Controversies in the

PDA: Traditional View

Management of PDA:
Rapid DA constriction is critical for postnatal circulatory adaptation
Arguments For and Against
Fetal DA Newborn DA
Treatment must
~
must remain
remain widely
widely patent
patent must
Newhnco
must close
close soon
PA
soon after
after birth
birth

Jeff
Jeff Reese,
Reese, M.D.
M.D.
The Mildred T. Stahlman Division of Neonatology
Department of Pediatrics
Vanderbilt University Medical Center

(no
(no conflicts
conflicts of
of interest
interest to
to disclose)
disclose)

PDA: Traditional View Closure of the DA

Consequences
Consequencesof
of Untreated
UntreatedPDA
PDA •• Normal
Normalphysiologic
physiologicclosure:
closure:
–- Overcirculation
Olercirculationofof the
the lungs:
lungs: –- First
First Phase:
Phase : Functional
Functional closure
closure (12-24
(12-24 hours)
hours)
Pulmonary
Pulmonary vascular
vasrular remodeling
remodeling –- Second
Second Phase:
Phase : Anatomic
Anatomic closure
closure (2-3
(2-3 weeks)
weeks)
Pulmonary
Pulmonary HTNHTN
Heart
Heart failure
failure
Chronic
Chroniclung
lung disease
disease • Failure
Failureof
of normal
normalclosure:
dosure: Patent
PatentDuctus
DuctusArteriosus
Meriosus (PDA)
(PDA)
–- "Steal
Steal" from
fromthe
the aorta:
aorta: –- Term
Term Infants
Infants (1
(1 in
in 2000
2000 live
live births)
births)
Hypotension -Conditions
-Conditions causing
causing low
low PaO2
PaO2 or
or increased
increased PGs
PGs
Poor perfusion of tissues; acidosis –- Preterm
Preterm Infants
Infants (~50-60%
(-50-60% <1000g)
<10009)
Renal failure -Hypoxia
-Hypox ia more
more common
common
Gut ischemia; Necrotizing enterocolitis -Increased
-Increased exposure
exposure toto elevated
elevated PGPG levels
levels
-Ineffective
-Ineffect ive contraction,
contraction, despite
despite increased
increased sensitivity
sensitivity to
to PGs
PGs

Limited Treatment Options The Feud over PDA Management

for Infants with PDA
Medical
Medical Surgical
Surgical

Conservative
Conservative Approach:
Approach :
• Manage
Manage symptoms
symptoms
•• Allow
Allow PDA
PDA at
at discharge
discharge

Medical
Medical Interventions:
Interventions :
• Oxygen
Oxygen(?) (?)
• Fluid
Fluid restriction
restriction
• NSAIDS:
NSAIDS :
–- Indomethacin
lndomelhacin (1974)
(1974)
–- Ibuprofen
Ibuprofen (1979;
(1979; 1995)
1995)
Mello
Mello DM,
OM. Kopf
KopfGS;
GS : www.ctsnet.org
- .ctsnet .org Evidence
Evidence For
For and
and Against
Against Treatment
Treatment
 Arguments Against
When to Call it a PDA?
Treatment
Human
Humanstudies:
studies: The Timing of DA Closure
Non-treatment
Non-treatmentof of PDA
PDAis is already
already common
common
DA
DA closure
dosure doesn’t
doesn't change
changeoutcome
outcome
Term
Term infant,
infant , no
no disease
disease 3d
3d Gentile
Genti le 1981
1981
PDA
PDAwill
will ultimately
ultimatelyclose
dose on on its
its own
own
DA
DA medications
medicationsare are risky
risky Preterm
Preterm 30-37
30-37 wks,
wks , no
no RDS
RDS <4d
<4d Reller
Reller 1990
1990
DA
DA ligation
ligationis is risky
risky Preterm
Preterm >1500g
> 1500g (95%)
(95%) 96h
96h Yu
Yu 1993
1993
Treatment
Treatmentexposes
exposesinfants
infantsto to unnecessary
unnecessary Preterm
Preterm <
< 27
27 wks,
wks , lung
lung dis.
dis. >5d
>5d Clyman
Clyman 2000
2000
therapy
therapy
PDA
PDAis is not
not harmful
harmful– - why
why should
should itit be
be closed
dosed ??

Animal
Animal studies:
studies:
long-term
long-termPDA
PDAexists
exists in
in nature
nature(Brown
(Brown
Norway
Norwayrat,
rat, poodles,
ooodles, etc.)
etc.)

PDA Non-Treatment: Paradigm

DA Closure in <1000g Infants
.. Shift ?
122
122infants
infants
p >
! 11: 20
t: •• Ment
Ment et
et al.
hemorrhage, ­
hemorrhage,
(1994): ¯
al. (1994): PDA,¯
,l.PDA,
t cognitive
,l.IVH
IVH &
cognitivefunction.
PVL, ¯
& PVL,
function. No
,l. pulmonary
No change
pulmonary
change inin CP,
CP,
52
52 spontaneous
spontaneous closure
closure t blindness,
blindness, deafness.
deafness. ! ·
ao42
80 PDAs
were permanent
44-~~-+
7t'frlOOmethacin
indomethacin sa
ii •• TIPP (2001 ): ¯
TIPP (2001): PDA, ¯ligation,
,l.PDA, -!-ligation,¯
,l.severe
severe IVH;
IVH; no
no change
change in
in
7Sprimary
3 ~+
+/-indo closure
+l=us
ligation- &o survival
survival without
without CNS
CNS impairment,
impairment, BPD,BPD, NEC,
NEC, or
or ROP;
ROP; 20
20
~ -,t :140
68 indo
indO -ngmlO(l
40
40 responders
28
responders
28 lig.
lig. due
due to
to failure
failure
i
•
-+ ... infants
infantswith
ligation.
ligation.
•• Clyman
with prophylaxis
prophylaxisneeded

(2007) : ­
Clyman(2007):
neededto

t prophylaxis
prophylaxisafter
to prevent
preventone

after Ment
one PDA

trial; ¯
Ment trial;
PDA

,l.
prophylaxis
prophylaxisafter
after TIPP.
TIPP. TIPP
TIPP included
includeddeath;
death; hadhad too
too
Koch
Koch J,
J , Hensley
Hentley G,G, Roy
Roy L,
L. Brown
Brown S,S, Ramaciotti
Ramaclotll C,
C, Rosenfeld
RoH nfekt CR.
CA . Prevalence
Prevalence of
of spontaneous
l?(>ntaneou, closure
clot ure of
of the
the
large
large of
of effect
effect size;
size; other
other encouraging
encouragingfollow-up
follow-up studies
studies
ductus
ductut arteriosus
e rteriot ut in
.i neonates
n eon■ tH at
at•a birth
birth weight
we6ght of
of 1000
1000 grams
gram, or
or less.
leH . Pediatrics.
Pedlalrict . 2006
2006 Apr;117(4):1113-21.
Apr, 117(4):1113·21 . support
support prophylaxis.
prophylaxis.

PDA Non-Treatment: Paradigm

PDA Treatment Fails to Improve
Shift ?
Outcomes of Interest
------
T.W, J. PucW druclr.........iltWfll~..tJ..pc,I ...,...t'IM. ltrwllt
bl\li.POA.~NIOP-ior~WW~ •v•z--1\'tl~)
••IIOf~,tll()P
T_.~, .......... ~~~· Patency of the ductus arterlosus In the premature Infant :
Is It pathologic? Should It be treated?
,., Decr IVH,,
DecrlVH
.,.
..
a • i.--:,11 Matthew M. Laughon.MichaelA. Simmonsand Carl L Bose
.......
M1•·o11n 0.b.)-.O_j•

,.,.
....
M1p~.tdClf
Mt-•
..,.
,
IOll
."
10lfl1-»
!4~
,.,
,.,
On-4M

.,,.."'.. Decr PDA

DecrPDA
................................
...._ ..............
_... ..
Ul.01.f-lf
"'

__
lfO l ►»U-JtU
,., 0'1-LU
o· .. u·
,.. .. ~ ........ _....,....., .. c.ct._~ .. .,.... .....

""' ...,.,....................
..
UlOlJU "
c.dlr-~llf.,..... .......
...................................
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~

1.:• oe•- :..-,

.•...... _...,...,
ljW,lfllOU-le
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....
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,., , No
No change
changeinin :: -
l'DA

,,""
lfO ...,.,,"
:tJl)ll)J,I

ji,.)J:J,t
....
.,.
"'
,,.
'
.,..,..
0-'"-UI
BPD,
BPD, ROP,
ROP, NEC,
NEC, - ------ ~
""' JIJJ.M
death
..,........
011-,1•
=._ ...........
.... ......,
.... ON-1.:.,
...
death
........
_,
..,
""
""'
SIC
_,,,.,1
.,,,r
.t•Jfo
"'
"'
"'
"'
'-"
OU-0 4'
0
OU--UIJ
O..,_.lU
Knight,
Knight, DB.
DB. Sem
Neonatology
Sem
Neonatology2001
2001
--
nM ._...
 Non-Treatment of PDA Avoids
Non-Treatment of PDA is
Unnecessary Exposure
Common
....
, D POAwkhout TrMCmfflt
Indometl1acinproph)'laxis
or expectanttreatmentof patent
162
162 sites
sites
1997-2004
1997-2004
9 ....
j

; ....
l
'I ....
.._
a....-0n1y
OlndblN
..
ductu arteriosus
LC'.ltnJn't
in extremel
1. C'A&."""
l' lowbirthweightinfants?
ts'. DDdMac-'_.PJ~

;=~~=-'="::=.."':!= .z-::~
1

~OIi
23-30
23-30 wks
wks EGA
EGA
.…... indomethacin
-.. -.....
34,602 j ....
34,602 infants
infants indomethacindoes
does not
ootshow
show

---------..----
TIMtt ~b,,....._PI»
18,136
18,136 nono Tx,
Tx , no
no PDA
POA 1=
~,...
any
any advantages
early
advantages over
eal1ytreatment
overexpectant
treatmenton
on the
expectant
the management
management
,
... ...... ......
232425212721H)O
&lim11tedGffta1ionli Aga (WU)
of
of sPDA
sPDAinin ELBW
ELBWinfants.
infants." .... 1'0III ..

.…... prophylaxis ........

~
rnt.,v
.... ali•N
""'
'"' "'"
•…
... non-treatment
non-treatment is
is an
an option
option exercised
exercised in
in some
some centers…
centers ... "
prophylaxisexposed
significant
significantnumber
may
mayhave
exposed aa
numberof
havenever
of infants
infantswho
neverdeveloped
who
developed sPDA
sPDAto
to
............
·•---w....
~--•N
N
... •..
,t1!ll

1'1Jlt
•1~1

\\1911
•…
... no
no definitive
definitive evidence
evidence that
that any
any strategy
strategy improves
improves outcome… ,.................... N
outcome ... "
potential
potentialindomethacin-related
indomethacir>-related ~~---•N .,,.
!Sl•II
!H~
:.u,
"
Laughon
L•ughonM, M, Bose
BoseC, C, Clark
ClarilR.
R. Treatment
TrHtm•nt strategies
stra;teglesto
to prevent
preventor
or close
ck>sea• patent
p1tentductus
ductus
complications.
complications. " .......... na---"._.,.. ..... ,_,....__
arteriosus
1rterfosu,in
in preterm
pret•rm infants
infantsand
and outcomes.
outcome,. JJ Perinatol.
Parinato'. 2007
2007 Mar;27(3):164-70.
Mar,27(3):1&4-70.

Non-Treatment of PDA: Non-Treatment of PDA:

Most will Close Most will Close
The Ductus Arterio us Rarely Require =:-.: .....
..- ... --
Treatment in Infants > 1000 Grams ....
ffl

...
... --
-·~." -- "
.... : :
.... ... -
Prospe ~ =...w.:,:~ei~:"!;.•:,;::.o~•'!;;.:
:~::.~: ., ..
.. - --
::
.. .: ..
Prospective
<1500g
<1500g (n
33
observational study
= 65)
- --------------------
33 >1000g: no indocin, one ligation
... ~... -·
m
m

.. --
- --
---
--
--
.
.
.". --
ai.--1, ...
..
..
..
....
--
>101 n-l lit&

.. . .".
32
32 <1000g:
<101 31% spont closure;
67% PDA
..
..
..
-..

.... ....
....
Retrospective
~
cohort study
1n,
observational
.-, -
-
--- -- -- .
28% ligation;
4 infants with PDA at discharge
.. .....
-No deaths ffl
.•.
,... ..,
Any PDA <1500g :
:. -
- --
--
--
.". ..
....
12
12 infants
infa, NNT to prevent one ligation
-No CHF
~-
~ ~·
,.. .
..
-......-- .................
.
...,...____ ..
·- ...... - -- ...
. Overall:
....
Nemerofsky
Nemerofsky et
et al.,
al., 2008
2008 Arch
=--=--===---••.-t--•18/95 = 19% closure rate
~---
Arch Dis
Dis Child
ChildFetal
Fetal Neonatal
Neonatal Ed;
Ed; Jan
Jan 2009
2009
-
Non-Treatment of PDA:
Most will Close Medical Treatment Poses Risks
A. B.
Indomethacin Ibuprofen

,j
lndomethacin Ibuprofen
•• Decr
Dea renal
renalblood
bloodflow
flow •• Less
Lesseffects
effectsrenal
renalblood
blood
•• Decr
Dea mesenteric
mesentericblood
blood flow
flow
flow
flow • Less
Lesseffects
effectson
on
•• Decr
Dea cerebral
cerebralblood
bloodflow,
flow, mesenteric
mesentericblood
bloodflow
flow
oxygenation
oxygenation •• Little
Littleor
or no
no effects
effectson

,.... . A. Fbwc:faartFclow-'4)olll't1..BWW..dilcNf9ld"""•~
W.U. e. ~~
IPClf'lt.lNCMIMc:llan ti• W,and
,,.-,,,-..,

ww, petllilUenl OAt, • 7). ADO. ~CLCI

---
,-,-,- ,,,-..,_,....,_c-=_-,,
_..,,"""'•,....,·,...,·
PDACM0,lffl_,.illly~\A.8W
. TimtotC...otW-OA..T..,_il~tlft'IOl'llhl.,,.,bffl...tlClucNd .... ~ ...
cerebral
cerebralblood
bloodflow
flow
on

effects •• Gut
Gut protective
protectiveeffects
effects??
oc:c1,o.,
•• Non-COX
Non-COXinhibitor
inhibitoreffects
50%
50% closed
closedby
by 99 months
months
52/321
52/321== 16%
16%spont
spontclosure
dosure rate
rate Weber
Weber et
et al.,
al., JJ Pediatr
Pediatr 2015
2015
 PDA Ligation may
PDA Ligation Poses Risks
Increase the Risks for BPD

__
__ ,,_-
T&bk II. Chuac.t -1t: dc:t ol Hudy lftf.atiu thac.
•• Bleeding,
Bleeding, atelectasis,
atelectasis , infection
infection
tul'ffl'N b4yon4 JS WMk, pottmffl,trwl
(n • 4:Z)
a..

•• Pneumothorax,
Pneumothora x, chylothorax,
chylothorax , effusions
effusions ..,, C-..0 li p.li on
–
- Kabra
Kabraet
et al.,
al., 2007
2007 (fl • If) (ft • lJ)

•• Inadvertent
Inadvertent ligation
ligation of
of other
other structures
structures 154:::a 111= 107
–
- Chorne
Chomeetet al.,
al., 2007
2007 17. 1 :!lt 11,~u
•• Vocal
Vocal cord
cord paralysis
paralysis (3-30%)
(3-30%) –
- Clyman
ayman et
et al.,
al., 2009
2009
t...alarpsadclMl
~("I
.. (I} • P"'l 11('4ft)
16("")
-("I 1)(6:nQ 1){17"}
•• Post-op
Post-op hypotensive crisis
hypotensive crisis (20-30%
(20-30% of

--""
of (reassessment
(reassessment of of HinuclAffll<• cs.
M<C,,.,,.-,Cl')
7p71j
IO(SnQ
4 fl7S)
700<)

•• Need
infants
infants <1000g)

Need for
<1000g)

for thoracotomy
thoracotomy and
and potential
potential long-
long-
Cassady
Cassady prophylactic
ligation
prophylactic
ligation trial)
trial)
--w....,.
,. ......t..,.,
-""
~,.........
--("I
14 (7:nQ
I.0.!: 41
6/14 (4:nQ

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..,,.....
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lllt{ 42S}

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("I
term
term skeletal
skeletal deformations
-·""
deformations o.n- .......... ,. .... 4 (21~ 11{-J- ◄ t,.
Hedwlkal ....... ,. ... O(Olll 6(26")° ◄ ..

PDA Ligation has Unexpected PDA Ligation has Unexpected

Adverse Neurologic Outcomes Adverse Neurologic Outcomes
NcurMcnsory lmpaim, cnt aftc:r Surgical Clo sure of Patent Ductu s
Artcrio su.s in Extremely Low Binh \Vc.ight Infant s: Rcsuhs from 1.hc Trial Merritt Wilkerson Tran Kabra Chorn Kobaly Lee * Madan
of lnd omct hacin Prophylaxi in Prete.rm, 1982 1985 2005 2007 e 2007 2008 2008 2009
~ iic-t-o..__S.: ~ t.iWOc -Mil Incr no no no
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---.'t'n1~t1w....,....., . ui ....... ..--.1n1a11w-,111iw.tcT1.w.,....,_.__r"..,.,u.;...._.111P1-,
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PDA Ligation may be Unnecessary PDA Studies Fail to Show Benefit

b...._. • ...._,..........,,.....
M•l ·IMlmt-il·i ·ll[◄ I ■
I$ $Urgicolligation of potent dudu$ orterio$U$nece$$0,Y7
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-
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4000
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Ix of
of
1500

The We$tern Au$trolionexperience of con$E!rvotive

Ot.....
Ote • ..,.. preterm
preterm PDA.
PDA . 75

..-
llflW
lo1061
75
management RCTs:
O..CLO )1'195 RCTs:

-
,,,,.,
NCC 21~
JMholu,JNT~SKPotol. , DAOoherty, KS-... 49
49 showed
showed benefit
benefit

-_...
Mt

....
1Ytb0fldt2
fl(M,,11

,....,. All
2l0f14
All encompassing
encompassing

--
_
..,,.0raa.2

......
aollaOtNll2

..
C,

--- ~-~ ~~ ~- = --- ~ -- ,o=~1

.......meta-analysis
-
meta-analysis of
11,~
2.Qllt
of
these
these studies
studies

G.1 1 10 0. 1 1
o..-..('llftClt Oik19.._.(fl'li,CI

Benitz
Benitz WE.
WE. JJ Perinatol
Perinatol 2010
201O
2005
 PDA Occurs Naturally in
AAP Statement on PDA (2016) Some Species

AmericanAcademy
of Pediatrics ·I U·,,..·....,:
. .. . t
I,

Texas A&M Univ.,

Patent Ductus Arteriosus

Bökenkamp
Bokenkampet
et al,
al, 2006
2006 ..
Coll of Vet
' Med.
''
Brown
Brown Norway
Norway Rat:Rat: has
has Dogs:
Dogs : most
most common
common congenital
conge nital heart
heart
in Preterm Infants defect
defect in in elastogenesis
elastogenes is and and disorder;
disorder ; females
females >> males.
males. Most
Most often
often in
in

______
.. ......_.,_..._-------'"4•-·""""-
.......,_
vascular
vascular fragility;
for
for life;
fragility ; have
life; localized
localized to
have PDA
to chr
PDA
chr 8,
8, 99
poodles,
poodles, Shetland
German
spaniels,
Shetland sheepdogs,
German shepherds,
sheepdogs, collies,
shepherds , Maltese,
spaniels , Chihuahuas,
collies ,
Maltese, Bichon
Bichon Frise,
Chihuahuas , Pomeranians,
Newfoundlands
Newfoundla nds
Pomera nians,
Frise,

Questions Left
Arguments For Treatment
Unanswered
Animal
Animal studies:
studies:
•• Which
Which infants
infants should
should we
we treat
treat ?
? DA
DAclosure
closureis is aa normal
normalphysiological
physiologicalevent
event in
in most
most
species
species
•• How
How long
long to
to observe
observe with
with non-treatment
non-treatment ?
? Significant
Significant sized
sized PDA
PDAis
is fatal
fatal or
or harmful
harmful
•• Relationship
Relationship toto other
other pathologies
pathologies ??
•• Is
Is surgery
surgery protective
protective or
or more
more harmful
harmful ?
? Human
Humanstudies:
studies:
DA
DAclosure
closureis is the
the natural
naturalontological
ontological event
event
Longstanding
LongstandingPDA PDAis is harmful
harmful
PDA
PDAhas
has lifelong
lifelongmortality
mortality
Non-treatment
Non-treatmentof of hsPDA
hsPDAcan can be
be risky
risky in
in neonates
neonates
DA
DAclosure
closureimproves
improvesclinical
clinicalcourse
course

DA Closure is a Normal Physiologic DA Closure is a Normal Physiologic

Event in Most Vertebrates Event in Most Vertebrates
Hamster
Hamster ~2-3
- 2-3 min
min
Vertebrate
Vertebrate
ancestors
ancestors
~
(M
, '.
'
Adult
Adult
lungfish
lungfish
Mouse,
Mouse, Rat
Rat ~3-6
- 3-6hh

Rabbit ~3-6
-3-6hh

J~ ._l~
Rabbit
Amphibian,
Amphibian,
tadpole
tadpole
stage
stage
C J '.... I f
Amphibian,
Amphibian,
adult
adult stage
stage Guinea
GuineaPig

Lamb,
Pig ~1-2
-1-2dd

Lamb, piglet
piglet ~1-2
- 1-2dd
Birds
Birds
.1IT
-.-.-. .1IT
-.-.- .-
Bergwerff
Bergwerlfet
et al.,
al., 1999
Mammals
Mammals
, .......

Smith
Smith and
,...,

and Nelson,
Nelson , 1976
C,I0,,\.11
_;

-- Horse
Horse ~2-3
- 2-3dd
1999 1976 Goat,
Goat, dog ~4-6
-4-6 dd
 Deletion or Inhibition of Mouse Models of PDA are
Cox-1 & Cox-2 Causes PDA Deleterious or Fatal
and Newborn Lethality in Mice
KNOCKOUT OUTCOME
Genetic Deletion Pharmacological Inhibition
EP4 Lg PDA, CHF, pulm congestion, death <24h
Cox-1;Cox-2 Lg PDA, CHF, pulm congestion, death <24h
Birth
Cox-1 or Cox-2 Small PDA
PGDH Incr PG levels, PDA, death
PGT Incr PG levels, PDA, death <2d
Myocardin PDA, death <3d
~1 hr.
SM-MHC myosin Transient PDA
TFAP2b PDA, death <2-3d
Itga2b, Nfe2 PDA, adult pulm vasc remodeling, PHTN
Nt3 Premature DA closure
Reese et al., Proc Natl Acad Sci 2000 Reese et al., Am J Physiol 2006
3 hrs.

The Untreated PDA is Harmful in The Untreated PDA is Fatal or

Small Animal Models Harmful in Large Animal Models

• Cattle: • Donkey, Horse,

– Thromboarteritis Pony
– Pulm HTN – CHF
– CHF, FTT • Zebra
Brown Norway Rat: No long-
term effects; but largest PDA is – sudden death – FTT, lethargy, death
Dog (4.7/1000): cardiomegaly, CHF,
only 25-30% of Aorta (Bökenkamp
2006)
pHTN, death (Jones 1981; Van Israel2003) • Buffalo • Harbor seal
– CHF, resp failure, – Pulmonary
Cat (0.2/1000): cardiomegaly, CHF, pHTN (Jones 1981; Jeraj1978) death congestion, death
Rhesus monkey: pHTN, arteritis (Freigang 1967)

Outcome of Untreated
PDA Requires Treatment
PDA in Adults
in the Elderly
- Left -to-right shunt: pulmonary
overcirculation, L heart volume overload, incr PDA is compatible
with survival to an old
pulm fluid volume, incr WOB
age, but much more
commonly involves
- CHF: incr LA & LV EDP, hypertrophy, incr substantial morbidity
O2 demand, potential ischemia and mortality in early
to midlife.

- Eisenmenger s Syndrome: medial

hypertrophy, intimal proliferation, obliteration
of pulm arterioles, incr PVR

…adult PDA is typically associated with inexorable cardiac disorders, including

-Endarteritis, vegetations, pulm emboli congestive heart failure, infective endocarditis, and pulmonary hypertension.
Schneider and Moore, Circulation 2006
- Satoh and Nishida, Intern. Med. 2008
PDA Non-Treatment: Incr Fatality PDA Non-Treatment:
Increased Fatality

2005 Noori et al., 2009

Prolonged Exposure to Adoption of a Conservative

Symptomatic PDA Approach may be Harmful
(RCT of Early Surgery vs Conservative Treatment)

Medical (15) vs. Surgical (10)

RCT; no cross-over; <1500g

Surgical Treatment:
- less vent dependent
- required fewer meds
- CVC discontinued sooner
- better nutrition from gut

Cotton et al., 1978

Adoption of a Conservative Adoption of a Conservative

Approach may be Harmful Approach may be Harmful

In conclusion, we agree with recent

comprehensive reviews that
aggressive PDA closure therapy is a
largely unproven therapy with no
clear benefits to the premature infant.
Our before-after observational study
suggests that INDO and LIGATE can
be reduced, with no significant
increase in mortality or individual
morbidities.

Kaempf et al., 2013

(2011)
 Adoption of a Conservative Adoption of a Conservative
Approach may be Harmful Approach may be Harmful

Brazil, 2014 Taiwan, 2015

PDA Treatment May Benefit the Resolution of Arguments

Smallest Infants For & Against Treatment
Against For
Human studies: Human studies:
Non-treatment common Natural ontological event
Doesn’t change outcome Long term PDA is harmful
Closes on its own PDA has lifelong mortality
Medications are risky Non-tx of hsPDA is risky
Ligation is risky Closure improves course
Unnecessary therapy
PDA is not harmful
Animal studies:
Animal studies: Normal physiological event
PDA exists in nature hsPDA is fatal/harmful
2018

PDA Staging System

Resolution of Arguments For
& Against Treatment
• Need better definitions for hsPDA
– Echo criteria
– Timing of expected closure
– Clinical relevance

• Need markers in population for

susceptibility to disease or treatment
failure
– Genetic
– Serologic Proposed staging system. McNamara and Sehgal, 2007
 PDA Staging System
Vanderbilt: Single-dose Prophylaxis

Resende et al., J Perinatol 2016 Krueger et al., 1987

Gestational Age Postnatal Age

Summary: Optimal Timing of
PDA Treatment ?

em

Rx
A
0.2 mg/kg dose

.H
PD

a ry

C
lm

NE
of

ss
Pu

lity
a tio
re

f
ce

ko

rta
su

&

ig

ne
VH

Mo
C lo

↓L

R is
Un
↓I
Prophylaxis +++++
+++ +++ ++++
…population model predicts a t1/2 of (first 12-24 hour)
22.3 h at a PNA of 8 days, and of Pre-symptomatic +++++
++ ++ ++
16.1 h at a PNA of 25 days. (echo-based)
- Smyth et al., 2004 Early symptomatic ++++
+ +
(hemodynamic symptoms)
Bhat et al., J Pediatr 1979 Late symptomatic
+++ ?
Vert et al., Eur J Clin Pharm 1980 (early signs of organ failure)
Very late
++ ++ ?
(heart failure)
No treatment + +++ +++
Yaffe et al., J Pediatr 1980
(Shahab Noori, unpublished)

Thank You ! Bibliography

• Bose CL, Laughon MM. Patent ductus arteriosus: lack of
evidence for common treatments. Arch Dis Child Fetal Neonatal
Ed. 2007 Nov;92(6):F498-502.

• Clyman RI, Chorne N. Patent ductus arteriosus: evidence for

and against treatment. J Pediatr. 2007 Mar;150(3):216-9.

• Schneider DJ, Moore JW. Patent ductus arteriosus. Circulation.

2006 Oct 24;114(17):1873-82.

• Hamrick SE, Hansmann G. Patent Ductus Arteriosus of the

Preterm Infant. Pediatrics. 2010