Download Enhanced ventricular pump function and decreased reservoir

Am J Physiol Regul Integr Comp Physiol 306: R273–R280, 2014.
First published January 8, 2014; doi:10.1152/ajpregu.00416.2013.
Enhanced ventricular pump function and decreased reservoir backflow sustain
rise in pulmonary blood flow after reduction of lung liquid volume in fetal
lambs
Joseph J. Smolich
Heart Research Group, Murdoch Childrens Research Institute, Melbourne, Australia
Submitted 2 September 2013; accepted in final form 29 December 2013
fetal pulmonary blood flow interactions; ductus arteriosus shunting;
wave intensity analysis; right ventricular power
PULMONARY PERFUSION IN THE fetus is characteristically low, with
blood flow measurements using microspheres in fetal lambs (2,
41, 43) or Doppler-echocardiography in human fetuses (20, 28,
29) indicating that only 10 – 40% of mean pulmonary trunk
(PT) flow passes to the lungs, as most of this flow crosses the
ductus arteriosus (DA) into the descending aorta to be distributed to the placenta and lower fetal body (7, 30). One factor
contributing to a low pulmonary flow in utero is the presence
of fluid (“lung liquid”) within the future airways and alveoli,
with a reduction of lung liquid volume producing a substantial
increase in mean pulmonary blood flow (14, 45) that is believed to result from decreased extravascular compression of
small pulmonary arteries (7, 8, 13, 45).
Address for reprint requests and other correspondence: J. J. Smolich, Heart
Research Group, Murdoch Childrens Research Institute, Flemington Road,
Parkville, Victoria, Australia, 3052 (e-mail: [email protected]).
http://www.ajpregu.org
Little is known, however, about changes in central flow
patterns that sustain increased pulmonary perfusion after a
decrease in lung liquid volume. This is especially pertinent as
recent findings from wave intensity (WI) and phasic blood flow
profile analyses indicate that the fetal PT, DA and pulmonary
artery (PA) region exhibits prominent phasic interactions in
systole and diastole (36, 39). Thus, unlike the distribution of
mean PT blood flow, the initial systolic right ventricular (RV)
flow impulse transmitted into the PT as a forward-running
compression wave (FCWis) mainly passes into major branch
PAs rather than the DA, as PA characteristic impedance is
lower (36). However, PA flow then falls abruptly in midsystole
because of an extremely large PA flow-reducing, backwardrunning compression wave (BCWms), which arises from the
pulmonary microvasculature in response to the PA FCWis (35,
37). Furthermore, this BCWms undergoes retrograde transmission into the PT as a BCWms that produces a midsystolic fall in
PT flow (35, 37), but antegrade transmission into the DA as a
forward-running compression wave (FCWms) that augments
DA flow (36). Finally, a portion of RV output is transiently
stored in a central PT and main PA reservoir which, together
with backflow from a conduit PA reservoir, discharges across
the DA in diastole (36, 39).
Emerging evidence also suggests that PT-PA-DA interactions can change substantially with increased fetal pulmonary
blood flow. Intrapulmonary adenosine infusion, for example,
abolished backflow from the conduit PA reservoir, but markedly augmented central reservoir discharge to the extent that it
provided ⬃40% of the rise in PA flow, and the entire DA flow
in diastole (40). However, the changes in PT-PA-DA interactions, which contribute to systolic and/or diastolic rises in PA
blood flow after a reduction in lung liquid volume are unknown, as is the role of two other central mechanisms. First,
constraint of the heart by the lungs may decrease, thereby
increasing RV pump function and PT flow (11). Second, the
apparent loss of a positive mean pressure difference between
the PT and aortic trunk (AoT), measured with fluid-filled
catheters (14), raises the possibility that right-to-left DA shunting may be diminished, with greater passage of PT flow to the
lungs. However, the relationship between changes in DA flow
patterns and the PT-AoT pressure difference has yet to be
assessed.
To address the foregoing issues, PT, DA, and PA phasic
flow and WI analyses were undertaken in anesthetized fetal
lambs, before and after a decrease in lung liquid volume. The
study had five specific aims: 1) to quantify systolic and diastolic contributions to increases in mean PA blood flow; 2) to
characterize systolic changes in PA blood flow via evaluation
of PT-PA-DA WI interrelationships and their associated flow
0363-6119/14 Copyright © 2014 the American Physiological Society
R273
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Smolich JJ. Enhanced ventricular pump function and decreased
reservoir backflow sustain rise in pulmonary blood flow after reduction of lung liquid volume in fetal lambs. Am J Physiol Regul Integr
Comp Physiol 306: R273–R280, 2014. First published January 8,
2014; doi:10.1152/ajpregu.00416.2013.—Although a reduction in
lung liquid volume increases fetal pulmonary blood flow, the changes
in central flow patterns that sustain this increased pulmonary perfusion are unknown. To address this issue, eight anesthetized lategestation fetal sheep were instrumented with pulmonary trunk (PT),
ductus arteriosus (DA), and left pulmonary artery (PA) micromanometer catheters and transit-time flow probes, with blood flow profile and
wave intensity analyses performed at baseline and after withdrawal of
lung liquid via an endotracheal tube. Reducing lung liquid volume by
19 ⫾ 6 ml/kg (mean ⫾ SD) augmented right ventricular power by
34% (P ⬍ 0.001), with distribution of an accompanying increase in
mean PT blood flow (245 ⫾ 63 ml/min, P ⬍ 0.001) to the lungs (169 ⫾
91 ml/min, P ⫽ 0.001) and across the DA (77 ⫾ 92 ml/min, P ⫽
0.04). However, although PT and DA flow increments were confined
to systole and were related to an increased magnitude of flowincreasing, forward-running compression waves, the rise in PA flow
spanned both systole (108 ⫾ 66 ml/min) and diastole (61 ⫾ 32
ml/min). Flow profile analysis showed that the step-up in PA diastolic
flow was associated with diminished PA diastolic backflow and
accompanied by a lesser degree of diastolic right-to-left DA shunting.
These data suggest that an increased pulmonary blood flow after
reduction of lung liquid volume is associated with substantial changes
in PT-DA-PA interactions and underpinned by two main factors:
1) enhanced right ventricular pump function that increases PA systolic
inflow and 2) decreased PA diastolic backflow that arises from a
fundamental change in PA reservoir function, thereby resulting in
greater passage of systolic inflow through the lungs.
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LUNG LIQUID REMOVAL AND PULMONARY BLOOD FLOW IN FETAL LAMBS
effects; 3) to define changes in PT and PA reservoir function
and their role in any alterations of diastolic PA flow patterns;
4) to determine whether an increased RV pump function
accompanied rises in PA blood flow; and 5) to relate the phasic
characteristics of the instantaneous PT-AoT pressure difference, measured with high-fidelity micromanometers (38), to
DA flow patterns.
METHODS
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Experiments were approved by the Murdoch Childrens Research
Institute Animal Ethics Committee and conformed to National Health
and Medical Council of Australia guidelines.
Surgical preparation. Similar to previous studies (36, 39, 40), eight
pregnant Border-Leicester cross ewes were anesthetized at a gestation
of 142 ⫾ 1 days (mean ⫾ SD; term ⫽ 147 days) with intramuscular
ketamine 5 mg/kg and xylazine 0.1 mg/kg, then 5% isoflurane delivered by mask. After tracheal intubation, anesthesia was maintained
with 2–3% isoflurane and nitrous oxide (10 –20%) in O2-enriched air
delivered via a ventilator (900C Servo, Siemens-Elema, Solna, Sweden), supplemented by an intravenous infusion of ketamine (1–1.5
mg·kg⫺1·h⫺1), midazolam (0.1– 0.15 mg·kg⫺1·h⫺1) and fentanyl (2–
2.5 mg·kg⫺1·h⫺1). Oxygen saturation was monitored continuously
with a pulse-oximetry sensor applied to the ear. The right common
carotid artery was cannulated for blood pressure monitoring and blood
gas analysis (ABL 800; Radiometer, Copenhagen, Denmark), with
ventilation adjusted to maintain arterial PO2 at 100 –120 mmHg and
PCO2 at 35– 40 mmHg.
Following uterine exposure through a midline laparotomy, the fetal
head was exteriorized and placed in a saline-filled glove to prevent
loss of lung liquid. A catheter was inserted into the left external
jugular vein for fluid administration, and a 6-Fr vascular sheath passed
via the left common carotid artery into the distal AoT for pressure
measurement and blood sampling. This sheath was later used for
passage of a 3.5-Fr micromanometer catheter (SPR-524; Millar Instruments, Houston, TX) into the AoT to obtain high-fidelity pressure.
After delivery of the left forelimb and upper thorax, a thoracotomy
was performed in the 3rd left interspace, the pericardium was incised,
and major vessels were carefully dissected for placement of transittime flow probes (Transonic Systems, Ithaca, NY) around the PT
(10 –14 mm “A series”), DA (8 –10 mm “A series”), and left PA (6
mm “S series”) in all fetuses. Through purse-string sutures, fluid-filled
catheters were inserted into the PT and left atrium (LA), and three
additional SPR-524 micromanometer catheters were placed into the
PT distal to the PT flow probe, with one directed toward the pulmonary valve, another into the proximal portion of the DA, and the third
advanced into the origin of the left PA. Finally, through a transverse
incision in a proximal intercartilaginous space, a 5-mm endotracheal
tube with a 3-way tap tied into its base was passed distally into the
trachea to a distance of ⬃3 cm and ligated in place, to measure
tracheal pressure and remove lung liquid.
Experimental protocol. After completion of surgery, an AoT sample was taken for blood gas analysis, and physiological data were
recorded in all fetuses for baseline hemodynamic and WI analyses.
Lung liquid was then gently withdrawn via the endotracheal tube
using a 50-ml syringe until increased resistance was encountered.
Hemodynamics were allowed to stabilize for 3–5 min, and physiological variables were again recorded after sampling of AoT blood. At
the end of the study, animals were killed with an overdose of
pentobarbital sodium (100 mg/kg).
Physiological data. AoT, PT, LA, and tracheal pressures were
measured with calibrated transducers referenced to atmospheric pressure at LA level. Signals from catheters, micromanometers and flow
probes were digitized at a sampling rate of 1 kHz and were displayed
using programmable acquisition and analysis software (Spike2, Cambridge Electronic Design, Cambridge, UK). No data filtering was
employed, apart from a 48-Hz low-pass filter at the time of analysis to
remove electrical interference from signals.
Mean PT and AoT micromanometer pressures were matched to the
corresponding mean catheter pressure, and the late-diastolic portions
of DA and left PA micromanometer waveforms then matched to the
same segment of PT micromanometer pressure (36). Zero-offset
calibrations of all flow probes were performed prior to each experiment and, to ensure that PT, DA, and PA flows were internally
consistent, RV output was derived as the sum of mean DA flow and
the combined left and right PA flow (calculated as the product of
measured left PA flow and the total-to-left lung weight ratio). Measured PT flow was then scaled to match calculated RV output (36, 39,
40), with the adjusted PT flow used in all subsequent hemodynamic
and WI analyses, which were performed on ensemble-averaged signals generated from 60 ⫾ 10 beats.
Right ventricular pump function. To quantify RV pump function,
total RV hydraulic power was calculated as the instantaneous product
of PT flow and micromanometer pressure (38), mean RV power as the
product of mean PT flow and pressure, and oscillatory RV power as
total minus mean RV power (31). To assess heart rate-independent
changes in RV pump function, RV stroke work was calculated as the
product of RV stroke volume (i.e., mean PT flow divided by heart
rate) and mean PT blood pressure.
Phasic blood flow analysis. The timing of the PT flow profile was
used to define systolic and diastolic flow components at all sites, with
forward systolic flow measured from the start of the PT systolic
upstroke to the point where this flow returned to zero in late systole,
and diastolic flow constituting the remaining flow in the cardiac cycle.
Note that 1) PT and PA diastolic flow included the transient negative
peak occurring around the time of pulmonary valve closure (36, 39);
2) raw average systolic and diastolic PT, DA, and PA flow values
were multiplied by the quotient of systolic or diastolic duration and
heart period to yield the reported systolic and diastolic flows, whose
sum equaled mean flow; 3) to permit direct comparison with PT and
DA flows, reported PA flows are the calculated combined left and
right PA values; 4) the PA backflow-to-inflow ratio equaled the
negative value of the PA diastolic-to-systolic flow quotient; and 5)
pulmonary vascular resistance (PVR) was computed as (mean PA
pressure ⫺ mean LA pressure)/(mean PA flow), and normalized to
wet lung weight.
Pulmonary reservoir function. Central and conduit PA reservoir
components were defined in relation to the location of the PA flow
probe, with discharge of the central PT and main PA reservoir
calculated as the difference between mean PT flow and the sum of the
PA and DA systolic flows, while discharge arising from the conduit
PA reservoir was equated to absolute PA diastolic flow (39, 40). Note
that the sum of discharge from the central reservoir and backflow from
the conduit PA reservoir equaled DA diastolic flow.
Pulmonary-aortic pressure difference. An instantaneous PT-AoT
pressure difference (IPDPT-AoT) profile was derived from the respective micromanometer pressures (38), with measurement of mean
IPDPT-AoT, as well as the average systolic and diastolic IPDPT-AoT, as
per the timing defined for the phasic blood flow analysis.
Wave intensity analysis. Forward- and backward-running energy
waves accompanying changes in PT, PA, and DA flow waveforms
were characterized with WI analysis, as previously described (34 –36,
39). Briefly, after conversion of blood flow to velocity (U) using
cross-sectional area derived from in vivo caliper measurement of
maximal vessel diameters, the rates of change of blood pressure
(dP/dt) and velocity (dU/dt), and their product (net WI), were calculated. Net WI was then separated into forward and backward components using wave speed calculated with the PU-loop method (25). As
per convention, forward-running waves propagated away from the
ventricle and backward-running waves arose from the vasculature,
while compression waves increased pressure, and expansion waves
decreased pressure (25). WI of forward-running (WI⫹) and backwardrunning waves (WI⫺) was calculated as WI⫾ ⫽ (dP⫾/dt) (dU⫾/dt),
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LUNG LIQUID REMOVAL AND PULMONARY BLOOD FLOW IN FETAL LAMBS
Decrease in LA pressure (mmHg)
6
4
Y = 0.9X - 2.1
R² = 0.91, P < 0.001
2
0
Decrease in tracheal pressure (mmHg)
Fig. 1. Relationship between decreases in fetal mean left atrial (LA) and
tracheal pressures after reduction of lung liquid volume.
RESULTS
Blood gases and hemodynamics. Lung liquid volume was
reduced by 19 ⫾ 6 ml/kg body wt and was not associated with
any significant change in fetal AoT pH (7.32 ⫾ 0.02 vs. 7.32 ⫾
0.03, P ⫽ 0.73), hemoglobin O2 saturation (59 ⫾ 9 vs. 57 ⫾
8%, P ⫽ 0.41), PO2 (24.7 ⫾ 3.4 vs. 23.9 ⫾ 3.7 mmHg, P ⫽
0.26) or PCO2 (47.9 ⫾ 3.5 vs. 47.1 ⫾ 3.5 mmHg, P ⫽ 0.21).
With reduction of lung liquid volume, heart rate increased,
while mean tracheal pressure, mean LA pressure, and PVR
decreased, with no change in PT and AoT blood pressures, or
PT-AoT pressure differences (Table 1). Moreover, falls in
tracheal and LA pressures were linearly related (R2 ⫽ 0.91,
P ⬍ 0.001; Fig. 1).
Right ventricular pump function. With a decrease in lung
liquid volume, RV stroke work, as well as RV total, mean and
oscillatory power increased (all P ⬍ 0.001, Table 2), but the
oscillatory-to-total power ratio was unchanged (10.6 ⫾ 2.0%
vs. 10.4 ⫾ 1.5%, P ⫽ 0.65).
Table 1. Fetal hemodynamics before and after lung liquid
reduction
PT blood pressure, mmHg
Systolic
Mean
Diastolic
AoT blood pressure, mmHg
Systolic
Mean
Diastolic
PT-AoT difference, mmHg
Average systolic IPDPT-AoT
Mean IPDPT-AoT
Average diastolic IPDPT-AoT
Mean LA blood pressure, mmHg
PVR, mmHg·ml⫺1·min⫺1·100 g⫺1
Mean tracheal pressure, mmHg
Heart rate, beats/min
Baseline
LL reduction
P
75.7 ⫾ 6.6
61.8 ⫾ 4.9
50.8 ⫾ 4.4
78.1 ⫾ 5.8
63.8 ⫾ 3.9
51.3 ⫾ 3.2
0.20
0.28
0.72
69.2 ⫾ 5.3
60.0 ⫾ 4.4
50.8 ⫾ 4.6
71.8 ⫾ 2.9
61.7 ⫾ 1.8
51.1 ⫾ 3.4
0.31
0.45
0.82
2.0 ⫾ 2.2
1.8 ⫾ 2.5
⫺0.1 ⫾ 0.5
7.4 ⫾ 2.7
1.13 ⫾ 0.69
6.7 ⫾ 2.4
151 ⫾ 17
2.1 ⫾ 2.5
2.1 ⫾ 2.7
⫺0.1 ⫾ 0.3
5.1 ⫾ 2.4
0.46 ⫾ 0.24
0.9 ⫾ 1.9
163 ⫾ 17
0.47
0.36
0.46
0.01
0.002
⬍0.001
0.02
Data are expressed as means ⫾ SD; n ⫽ 8. LL, lung liquid; PT, pulmonary
trunk; AoT, aortic trunk; IPDPT-AoT, maximal instantaneous pressure difference between pulmonary and aortic trunks; LA, left atrium; PVR, pulmonary
vascular resistance.
Blood flow patterns. Changes in PT, PA, and DA flow
patterns are presented in Table 3. With a fall in lung liquid
volume, mean blood flow increased by 245 ml/min in the PT
and 169 ml/min in the PA, but only 77 ml/min in the DA, so
that the distribution of PT flow toward the lungs rose from
16 ⫾ 9 to 28 ⫾ 10% (P ⫽ 0.003), with a corresponding
decrease in the proportion of PT flow passing across the DA.
Unlike the mean flow pattern, the increase in systolic PT
flow (218 ml/min) was distributed in approximately similar
proportions to the PA (108 ml/min) and DA (117 ml/min).
However, the pattern of diastolic flow changes differed, with a
trend to an increase in the PT (by 27 ml/min, P ⫽ 0.10), a fall
in the DA (by 42 ml/min, P ⫽ 0.04) and an increase in the PA
(by 61 ml/min, P ⬍ 0.001). As a result, the proportion of DA
flow occurring in diastole decreased from 23 ⫾ 9 to 15 ⫾ 8%
(P ⫽ 0.002), while the fraction of the PA systolic inflow
undergoing backflow in diastole fell from 37 ⫾ 27 to 6 ⫾ 21%
(P ⬍ 0.001), with a significant relationship present between
PVR and the PA backflow-to-inflow ratio (R2 ⫽ 0.65, P ⬍
0.001; Fig. 2). Overall, of the increase in PA blood flow
evident after a reduction in lung liquid volume, 64% occurred
in systole and 36% in diastole.
Pulmonary reservoir function. Baseline total pulmonary reservoir discharge in diastole was 154 ⫾ 76 ml/min, with a
similar degree of discharge evident from central and conduit
PA components (83 ⫾ 68 vs. 71 ⫾ 59 ml/min, P ⫽ 0.76).
However, after a decrease in lung liquid volume, total reservoir
discharge fell to 112 ⫾ 62 ml/min (P ⫽ 0.03), with a trend to
Table 2. Fetal right ventricular pump function before and
after lung liquid reduction
RV
RV
RV
RV
total power, W ⫻ 10
mean power, W ⫻ 10⫺2
oscillatory power, W ⫻ 10⫺2
stroke work, J ⫻ 10⫺2
⫺2
Baseline
LL Reduction
P
12.6 ⫾ 2.8
11.2 ⫾ 2.4
1.4 ⫾ 0.4
4.5 ⫾ 1.1
16.7 ⫾ 2.9
15.0 ⫾ 2.6
1.7 ⫾ 0.4
5.5 ⫾ 0.9
⬍0.001
⬍0.001
⬍0.001
⬍0.001
Data are expressed as means ⫾ SD; n ⫽ 8. LL, lung liquid; RV, right
ventricle.
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where P and U differentials associated with these waves were given
by dP⫾/dt ⫽ 1/2 (dP/dt ⫾ ␳c·dU/dt) and dU⫾/dt ⫽ 1/2 (dU/dt ⫾
1/␳c·dP/dt), respectively. The forward and backward components of
pressure (P⫾) and velocity (U⫾) were obtained by integrating P or U
differentials. Wave size was quantified with the cumulative intensity
(CI), calculated as the integral of WI⫾ over wave duration, with
FCWis and FCWms CI summed to yield the total FCW (FCWtot) CI.
The U change related to each wave (i.e., ⌬U) was obtained as the
difference in U⫾ measured between the start and end of the wave. To
evaluate the associated flow effect, ⌬U was converted back to a flow
value (i.e., ⌬Q) via multiplication by vessel cross-sectional area, with
left PA ⌬Q then multiplied by the total-to-left lung weight ratio to
obtain the combined left and right PA ⌬Q (36, 39).
Statistical analysis. Results were analyzed using IBM SPPS Statistics 20, preceded by logarithmic transformation where data were
nonnormally distributed. Changes in PT, PA, and DA hemodynamic
and WI data were compared using repeated-measures ANOVA. The
relationship between changes in mean tracheal and LA pressures, and
between PVR and the PA backflow-to-inflow ratio, were evaluated
with least-squares regression analysis. Data are expressed as means ⫾
SD, with significance taken at P ⬍ 0.05.
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Table 3. Fetal blood flows before and after lung liquid
reduction
Baseline
LL reduction
P
816 ⫾ 173
133 ⫾ 85
683 ⫾ 171
1,061 ⫾ 208
302 ⫾ 134
760 ⫾ 170
⬍0.001
0.001
0.04
826 ⫾ 197
204 ⫾ 61
529 ⫾ 152
1,044 ⫾ 212
312 ⫾ 81
648 ⫾ 171
⬍0.001
0.002
⬍0.001
17 ⫾ 68
⫺10 ⫾ 71
112 ⫾ 61
0.10
⬍0.001
0.04
⫺10 ⫾ 65
⫺71 ⫾ 59
154 ⫾ 76
*
200
150
#
100
50
0
a rise in central reservoir discharge to 101 ⫾ 44 ml/min (P ⫽
0.08) more than offset by a decrease in conduit PA reservoir
backflow (P ⫽ 0.001) to a level not significantly different from
zero (10 ⫾ 71 ml/min, P ⫽ 0.69; Fig. 3).
WI analysis. Apart from an increase in the size of FCWis and
FEWls at all sites, and FCWms in the DA, no consistent changes
were evident in the morphology of WI profiles with a fall in
lung liquid volume (Fig. 4).
PT, PA, and DA wave speeds were unaffected by a decrease
in lung liquid volume. However, FCWis, FCWtot, and FEWls
CI were augmented at all sites, while FCWms CI tended to rise
in the PT and PA and increased in the DA (Table 4). The
BCWms CI was unaltered at all sites, while CI ratios were
unchanged apart from a rise in the DA FCWms/PA BCWms
ratio. Changes in ⌬Q related to waves largely mirrored CI data,
except for a lack of change in the DA FCWis ⌬Q and a minor
decrease in the PA BCWms/FCWis ⌬Q ratio (Table 5).
DISCUSSION
This study, which is the first to have undertaken a detailed
evaluation of changes in central blood flow patterns sustaining
an increased pulmonary perfusion after reduction of lung liquid
volume in the fetus, has produced four main findings. First,
PA backflow-to-inflow ratio (%)
100.0
80.0
Y = 30.8 ln(X) + 36.2
R² = 0.65, P < 0.001
60.0
40.0
20.0
0.0
-20.0
-40.0
Pulmonary vascular resistance
(mmHg/ml/min/100g)
Fig. 2. Relationship between fetal pulmonary arterial (PA) backflow-to-inflow
ratio and pulmonary vascular resistance.
Before
After
Lung liquid reduction
Fig. 3. Discharge of total (black), central (dark gray), and conduit pulmonary
arterial (light gray) reservoirs before and after lung liquid reduction. *P ⫽
0.03, #P ⫽ 0.001, compared with corresponding “before” value.
reducing lung liquid volume augmented RV pump function and
increased PT blood flow. Second, ⬃60% of the rise in mean
PA blood flow was due to increased PA systolic inflow resulting from a higher PT flow. Third, the remaining rise in mean
PA blood flow arose from a decrease in the proportion of PA
systolic inflow undergoing backflow in diastole, due to a
fundamental change in conduit PA reservoir function that was
also accompanied by diminished right-to-left DA diastolic
shunting. By contrast, systolic and mean DA blood flows
increased, but all DA flow changes occurred without any
alteration in corresponding PT-AoT pressure differences.
While the extravascular compressive effects of fluid within
the future airways and alveoli limits blood flow through the
pulmonary microvasculature (7, 8, 13, 45), the fluid-filled fetal
lungs also impose a constraint on the heart that reduces its
effective compliance, thereby limiting cardiac preload, output,
and pump function (9). The effect of such lung constraint on
fetal RV pump function is substantial, as complete retraction of
the lungs away from the heart can more than double RV stroke
work (11). That a reduction in lung liquid volume lessened
external constraint on the heart in the present study is suggested by the observed fall in mean LA pressure (Table 1),
given that a greater pulmonary venous return accompanying an
increased fetal PA blood flow typically either does not change
(12, 44) or elevates LA pressure (16, 40). This conclusion is
also in accord with the linear relation evident between falls in
tracheal and LA pressures (Fig. 1), as well as the decrease in
left ventricular end-diastolic pressure observed when cardiac
constraint (measured directly with a flat pericardial balloon)
was reduced by retracting the lungs away from the heart (10).
Consistent with an enhanced RV pump function, total, mean
and oscillatory RV power rose with a decrease in lung liquid
volume (Table 2). However, an unusual feature of fetal RV
pump function at both baseline and after removal of lung liquid
was that the oscillatory-to-total power ratio, which represents
the proportion of RV energy used to generate the pulsatile
components of pressure and flow (31), was quite low (⬃10%)
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Data are expressed as means ⫾ SD; n ⫽ 8. PA, pulmonary artery; DA,
ductus arteriosus.
Reservoir discharge (ml/min)
Mean flow, ml/min
PT
PA
DA
Systolic flow, ml/min
PT
PA
DA
Diastolic flow, ml/min
PT
PA
DA
250
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LUNG LIQUID REMOVAL AND PULMONARY BLOOD FLOW IN FETAL LAMBS
PT wave intensity W/m2/s2 x106
A
4
After LL reduction
Baseline
FCWis
3
FEWls
FCWis
2
FEWls
1
FCWms
FCWms
0
BCWms
BCWms
-1
PA wave intensity W/m2/s2 x106
4
FCWis
FEWls
FCWis
FEWls
2
FCWms
FCWms
0
BCWms
BCWms
-2
-4
C
Table 4. Fetal wave intensity analysis before and after lung
liquid reduction
2
DA wave intensity W/m2/s2 x106
FCWis
FCWis
1
FEWls
FEWls
FCWms
FCWms
0
-1
0.1 sec
0.1 sec
Fig. 4. Forward-running (black line) and backward-running (gray line) wave
intensity profiles in the pulmonary trunk (A), left pulmonary artery (B) and
ductus arteriosus (C) at baseline and after lung liquid reduction. Abbreviations
are the same as in Table 4.
compared with the range of 21–28% reported for the adult right
ventricle (17, 21, 31), but similar to the 10 –13% observed with
the adult left ventricle (1, 22, 23). Whether this low fetal ratio
reflected the systemic role of the RV in utero, or a more
fundamental developmental difference in RV pump function,
remains to be determined. The unchanged RV oscillatory-tototal power ratio following a fall in lung liquid volume presumably represented a net effect of the opposing actions of
increases in heart rate and ventricular output on this ratio (23).
One contributory factor to enhanced RV pump function after
a fall in lung liquid volume was a higher heart rate (Table 1),
with comparison of increases in RV mean power (34%) and
stroke work (22%; Table 2), suggesting that it accounted for
Wave speed, m/s
PT
Left PA
DA
FCWis CI, W·m⫺2·s⫺1 ⫻ 104
PT
Left PA
DA
FCWms CI, W·m⫺2·s⫺1 ⫻ 104
PT
Left PA
DA
FCWtot CI, W·m⫺2·s⫺1 ⫻ 104
PT
Left PA
DA
BCWms CI, W·m⫺2·s⫺1 ⫻ 104
PT
Left PA
DA
FEWls CI, W·m⫺2·s⫺1 ⫻ 104
PT
Left PA
DA
CI ratios
PT BCWms/PT FCWis
PA BCWms/PA FCWis
DA BCWms/DA FCWis
PT BCWms/PA BCWms
DA FCWms/PA BCWms
Baseline
LL reduction
P
4.7 ⫾ 1.5
3.2 ⫾ 0.8
7.5 ⫾ 2.1
4.3 ⫾ 0.9
3.2 ⫾ 0.8
7.1 ⫾ 1.2
0.26
0.83
0.45
2.17 ⫾ 0.53
2.23 ⫾ 0.48
1.11 ⫾ 0.36
2.60 ⫾ 0.75
2.60 ⫾ 0.51
1.26 ⫾ 0.42
0.008
0.006
0.05
0.14 ⫾ 0.06
0.12 ⫾ 0.08
0.50 ⫾ 0.24
0.22 ⫾ 0.11
0.18 ⫾ 0.10
0.79 ⫾ 0.25
0.12
0.12
0.004
2.31 ⫾ 0.54
2.34 ⫾ 0.51
1.60 ⫾ 0.54
2.82 ⫾ 0.73
2.78 ⫾ 0.52
2.05 ⫾ 0.52
0.009
0.002
⬍0.001
0.72 ⫾ 0.12
1.97 ⫾ 0.93
0.09 ⫾ 0.05
0.83 ⫾ 0.21
2.08 ⫾ 0.89
0.09 ⫾ 0.04
0.23
0.35
0.57
1.03 ⫾ 0.35
0.88 ⫾ 0.36
0.68 ⫾ 0.29
1.33 ⫾ 0.44
1.30 ⫾ 0.57
0.92 ⫾ 0.28
0.01
0.004
0.008
0.35 ⫾ 0.11
0.88 ⫾ 0.33
0.09 ⫾ 0.06
0.45 ⫾ 0.23
0.27 ⫾ 0.13
0.34 ⫾ 0.11
0.78 ⫾ 0.23
0.09 ⫾ 0.06
0.44 ⫾ 0.16
0.43 ⫾ 0.21
0.61
0.22
0.98
0.88
0.004
Data are expressed as means ⫾ SD; n ⫽ 8. FCWis, initial systolic forwardrunning compression wave; BCWms, midsystolic backward-running compression wave; FCWms, midsystolic forward-running compression wave; FCWtot,
total forward-running compression wave; FEWls late-systolic forward-running
expansion wave; CI, cumulative wave intensity.
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B
one-third of the rise in RV power. The specific mechanism
underlying this elevation in heart rate is unclear, but a similar
phenomenon has been observed with rises in pulmonary blood
flow accompanying decreased lung liquid production due to
agents such as 8-bromo-cGMP (6, 15) and prostaglandin D2 (5).
While a rise in PT flow after removal of lung liquid was
confined to systole, the increment in PA flow spanned both
systole and diastole. WI analysis indicated that the PA systolic
component occurred in early- and mid-systole and was of ventricular origin, with a larger PT FCWtot CI and ⌬Q resulting in
correspondingly bigger PA FCWtot CI and ⌬Q, without greater
transmission of PT FCWs into the PA (Tables 4 and 5). Somewhat surprisingly, the midsystolic rise in PA flow was not associated with a decrease in the magnitude of the PA BCWms, a
finding likely to be related to two counteracting effects. Thus, a
larger PA FCWis (Table 4) would be expected to generate a bigger
PA BCWms (35). However, it is likely that an expansion of small
PA occurring with removal of lung liquid (45) reduced peripheral
wave reflection, thus diminishing PA BCWms amplitude.
On the other hand, phasic flow profile analysis suggested
that increased diastolic PA flow was due to a fundamental shift
in conduit PA reservoir function. Thus, in accord with prior
findings (39, 40), ⬃35% of PA systolic inflow was stored in a
conduit PA reservoir at baseline and then discharged as a
backflow that passed across the DA in diastole (Table 3), with
such a reservoir function indicated by a negative offset in the
R278
LUNG LIQUID REMOVAL AND PULMONARY BLOOD FLOW IN FETAL LAMBS
Table 5. Blood flow effects of waves before and after lung
liquid reduction
Baseline
P
3,223 ⫾ 838
2,056 ⫾ 540
942 ⫾ 339
3,487 ⫾ 644
2,184 ⫾ 559
904 ⫾ 202
0.10
0.002
0.64
858 ⫾ 319
387 ⫾ 195
729 ⫾ 287
1,123 ⫾ 466
518 ⫾ 142
972 ⫾ 270
0.08
0.04
⬍0.001
4,081 ⫾ 1,089
2,443 ⫾ 649
1,670 ⫾ 561
4,610 ⫾ 897
2,702 ⫾ 573
1,876 ⫾ 394
0.02
0.003
0.04
⫺2,049 ⫾ 543
⫺1,963 ⫾ 577
⫺293 ⫾ 116
⫺2,188 ⫾ 412
⫺1,935 ⫾ 671
⫺287 ⫾ 84
0.53
0.62
0.88
⫺1,778 ⫾ 501
⫺958 ⫾ 298
⫺602 ⫾ 214
⫺2,059 ⫾ 525
⫺1,156 ⫾ 335
⫺701 ⫾ 146
0.007
⬍0.001
0.02
0.65 ⫾ 0.14
0.95 ⫾ 0.13
0.32 ⫾ 0.14
0.57 ⫾ 0.20
0.38 ⫾ 0.16
0.63 ⫾ 0.08
0.87 ⫾ 0.15
0.33 ⫾ 0.14
0.64 ⫾ 0.23
0.54 ⫾ 0.24
0.72
0.03
0.68
0.34
0.02
Data are expressed as means ⫾ SD; n ⫽ 8. ⌬Q, flow change; other
abbreviations are the same as in Table 4.
PA diastolic flow profile. With lung liquid removal, however,
no net PA backflow occurred in diastole, resulting in increased
passage of the PA systolic inflow through the lungs. Although
the regulation of conduit PA reservoir function has yet to be
fully characterized, PVR appears to be an important modulatory factor, with a fall in PVR associated with decreased fetal
PA backflow (Fig. 3).
As well as increasing pulmonary blood flow, loss of PA
backflow after a reduction in lung liquid volume also had
significant consequences for diastolic right-to-left DA shunting, a phenomenon evident in both clinical and experimental
settings (18, 19, 32). In accord with prior studies (36, 39, 40),
about half of this flow at baseline was due to diastolic discharge of the central PT and main PA reservoir, and the
remainder to backflow from the conduit PA reservoir. However, although discharge from the central reservoir provided
⬎90% of diastolic DA flow after loss of PA backflow occurring with a reduction in lung liquid volume (Fig. 4), this was
insufficient to preserve such DA flow (Table 3). It is also
noteworthy that this greater contribution of central reservoir
discharge to diastolic DA flow was not due to increased
reservoir capacity per se, as the proportion of RV output stored
in the central reservoir, equal to the quotient of central reservoir discharge (Fig. 3) and mean PT flow (Table 3), was similar
before and after a fall in lung liquid volume (⬃10%).
In contrast to a diminution of DA diastolic flow, systolic and
mean DA flows both rose after a reduction in lung liquid
volume. Importantly, the rise of DA flow in systole had no
initial systolic component, as DA FCWis ⌬Q was unchanged
(Table 5). Instead, this increase primarily occurred in midsystole and resulted from a larger DA FCWms that, as indicated by
the elevated DA FCWms/PA BCWms CI and ⌬Q ratios (Tables
Perspectives and Significance
The present findings, combined with those obtained during
graded DA constriction (39) and increased pulmonary blood flow
produced by adenosine infusion (40), further support a major role
for changes in the PA diastolic flow offset (and, therefore, the
status of conduit PA reservoir function) to alterations of pulmonary blood flow in the fetus. However, comparison of the present
results (Table 3 and Fig. 4) with those of adenosine infusion (40)
also suggest that increases in diastolic fetal pulmonary blood flow
may be accompanied by a diverse range of changes in PT-PA-DA
flow interactions. Furthermore, although a fall in lung liquid
volume occurs before and during labor (3, 26, 42), it is but one of
many physiological changes occurring in the birth transition (7–9,
13, 30). However, the findings of the present study imply that this
fall 1) is a significant component of birth-related rises in pulmonary perfusion (4, 7, 30); 2) via a reduction in cardiac constraint
(9 –11), ameliorates a fall in RV output (4) and contributes to an
increased LV output (9, 30, 41) observed with birth; and 3)
abolishes backflow from the conduit PA reservoir across the DA
and, thus, facilitates a reversal of DA shunting which occurs with
birth (4).
AJP-Regul Integr Comp Physiol • doi:10.1152/ajpregu.00416.2013 • www.ajpregu.org
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FCWis ⌬Q, ml/min
PT
PA
DA
FCWms ⌬Q, ml/min
PT
PA
DA
FCWtot ⌬Q, ml/min
PT
PA
DA
BCWms ⌬Q, ml/min
PT
PA
DA
FEWls ⌬Q, ml/min
PT
PA
DA
⌬Q ratios
PT BCWms/PT FCWis
PA BCWms/PA FCWis
DA BCWms/DA FCWis
PT BCWms/PA BCWms
DA FCWms/PA BCWms
LL reduction
4 and 5), mainly resulted from greater antegrade transmission
of the PA BCWms into the DA. The basis of this altered fate of
the PA BCWms is presently unclear, with the stability of PA
and DA wave speeds (Table 4), suggesting it was not due to a
relative change in PA and DA biomechanical properties.
Despite substantial alterations in systolic, mean, and diastolic DA flows after reduction of lung liquid volume, the
corresponding high-fidelity PT-AoT pressure differences were
unchanged (Table 1), implying that this pressure difference is
not an accurate reflection of the transductal pressure difference.
This conclusion is also in accord with the notion that the aortic
isthmus, which lies between the AoT and the distal end of the
DA, constitutes a site of functional separation between ascending and descending aortic segments (7, 30). Indeed, recent
findings indicate that the fetal PT-AoT pressure difference is a
systolic phenomenon principally related to the combination of
a higher RV-than-LV pump function and a greater pressureincreasing effect of a larger PT-than-AoT BCWms (38). That
the PT-AoT pressure difference was unaltered therefore suggests that the proportionality between these factors was unaffected by a fall in lung liquid volume.
Because of the extent and type of surgical instrumentation
required for physiological measurements, studies were performed under general anesthesia, and with the fetus partially
exteriorized and acutely instrumented. However, baseline
blood gas and pressure data, as well as mean RV power and the
morphology of the PA blood flow profile in our preparation,
were comparable to those of unanesthetized, chronically instrumented late-gestation fetal lambs (2, 24, 27, 32, 33, 41, 43).
Furthermore, an advantage of acute instrumentation was that it
permitted zero calibration of all flow probes immediately
before the experimental protocol (39). Nonetheless, it is possible that dissection around the PT, DA, and left PA, with
placement of flow probes and insertion of micromanometers at
these sites, altered vessel compliance, flow interactions, and
WI profiles, although any such effect is likely to be minor.
LUNG LIQUID REMOVAL AND PULMONARY BLOOD FLOW IN FETAL LAMBS
ACKNOWLEDGMENTS
Thanks are extended to Magdy Sourial, Amy Tilley, and Melissa Arnold for
assistance with experimental studies, and to Dr. Jonathan Mynard for providing technical support and reviewing the manuscript.
GRANTS
This work was supported by a Grant-in-Aid from the National Heart
Foundation of Australia and the Victorian Government’s Operational Infrastructure Support Program.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
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Author contributions: J.J.S. conception and design of research; J.J.S. performed experiments; J.J.S. analyzed data; J.J.S. interpreted results of experiments; J.J.S. prepared figures; J.J.S. drafted manuscript; J.J.S. edited and
revised manuscript; J.J.S. approved final version of manuscript.
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