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 end-diastolic 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

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

infants and controls

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

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

• 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 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

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 high-risk group of preterm infants