Abnormal Doppler Enteral

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• Abnormal Doppler Enteral
• Prescription Trial (ADEPT)
• Study Background

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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

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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

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Fear of necrotising enterocolitis (NEC)?

• Affects 7 of very low birth weight infants
  (Lemons et al, Pediatrics 2001)
• Has gt20 mortality (in BPSU surveys 1981-2
  1993-4)
• Has drastic effects on nutrition, cholestasis
• 90 of babies who develop NEC are receiving
  enteral feeds

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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 lt10th centile OR 6 (1.3-26) for NEC
• Beeby and Jeffrey. 1991, ADC67432-5
• Observational study Oxford 1985-91
• 69 cases of definite/proven NEC
• At 30-36 weeks, 71 lt10th centile (vs 49
  overall)
• McDonnell and Wilkinson. Sem Neonatol 1997

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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 197555376-87
• 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

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Normal Doppler blood flow in Umbilical Artery
Systole
Diastole
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Umbilical Artery Doppler Absent flow in
diastole. Associated with fetal hypoxia and
acidosis
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Antenatal Doppler reversed end-diastolic flow.
Associated with fetal hypoxia and acidosis
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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 (95CI 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

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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 (95CI) are given.
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Confirmed NEC
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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

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First day superior mesenteric artery blood flow
velocity in small for gestational age infants
and controls
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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

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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

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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

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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 lt4 days late gt4 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

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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
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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

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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, lt25 kcal/kg/day (lt35
  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)

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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, plt0.03
• Berseth 2003

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Trophic feeds vs advancing feedsBerseth C.
Pediatrics 2003111529-34

• 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 p0.3

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Position of equipoise

• IUGR babies with AREDFV on antenatal Dopplers do
  have increased risk of NEC
• BUTno evidence that delaying feeds is of benefit
• ANDdelaying feeds may increase risks of sepsis
  and cholestasis
• AND increase duration of intensive care and
  length of hospital stay

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The ADEPT Study
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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

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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

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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

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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

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