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Abnormal Doppler Enteral Prescription Trial (ADEPT) Study Background

Abnormal Doppler Enteral Prescription Trial (ADEPT) Study Background. ADEPT Study Background. Uncertainty about best feeding practice High risk group of infants – intrauterine growth restriction (IUGR) with abnormal antenatal blood flow

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Abnormal Doppler Enteral Prescription Trial (ADEPT) Study Background

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  1. Abnormal Doppler Enteral Prescription Trial (ADEPT) Study Background

  2. ADEPT Study Background • Uncertainty about best feeding practice • High risk group of infants – intrauterine growth restriction (IUGR) with abnormal antenatal blood flow • Considerable variation in feeding practice throughout UK • Surveys carried out in Southwest and East Anglia 1999 / 2000

  3. Why worry about enteral feeding? Enteral feeding may result in: • Compromise of diaphragmatic function • Impaired ventilation, ↑PaCO2 (Heldt 1988, Blonheim et al 1993) • Gastro-oesophageal reflux • Apnoea, bradycardia • Necrotising enterocolitis

  4. Fear of necrotising enterocolitis (NEC)? • Affects 7% of very low birth weight infants (Lemons et al, Pediatrics 2001) • Has >20% mortality (in BPSU surveys 1981-2 & 1993-4) • Has drastic effects on nutrition, cholestasis • 90% of babies who develop NEC are receiving enteral feeds

  5. Does NEC occur more frequently in small for gestational age babies? • Early case-control studies matched for birth weight • Case-control study of 74 cases of NEC in preterm infants: at 30-36 weeks gestational age • Birthweight <10th centile: OR 6 (1.3-26) for NEC • Beeby and Jeffrey. 1991, ADC:67:432-5 • Observational study Oxford 1985-91: • 69 cases of definite/proven NEC • At 30-36 weeks, 71% <10th centile (vs 49% overall) • McDonnell and Wilkinson. Sem Neonatol 1997

  6. Why should NEC occur more frequently in some IUGR babies? • Pathogenesis of NEC may include enteral feeding, gut ischaemia, bacterial infection • Santulli et al. Paediatrics 1975;55:376-87 • Abnormal gut blood flow in IUGR subgroup • Antenatal absent or reversed end-diastolic flow velocities on Doppler in umbilical artery and aorta • Postnatal reduced flow velocities in the superior mesenteric artery • Hypoxic-ischaemic or reperfusion damage to gut • Alteration of postnatal gastrointestinal tract function

  7. Normal Doppler blood flow in Umbilical Artery Systole Diastole

  8. Umbilical Artery Doppler: Absent flow in diastole. Associated with fetal hypoxia and acidosis

  9. Antenatal Doppler: reversed end-diastolic flow. Associated with fetal hypoxia and acidosis

  10. Does NEC occur more often after fetal absent or reversed end diastolic flow velocities (AREDFV)? • 14 studies comparing NEC rates in babies born after AREDFV with controls • 9 studies showed excess of NEC in babies with AREDFV: OR 2.13 (95%CI 1.49-3.03) • Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch. Dis. Child. Fetal Neonatal Ed. 2005; 90: F359-F363

  11. Figure 1 Studies comparing rates of NEC in fetuses with AREDF in the umbilical artery or aorta, compared with controls who had forward end diastolic flow. Total number of cases of NEC (all grades, confirmed or unconfirmed) per live births in each group. Odds ratio (95%CI) are given.

  12. Confirmed NEC

  13. Antenatal changes are associated with risk of NEC – but what happens postnatally in small for gestational age infants? • Reduced velocity of blood flow in the superior mesenteric artery - Kempley et al 1991 - Martinussen et al 1997 - Maruyama et al 2001 • Impaired response to enteral feeding of superior mesenteric artery blood flow velocity - Murdoch et al 2002

  14. 60 50 40 SMA blood flow velocity (cm/s) 30 20 10 0 SGA Weight GA SGA Weight GA Controls Controls AREDF EDF+ First day superior mesenteric artery blood flow velocity in small for gestational age infants and controls

  15. Blood flow, Hypoxia and Feeding • Feeding increases intestinal blood flow • Feeding also increases intestinal oxygen consumption • When feed are given, hypoxia has a more significant effect on intestinal oxygen delivery

  16. Strategies to prevent NEC? • Enteral antibiotics (reduced risk, but more antibiotic resistance) • Enteral immunoglobulins (no significant effect) • Feeding with breast milk • Delay enteral feeding with total parenteral nutrition • Slow increase in enteral feeds • Trophic non-nutritive feeds

  17. Is there any evidence to support these feeding strategies? • 3 systematic reviews in Cochrane Library: • “Early vs delayed initiation of progressive enteral feeding for perenterally fed low birth weight or preterm infants”Kennedy KA, Tyson JE. 1999 • “Rapid vs slow advancement of feeding for promoting growth and preventing NEC in parenterally fed low birth weight infants”Kennedy KA, Tyson JE. 1998 • “Minimal enteral nutrition to promote feeding tolerance and prevent morbidity in perenterally fed neonates”Tyson JE, Kennedy KA. 1998 revised and republished as: • “Trophic feedings for parenterally fed infants (Review)”Tyson JE, Kennedy KA. 2005

  18. “Early vs delayed initiation of progressive enteral feeding for parenterally fed low birth weight or preterm infants”Kennedy and Tyson 1999 • Only 2 studies: total 72 babies (60 and 12) • All had parenteral nutrition • Early <4 days; late >4 days • Progressive feeds within 72 hours of starting • Early: less parenteral nutrition, less sepsis investigation • No difference in weight gain, length of stay • No ability to detect differences in NEC

  19. Authors' Conclusions ‘For such a fundamental issue in the care of sick preterm infants, we have embarrassingly limited data on which to base decisions about when to start enteral feedings’ ‘… it is unclear whether high-risk infants should receive early or delayed feedings’ ‘To be feasible and valid, such a large trial would require a simple protocol .…. and a well organized group of participating centres’

  20. “Rapid vs slow advancement of feeding to promote growth and prevent NEC in parenterally fed preterm infants”Kennedy and Tyson 1998-2005 • Rapid: 20-35 ml/kg/day • Slow: 10-20 ml/kg/day • 3 studies including 369 babies; all had parenteral nutrition • Rapid = reduced days to full enteral feeds and regain birthweight (weighted mean difference (wmd) - 3.2 days) • No difference NEC or length of stay

  21. “Trophic feedings for parenterally fed infants (Review)”Tyson JE and Kennedy KA 2005 Trophic vs no feedings: 10 studies – 617 patients • Started day 1 – day 8, <25 kcal/kg/day (<35 ml/kg/day) • Trophic feeds of 12-24mls/kg/day for 5-10 days • Controls no feeding for 6-18 days • Reduction in days to full feeds (WMD - 2.6 days) and length of hospitalisation (WMD - 11.4 days) • No significant difference in NEC (OR 1.16, 95% CI 0.75-1.79)

  22. “Trophic feedings for parenterally fed infants (Review)”Tyson JE and Kennedy KA 2005 Trophic vs progressive feeding: 1 study, 144 patients • Trophic took longer to reach full feeds (WMD +13.4 days) and longer hospitalisation (WMD +11.0 days). ‘…trophic feedings associated with a marginally significant reduction in NEC (relative risk =0.14 [0.02, 1.07]; risk difference = -0.09 [-0.16, -0.01].’ • Trial terminated early because of increased NEC, 7/70 progressive vs 1/70 trophic, p<0.03 Berseth 2003

  23. Trophic feeds vs advancing feedsBerseth C. Pediatrics 2003;111:529-34 • Minimal enteral nutrition (MEN) 20 ml/kg/day for 10 days • Advancing: increase 20 ml/kg/day each day • 2 hourly infusion then 2 hourly fast • Late start both groups (mean 10.3/9.3 days) • Breast milk fortifier • added at 120 ml/kg/day; doubled at 140 ml/kg/day • NEC: 1/70 MEN; 7/71 Advancing: p=0.3

  24. Position of equipoise • IUGR babies with AREDFV on antenatal Dopplers do have increased risk of NEC • BUT…no evidence that delaying feeds is of benefit • AND…delaying feeds may increase risks of sepsis and cholestasis • AND increase duration of intensive care and length of hospital stay

  25. The ADEPT Study

  26. Study Design • Premature babies who had abnormal antenatal Doppler studies • Randomisation to early or late enteral feeding • Primary outcomes of days to full enteral feeding and necrotising enterocolitis

  27. Study Management • Supported by NPEU, Oxford • Clinical Investigators group • Study administrator based at NPEU • Multi-centre Research Ethics Committee approval • Trial Steering Committee • Data Monitoring Committee

  28. Study Management • 400 babies • Recruit over 2 years, plus six months to complete data collection and analysis • 30-40 hospitals in UK • Good Study Administrator is key! • Ensure information, data sheets etc. sent out • Ensure data returned, computerised, analysed • Organise meetings, ensure communication

  29. Action Medical Research • Grant for £143,000 • 2 years 9 months • 3 months run-in, 2 years recruitment, 6 months analysis and writing up • Main cost – salary for Study Administrator • Plus Data Clerk and Statistician support, consumables

  30. We hope the ADEPT Study will help clarify the best early feeding strategy for this high-risk group of preterm infants

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