AIIMS- NICU protocols 2007

Patent Ductus Arteriosus in Preterm Neonates

Ramesh Agarwal, Ashok K Deorari, Vinod K Paul
Division of Neonatology, Department of Pediatrics
All India Institute of Medical Sciences
Ansari Nagar, New Delhi 11!"
Address for correspondence
Dr Ashok K Deorari
Professor
Department of Pediatrics
All India Institute of Medical Sciences
Ansari Nagar, Ne Del!i ""002#
$mail% as!o&deorari'()*!otmail+com
Donloaded from +ne,orn!occ+org
Abstract
-ailure of t!e ductus arteriosus to close it!in ./-#) !ours of postnatal age results in a
left to rig!t s!unt across t!e ductus and o0erloading of t!e pulmonar1 circulation+ 2!is is
more li&el1 to !appen in premature neonates it! respirator1 distress s1ndrome+
Deterioration in t!e respirator1 status on da1 3-. in a 0entilated neonate and une4plained
meta,olic acidosis ma1 ,e t!e earliest indicators of a patent ductus arteriosus 5PDA6+
Indomet!acin is t!e main sta1 of medical management of PDA in preterm neonates+
7uidelines for administration of indomet!acin !a0e ,een descri,ed in t!e protocol+
8estricted fluid t!erap1 ma1 ,e ,eneficial in t!e pre0ention of PDA in preterm neonates+
Presence of PDA in a term neonate s!ould ,e in0estigated to rule out an underl1ing
congenital !eart disease+
Key words: Preterm, patent ductus arteriosus, indomet!acin, i,uprofen
2
! "ntroduction
During intrauterine life, "09 of t!e cardiac output passes t!roug! t!e lungs+ 2!e
remaining #09 is s!unted 0ia t!e ductus arteriosus 5DA6 to t!e aorta and s1stemic
circulation+ After ,irt!, most of t!e rig!t 0entricular output s!ould pass t!roug! t!e lungs
to facilitate proper gas e4c!ange+ In order to ma&e t!is possi,le, t!e ductus undergoes
constriction and functional closure soon after ,irt! in term neonates+ $ig!t1 percent
5/096 of t!e DA in term infants close ,1 ./ !ours and nearl1 "009 ,1 #) !ours+ -ailure
of t!is normal closure results in pro,lems especiall1 in preterm neonates+
#! Physiology
:41gen and endot!elin are 0er1 strong 0asoconstrictors and prostaglandins $
2
and I
2
are
strong 0asodilators of t!e DA+ ;oer o41gen concentrations in utero and !ig! circulating
Pg$
2
and PgI
2
le0els !elp in &eeping t!e ductus patent+ Sudden ele0ation in circulating
o41gen tension and fall in prostaglandin le0els soon after deli0er1 results in strong
0asoconstriction and functional closure of t!e DA soon after deli0er1+ It is ,elie0ed t!at
t!is action of o41gen is mediated 0ia t!e formation of t!e endot!elin molecule+ 2!is
functional closure is folloed ,1 anatomical closure in t!e ne4t "-3 mont!s+
$! Ductus arteriosus in preterm neonates
2!e normal mec!anisms of ductal closure fail to or& in preterm neonates+ 2!e 0arious
factors contri,uting to an increased incidence of PDA in preterms include% 5a6 Increased
sensiti0it1 of t!e ductus to prostaglandins as compared to term neonates 5,6 Sensiti0it1 to
3
prostaglandins is sustained for a longer period 5c6 <ig!er incidence of !1po4ia and
acidosis 5d6 Defecti0e smoot! muscle migration resulting in compromised anatomical
closure+
%! &emodynamic conse'uences of PDA
S!unting of ,lood from t!e s1stemic circulation to t!e pulmonar1 circulation results in
congesti0e cardiac failure, !ic! manifests clinicall1 it! ide pulse pressure and
,ounding pulses+ :0erloading of t!e pulmonar1 0asculature leads to pulmonar1 edema=
!emorr!age !ic! predisposes t!e neonate to c!ronic lung disease+ >lood flo to t!e
&idne1 and gastrointestinal tract is compromised predisposing to acute renal failure
5A8-6 and necroti?ing enterocolitis 5N$C6+ <1po-perfusion folloed ,1 reperfusion
increases t!e ris& of intra0entricular !emorr!age 5I@<6+
(! Risk factors for PDA in preterm neonates
2!e incidence of PDA is in0ersel1 related to gestational age and ,irt! eig!t+ A
!emod1namicall1 significant s!unt due to PDA !as ,een reported in .09 of infants less
t!an "000 grams and 209 of infants ,eteen "000-"(00 grams+
"-3
8espirator1 distress
s1ndrome 58DS6 in preterm neonates needing 0entilation and surfactant is an additional
ris& factor for PDA+ Prop!1lactic use of s1nt!etic surfactant !as ,een associated it! an
increased ris& of PDA+ ;ac& of antenatal steroids, presence of sepsis, and li,eral fluid
t!erap1 are ot!er ris& factors for de0eloping PDA+
.
)! *linical features%
)!a! <1perd1namic circulation
A ide pulse pressure 5A2( mm <g6, prominent precordial pulsations B ,ounding pulses
and an eCection s1stolic murmur 5occasionall1 pan s1stolic and continuous murmur6
!eard ,est at t!e 2
nd
left parasternal area
.
are usuall1 present on clinical e4amination+
)!b! Indicators of ductus opening on a 0entilated ,a,1
Meta,olic acidosis not attri,uta,le to !1poperfusion and sepsis, deteriorating respirator1
status on da1 3-. after a period of relati0e sta,ilit1, increasing 0entilator1 reDuirements
on da1 3-., une4plained C:
2
retention, fluctuating -i:
2
reDuirements and recurrent
apneas in a 0entilated ,a,1 s!ould raise clinical suspicions of a s1mptomatic PDA+
Studies !a0e re0ealed t!at ec!ocardiograp!ic criteria of a significant left to rig!t s!unt
usuall1 precede clinical s1mptoms ,1 an inter0al of 2-3 da1s+ <oe0er, clinical features
!a0e a ,etter correlation it! long-term mor,idit1 and a0aila,le e0idence does not
recommend routine screening it! ec!ocardiograp!1 for at-ris& neonates
3
+
+! Differential Diagnosis
A@ fistula
8uptured sinus of 0alsal0a
Aorto-pulmonar1 indo+
,! "n-estigations
,!a! #hest $ray% 8adiograp!ic findings are non-specific for diagnosis of PDA+ 2!e1
include cardiomegal1, upturned left ,ronc!us due to left atrial enlargement and
pulmonar1 plet!ora+
(
,!b! &chocardiography
$c!ocardiograp!1 is not recommended routinel1 for all preterm neonates+ A clinical
diagnosis of PDA s!ould prefera,l1 ,e confirmed ,1 ec!o prior to starting medical
t!erap1+ $c!ocardiograp!ic criteria include 5a6 ;eft atrial dilatation 5;eft atrial% Aortic
rootA"+)6 5,6 Diastolic tur,ulence 5,ac&flo6 on doppler in t!e pulmonar1 arter1 and 5c6
Direct imaging to measure t!e diameter of PDA+
A !emod1namicall1 significant PDA is diagnosed in t!e presence of a ductus diameter
A"+(mm and a,sent= retrograde diastolic flo in t!e post-ductal aorta+ Doppler ec!o is
more specific and sensiti0e for t!e diagnosis of PDA !ile an M mode ec!o is useful for
assessing t!e se0erit1 of t!e s!unt across t!e PDA+
.! /trategies of management
(
.!a! Prophylactic treatment: In t!is strateg1, treatment is started ,efore t!e appearance
of PDA, usuall1 it!in t!e first 2. !ours of ,irt!+ Indomet!acin !as ,een tried as
prop!1lactic treatment in 0er1 preterm neonates, especiall1 E"000 grams+ Alt!oug! it
as found to decrease s1mptomatic PDA and I@<, it as not associated it! an1 c!ange
in long-term mor,idit1 and neuro-de0elopmental outcome+ More o0er, indomet!acin !as
also ,een found to decrease cere,ral and renal ,lood flo and !ence is not recommended
as a prop!1lactic agent in t!e pre0ention of PDA
)
+ 2rials it! prop!1lactic i,uprofen are
still going on
7
+
.!b! 0arly /ymptomatic: In t!is strateg1, treatment is started as soon as t!e PDA is
detected e0en if it is not !emod1namicall1 significant+
)
'eight (1 grams% Among neonates detected to !a0e a PDA, /09 of neonates
ould progress to de0elop a !emod1namicall1 significant s!unt+ <ence, it is
recommended to treat PDA in t!is group earl1 e0en t!oug! it ma1 not ,e
!emod1namicall1 significant+ <oe0er, in 0ie of t!e recent e0idence, t!e ris&s and
,enefits of suc! treatment must ,e eig!ed ,efore treating as1mptomatic ,a,ies+
/
Weight >1000 grams: $arl1 treatment is not recommended in t!is group as
progression to s1mptomatic PDA is less common and spontaneous closure are &non
to occur in t!is group
/
+
.!c! 1ate /ymptomatic
:nl1 !emod1namicall1 significant PDA is treated in t!is strateg1 and it is t!e
recommended approac! for neonates A"000 grams+
2! 3anagement
2!a! 4eneral measures
-luid restriction% )09 of maintenance fluids
A0oid !1po4ia and acidosis
<ig! pee& end e4pirator1 pressure 5P$$P6 and loer inspirator1 time 52i6, if
ot!erise appropriate
#
+
-rusemide is generall1 not reDuired+ -rusemide increases prostaglandin le0els, !ic!
ma1 interfere it! t!e t!erapeutic effect of indomet!acin+ <oe0er enoug! e0idence
for t!is concern is not 1et a0aila,le
"0
+ In intracta,le C<-, e occasionall1 use
frusemide in a dose of " mg=&g=dose "2 !ourl1+ Careful e0aluation of !1dration status
is essential ,efore and during treatment it! frusemide+
Digo4in !as no role in management of PDA+
7
2!b! 3edical 3anagement
2!b!i! "ndomethacin
Mechanism of action
2!e postulated mec!anism of action is an in!i,ition of c1clo-o41genase 5C:F6 en?1me
in t!e prostaglandin pat!a1+ Indomet!acin !as a greater affinit1 for C:F " 5renal6 as
against C:F 2 5e4tra-renal6+ Due to t!is greater affinit1 for renal C:F", t!e incidence of
renal complications is !ig!er it! indomet!acin as compared to ot!er in!i,itors of
prostaglandin s1nt!esis+
Indications for indomethacin use%
$arl1 s1mptomatic treatment of PDA in E"000 grams
;ate s1mptomatic treatment of PDA in A "000 grams
8e-treatment after failure of t!e first course of Indomet!acin+
8ecurrence of PDA after t!e first course of indomet!acin+
)ral medication
Due to non-a0aila,ilit1 of t!e I@ formulation, e !a0e ,een using oral indomet!acin for
closure of PDA+ :ral indomet!acin is a0aila,le as 2( mg ta,lets and it can ,e ,ro&en into
loer doses+ Ge usuall1 mi4 t!e dose it! 2-( ml e4pressed ,reast mil& and administer it
t!roug! t!e oro-gastric tu,e+
Side effects and monitoring
Ad0erse effects include renal compromise due to its effect on C:F ", ,leeding tendenc1
due to its effect on platelet function and increased ris& of necroti?ing enterocolitis+
Decreased cere,ral ,lood flo associated it! t!e use of indomet!acin ma1 ,e associated
it! poor neuro-de0elopmental outcome+ @arious parameters t!at s!ould ,e monitored
/
include 5a6 Urine output% If urine output falls ,elo " ml=&g=!r lo dose dopamine at "-2
g=&g=min for its renal effect ma1 ,e used
""
5,6 8enal function 5alternate da1s6 and 5c6
Platelet counts 5dail16
#ontraindications
Renal% Urine outputE 0+) ml=&g=!, ,lood ureaA30 mg=dl, creatinineA"+/ mg=dl
Bleeding% >leeding from I@ sitesH gastrointestinal ,leeding, enlarging or e0ol0ing
intra0entricular !emorr!age 5I@<6H platelet count E )0,000=mm
3
Gastrointestinal% necroti?ing enterocolitisH ,lood in stool
&fficacy
2!e closure rate it! indomet!acin is /09+ 2!e efficac1 is unaffected ,1 gestation or
,irt! eig!t+ 2!e full course s!ould ,e completed e0en if closure is ac!ie0ed ,efore t!e
t!ird dose+ ;onger treatment it! loer doses 50+" mg=&g=dose for ) doses6 !as similar
to4icit1 and efficac1 and are not recommended
"2
2!b!ii! "buprofen
I,uprofen is also an in!i,itor of prostaglandin s1nt!esis and is effecti0e in closing t!e
ductus+ It !as an eDual efficac1 as compared to indomet!acin it! feer side effects
"3
+
Its use is associated it! a loer incidence of oliguria and renal compromise+ It !as ,een
found to !a0e a lesser effect on mesenteric and cere,ral ,lood flo as compared to
indomet!acin+ 2!e dose is "0 mg=&g stat folloed ,1 ( mg=&g=dose 4 2 doses at 2. !our
inter0als gi0en orall1+
#
2!c! /urgical ligation
2!e indications for surgical t!erap1 include a contraindication to medical t!erap1 and
failure of a second course of indomet!acin+ Surgical ligation ma1 ,e carried out ,1
2!oracotom1 or @ideo assisted t!oracoscop1
".
+
! Restricted fluid intake for pre-ention of PDA
>ell et al
"(
!a0e conducted a meta-anal1sis on studies e0aluating fluid t!erap1 and !a0e
s!on t!at restricted fluid inta&e in t!e initial .-( da1s of life is associated it! a loer
incidence of PDA+ In our unit, e usuall1 start it! )0 ml=&g in ,a,ies eig!ing ,eteen
"000-"(00 grams and /0 ml=&g for ,a,ies ,eteen 7(0-"000 grams+ Ge tr1 to maintain
serum sodium of "3(-".( meD=;, urine output of "-3 ml=&g=!r and a urine specific
gra0it1 of "+00( to "+0"2+ Ge use t!in transparent plastic ,arriers 5clingrap6 to create a
microen0ironment around t!e ,a,1 in order to decrease insensi,le ater losses+ Ge
ould allo a eig!t loss of at least 2-39 per da1 and generall1 do not e4ceed a fluid
inta&e of "(0-")0 ml=&g=da1 ,1 da1 (-7 da1 of life+ Using t!is sc!eme of fluid t!erap1,
e !a0e ac!ie0ed a lo incidence of PDA in our unit+
#! 4uidelines for treatment
Preterm ,a,ies are at ris& of de0eloping !emod1namicall1 significant PDA+
Prematurit1, lac& of antenatal steroids, 8DS and sepsis increase t!e ris& of PDA+
At-ris& preterm neonates s!ould ,e monitored for clinical features suggesti0e of PDA+
$c!ocardiograp!1 s!ould ,e used to confirm a clinical suspicion of PDA+ In t!e
a,sence of an ec!o, treatment ma1 ,e started it! a clinical diagnosis+
"0
>a,ies E"000 grams it! a diagnosis of PDA 5irrespecti0e of !emod1namic effect6
s!ould ,e treated+ <oe0er, t!e ris&-,enefit ratio must ,e carefull1 eig!ed
especiall1 in grot! retarded ,a,ies it! a,sent or re0erse diastolic ,lood flo+
>a,ies A"000 grams it! a diagnosis of PDA s!ould ,e treated onl1 if a
!emod1namicall1 significant left to rig!t s!unt is present+
Prop!1lactic treatment it! indomet!acin is not recommended+
Platelet counts and renal parameters s!ould ,e c!ec&ed prior to starting t!erap1 it!
indomet!acin and repeated after 2. !ours+
A second course of indomet!acin s!ould ,e tried after failure of t!e first course or
recurrence after t!e first course+
Preliminar1 studies seem to suggest t!at i,uprofen is a safe alternati0e to
indomet!acin in t!e treatment of PDA+
Surgical ligation s!ould ,e considered if PDA recurs after t!e second course or if
contraindications to indomet!acin= i,uprofen e4ist+
>ot! i,uprofen and indomet!acin ma1 ,e used orall1+
*hese recommendations do not apply to PDA in term neonates+ *erm neonates with
PDA should not ,e treated with indomethacin- i,uprofen and should have a detailed
echo to rule out an underlying congenital heart defect+ *hey would re.uire surgery for
closure of an isolated patent ductus arteriosus+
""
"2
5able6 Dosage of indomethacin and ibuprofen for closure
of patent ductus arteriosus
"ndomethacin
Initial Dose
0+2 mg=&g stat folloed ,1 age adCusted doses%
Su,se.uent dose
E 2 da1- 0+" mg=&g=dose "2 !ourl1 for 2 doses
2-7 da1- 0+2 mg=&g=dose "2 !ourl1 for 2 doses
A 7 da1- 0+2( mg=&g=dose "2 !ourl1 for 2 doses
"buprofen
"0 mg=&g stat folloed ,1
( mg=&g=dose 2. !ourl1 for 2 doses

"3
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Clo!ert1 IP, Star& A8+ .
t!
$dn pp .30-.32+
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8o,erton N8C+ 3
rd
$dn pp )/7-)/#+
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t!e ne ,orn+ $ds% 2aeus! <G, >allard 8A+ 7
t!
edn G> Saunders pp )##-7"0+
.+ Ka!a&a L7, Patel C8+ Congenital cardiac defects+ In Neonatal perinatal medicine
M Disorders of t!e fetus and infants+ $ds- -anaroff AA, Martin 8I+ )
t!
$dn+ "##7
pp""((-""(7+
(+ Cl1man 8I+ 2reatment of premature neonates it! patent ductus arteriosus%
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)+ -oulie GP+ Prop!1lactic Indomet!acin - s1stematic re0ie and meta-anal1sis+
Arc! Dis C!ild "##)H 7.% -/"--/7+
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I Pediatr 2000H "(#%3).-3)/+
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treatments+ Arc! Dis C!ild -etal Neonatal $d 2007H#2 %- .#/-(02 +
#+ @an!aese,rouc& S, Konnen,erg I, @ander0oot P, et l +Conser0ati0e treatment for
patent ductus arteriosus in t!e preterm + Arc! Dis C!ild -etal Neonatal $d
2007H#2 %- 2..-2.7 +
".
"0+ >rion ;P, Camp,ell D$+ -urosemide in indomet!acin treated infants - s1stematic
re0ie and meta-anal1sis+ Pediatr Nep!rol "###H"3% 2"2-2"/+
""+ -aCardo CA, G!1te 8L, Stele >2+ $ffect of dopamine on failure of indomet!acin
to close patent ductus arteriosus+ I Pediatr "##2H"2"%77"-77(
"2+ 2ammela :, :Cala 8, ;i0ainen 2, ;autamatti @, Po&ela M;, Ianas M etal+ S!ort
0ersus prolonged indomet!acin t!erap1 for patent ductus arteriosus in preterm
infants+ I Pediatr "###H "3.% ((2-((7+
"3+ @an :0ermeire >, Smets L, ;ecoutere D, @an de >roe& <, Ge1ler I, Degroote L
et al+ A comparison of i,uprofen B indomet!acin for closure of patent ductus
arteriosus+ N $ngl I Med 2000H3.3% )7.-)/"+
".+ >ur&e 8P, Iaco,s IP, C!eng G, 2rento A, -ontana 7P+ @ideo-assisted
t!oracoscopic surger1 for patent ductus arteriosus in lo ,irt! eig!t neonates
and infants+ Pediatrics "###H"0.% 227-230+
"(+ >ell $-, Acarregui MI+ 8estricted 0ersus li,eral ater inta&e for pre0enting
mor,idit1 and mortalit1 in preterm infants+ Coc!rane Data,ase S1st 8e0 2000H
526%CD000(03
")+ McNamara, Se!gal A+ 2oards rational management of t!e patent ductus
arteriosus% t!e need for disease staging+ Arc! Dis C!ild -etal Neonatal 2007H#2%-
.2(-27+
"(
3anagement of PDA in preterm neonates
Presence of PDA
>irt! eig!t
E"000 gramsN A"000 grams
Contraindication <emod1namicall1
2o indomet!acin significant PDA
Oes No
No
Indomet!acin -ollo up
Closure
No Oes
Oes 8epeat indomet!acin
Closure
Surger1 No Oes
/ 0 1is20,enefit ratio must ,e weighed for asymptomatic growth retarded ,a,y
")