Transcript 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
• Considerable variation in feeding practice
throughout UK
– Surveys carried out in Southwest and East
Anglia 1999 / 2000
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
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
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
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
Normal Doppler blood flow in Umbilical
Artery
Systole
Diastole
Umbilical Artery Doppler: Absent flow
in diastole. Associated with fetal
hypoxia and acidosis
Antenatal Doppler: reversed enddiastolic flow. Associated with fetal
hypoxia and acidosis
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
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.
Confirmed NEC
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
SMA blood flow velocity (cm/s)
First day superior mesenteric artery blood
flow velocity in small for gestational age
infants and controls
60
50
40
30
20
10
0
SGA Weight GA
AREDF Controls
SGA Weight GA
Controls
EDF+
Blood flow, Hypoxia and Feeding

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
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
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
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
“Early vs delayed initiation of progressive
enteral feeding for parenterally fed low birth
weight or preterm infants” Kennedy and Tyson 1999
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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
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’
“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
“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)
“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
Trophic feeds vs advancing feeds
Berseth 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
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
The ADEPT Study
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
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
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
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
We hope the ADEPT Study
will help clarify the best early
feeding strategy for this highrisk group of preterm infants