mihatsch WA, von Schoenaich P, Fahnenstich H, et al. The significance of gastric residuals in the early enteral feeding advancement of extremely low birth weight infants. Pediatrics 2002;109:457-9.
  3. Fallon EM, Nehra D, Potemkin AK, et al. A.S.P.E.N. clinical guidelines: nutrition support of neonatal patients at risk for necrotizing enterocolitis. JPEN Journal of parenteral and enteral nutrition 2012;36:506-23.
  4. Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. The Cochrane database of systematic reviews 2014;12:CD001241.

4 Comments


  1. Given the potential number of preterm infants that could be eligable for intervention studies about feeding, the lack of well-powered RCTs is surprising. The Cochrane review (ref#4 above) identified six trials in which a total of only 618 infants participated.

    If we (the neonatal community) would be more interested in investigating feeding protocols, and their related risks and benefits, we should be able to include many hundreds of infants in well-conducted multicenter RCTs.


  2. I find two points interesting in this article:
    1) the article states: “feeding was increased by 20ml/kg per day”. if this were strictly enforced there should have been no difference between groups. how did the difference between the 2 groups then arise? was there some algorithm on when to increase feedings and when not to?
    2) secondly the authors mention that for the first 3-5 days only minimal enteral feedings were fed which seems to be a Northern American practice (compare: http://fn.bmjjournals.com/content/97/1/F56.full ). I wonder if the results of the study would be applicable to places that start with more aggressive (from day 1) feeding regimens as well.
    Other than that I agree with Stefan that even though feeding is an issue neonatal staff are confronted with every day on neonatal wards, there is not much data to help on deciding what course is best for the individual infant.


    • While an interesting study, the investigators missed an opportunity to also assess the impact of re-feeding residuals on nutritional intake and growth. As I understand the study, in both groups the infant was “short changed” from the volume of residual that wasn’t digested. In other words, the care providers might have though the infant was receiving 160 ml/kg/day, but might in fact be receiving much less (either by re-feeding residuals and subtracting them from the next feed’s volume, or by discarding the residual). The third option is to re-feed the residual and then give the next feed volume in its entirety, and assess growth trajectory and nutritional intake as well as time to reach full volume feeds and incidence of NEC.


      • @LauraBrown – good point! That would be a good methodological idea for future studies.

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