Microcirculation in Preterm Infants: Profound Effects of Patent

Ductus Arteriosus
Stephan Hiedl, MD,* Alexandra Schwepcke,* Florian Weber, and Orsolya Genzel-Boroviczeny, MD, PhD
Objectives To assess potential effects of a hemodynamically significant persistent ductus arteriosus (sPDA) in the
skin microcirculation in preterm neonates.

Study design In 25 patients (<32 weeks of gestation; birth weight <1250 g) with sPDA (n = 13) or no significant
PDA (non-sPDA; n = 12) functional vessel density and vessel diameters were investigated prospectively. Sidestream dark field imaging was performed in the skin of both arms from the third day of life until PDA closure or until
day 7 or 8 for the non-sPDA group.
Results Before PDA treatment, functional vessel density was significantly lower in the sPDA group compared with
the non-sPDA group. In the sPDA group, there were significantly fewer large vessels (diameter >20 mm) and significantly more small vessels (diameter <10mm). After successful PDA treatment, these differences disappeared. In
both groups, functional vessel density differed significantly between the left and right arm, persisting even after successful treatment. Regression analysis showed an inverse linear correlation between the hemodynamic echocardiographic findings and functional vessel density (P <.005).
Conclusion sPDA causes major changes in the microcirculation of premature neonates; functional vessel density
is reduced, with a shift in perfusion from larger toward smaller vessels. The redistribution of flow might be a compensatory mechanism to preserve physiologic metabolism. (J Pediatr 2010;156:191-6).

n infants born before 37 completed weeks of gestation, the risk of a patent ductus arteriosus (PDA) correlates inversely to
birthweight and gestational age.1,2 In these patients, a PDA increases morbidity and mortality.3 The left-to-right shunting
across the PDA increases with the size of the PDA and leads to systemic hypoperfusion and pulmonary overcirculation.4,5
Systemic hypoperfusion may contribute to a higher risk of intraventricular hemorrhage, periventricular leukomalacia, and
possibly necrotizing enterocolitis.6-9 Pulmonary overcirculation causes a higher incidence of bronchopulmonary dysplasia.4
Usually in preterm infants, closure of the PDA with cyclooxygenase inhibitors, such as indomethacin or ibuprofen, is attempted, followed by surgical ligation when pharmacologic closure fails.10,11
There is an ongoing debate about the benefit of these therapeutic strategies and the pathophysiology that causes increased
morbidity and mortality.3,12,13 Earlier studies investigating macrocirculatory variables demonstrated the hemodynamic consequences of a PDA: diastolic blood pressure and blood flow velocities in the cerebral and splanchnic arteries are reduced.14-16
However, microcirculation plays a key role in gas exchange, metabolic, immunologic, and coagulatory homeostasis. The microcirculatory scenario is not necessarily reflected by macrocirculatory variables.17-19
Microcirculation in neonates can be observed with new non-invasive in vivo microscopy methods. We have used orthogonal
polarized spectral imaging successfully to assess microvascular variables such as vessel density and vessel size in the skin of premature infants.20-23 Sidestream dark field imaging is the further development of this technique and provides an improved image quality. Sidestream dark field imaging uses a light guide, which is surrounded by green light (530 nm) emitting diodes
(LED). The light penetrates the tissue, illuminates the microcirculation, and is absorbed by hemoglobin of the erythrocytes.
Perfused vessels are visualized, and quantitative assessments of microvascular variables are possible.24
The objective of this prospective study was to assess potential effects of a hemodynamically significant PDA on the microcirculation in the skin of very premature neonates. Furthermore, the effects of successful treatment on microcirculation are
investigated, and microcirculatory variables are compared with established diagnostic criteria for PDA as defined with echocardiography.

Ao
Dia S
Dia M
Dia L
LA
LED
non-sPDA
PDA
sPDA

Aortic root
Percentage of small vessels (diameter <10 mm)
Percentage of medium vessels (diameter 10-20 mm)
Percentage of large vessels (diameter >20 mm)
Left atrium
Light emitting diodes
Non-hemodynamically significant ductus arteriosus
Patent ductus arteriosus
Hemodynamically significant ductus arteriosus

From the Division of Neonatology Perinatal Center at

Department of Gynecology and Obstetrics, University
Childrens Hospital University of Munich IS, Munich,
Germany
These data are part of the thesis of A. S. The authors
declare no conflicts of interest.
*Contributed equally and share first authorship
0022-3476/$ - see front matter. Copyright 2010 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2009.08.034

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Methods
The single-center, prospective, observational study was conducted between January 2006 and December 2007 at the neonatal intensive care unit of Ludwig-Maximilians-University
of Munich, Germany. Twenty-seven preterm infants with
gestational ages <32 weeks and birth weights <1250 g admitted to the neonatal intensive care unit were consecutively included before echocardiographic investigation was
performed. Parents gave written informed consent. Exclusion criteria were signs of infection, a C-reactive protein level
>1.5 mg/dL, or congenital malformation. The nature of the
study was observational, and no number of participants
was calculated. Because of the time required for the measurements and analysis of the data, the number of patients was
designed to be at least 10 patients per group. The institutional
review board of the Medical Faculty of Ludwig-MaximiliansUniversity Munich approved the study protocol and the consent forms.
All infants had echocardiographic assessment for PDA on
day 3 or 4 of life and were accordingly stratified into 2 groups.
Infants with a hemodynamically significant PDA were assigned to group sPDA. Infants with a hemodynamically
not significant PDA or no PDA were assigned to group
non-sPDA (Figure 1). Hemodynamic significance was defined as either a diameter of the duct >2.5 mm, a left atrium
(LA) to Aortic root (Ao) ratio of >1.4 and a reduced or negative end-diastolic flow in the celiac trunk.16,25
For a detailed comparison of microcirculation with echocardiography of a PDA, the echocardiographic results were
described as: 1) echoscore 0, no PDA could be identified
with echocardiography; 2) echoscore 1, visible flow in the
PDA, ductal diameter <2.5 mm, LA/Ao ratio <1.4, and normal positive end-diastolic flow in the celiac trunk; 3) echoscore 2, moderately hemodynamically significant PDA,
ductal diameter >2.5 mm, LA/Ao ratio >1.4, and reduced
end-diastolic flow in the celiac trunk; and 4) echoscore 3, severe hemodynamically significant PDA, ductal diameter >2.5
mm, LA/Ao ratio >1.4, and no end-diastolic flow or negative
end-diastolic flow in the celiac trunk.

Vol. 156, No. 2

Clinical signs of a sPDA in preterm neonates can be nonspecific. In this investigation, the stratification was exclusively based on echocardiography results. Decision to treat
was made independently by the attending neonatologist,
who was aware of the echocardiographic findings. No decision to treat was based on clinical symptoms alone without
sPDA-findings on echocardiography. Echocardiography
was repeated at the end of treatment and 48 hours later to
confirm closure in the sPDA-group. The non-sPDA group
underwent echocardiography on day 7 or 8 of life to verify
the initial echocardiographic result of a closed or hemodynamically non-significant PDA.
Treatment consisted of 3 doses of 0.2 mg/kg indomethacin, which were given intravenously every 12 hours. In case
of a persistent hemodynamically significant PDA, the course
was repeated.11,26 When indomethacin was contraindicated,
ibuprofen was administered intravenously (10 mg/kg, followed by 5 mg/kg after 24 and 48 hours).10 Echocardiography
was performed by a pediatric cardiologist using an Image
Point Hewlett Packard (Palo Alto, California) ultrasound
scanning system (8 MHz).
Following the orthogonal polarized spectral imaging technique, sidestream dark field imaging is a novel technique to
visualize the microcirculation. It uses a light guide, which is
surrounded by green (530 nm) LEDs. The light from the
LEDs is absorbed by hemoglobin in the erythrocytes, but reflected by other structures of the tissue. This results in an image of the red blood cells in the microvasculature to a depth
of 3 mm.24 In this study, we used the handheld video microscope MicroScan (Microvision Medical, Wallingford,
Pennsylvania). Orthogonal polarized spectral imaging was
validated against conventional capillary microscopy in nailfold skin at rest and after venous occlusion in healthy volunteers. The results demonstrated that the images provided
similar values for red-blood-cell-velocity and capillary diameter compared with those obtained with conventional capillary microscopy.23 For our study, we used 5-times
magnification. Sidestream dark field images of 10 seconds
were obtained on 3 different spots on each of the left and
right inner upper arm. In contrast to adults, it is not possible

Figure 1. Study design and assessment of microcirculation. The pictures show the handling of the sidestream dark field imaging
microscope and an image of the microcirculation (5 X magnification).
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to assess microcirculation sublingually in preterm neonates.
As we have shown previously, the upper arm region provides
a good image quality.20-22 We chose the inner side of the arm
to reduce artifacts caused by Lanugo hair.
Measurements started after the first echocardiography on
day 3 or 4 of life and were repeated until successful closure
of the duct in the sPDA group and on day 7 or 8 of life in
the non-sPDA group (Figure 1). All measurements were performed by 1 investigator. Images underwent blinded off-line
analysis with microvision analysis software. This software enables a semi-automatic analysis, which automatically detects
vessels on the screen and allows individual corrections for artifacts such as hair. The program subsequently calculates the
functional vessel density, which represents total vessel length
in centimeters per image area in cm2 and the distribution of
vessel diameter (Dia). That results in the distribution of small
(<10 mm; Dia S), medium (10-20mm; Dia M), and large (20100mm; Dia L) vessels as a percentage of the total vessel
length. The investigator assessing microcirculation was
blinded to echocardiographic results. These results were first
de-blinded after analysis of the microcirculation variables.
Statistical analysis was performed with GraphPad 4.0
(GraphPad Software Inc., La Jolla, California). Data are presented as mean values with 95% CIs. For each time point, 3
video scans per arm were analyzed, and the mean value of
a variable was used for statistical analysis. For left-to-right
comparison, the paired t test was used after the normality
test for parametric data. Intergroup comparison was performed with the unpaired t test. One-way analysis of variance, post-test for linear trend, and a linear regression
analysis were applied on the echoscore analysis. A P value
<.05 was considered to be significant.

Results
Of the 27 preterm infants prospectively enrolled in the study,
the data for 25 neonates were analyzed. Two neonates were
excluded from the study; 1 died of sepsis during the study period, and 1 had a hemodynamically significant PDA, but it
was clinically asymptomatic, and the neonate did not receive
treatment. The data for this infant were only used for correlation of echoscores with microcirculatory variables. In the
sPDA group, data from 2 infants at day 7/8 of life are missing
because of technical problems.
The 12 patients in the non-sPDA group had higher gestational age and birth weight compared with the 13 neonates
with sPDA (mean gestational age, 27.9 weeks; 95% CI, 26.928.9 versus 26.5 weeks; 95% CI, 25.7-27.8; P <.05; mean
weight, 940 g; 95% CI, 828-1053 versus 785 g; 95% CI, 6861004; P <.05). On day 3 of life, at enrollment, all infants in
the sPDA group received ventilatory support, and most
(69%) were intubated, whereas 58% of the non-sPDA group
were receiving nasal continuous positive airway pressure, and
25% were intubated. Seventeen percent of infants in the nonsPDA group did not need ventilatory support. Before treatment, the mean diastolic blood pressure was significantly

Table. Microcirculatory variables in the

hemodynamically significant ductus arteriosus and nonhemodynamically significant ductus arteriosus groups

FVD (cm/cm2)
Left arm
Right arm
Small vessel
diameter (%)
Left arm
Right arm
Medium vessel
diameter (%)
Left arm
Right arm
Large vessel
diameter (%)
Left arm
Right arm

sPDA
Day 3 or 4 of life
(before treatment)
n = 13

P value

Non-sPDA
Day 3 or 4 of life
n = 12

260* (245-274)
240* (222-257)

.003
.008

295* (277-313)
269* (256-283)

43 (36-49)
40 (32-47)

.012
.010

30* (23-38)
25* (16-34)

51 (46-56)
53 (48-57)

.040
.014

58 (54-61)
61 (56-66)

6.1 (4.4-7.7)
8.1 (5.0-11.0)

.04
.04

12 (6.7-18.0)
14 (8.4-20.0)

sPDA
After treatment
(median, day 12 of life)
n = 11

P value

Non-sPDA
Day 7 or 8 of life
n = 12

FVD (cm/cm )
Left arm
Right arm
Small vessel
diameter (%)
Left arm
Right arm
Medium vessel
diameter (%)
Left arm
Right arm
Large vessel
diameter (%)
Left arm
Right arm

270* (252-286)
234* (222-255)

NS
NS

273* (252-293)
252* (230-274)

39 (29-49)
31 (18-44)

NS
NS

32 (25-39)
30 (24-36)

54 (46-62)
58 (49-68)

NS
NS

57 (53-61)
59 (55-63)

7.4 (5.1-9.6)
11 (6.3-15.0)

NS
NS

10 (6.1-15.0)
11 (7.8-17.0)

Values are means (95% CI). Unpaired t tests were used for comparisons between the sPDA and
non-sPDA groups. Paired t tests were used for comparison between left and right arms. Statistical significance: P < .05.
FVD, Functional vessel density; NS, not significant.
*Significant difference between the arms.

lower and blood pressure amplitude higher in the sPDA

group. None of the other clinical or laboratory variables, including lactate, showed any significant difference. Treatment
with cyclooxygenase inhibitors was successful for all infants in
the sPDA group. In 11 neonates, indomethacin was used, and
2 infants received ibuprofen. After successful treatment, there
were no significant clinical differences in the groups.
Microcirculatory Variables
sPDA group. Before treatment, functional vessel density
was significantly (P < .05) lower in the right arm compared
with the left arm. After treatment (day of life: median, 12;
mean: 16; 95% CI, 8-20), functional vessel density still remained significantly lower in the right arm (P < .05; Table).
Vessel diameter distribution did not differ significantly between the arms and did not change before and after treatment. There was no significant change in functional vessel
density before and after treatment in both arms.

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Figure 2. Functional vessel density in the sPDA group before and after treatment, compared with the non-sPDA group on day 3
or 4 of life and day 7 or 8 of life.

non-sPDA group. Functional vessel density was significantly lower in the right arm compared with the left arm
on day 3 or 4 and day 7 or 8 of life (P < .05; Table). Moreover,
on day 3 or 4 of life, there was a significantly smaller proportion of small vessels (Dia S) in the right arm compared with
the left arm (P < .05). In both arms, functional vessel density
and the diameter distribution of vessels did not differ
between the points of measurement.

groups. Functional vessel density decreased linearly (r2 =

0.26; P = .003), with increasing hemodynamic relevance as
defined with echoscore (Figure 3), although the correlation
was not strong. The percentage of small vessels (Dia S) increased linearly with higher echoscores. Medium vessels did
not differ between the echoscores. Decrease in large vessels
did not reach statistic significance.

Discussion
sPDA versus non-sPDA group. Before treatment, all microcirculatory variables significantly differed between the
sPDA group and the non-sPDA group (Table; Figure 2).
In both arms, functional vessel density was significantly lower
in the sPDA group (left arm: P = .003; right arm: P = .008).
The percentage of large and medium-size vessels (Dia M and
Dia L) were significantly (P < .05) reduced in both arms in
the sPDA group compared with the non-sPDA group. Thus
the percentage of small vessels (Dia S) significantly increased
(left arm: P = .012, right arm: P = .01). After successful treatment, there were no significant differences in the groups in
either arm. Functional vessel density and the distribution
of vessel diameters did not differ any more.
Microcirculation in relation to echoscores
Microcirculatory variables of the left arm were analyzed in
accordance with their corresponding echoscores for both
194

Our results demonstrate major differences in the microcirculation of premature neonates with hemodynamically significant PDA.
Before treatment, functional vessel density in neonates
with sPDA was significantly lower compared with neonates
without sPDA. Microcirculation in infants with sPDA was
predominately represented by small vessels, whereas the proportion of medium and large vessels were reduced compared
with that in neonates without sPDA. After successful treatment, these differences were not present. Left-to-right shunting through the PDA results in systemic hypoperfusion with
reduced blood volume in the periphery. Spach et al examined
pulsatile aortopulmonary pressure-flow dynamics in patients
with a PDA; when a large left-to-right shunt was present, the
forward pulse volume in the aorta was divided equally in
backward and net forward flow, diminishing flow to the
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February 2010

Figure 3. Linear regression analysis of functional vessel

density in relation to the echocardiographic results. Echoscore 0: no duct; echoscore 1: PDA visible without hemodynamic relevance; echoscore 2: PDA with moderate
hemodynamic relevance; echoscore 3: PDA with severe hemodynamic relevance. P = .003.

lower body.27 Accordingly, Clyman et al showed in a preterm lamb model that an artificial PDA resulted in increased
left ventricular output and a parallel decreased perfusion
pressure and localized vasoconstriction.14 Shimada et al investigated the effects of a PDA in preterm infants by evaluating left ventricular output and organ blood flow. Their results
suggest that despite cardiac compensatory mechanisms the
post-ductal blood-flow cannot be maintained because of decreased perfusion pressure and increased localized vascular
resistance. After PDA closure, these changes disappeared.15,16
Thus the authors demonstrate the potential pathologic impact of a patent duct on individual organ blood flow. We postulate that hypoperfusion in our sPDA cohort leads to
vasoconstriction of larger vessels of the microcirculation to
maintain adequate volume. Reacting to reduced organ blood
flow for opening of small vessels aims to preserve metabolic
cell supply. Tissue oxygenation is regulated by complex
mechanisms of opening and closing precapillary sphincters
and vasomotion. Ursino et al proved that vasomotion could
increase microcirculation by recruiting previously inactive
sites of microcirculation.28,29
Noori et al have very recently reconfirmed that mortality
rates are significantly higher in patients with PDA (71% versus
11%).3 The most common cause in their retrospective study
was multiorgan failure, which might support the hypothesis
of compromised systemic blood flow with decreases in oxygen
delivery and subsequent abnormal organ function and tissue
injury. Infants with moderate to large PDA had higher mortality rates than infants with a small PDA.3 Our study demonstrates consequences of a hemodynamic significant PDA at
the microcirculatory level. These results might help to explain
the pathomechanism of clinical complications and mortality.

In both groups (sPDA and non-sPDA), functional vessel

density was persistently lower in the right arm than in the
left arm. In normal anatomy, the duct enters the aortic arch
distal to the origin of the left subclavian artery; therefore
both subclavian arteries are preductal vessels.30 However,
the left subclavian artery is closer to the duct. In presence of
a PDA, the aortic preductal flow is accelerated, whereas the
postductal diastolic flow is, to some extent, retrograde. It remains speculative whether this flow acts as a steal phenomenon, diverting volume from the right subclavian artery. The
backward flow in the isthmic area could account for a contrary
effect, providing more volume to the left subclavian artery.
Because of the significant difference between the left arm
and right arm for perfusion in infants with sPDA, we suggest
that in future investigations of neonatal microcirculation the
site used for measurement needs to be considered.
In our study, changes in microcirculation correlate well to
the hemodynamic significance of the PDA as determined
with echocardiographic scoring; increasing echoscores lead
to a decrease in functional vessel density. Our results show
an influence on microcirculation even for a PDA that is not
hemodynamically significant according to the usual echocardiographic criteria.
There are some limitations to our study. The microcirculation in preterm neonates is influenced by many factors,
such as hemoglobin level, incubator temperature, and increasing maturity, which are also interrelated. The sPDA
group had a higher percentage of infants intubated and receiving mechanical ventilation, which, in theory, could have
influenced the hemodynamic variables and could have biased
our microcirculatory data. However, these factors should not
influence the microcirculation differently on one side of the
body compared with the other. Finally, because of the very
time consuming methods and analysis, the number of patients is low, and the statistical power is limited.
We concentrated on microcirculation of the skin of infants. At present there is no possibility to measure non-invasively the microcirculation in central organs (brain, intestine,
lungs) that are most affected by a PDA. Therefore, our results
might not reflect deep organ oxygen delivery.
In conclusion, this study demonstrates major differences
in the microcirculation of premature neonates with a hemodynamically significant PDA. Functional vessel density is significantly reduced, with a shift of perfusion from larger
vessels towards smaller vessels. This effect is more pronounced on the right arm than on the left arm. The redistribution of flow in favor of small vessels (<10 mm) might be
a compensatory mechanism to preserve the integrity of small
vessel function, which is responsible for tissue oxygenation
and essential for maintenance of physiologic metabolism.
Effects on microcirculation correlate with hemodynamic
significance of the PDA with echocardiography. n
Submitted for publication Feb 9, 2009; last revision received Jun 12, 2009;
accepted Aug 17, 2009.
Reprint requests: Prof Orsolya Genzel-Boroviczeny, Maistr 11, 80337 Munich,
Germany. E-mail: genzel@med.lmu.de.

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