ductus arteriosus

The HIP Trial is funded by the European Commission within the 7th Framework Programme

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


Patent ductus arteriosus


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.

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

• 96% of VLBW up to 18 months

- Kucera, Sirc, Semberova, Stranak 2011


- Herman et al. Arch Dis Child Fetal Neonatal Ed 2009



VLBW

0102030405060708090

100

Day 7

Day 14

Day 21

Day 28

Day 35

Day 42

Day 49

Day 56

Day 63

Day 70

PDA %

PDA %

Letshwiti et al. Irish & American Paediatic

Society Meeting 2010 Dublin


• 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

PDA - diagnosis


Week

(patients)

1st

week

2nd

week

3rd

week

4th

week

5th

week

6th

week

7th

week

8th

week

9th

week

10th

week

PDA

clinical

assessment

vs. ECHO

(% correct

dg.)

80 75 92 67 56 57 57 43 33 50

PDA – clinical/echo diagnosis

Letshwiti et al. Irish & American Paediatic Society Meeting 2010

Dublin


• 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.)

PDA - diagnosis


PDA staging

McNamara et al. Arch Dis Child Fetal Neonatal Ed. 2007 Nov;92(6):F424-7


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)

Echocardiography - components


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


• 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)

Direction and pattern of ductal flow


• 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

Left atrial and ventricular size

LA:Ao ratio

Small PDA < 1.4:1

Moderate 1.4:1 – 1.6

Large PDA > 1.6


• 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

Flow in main pulmonary artery (MPA)


• Short axis view - three-legged

stool

• Left pulmonary artery is mostly

used

• End-diastolic antegrade flow

Diastolic flow in pulmonary arteries

PDA size flow

Small > 20-30 cm/s

Moderate 30-50 cm/s

Large > 50 cm/s


• Subcostal view in the

middle of aorta at the

level of diaphragm

• Restrictive flow or

„steal“ phenomena

when PDA is significant

Diastolic flow in abdominal aorta


• Foramen ovale decompress left atrium and ventricle

• Decreases LA/Ao

Patency of foramen ovale (FOA)


• Nonspecific

• Cardiomegaly

• Pulmonary edema

• Horizontal position of

left pulmonary artery

Diagnosis – X-ray


• Specific markers of heart

overload: pro-BNP, BNP,

NT-proBNP

Troponin T, I – cTnT, cTnI

• Metabolic acidosis

• Elevated lactate

Biochemical diagnosis

Pre-prohormone

(134 AA)

ProBNP

(108 AA)

BNP

(32 AA, t ½ = 20 min)

NTproBNP

(inactiv, t ½ = 60 min)


• 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

Brain natriuretic peptide (BNP)


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


NTproBNP, TNT and outcome

• 80 infants below 32 gt, BW 1060 g

• NTproBNP and Troponin T at 48 hrs of life

PDA 0 PDA+ PDA+PIVH III/IV, † p < 0,001 p < 0,001

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


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.

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

PDA treatment


Subsequent studies confirmed the association of PDA with

• Pulmonary haemorrhage

• Severe RDS

• CLD/BPD

• NEC

• Renal impairment

• IVH

• PVL

• Cerebral palsy

• Death

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



• 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



• 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)

PDA treatment - Conclusions


Thanks a lot for your attention

ductus arteriosus

Health & Medicine