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F156 Archives of Disease in Childhood 1995; 72: F156-F161
Longitudinal changes in the diameter of theductus arteriosus in
ventilated preterm infants:correlation with respiratory
outcomes
Nick Evans, Parvathi Iyer
Department ofPerinatal Medicine,King George VHospital for
Mothersand Babies, Part ofRoyal Prince AlfredHospital,Camperdown,
Sydney,NSW 2050, AustraliaN EvansP Iyer
Correspondence to:Dr Nick Evans.Accepted 2 February 1995
AbstractThis study aimed to examine the earlynatural history of
ductal shunting in ven-tilated preterm infants (
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Early natural history of ductal shunting in ventilated preterm
infants F157
S~~~~~~~~--4
I A~~~~~~~~~~~~~~~A~A
Figure 1 Measurement ofcolourflow Doppler of ductal shunt
(orange). The calipers (marked by arrows) are positionedat the site
ofmaximum constriction. In this case the minimum diameter was 2 1
mm near the pulmonary end of the ductus.Flow in the left pulmonary
artery (LPA) and descending aorta (Desc Ao) is shown in blue.
ECHOCARDIOGRAPHIC DATA COLLECTIONThis was performed with an
Acuson 128/XP10scanner with a 7 MHz transducer, incorporatingcolour
flow, pulsed wave, and continuous waveDoppler. Scans were performed
daily for thefirst seven days of life, twice in the second week,and
then periodically as indicated until dis-charge home or to the
referring hospital. Thescans were recorded on to videotape and
themeasurements then taken from the videotapelater. Structural
normality of the heart wasestablished on the initial scan; one
infant with aventricular septal defect was excluded.
DUCTUS ARTERIOSUSThis was imaged from the high left
parasternalview. Colour Doppler was set for automaticpreprocessing,
lowest velocity variance setting,and filters were set for maximum
range forvolume and velocity settings with a mediumdegree of motion
discrimination (Acuson128/XP10 filter setting 3). The colour
flowDoppler mapping scale was set to the maxi-mum range of the
automatic preprocessing,usually the maximum velocity was between064
to 08 m/second. The gain was set tooptimise the colour flow image
within thecourse of the duct and eliminate any peripheralcolour
interference. When patent, the mini-mum diameter (the site of
maximum constric-tion) of the colour flow jet within the course
ofthe ductus was measured from a frame byframe analysis ofthe
videotape (fig 1). End sys-tolic frames with the clearest discrete
appear-ance to the shunt within the duct were used formeasurement.
A mean was taken from three tofive of the best quality cardiac
cycles.9 Theshunt was assessed with pulsed and or contin-uous wave
Doppler with the sample volume in
the pulmonary end of the duct. The shuntpattern was classified
as left to right, bidirec-tional, or right to left. Intra-observer
variabilityfor measurement of ductal diameter was testedby
repeating the measurements from the video-tape of 27 studies,
blinded as to the originalmeasurement. The coefficient of variation
was12%.
Postductal aortic diastolic flow (PADF)The descending aorta was
imaged from thehigh left parasternal or suprasternal position.The
insertion of the ductus arteriosus into theaorta was determined by
colour flow Dopplermapping. The pulsed Doppler range gate wasplaced
postductally in the aorta and the flowvelocity time signal
recorded. The PADF wasclassified into three groups:
antegradethroughout diastole; no clear direction to dias-tolic
flow; and retrograde throughout diastole(fig 2).9
Atrial shuntingColour Doppler diameter of the atrial shuntwas
measured as described in previously pub-lished data.8 Minimal
atrial shunting wasdefined from these data as no shunt on
colourDoppler or one with a diameter of less than2 mm. Atrial shunt
diameter has a significantcorrelation with atrial shunt size,8 so
atrialdiameter was used to describe longitudinalpatterns of atrial
shunting into three groups:(1) no atrial shunt or a small shunt
(
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F158 Evans, Iyer
* ~ ~~~4v
.U
Figure2 Post-ductal aorticDoppler..From. ahigh r
08 .. ...a
paatra wido the ineto of. th duct-u-sint the........ ..
isrecorded.The fLa
.. ....
DX. .~i0L
F.
diastolic flow seen with a closed or small PDA (top) withthe
absent diastolic flow seen with a moderate PDA(middle) and the
retrograde diastolic flow seen with a largePDA. The ductus was
patent in all examples shown here.The diameters were (from top to
bottom) 1 i mm, 11- mm,and 2S- mm (reprinted with kind permission
ofMosbyYear Book Inc9).
30 days and in six the shunt remained for theperiod of follow
up. This analysis has beendescribed in detail before.8
Echocardiographic findings were not madeavailable to the
clinical staff unless there wereclinical concers about the presence
of a PDA.
Traotmsientifewasndirethedlo pattheirnbeodteiscrertiononthe
basised ohfiga clinically appaenrantePDadwitchaacteriscfl pyscas
ignsanhals d or s ympPA tomsitwhicibsnvariabtlyclorelaedwto
respierator insAb-(itye, adte erorddiffiulyowanngfrom
theventwithalatrgor,. Thoedcase,wahypotension.Thieamls wshoin
lierewith establrepished protocokn enion thi unit.
Indomethacin was given on a schedule of0 1 mg/kg daily for six
days unless contraindi-cated. Surgical ligation was used where a
PDAremained symptomatic and haemodynamicallyimportant, despite a
course of indomethacin.Infants with contraindications to
indomethacinreceived conservative medical treatmentwhich involved
fluid intake reduction by30 ml/kg/day.
Surfactant treatment comprised two dosesof Exosurf, 12 hours
apart, administered asrescue treatment when the alveolar to
arterialoxygen ratio was less than 0-22.For each of the first five
postnatal days, a
mean oxygenation index was calculated fromaveraged percentage
inspired oxygen, meanairway pressure, and arterial partial
pressureof oxygen. Using the formula (mean
airwaypressureXpercentage inspired oxygen)/arterialpartial pressure
of oxygen, two measures werecalculated: the mean oxygenation index
for thefirst 24 postnatal hours as an index of initialdisease
severity; and the mean oxygenationindex for all the first five
postnatal days as anindex of both initial severity and
recovery.Total days requiring positive pressure ventila-tion and
supplemental oxygen were recordedas long term respiratory
outcomes.The study was approved by the Royal Prince
Alfred Hospital ethics committee andinformed written parental
consent wasobtained in all cases studied.
Statistical analysis was done with acomputer statistics package
(SPSS/PC) usingstepwise logistic regression analysis, the
MannWhitney U test, and x2 test. P values of lessthan 0 05 were
regarded as significant.
ResultsDuctal shunt flow patterns have beendescribed before9 and
were mainly left to right(90%). Nine per cent showed
bidirectionalflow, but in these an average of 82% of thecardiac
cycle was left to right. Just two (1%)studies showed right to left
ductal shunting.After the first 48 hours all shunting was left
toright.
In the 163 studies where the ductus wasclosed and the PADF was
assessed, it wasantegrade throughout diastole in all except
onestudy where there was no clear direction toflow. When the PDA
was less than 1-5 mm indiameter (n=61), PADF was antegrade in
58(95%), with three showing no clear directionto flow. When the PDA
was 1-5 to 1-7 mm(n= 23), PADF was antegrade in 11, indeter-minate
direction in eight, and retrogradein four. And when the PDA was
more than1-7 mm (n=58), PADF was antegrade in one,indeterminate
direction in seven, and retro-grade in 50 (86%). Retrograde flow
was alwaysseen when the PDA diameter was greater than2X1 mm
(n=36).The same association holds in studies done
in the first 36 hours. All studies with a PDA of1v5 mm or less
had antegrade PADF (n=19),and all studies with a PDA of more
than1-5 mmn had indeterminate or retrogradePADF (n=24). All PDAs of
more than 2 mm
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Early natural history ofductal shunting in ventilated preterm
infants Fl 59
Clinical comparisons between ductal shunting groups (figures are
presented as medians andrange or percentage*)
Asymptomatic Symptomatic Symptomaticspontaneous PDA, constricted
PDA, minimalclosure (n=31) after birth (n=9) constricton (n=8)
Gestation (weeks) 28 (24-33)* 26 (25-27)*t 27-5
(26-29)tBirthweight (g) 1030 (512-1490) 906 (700-1030) 1047
(650-1340)Antenatal steroids 90% 77% 75%Surfactant 61% 66%
75%Oxygenation indexDay 1 mean 4-73 (1 1-10 7) 4-6 (2 9-19 1) 7 0
(3-1-12-1)Mean of first 5 days 3-5 (1-0-7-9)*t 5-3 (2-21-9)* 5-6 (2
7-8 7)t
Ventilator days 7 (2-43)* 24 (9-58)*t 5 (5-29)tDays in oxygen 29
(1-140) 44 (9-172)t 17 (6-39)t
*Indicate different pairings in same group of 3; tp
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F160 Evans, Iyer
influence on this outcome (p values, respec-tively, 0 007 and
0-016).
Days ventilatedGestation, birthweight, day 1 and five day
oxy-genation index, antenatal steroids, five minuteApgar score,
maternal hypertensive disease,atrial and ductal shunting groups
wereanalysed against days ventilated as a dichoto-mous dependent
variable of more or less than14 days. Gestation was the only
significantfactor (p=0004).
Days in oxygenThe same factors were analysed against days
inoxygen as a dichotomous dependent variableof more or less than 28
days. The two factorsincorporated as significant were
gestation(p=0003) and atrial shunt group (p=0*043).
DiscussionThe normal postnatal course for the ductusarteriosus
is constriction and functionalclosure. In babies born at term and
in pretermbabies without respiratory problems thisprocess is
usually completed within the first 48postnatal hours.'O 1 l This is
not the case in verypreterm infants with respiratory problems,where
about 35% ofbabies will have symptomsresulting from persisting PDA.
Previousstudies of the natural history of the pretermPDA have
looked either at whether the ductwas open or closed - without
taking intoaccount the size of the ductal shuntl 2 or haveserially
plotted indirect measures which haveonly a loose association with
ductal shuntsize.12 13 The closest association with ductalshunt
size is provided by the diameter of theduct, as assessed by colour
Doppler and thepresence of retrograde PADF.9 These datahave
confirmed that, regardless of postnatalage, there is also a close
correlation betweenthese two assessments. When the PDA is lessthan
1 5 mm, the PADF was almost alwaysnormal antegrade; when more than
this, thePADF was usually absent or retrograde. Thiswas also true
in studies performed within thefirst 36 hours with retrograde PADF
seen asearly as 7 hours of age, confirming that earlyshunting
through large PDAs is usuallyhaemodynamically important. Plotting
thelongitudinal change in colour flow Dopplerductal diameter
therefore provides usefulinformation about changes in the
haemo-dynamics of a duct. Measurement of defectsize with colour
Doppler mapping is reason-ably accurate14 but there are
limitations. Forexample, other machines with different
colourDoppler settings could give different results.To minimise
error, we used a standardised-colour Doppler setup and took
averagedmeasurements from only the clearest videotapeframes.
Although functional immaturity of the ductis important in the
pathophysiology of PDA, itmay not be the only factor. First, PDA
israre in preterm babies without respiratory
problems1o 11 and secondly, 65% of verypreterm babies with
respiratory problems donot develop PDA. In 20 (42%) of the babies
inthis study the duct was closed within 48 hoursof birth, much the
same time frame as might beseen in a term baby. 1 This group of
babieswere of comparable gestation to the othergroups, though they
tended to have less severeacute lung disease. The others display a
widespectrum of failure of constriction of theductus arteriosus. In
a further 11 (23%)infants the duct closed spontaneously after
48hours without causing symptoms. In seven(15%) spontaneous closure
occurred after day3. This is in contrast to previous studies
whichhave suggested that if the duct was patent onday 3 or 4 then
it was unlikely to closespontaneously.1 2The other 17 infants
developed sympto-
matic PDA. The factors determining PDA inthe preterm are likely
to represent an interplaybetween immaturity of the ductal
constrictivemechanisms and exogenous factors relating tothe
respiratory disease, and possibly circulatingprostaglandins. 15 In
eight babies in group 3 theabsence of any evidence of constriction
wouldsuggest that factors such as high circulatingprostaglandins
were maintaining ductalpatency. In nine babies in group 2
ductalclosure failed after initially constricting. Thesebabies were
of significantly lower gestation,and functional immaturity may have
had amore important role here. In most of thebabies with
asymptomatic spontaneous closurethe duct was always small, but five
of thesebabies had large ducts (>1-5 mm) during thefirst 48
hours. These five babies had a higheraverage gestation that the
group as a whole -29 weeks (range 28-30) - and a more matureduct
may have been able to overcome theinitial dilating stimulus from
the respiratorydistress. Some babies do have large PDAs earlyon
which then close spontaneously, and somehave small PDAs early on
which then reopen,but in most infants where the duct
becamesymptomatic, the duct was more than 1-5 mmon the first scan.
Thus the rate of early post-natal constriction of the duct seems to
relate tothe likelihood of persisting PDA. This observa-tion may
provide a means for early predictionof symptomatic PDA, thus
allowing targetedprophylaxis. We are currently testing
thishypothesis prospectively.What are the clinical effects of
ductal
patency on respiratory outcomes? An increasein pulmonary blood
flow from a ductal shunthas been shown to reduce lung
compliance,16increase capillary protein leakage,'7 18 andpossibly
inhibit responsiveness to endogenousand exogenous surfactant.19 The
suggestedclinical impact of this has been prolongation ofthe
requirement for ventilation and subsequentoxygen therapy.1 6 7 In
this study none of thefactors examined seemed to influence themean
day 1 oxygenation index, suggesting thata PDA was neither the
cause, nor simply theresult of, the initial severity of the
respiratorydisease. Ductal shunting was, however, signifi-cantly
related to the mean oxygenation indexover the first five days. This
would fit in with
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Early natural history of ductal shunting in ventilated preterm
infants F161
the clinical observation that a PDA oftenpresents with
respiratory instability and failureto wean from ventilation during
recovery. Wewere unable, using multivariant analysis, todemonstrate
an independent association ofductal shunting to ventilator time or
days inoxygen. Gestation has the most significantcorrelation with
both these outcomes andprobably accounts for the univariant
differ-ences in these outcomes for group 2 (table).When oxygen
requirement beyond 28 days wasthe dependent variable, the only
other factorincorporated into the equation as significantwas atrial
shunting group. While gestation isclearly the most important
factor, these datasupport our previous observation that the
pro-longed nature of atrial shunting may have moreinfluence on long
term respiratory outcomesthan ductal shunting.8Why is this so, when
other studies have
linked PDA to time on the ventilator and daysin oxygen? These
studies all analysed this asso-ciation in a univariant manner and
did notcontrol for confounding variables which willinfluence the
incidence ofPDA - most import-antly, gestation and respiratory
disease.' 6 7 20In the study by Reller et al 20 most of the
babieswithout PDA did not need ventilation for theirinitial
respiratory distress: this is likely to havebeen an important
factor in their reduced timeon ventilators and in oxygen. By
controlling forthese factors in a multivariant manner andexcluding
infants without significant respira-tory problems, our study has
shown that gesta-tion, independent of ductal status, is thedominant
influence on these respiratory out-comes. Progress in perinatal and
neonatal caremay have blunted the effect of a PDA onrespiratory
outcomes. Eighty five per cent ofour infants were treated with
antenatal steroidsand exogenous surfactant was routinely usedas
rescue treatment. The former interventionprobably reduces the
incidence of PDA,2' thelatter reduces the incidence of chronic
lungdisease.22 The other important differencebetween this and
previous studies is the timingof treatment. In the studies by
Dudell andGersonyl and Reller et al,20 where gestationwas
controlled for in a univariant manner,most PDAs were not treated
until the secondweek or later. Most babies in our study weretreated
well within the first week. Duration isprobably as important as
degree of left to rightshunt in determining long term
respiratoryeffects. This observation may explain whyrandomised
trials of early prophylacticindomethacin have not shown any
beneficialeffects on long term respiratory outcomes. Inthese trials
infants in* the placebo controlarms had symptomatic PDAs treated
withindomethacin well within the first week,23often within the
first three days.24 25
In conclusion, the preterm duct displays awide spectrum of
postnatal constrictiveactivity, and to classify the ductus
arteriosus assimply open or closed is to ignore the breadthof this
spectrum. The range of haemodynamic
effects needs to be taken into account whenexamining outcomes in
relation to the ductusarteriosus. Ducts which eventually
becomesymptomatic usually display slower early post-natal
constriction, which may permit earlyprediction of a symptomatic
PDA. Ductalshunting in this study group was significantlyrelated to
short term respiratory outcomesonly.
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