Prof Sanjay Patole, MD, DCH, FRACP, MSc, DrPH Centre for Neonatal Research and Education

1. Gastric residuals in preterm neonates –what to do with them? Prof Sanjay Patole, MD, DCH, FRACP, MSc, DrPH Centre for Neonatal Research and Education KEM Hospital for Women, University of Western Australia, Perth

2. Gastric residuals in preterm neonates Why do we monitor gastric residuals? Benefits and risks? How do we define normal/abnormal gastric residuals? How do we interpret their volume and colour? What factors may affect gastric residuals? Any correlation of aspirates with abdominal ‘distension’? What to do with gastric residuals?

3. Gastric residuals in preterm neonates Can ultrasound measurement of gastric volume help? Are there any interventions that may help? What is the role of bile acids in NEC? What is the role of ‘Amylin peptide’ in feed intolerance?

4. Gastric residuals and NEC Methods: Gestation and BW matched controls for NEC cases. Feed tolerance assessed by Max. GRV, Max. GRV as % of previous feeds, and its appearance. 844 VLBW, mortality 4.6%. NEC: 2%. PDA significantly associated with NEC. Bertino et al . JPGN. 2009

5. Results: Mean Max. GRV from birth to NEC onset and Max. GRV as the % of previous feed volume, and hemorrhagic residuals were significantly higher in NEC vs. controls Conclusion: GRV are a marker of feed intolerance, and bloody residuals seemed to be the best predictor for NEC. Bertino et al . JPGN. 2009

6. Gastric residuals and NEC Methods: Gestation, BW, race, gender matched controls (n=102) for proven NEC cases (n=51). Data from 6days before NEC Results: Median BW and gestation: 822 g and 26 weeks in both groups. Feeds started on 5th day, with planned increase to FF over 10 days (median) in both groups. Median TFEF: 13 days in both groups. Median age at onset of NEC: Day 24. Cobb et al Pediatrics. 2004

7. Max GRV [median (IQR)]: Controls: 2 ml/feed (0.5-3.5) or 14% of a feed (4-33) NEC: 4.5 ml/feed (1.5-9.8) or 40% of a feed (24-61) Total GRV as % of feeds and the average max GRV increased from the first 3 days to the 3 days before NEC. Conclusion: NEC infants had more residuals but data overlapped with controls. Max residual seemed to be the best predictor for NEC in the subsequent days Cobb et al Pediatrics. 2004

8. Abdominal girth • GR volume (GRV) measured in 50 healthy preterm neonates • Gestation: 28-36 weeks, AGA: 38, SGA:12 • The mean basal 4-hour (B4 GRV) was 2.8 +/- 0.63 ml in parenterally fed neonates • Marked decrease in (mean ± SD) gastric residuals with time: Day 4: 20.7±15.2% vs. Day 7: 8.6±4.3% (p< 0.001) Malhotra et al J Trop Pediatr. 1992

9. 27 EBM fed neonates: Mean GR 24.4 ±10.2% in supine and 12.8 ±4.3% in prone position (p< 0.01). • 21 prone nursed neonates: Mean GRV in EBM vs. Formula: 12.8 ± 4.3 % vs. 13.6 ± 2.7% • No difference in residuals of AFD v. SFD • No linear correlation between increased girth and GR • However, GRV was ≥ 23%if increasein girth was ≥ 2 cm Malhotra et al J Trop Pediatr. 1992

10. Abdominal circumference (AC) vs. GRV Aim: • Compare pre-feed AC and GRV as a measure of feed intolerance Methods • 80 VLBW infants randomized to monitoring feed intolerance by measuring either GRV or pre-feed AC • Primary outcome: TFEF (180 ml/kg/day) • Other outcomes: Feed interruption days, LOS, NEC, mortality and duration of TPN and hospital stay Kaur et al JPGN 2014

11. Median (IQR) TFEF in AC vs GRV: 10 (9,13) vs. 14 (12,17.5) days, (p < 0.001) • AC group: Fewer feed interruption days [0 (0, 2) vs. 2.0 (1, 5), p < 0.001] and shorter duration of TPN (p < 0.001) • LOS (AC vs. GRV): 17.5 % vs. 30 %, (p = 0.18) • Duration of hospital stay and mortality comparable Conclusion: Pre-feed AC as a measure of feed intolerance in VLBW infants may shorten the TFEF. Kaur et al JPGN 2014

12. Abdominal circumference: Body weight ratio Hypotheses: (1) The AC/BW ratio of preterm infants decreases in serial measurements with increasing BW during first 28 days (2) Higher volume of enteral nutrition and CPAP raise the ratio Methods: • 30 preterm infants (27.5 ± 2.2 weeks; 16 male, 2200 measurements) • Daily recording during the first 28 days: AC, BW, fluid intake, feed details including GRV, CPAP Heimann et al Klin Padiatr. 2014

13. Increase in AC/BW ratio (mean ±Std) from 19.9 ±3.2 (D1) to 25.0 ±5.2 (D6), followed by continuous decrease to 19.9 ±4.4 on (D28) • Gestation, total feed volume had significant effect (p < 0.05) • The ratio decreased with increasing total volume of feeds • Changes in feed volume, CPAP had no significant effect Conclusion: AC/BW ratio may be a more objective parameter to avoid withholding feds or to detect early clinical deterioration. Heimann et al Klin Padiatr. 2014

14. Refeeding gastric residuals: RCT • Parallel-group RCT with a 1:1 allocation ratio • 72 preterm neonates (23 to 28 weeks) receiving MEN <24 mL/kg/day during 1st week after birth. • Randomised to either be re-feed with GRV group or receive fresh-feed with formula/human milk group whenever large GRV were noted. Primary outcome: TFEF: ≥120 mL/kg/day) after randomisation Salas et al Arch Dis Child Fetal Neonatal Ed. 2014

15. Results • Mean TEFF was 10.0 (Re-feed) vs. 11.3 days in the Fresh-feeding group (mean diff. favouring re-feeding: -1.3 days; 95% CI -2.9 to 0.3; p=0.11). • The composite safety end point ‘SIP/Surgical NEC/Death’ occurred in 6/36 (17%) in the Re-feeding vs 10/36 (28%) infants in the Fresh-feeding group (p=0.26). • Conclusion: Re-feeding GRV in extremely preterm neonates does not reduce TEFF. Further research is needed for safety analysis.

16. Warming milk • Background: No evidence-based standards exist for warming breast milk or determining the optimal milk temperature for preterm infants. • Methods: Randomly selected experienced nurses (n=61) observed as they prepared and administered BM feeds. • Physiological responses of the 33 preterm infants were observed before and at 5 and 30 minutes after the start of feedings. Gastric residuals measured 3 hours after the feeds. Dumm et al. Adv Neonatal Care. 2013

17. Results • Water bath temp.: 23.3°C to 45.5°C at start of warming and 23.8°C to 38.4°C when milk was removed. • Refrigerated milk was 3.8°C to 27.1°C; warmed to 21.8°C to 36.2°C at feeding time. • Warming times: 133 to 3061 seconds. • Infant axillary temp. increased at 5 and 30 minutes (p<.05). • No significant changes in HR, RR, saturation, feed tolerance. • Further research to assess benefit vs. risks of warming feeds. Dumm et al. Adv Neonatal Care. 2013

18. Positioning Right lateral position for enhancing gastric emptying and left lateral position for GER in the uncomplicated patient. Most extremely preterm neonates have decreased gastric motility needing RL position and GER symptoms that need LR position!! The best compromise for such neonates is the prone position. Further research needed to provide a clear choice for correct positioning in the NICU population. Else HE. Adv Neonatal Care. 2012 Jun

19. Positioning ‘Prone vs. Supine’ Preterm infants (n=35) who were asymptomatic for GOR, other GI diseases or other significant morbidities. Infants were randomly assigned to the following treatments: 3 hrs each in supine followed by prone position, or vice versa. Measurements of GRV were taken by syringe at 30, 60, 90, 120 and 150 min following feeding when the enteral intake was set at 50 or 100ml/kg/day. Chen et al Int J Nurs Stud. 2013 Nov

20. Conclusion Placing preterm infants in the prone position for the first half an hour post-feeding and then changing the position according to the behavior cues of the infants is suggested. Chen et al Int J Nurs Stud. 2013 Nov

21. Ultrasound assessment of gastric volume • 24 infants monitored during a single OGT feed, with 2 US images of the entire stomach and an image of the antral cross-sectional area (ACSA) before, during, and after the feed. • Raw measurements, 3 stomach volume calculations, and ACSA tested for intra- and interrater agreement. • Calculated stomach volumes and ACSA compared with delivered feed volumes, and characteristics of stomach image echogenicity graded at each time point. Perrella et al JPGN 2014

22. Results Spheroid calculation was the most reliable and valid measure of stomach volume. Fortified BM feeds more echogenic than unfortified BM feeds. Residual stomach volumes (median 2.12 mL, range 0.59-9.27 mL) were identified in 18/24 infants. Conclusion: Direct US stomach measurement (spheroid) will provide a useful research and clinical tool for assessing gastric emptying and feeding intolerance in preterm infants. Perrella et al JPGN 2014 Oct

23. Repeatability of gastric volume assessment For preterm infants serial gastric volumes are repeatable and ratings of intragastric echogenicity and curding are moderately consistent when fed milk of the same volume and composition. Ultrasound has the potential to further explore factors that influence gastric emptying in the preterm infant. Perrella et al JPGN 2014 Aug

24. Powder vs liquid formula • Double blind RCT in 78 preterm neonates • Increased incidence of feed intolerance and delayed growth in the first weeks of life in preterm infants fed with liquid formula might be caused by altered gastric acidity or possible disrupted protein bioavailability due to different production and sterilization processes. Surmeli-Onay et al Eur J Pediatr. 2013

25. Abdominal massage • RCT (40 vs 40) assessing effects of abdominal massage on GRV in neonates on intermittent OGT feeds. • High GRV (Massage vs Control): 2.5% vs. 30.0% • 20% of control and only 2.5% of neonates in the massage group developed abdominal distension (p = .044). • Vomiting: 10% vs 0% • Suggestion: Nurses should apply abdominal massage to prevent high GRV and abdominal distension. Uysal et al Gastroenterol Nurs. 2012

26. Gastric residual volume and colour • Can mean GRV and green GR predict feed intolerance? • 99 ELBW infants fed following a SFR (day 3-14). At 48 hours of age, milk feeding was started (12 mL/kg/d increments, 12 feeds/day). • GR checked before each feed, and a GRV up to 2 mL/3 mL in infants ≤750 g/>750 g was tolerated. • Feeds were reduced or withheld if GRV increased Mihatsch et al J Pediatr 2002

27. Colour of gastric residuals and feed tolerance GR assessed as clear, milky, green-clear, green-cloudy, blood-stained, or hemorrhagic. Multiple regression used to study the effect of the mean GRV and its colour on feed volume on day 14 (V14). The median V14 was 103 mL/kg/day (0-166). V14 increased with an increasing percentage of milky GR, whereas the mean GRV and the colour green did not have a significant effect.

28. Early enteral feeds could be established in ELBW infants. The critical GRV seemed to be >2 mL/3 mL as there was no significant negative correlation between mean GRV and V14. Green GR were not negatively correlated with V14 and should not slow down advancement of feed volumes in absence of other signs and symptoms. Mihatsch et al J Pediatr 2002

29. Other interventions and issues • Meconium evacuation (Suppositories, enemas) • Cisapride, Erythromycin, Metoclopramide • Probiotics, Prebiotics, Breast milk, ‘Trophic’ feeds • Effect of phototherapy and CPAP ? • Other causes of bile stained gastric residuals?

30. Thank you!!