Slides presented at neonatology workshops in Dubai, SaudiArabia and Kuwait, May 2012.

1. news & views on
the Patent Ductus Arteriosus
STEFAN JOHANSSON, MD PhD
Karolinska university hospital
Karolinska institutet
Stockholm, Sweden

2. 99nicu.org
the #1 web community for neonatal staff

5. • What?
• Why?
• How?
• When?
• The Karolinska Way!

6. STEFAN JOHANSSON
MD PhD
at KAROLINSKA

8. Karolinska institutet
• university founded in 1810
• education & research
• Nobel prize

9. Neonatology research
• surfactant - discovery and development
• brain imaging
• respiration
• epidemiology
• NIDCAP

10. Karolinska university hospital
• regional hospital, opened in 1937
• health care
• education and research connect the hospital
to Karolinska institutet

11. Karolinska university hospital (-s)

12. • What?
• Why?
• How?
• When?
• The Karolinska Way!

13. Fetal duct
• Essential for fetal circulation
• ”shunt” is right to left
• Fetal ductal closure can induce
primary pulmonary hypertension

14. Postnatal duct – term infant
• Shunt direction reversed
• Muscular tissue in the duct
sensitive to oxygen
• Duct closes during
the first days of life

15. Postnatal duct – preterm infant
• Constriction can be delayed
– pulmonary disease
– oxygenation problems
– inflammation
• Blood volume shunted through
the duct can be LARGE!

16. PDA – common clinical problem
PDA rate (%)
100
80
60
40
20
0
22 w 23 w 24 w 25 w 26 w
the EXPRESS study, all live-born infants <27 weeks in Sweden 2004-2007.
Acta Paediatrica 2010;99:978-992

17. PDA

18. PDA PDA
PDA PDA
PDA PDA
PDA
PDA
PDA PDA
PDA
PDA PDA
PDA PDA

19. PDA PDA
PDA PDA
PDA PDA
PDA
PDA
PDA PDA
PDA
PDA PDA
PDA PDA

20. PDA – what do we mean?
• the duct is open
• symtoms and signs
– ”I see them when I examine the infant”
– ”I see them with my machine”

21. PDA – what do we mean?
☞ ”hemodynamically significant PDA”
• physiological consequences counts!
• duct as anatomic structure

22. Hemodynamic effects
Increased perfusion of pulmonary circulation
Reduced perfuson of systemic vascular beds
• Brain
• GI tract
• Kidneys

23. PDA – what do we really mean?

24. PDA – what do we really mean?
Clinical symtoms/signs Echocardiographic signs
• murmur • patency of the duct
• bounding pulses • left-right shunt
• sBP >> dBP • large left atrium
• hypotension • diastolic ”steal”
• feeding intolerance • diastolic flow in LPA

25. PDA – what do we
really really mean?

26. PDA – what we really really mean
• ”diastolic flow easily detectable… main
pulmonary artery”
• ”diastolic backflow in the aorta immediately
beneath the ductus”
• ”LA-to-Ao-ratio >1.6”
* van Overmeire et al, New
Engl J Med 2000;343:674-81

27. PDA – what we really really mean
• ”left to right ductal shunting”
• ”increased LA-to-Ao-ratio”
• ”failure to wean from mechanical ventilation
* Richards et al, Pediatrics 2009;124:e287

28. PDA – is there a definition?

29. PDA – review of definitions
*Zonnenberg, de Waal, Acta Paediatrica 2012;101:247-251

30. PDA – review of definitions
Criteria for definition of a significant PDA studies (n)
- not mentioned 3
- clinical only 7
- clinical and echocardiographic 44
- echocardiographic only 13
*Zonnenberg, de Waal, Acta Paediatrica 2012;101:247-251

31. Tools

32. Stethoscope ≠ good
• Murmur - good specificity, poor sensitivity
– hear a murmur - probably a PDA
– don’t hear a murmur - could be a PDA anyway
Skelton. J Peaditr Child Health. 1994;30:406
Davis. Arch Pediatr Adolesc. 1995;149:1136

33. ”I know it when I see it”
• Echocardiography!
• Echocardiography!
• Echocardiography!

34. My take
Visualise the problem with echo
Functional measurements first
Structural changes is a consequence of
functional changes (that you can measure)

35. My take
Functional measurements
• Ductal blood flow pattern
• End-diastolic velocity in LPA
• Diastolic flow in postductal aorta
Structural measurements
• LA/Ao-ratio
• Ductal diameter

36. My take
Functional measurements
• Ductal blood flow pattern: pulsatile
• End-diastolic velocity in LPA: >0.3 m/s
• Diastolic flow in postductal aorta: reversed
Structural measurements
• LA:Ao-ratio >1.4
• Ductal diameter >2 mm

37. My advice
Make your own definition and use it!
… until there is a validated definition.
Learn echocardiography!

38. • What?
• Why?
• How?
• When?
• The Karolinska Way!

40. Do you care about a PDA…
…as a risk factor for other
…as such, for example to
problems, such as BPD or
find ways to prevent it?
ROP?

41. ”PDA increase the risk of…”
• mechanical ventilation
• pulmonary haemorrhage
• NEC
• IVH / PVL
• ROP
• BPD
PDA is even related to
an increased mortality

42. Are these associations true?
• Conflicting results.
• Small studies!
• PDA treatment does not reduce risks. 

43. Causality or co-occurence?
PDA BPD
PDA
Short gestational age
BPD

44. Should PDAs be treated at all?
Benitz, Arch Dis Child Fetal Neonatal Ed 2012;97:F80-F82

45. Personal reflection
What we have…
• associations plausible
• underpowered studies
What we need…
• large observational studies
• placebo-controlled RCT

46. 7 April 2007 Stefan Johansson 46

47. • What?
• Why?
• How?
• When?
• The Karolinska Way!

49. Medical treatment of sign PDA
Ibuprofen vs indomethacin (n=1092)
• Equal efficacy
• Ibuprofen – lower risk of NEC and transient
renal insufficiency.
• Studies need to evaluate long-term outcomes

50. Medical or surgical treatment
Surgery vs indomethacin (n=154)
• insufficient data to make a conclusion
• three recent studies indicates an increased
risk of BPD, ROP and neurosensory
impairment .

51. Dosing schedules – indomethacin
Several regimes
• slow injection vs infusion
• three doses vs six doses
• 0.2 mg/kg most common?

52. Dosing schedules – ibuprofen
One approved dosing schedule
• 10 + 5 + 5 mg/kg
• slow injection

53. Future directions on ”How”
• Dosing schedules?
• Combination of drugs?
• Role for surgical closure?

54. • What?
• Why?
• How?
• When?
• The Karolinska Way!

55. When is the shunt significant?
• ”…the shunt develops when the pulmonary
pressure drops during the first days in life”

56. When is the shunt significant?
It is not true that…
• ”…the shunt develops when the pulmonary
pressure drops during the first days in life”

57. Early ductal shunting
• Echocardiography!
• First hours of life:
– large shunt volumes
– most pronounced hemodynamic impact
– most strongly associated with morbidities

58. When to treat?
• Prophylactic treatment?
• Early ”pre-symtomatic” treatment?
• Treating the clinically apparent PDA?

59. When to treat?
…one of the big
unsanswered
questions in
neonatology.

60. DETECT trial
• infants <29 weeks
• echo within 12 hours
• infants with PDAs – indomethacin or placebo
• Results reported (PAS May 2012)
– reduced risk for lung hemorraghe
– no effect on other outcomes

61. 7 April 2007 Stefan Johansson 61

62. • What?
• Why?
• How?
• When?
• The Karolinska Way!

63. Ibuprofen @ Karolinska
• Pro’s and con’s with both drugs.
• Change to ibuprofen in 2001
– less water balance problems
– cerebral circulation unaffected by ibuprofen

64. Current protocol
Echocardiography day 1-3
• ≤ 27 weeks
• any preterm on mechanical ventilation
Echocardiography day 4-5 (or later)
• preterm on CPAP and FiO2>0.30
• clinical suspicion

65. sign PDA
Contraindications?
• trombocytopenia Yes
• hyperbilirubinemia
• low urinary output Watchful waiting
• active NEC
• IVH grade 2-4
• DIC
No
Postnatal age?
• <14-21 days – ibuprofen
• >14-21 days – surgery

66. Candidates for surgery
• Late relapse
• Unresponsive PDA
• Severe lung disease

67. ”Conservative” strategy
In well infants >3 weeks – we wait and see
• Repeat echo’s on a weekly/bi-weekly basis
• Wean CPAP slowly
• Keep EVF > 40%

68. Our own data (2001-2004)
• 83 infants, 98 courses
– 49 boys, 34 girls
– gestational age 27 weeks
– birth weight 979 grams

69. Clinical characteristics
• RDS diagnosis 65 of 83 (78%)
• Inotropic support, day 1 57 of 83 (69%)
• Ventilatory support 41 MV
34 nCPAP
8 none

70. 83 infants, 98 courses
1st course conservative (5)
(83) surgery (4)
2nd course (8) conservative (1)
surgery (3)
response (66) response (4)
relapse
surgery (7)
2nd course (6) surgery (2)
3rd course (1) response (1)
response (3) relapse
3rd course (1) response (1)

71. Pharmacological closure rates
• closure rate - 1st course 66 / 83 (80%)
• closure rate - 2nd course 7 / 14 (50%)
(assessed with echo 12-24 hours after dose 3)

72. Closure rates, by gestational age
23-24 weeks 25-26 weeks 27-28 weeks 29- weeks
(n=14) (n=31) (n=20) (n=18)
Short term closure 10/14 (71) 23/31 (78) 18/20 (90) 13/18 (72)
Relapses 6/10 (60) 5/23 (22) 2/18 (11) 1/13 (8)
Final non-surgical
8/14 (57) 23/31 (78) 18/20 (90) 17/18 (94)
closure
Surgical PDA-closure 6/14 (43) 8/31 (26) 2/20 (10) 1/18 (6)

73. Surveillance of renal function
• Measurements over treatment
– urine output
– s-sodium
– s-creatinine
– s-urea

74. Urinary output
ns

75. S-sodium
p<0.05 dose 1
p<0.05 dose 2

76. S-creatinine
p<0.05 dose 1
p<0.05 dose 2

77. S-urea
p<0.10 dose 1

78. Our experience
• Transient renal dysfunction during ibuprofen treatment;
surveillance indicated.
• Short term closure achieved in most preterm infants.
• Surgical ligation common in 23-24 week infants,
due to relapses.

79. Conclusions
• More research!
• In the meantime, we should do our best!
7 April 2007 Stefan Johansson 79