International conference «Actual approaches to the extremely preterm babies: International experience and Ukrainian realities» (Kyiv, Ukraine, March 5-6, 2013)

1. Ductus Arteriosus
Kyiv March 2013
Jan Širc
Institute for the Care of Mother and Child, Prague, Czech Republic
Third Faculty of Medicine, Charles University, Prague, Czech Republic
The HIP Trial is funded by the European Commission within the 7th Framework Programme

2. Patent ductus arteriosus
The HIP Trial is funded by the European Commission within the 7th Framework Programme

3. Ductus arteriosus – spontaneous closure
1. stage. Blood entering the ductus and its vasa vasorum from
the aorta has a high Po2 after delivery, which, along with
alterations in prostaglandin metabolism, leads to constriction
and closure of the ductus arteriosus.
2. stage. A second stage of closure related to fibrous proliferation
of the intima is complete in 2-3 weeks. Patency after 3 months
is considered abnormal.
The HIP Trial is funded by the European Commission within the 7th Framework Programme

4. Ductus arteriosus – spontaneous closure
• Spontaneous closure during 96 hrs in term infants
• VLBW between day 3 and 7
– 44% below 32 weeks of gestation
(Van Overmeire et al. J Pediatr 2001; 138; 205-211)
• VLBW Day 8
– 34% in ELBW infants
(Koch et al. Pediatrics 2006; 117; 1113-1121)
• 24% in 23-27 weeks of gestation
- (Dani et al. Acta Paediatr 2008; 97; 1176-1180)
• Spontaneous closure in 100% of very low birth weight infants up to 1 year
- Herman et al. Arch Dis Child Fetal Neonatal Ed 2009
• 96% of VLBW up to 18 months
- Kucera, Sirc, Semberova, Stranak 2011
The HIP Trial is funded by the European Commission within the 7th Framework Programme

5. Ductus arteriosus – spontaneous closure
VLBW
PDA %
100
90
80
70
60
50
40 PDA %
30
20
10
0
Day Day Day Day Day Day Day Day Day Day
7 14 21 28 35 42 49 56 63 70
Letshwiti et al. Irish & American Paediatic
Society Meeting 2010 Dublin
The HIP Trial is funded by the European Commission within the 7th Framework Programme

6. PDA - diagnosis
• Early
1. Clinical - mostly silent, with no murmur. BP may be low (systolic,
diastolic and mean) with normal pulse pressure
2. Biochemical – influenced by clinical condition during transitional
period
3. Echocardiographical
• Late
1. Clinical – murmur, hypotension, increased pulses, wide pulse
pressure, Respiratory deterioration, congestive heart failure
2. Biochemical - BNP, pro-BNP, NT-proBNP, Troponin T – cTnT,
metabolic acidosis, lactate
3. Echocardiographical
The HIP Trial is funded by the European Commission within the 7th Framework Programme

7. PDA – clinical/echo diagnosis
Week 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th
(patients) week week week week week week week week week week
PDA
clinical
assessment
80 75 92 67 56 57 57 43 33 50
vs. ECHO
(% correct
dg.)
Letshwiti et al. Irish & American Paediatic Society Meeting 2010
Dublin
The HIP Trial is funded by the European Commission within the 7th Framework Programme

8. PDA - diagnosis
• Echocardiogram is required for early diagnosis of PDA in
preterm infants, as clinical signs are not reliable in the first few
days of life
– (Alagarsamy S et al. J Perinat Med. 2005;33(2):161-4.)
The HIP Trial is funded by the European Commission within the 7th Framework Programme

9. PDA staging
McNamara et al. Arch Dis Child Fetal Neonatal Ed. 2007 Nov;92(6):F424-7
The HIP Trial is funded by the European Commission within the 7th Framework Programme

10. Echocardiography - components
1. Ductal size
2. Direction and pattern of ductal flow
3. Left atrial and ventricular size, Left atrium to aorta ratio
(LA:Ao ratio)
4. Flow in main pulmonary artery (MPA)
5. Diastolic flow in pulmonary arteries
6. Diastolic flow in abdominal aorta
7. Patency of foramen ovale (FOA)
The HIP Trial is funded by the European Commission within the 7th Framework Programme

11. Ductal size
• Combine cross-sectional 2D image with colour Doppler
• Short-axis view - three-legged stool is usually seen
• Ductal constriction begins at the pulmonary end or in the middle
• Measure internal diameter of narrowest part
• Measurement from colour Doppler – appropriate gain !
Size – preterms
Small < 1.5 mm
Medium 1.5 – 2.0 mm
Large > 2 mm
The HIP Trial is funded by the European Commission within the 7th Framework Programme

12. Direction and pattern of ductal flow
• By pulsed and/or CW Doppler
• Bidirectional flow – first 48
hrs, PPHN
• Small, restricted PDA – high
velocity in both systole and
diastole ( > 1 m/s)
• Large PDA – lower velocity in
systole, very low flow in
diastole (almost zero)
The HIP Trial is funded by the European Commission within the 7th Framework Programme

13. Left atrial and ventricular size
• Most often used left atrium to aorta ratio (LA:Ao ratio)
• Long axis view
• Poor specificity and sensitivity – affected by LV dysfunction,
hydratation, atrial shunting
• Not reliable in the first 24-48 hours of life
LA:Ao ratio
Small PDA < 1.4:1
Moderate 1.4:1 – 1.6
Large PDA > 1.6
The HIP Trial is funded by the European Commission within the 7th Framework Programme

14. Flow in main pulmonary artery (MPA)
• Suprasternal short axis view/adjusted
parasternal view
• Colour Doppler
small PDA – narrow jet, does not reach
pulmonary valve
moderate – wider jet to the pulmonary valve
large PDA – very wide jet reaches valve and
swirls back
• Pulsed and/or CW Doppler
small PDA – flow curve is surrounded, no flow
in diastole
large PDA – „hairy“ curve with diastolic flow
The HIP Trial is funded by the European Commission within the 7th Framework Programme

15. Diastolic flow in pulmonary arteries
• Short axis view - three-legged
stool
• Left pulmonary artery is mostly
used
• End-diastolic antegrade flow
PDA size flow
Small > 20-30 cm/s
Moderate 30-50 cm/s
Large > 50 cm/s
The HIP Trial is funded by the European Commission within the 7th Framework Programme

16. Diastolic flow in abdominal aorta
• Subcostal view in the
middle of aorta at the
level of diaphragm
• Restrictive flow or
„steal“ phenomena
when PDA is significant
The HIP Trial is funded by the European Commission within the 7th Framework Programme

17. Patency of foramen ovale (FOA)
• Foramen ovale decompress left atrium and ventricle
• Decreases LA/Ao
The HIP Trial is funded by the European Commission within the 7th Framework Programme

18. Diagnosis – X-ray
• Nonspecific
• Cardiomegaly
• Pulmonary edema
• Horizontal position of
left pulmonary artery
The HIP Trial is funded by the European Commission within the 7th Framework Programme

19. Biochemical diagnosis
• Specific markers of heart
overload: pro-BNP, BNP,
NT-proBNP
Troponin T, I – cTnT, cTnI Pre-prohormone
• Metabolic acidosis (134 AA)
• Elevated lactate
ProBNP
(108 AA)
BNP NTproBNP
(32 AA, t ½ = 20 min) (inactiv, t ½ = 60 min)
The HIP Trial is funded by the European Commission within the 7th Framework Programme

20. Brain natriuretic peptide (BNP)
• Secreted from ventricular and atrial myocytes during pressure and
volume overload
• Renin-angiotensin antagonist - diuretic, natriuretic and vasodilatation
effects
↓ intravascular volume
↓ preload
↓ afterload
Neonates
• Corelation with left-to-right shunting and systolic pressure of RV
• Negative correlation with LV ejection fraction
• Increases after birth, reaches maximal levels 3-4 days after the birth,
then decreases
The HIP Trial is funded by the European Commission within the 7th Framework Programme

21. cTnT
• Increases 2 hrs after insult, max levels at 12 hrs
• No corelation with gestation age or ECHO parameters of myocardial
dysfunction
• Significantly ↑ in RDS and RDS+inotropic support (0.15 resp. 0.3 ug/l)
• Marker of hemodynamicaly significant PDA (hsPDA) with poor
outcome
Normal values
Term infants < 0.05 ug/l
Preterm 0.15 – 0.3 ug/l
The HIP Trial is funded by the European Commission within the 7th Framework Programme

22. NTproBNP, TNT and outcome
• 80 infants below 32 gt, BW 1060 g
• NTproBNP and Troponin T at 48 hrs of life
p < 0,001 p < 0,001
PDA 0 PDA+ PDA+PIVH III/IV, †
LA/Ao ratio, flow in abdominal aorta, PDA diameter did not change
El-Khuffash et al, Arch Dis Fetal Neonatal Ed 2008,93:407-412
The HIP Trial is funded by the European Commission within the 7th Framework Programme

23. PDA treatment
1. Prevention - noninvasive ventilation, avoid of infection, stable
circulation, fluid management, normoxemia, permisive hypercapnia,
minimal correction of metabolic acidosis
2. Conservative approach – fluid restriction, diuretics
3. Pharmacotherapy
a) profylactic – first 24 hrs
b) early presymptomatic
c) late symptomatic
• Reduction of PG synthesis by inhibition of cyclooxygenase (COX)
produces constriction of the ductus.
The HIP Trial is funded by the European Commission within the 7th Framework Programme

24. PDA treatment
Pharmacotherapy
• Indomethacin
• Ibuprofen
– Ibuprofen therapy on the third day of life is as efficacious as indomethacin for the
treatment of patent ductus arteriosus in preterm infants with the respiratory distress
syndrome and is significantly less likely to induce oliguria
(Van Overmeire et al N Engl J Med. 2000 Sep 7;343(10):674-81.)
4. Surgical ligation
The HIP Trial is funded by the European Commission within the 7th Framework Programme

25. PDA treatment – should we do it?
Subsequent studies confirmed the association of PDA with
• Pulmonary haemorrhage
• Severe RDS
• CLD/BPD
• NEC
• Renal impairment
• IVH
• PVL
• Cerebral palsy
• Death
The HIP Trial is funded by the European Commission within the 7th Framework Programme

26. PDA treatment – should we do it?
Cochrane reviews
• Prophylactic indomethacin decreasing IVH, however no impact on
neurodevelopmental outcome
• Indo/Ibuprofen treatment – higher closure rate, but not any meaningful short
term or long term benefit
• Prophylactic ligation decreasing NEC stage II and III, however exposing large
number of infant to very invasive therapy (with unknown long term outcomes)
Peter W Fowlie, Peter G Davis, William McGuire, 2010
TIPP study (2001) – 1202 infants; 2872 infants in all trials
Lucy Cooke, Peter A Steer, Paul G Woodgate, 2009
Arne Ohlsson, Sachin S Shah, 2009
Arne Ohlsson, Rajneesh Walia, Sachin S Shah, 2010
Rafat Mosalli, Khalid AlFaleh, 2010
Manoj N Malviya, Arne Ohlsson, Sachin S Shah, 2008
The HIP Trial is funded by the European Commission within the 7th Framework Programme

27. PDA treatment – should we do it?
• Treatment of persistent patent ductus arteriosus in preterm
infants: time to accept the null hypothesis?
Benitz WE Journal of Perinatology, 2010; 30:241
• Meta – Analysis
• 49 trials, 4728 subjects
• Objective to ascertain whether there is any evidence, however weak, to
support prophylaxis or treatment
Conclusion
• The data do not permit to reject null hypothesis
• Early treatment of PDA does not improve outcomes in preterm infants
The HIP Trial is funded by the European Commission within the 7th Framework Programme

28. PDA treatment - Conclusions
• Ligation, indomethacine and ibuprofen are effective for achieving ductal closure
• Prophylactic indomethacine reduces incidence of IVH without improvement of
neurodevelopmental outcomes
• There is no evidence for improvement in the incidence of death, BPD, NEC or other
morbidity with PDA treatment
• More conservative approach to management of PDA seems to be feasible
• Routine use of COX inhibitors or surgery to achieve early ductal closure is no longer
recommended
• ? Early targeted treatment with use of echocardiography (identifications of infants in the
risk - if there is causal linkage of PDA to adverse outcomes)
• ? Late treatment using strict echocardiographic/clinical signs of cardiovascular
compromise (staging)
The HIP Trial is funded by the European Commission within the 7th Framework Programme

29. Thanks a lot for your attention
The HIP Trial is funded by the European Commission within the 7th Framework Programme