Measurement of pulmonary flow reserve and pulmonary index of microcirculatory resistance for detection of pulmonary microvascular obstruction.

Abstract

The pulmonary microcirculation is the chief regulatory site for resistance in the pulmonary circuit. Despite pulmonary microvascular dysfunction being implicated in the pathogenesis of several pulmonary vascular conditions, there are currently no techniques for the specific assessment of pulmonary microvascular integrity in humans. Peak hyperemic flow assessment using thermodilution-derived mean transit-time (T(mn)) facilitate accurate coronary microcirculatory evaluation, but remain unvalidated in the lung circulation. Using a high primate model, we aimed to explore the use of T(mn) as a surrogate of pulmonary blood flow for the purpose of measuring the novel indices Pulmonary Flow Reserve [PFR = (maximum hyperemic)/(basal flow)] and Pulmonary Index of Microcirculatory Resistance [PIMR = (maximum hyperemic distal pulmonary artery pressure)x(maximum hyperemic T(mn))]. Ultimately, we aimed to investigate the effect of progressive pulmonary microvascular obstruction on PFR and PIMR.
Temperature- and pressure-sensor guidewires (TPSG) were placed in segmental pulmonary arteries (SPA) of 13 baboons and intravascular temperature measured. T(mn) and hemodynamics were recorded at rest and following intra-SPA administration of the vasodilator agents adenosine (10-400 microg/kg/min) and papaverine (3-24 mg). Temperature did not vary with intra-SPA sensor position (0.010+/-0.009 v 0.010+/-0.009 degrees C; distal v proximal; p = 0.1), supporting T(mn) use in lung for the purpose of hemodynamic indices derivation. Adenosine (to 200 microg/kg/min) & papaverine (to 24 mg) induced dose-dependent flow augmentations (40+/-7% & 35+/-13% T(mn) reductions v baseline, respectively; p<0.0001). PFR and PIMR were then calculated before and after progressive administration of ceramic microspheres into the SPA. Cumulative microsphere doses progressively reduced PFR (1.41+/-0.06, 1.26+/-0.19, 1.17+/-0.07 & 1.01+/-0.03; for 0, 10(4), 10(5) & 10(6) microspheres; p = 0.009) and increased PIMR (5.7+/-0.6, 6.3+/-1.0, 6.8+/-0.6 & 7.6+/-0.6 mmHg.sec; p = 0.0048).
Thermodilution-derived mean transit time can be accurately and reproducibly measured in the pulmonary circulation using TPSG. Mean transit time-derived PFR and PIMR can be assessed using a TPSG and adenosine or papaverine as hyperemic agents. These novel indices detect progressive pulmonary microvascular obstruction and thus have with a potential role for pulmonary microcirculatory assessment in humans.

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Measurement of Pulmonary Flow Reserve and
Pulmonary Index of Microcirculatory Resistance for
Detection of Pulmonary Microvascular Obstruction
Rahn Ilsar1,2, Chirapan Chawantanpipat1, Kim H. Chan1, Timothy A. Dobbins3, Richard Waugh1,
Annemarie Hennessy4, David S. Celermajer1,2, Martin K. C. Ng1,2*
1Royal Prince Alfred Hospital, Sydney, New South Wales, Australia, 2Department of Medicine, University of Sydney, Sydney, New South Wales, Australia, 3School of
Public Health, University of Sydney, Sydney, New South Wales, Australia, 4University of Western Sydney, Sydney, New South Wales, Australia
Abstract
Background: The pulmonary microcirculation is the chief regulatory site for resistance in the pulmonary circuit. Despite
pulmonary microvascular dysfunction being implicated in the pathogenesis of several pulmonary vascular conditions, there
are currently no techniques for the specific assessment of pulmonary microvascular integrity in humans. Peak hyperemic
flow assessment using thermodilution-derived mean transit-time (Tmn) facilitate accurate coronary microcirculatory
evaluation, but remain unvalidated in the lung circulation. Using a high primate model, we aimed to explore the use of Tmn
as a surrogate of pulmonary blood flow for the purpose of measuring the novel indices Pulmonary Flow Reserve
[PFR=(maximum hyperemic)/(basal flow)] and Pulmonary Index of Microcirculatory Resistance [PIMR=(maximum hyperemic
distal pulmonary artery pressure)6(maximum hyperemic Tmn)]. Ultimately, we aimed to investigate the effect of progressive
pulmonary microvascular obstruction on PFR and PIMR.
Methods and Results: Temperature- and pressure-sensor guidewires (TPSG) were placed in segmental pulmonary arteries
(SPA) of 13 baboons and intravascular temperature measured. Tmnand hemodynamics were recorded at rest and following
intra-SPA administration of the vasodilator agents adenosine (10–400 mg/kg/min) and papaverine (3–24 mg). Temperature
did not vary with intra-SPA sensor position (0.01060.009 v 0.01060.009uC; distal v proximal; p=0.1), supporting Tmnuse in
lung for the purpose of hemodynamic indices derivation. Adenosine (to 200 mg/kg/min) & papaverine (to 24 mg) induced
dose-dependent flow augmentations (4067% & 35613% Tmnreductions v baseline, respectively; p,0.0001). PFR and PIMR
were then calculated before and after progressive administration of ceramic microspheres into the SPA. Cumulative
microsphere doses progressively reduced PFR (1.4160.06, 1.2660.19, 1.1760.07 & 1.0160.03; for 0, 104, 105& 106
microspheres; p=0.009) and increased PIMR (5.760.6, 6.361.0, 6.860.6 & 7.660.6 mmHg.sec; p=0.0048).
Conclusions: Thermodilution-derived mean transit time can be accurately and reproducibly measured in the pulmonary
circulation using TPSG. Mean transit time-derived PFR and PIMR can be assessed using a TPSG and adenosine or papaverine
as hyperemic agents. These novel indices detect progressive pulmonary microvascular obstruction and thus have with a
potential role for pulmonary microcirculatory assessment in humans.
Citation: Ilsar R, Chawantanpipat C, Chan KH, Dobbins TA, Waugh R, et al. (2010) Measurement of Pulmonary Flow Reserve and Pulmonary Index of
Microcirculatory Resistance for Detection of Pulmonary Microvascular Obstruction. PLoS ONE 5(3): e9601. doi:10.1371/journal.pone.0009601
Editor: Jose A. L. Calbet, University of Las Palmas de Gran Canaria, Spain
Received November 17, 2009; Accepted February 16, 2010; Published March 9, 2010
Copyright: ? 2010 Ilsar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work is supported by a National Health and Medical Research Council of Australia (www.nhmrc.gov.au), Project Grant #512404. The funders had
no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: mkcng@med.usyd.edu.au
Introduction
The pulmonary microvasculature is the principal site regulating
resistance, and thus pressure, in the pulmonary circulation[1].
Diseases of the pulmonary microcirculation, such as pulmonary
vascular disease (PVD)[2] and chronic thromboemobolic pulmo-
nary hypertension (CTEPH)[3], are characterized by progressive
microvascular obstruction[2,3], presenting with markedly elevated
pulmonary artery pressures (PAP)[4,5] and thus portending poor
prognosis[5,6]. Currently under recognized[5,7], both PVD and
CTEPH rely on pressure-based diagnostic modalities for detection
(eg. echocardiography and right heart catheterization[8]), which
are inherently insensitive to the initial pulmonary microvascular
losses that precede PAP rise. A more direct assessment of
pulmonary microcirculatory status may potentially facilitate
improved detection of such conditions.
Advances in miniaturized sensor guidewire technology have
enabled the use of both Doppler flow velocity[9] and thermodi-
lution-derived mean transit-time (Tmn)[10] for assessment of the
coronary circulation in ischemic heart disease. The index of
coronary flow reserve (CFR = maximum hyperemic divided by basal
coronary blood flow) aims to evaluate coronary lesion hemodynamic
significance by recruiting all available vascular reserves and
expressing maximum resultant flow as a multiple of basal flow.
Although capable of detecting microvascular obstruction[11],
CFR is not specific to the coronary microcirculation, denoting the
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combined extent of both epicardial and coronary micrvascular
disease in the territory assessed[12]. The recently described index
of microcirculatory resistance[13] (IMR = maximum hyperemic distal
coronary artery pressure times maximum hyperemic Tmn) has been proven
to be more microcirculation-specific[14], reproducible[15] and
independent of systemic hemodynamics[15] than CFR, tracking
true microcirculatory resistance[13]. In contrast, there are
currently no established techniques for evaluating the pulmonary
microcirculation in vivo, a unique vascular bed characterized by
low arterial pressure, high vessel compliance and close proximity
to alveolar air.
We previously described the use of Doppler flow velocity in
hemodynamic assessment of the pulmonary circulation[16] and
thus utilized this technology to recently validate and measure
pulmonary flow reserve (PFR = maximum hyperemic divided by basal
pulmonary blood flow) in healthy baboons[17]. The use of
temperature and pressure sensor-guidewire (TPSG) technology
(which facilitates simultaneous thermodilution-derived flow and
pressure recordings thus enabling concurrent CFR and IMR
evaluations in the coronary circulation[15]), however, has not
been described in the pulmonary circulation. We hypothesized
that: 1) PFR and a novel pulmonary index of microcirculatory
resistance (PIMR = maximum hyperemic distal PAP times maximum
hyperemic mean transit-time) could be measured accurately using a
TPSG and; 2) that these novel flow and resistance indices may
allow the detection of microvascular obstruction. We thus utilized
a high-primate model of invasive pulmonary hemodynamic
assessment[17] in order to: 1) demonstrate the feasibility of
thermodilution-derived mean transit-time (Tmn)-based pulmonary
blood flow assessments using a TPSG and; 2) demonstrate the
feasibility and reproducibility of measuring a PFR and PIMR
using a TPSG. Ultimately, we aimed to, for the first time, study the
effect of progressive, experimentally induced microcirculatory
obstruction on these novel pulmonary indices of resistance and
flow. Our results demonstrate that both PFR and PIMR can
detect progressive, partial obstruction of the pulmonary microcir-
culation, with potential implications for the improved detection of
pulmonary microvascular disease.
Methods
(See a more detailed description of pre-, intra- and post-
procedural animal care in Methods S1 and its accompanying
Figure S1):
Ethics Statement
The study was conducted in accordance with the Australian
Code of Practice for the Care and Use of Animals for Scientific
Purposes (7th Edition, 2004) and the National Health and
Medical Research Council Policy on the Care and Use of Non-
Human Primates for Scientific Purposes. The study was
approved by the Sydney South Western Area Health Service
Animal Ethics Committee (Eastern Zone). All aspects of animal
care prior to, during and following the study procedures outlined
below were overseen by the veterinary team of the Australian
National Baboon Colony. Any untoward events were monitored
for and managed using established animal welfare and behavior
protocols. Two procedures were abandoned prematurely, one
due to in situ thrombus formation within the distal segmental
pulmonary artery being studied and the other due to limited
radio-contrast agent extravasation within the lung. All animals
returned to normal function within 24 hours, with minimal signs
of distress or discomfort. Finally, in keeping with the ethical
principles of Replacement, Reduction and Refinement with
relation to the use of non-human primates in medical research,
experiments were only repeated until statistically meaningful
results were observed. Thus, different groups of animals were
utilized for different aspects of the below-described research
protocol.
Animal Model and Preparation
Thirteen healthy baboons (Papio hamadryas; weight 19.961.3 kg)
were chosen for the species’ anatomic and hemodynamic similarity
to humans. We used a modification of our previously described
methods for invasive pulmonary hemodynamic assessments in
higher primates[17], as seen in Figure 1. In brief, following
ketamine anesthesia, bilateral femoral venous access was estab-
lished. A 7F multipurpose (MP) 55 cm guiding catheter was placed
at the ostium of a left lower lobe segmental pulmonary artery and
a 5F 100 cm MP guide positioned just proximal. Femoral arterial
access allowed for continuous systemic hemodynamic monitoring.
Following heparin (50–100 U/kg) administration, a 0.0140 TPSG
(PressureWire-5 or PressureWire-Certus, Radi Medical Systems,
Uppsala, Sweden) was inserted via the 7F-MP, advanced to the
distal third of the segmental pulmonary artery of interest and
connected to its dedicated monitoring console (Radi Analyzer-X,
Radi Medical Systems, Uppsala, Sweden). Finally, we note that all
aspects of animal care were delivered by a dedicated veterinary
team and all animals recovered uneventfully.
Control Measurements
Constant intravascular temperature is a prerequisite for
thermodilution-derived assessments of flow. We thus recorded
distal, mid and proximal segmental pulmonary artery tempera-
tures in triplicates, using a TPSG pullback maneuver, after
calibrating the TPSG to an arbitrary zero reference point within
the left main pulmonary artery (n=4).
TPSG-Derived Mean Transit Time for the Assessment of
Flow
The TPSG utilized in our study consists of a distal temperature
and pressure sensor mounted on an electrically conductive shaft
capable of acting as a proximal second thermistor. Fundamentally,
Figure 1. Experimental setup: Using femoral vascular access, a 7F
multipurpose (MP) guiding catheter was placed in a left lower lobe
segmental pulmonary artery (PA). A 5F-MP was placed alongside the 7F-
MP and positioned proximal to it. A temperature and pressure sensor
guidewire (TPSG) was passed through the 7F-MP and placed within the
distal PA.
doi:10.1371/journal.pone.0009601.g001
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its use for measuring flow is based on the indicator-dilution theory
relating flow (Q), intravascular volume sampled (V) and mean
transit-time (Tmn) required for blood to traverse the sample
space[10]:
Q~V
Tmn
ðEquation 1Þ
The use of TPSG for Tmn-based assessment of flow was
initially described in an in vitro system, validated against
absolute flow in the canine coronary circulation[10] and then
validated in the human coronary circulation[18]. In examining
the utility of Tmnin the primate pulmonary circulation, we have
therefore carefully adapted methods originally described above,
in accordance with the literature and with our previous
pulmonary vascular physiology studies in high primates[17].
In particular, TPSG-derived Tmnwas defined (and automati-
cally computed by the RadiAnalyzer-X console; Radi Medical
Systems, Uppsala, Sweden) by expressing the distally-sensed
thermodilution curve inscribed by room-temperature saline
bolus-injection as a function of the time elapsed from the
saline’s arrival at the wire’s proximal thermistor, using the
following equation:
Tmn~
Ð?
0t:c t ð Þdt
Ð?
0c t ð Þdt
where t is time and c is temperature
ðÞ ½10?
ðEquation 2Þ
Thermodilution-derived mean transit-time assessments have
been shown to be independent of indicator volume and
temperature, provided that the amount utilized does not in itself
alter underlying flow and adequate indicator-blood mixing
occurs[10]. Thus, 3 mL room temperature saline boluses were
deemed optimal for Tmn-based assessment of coronary blood flow
using a 6F catheter[10]. Given that indicator boluses in our study
were to be administered via a larger 7F multipurpose catheter
(internal volume 3 mL) and that our previous baboon work
demonstrated no change in segmental pulmonary artery flow with
saline boluses up to 10 mL in volume, we chose a 3.5 mL bolus for
Tmn-based assessment of pulmonary blood flow. Thorough
flushing of the catheter with room temperature saline prior to
each triplicate Tmnrecordings ensured that subsequent indicator
boluses were of even temperature[19] allowing for use of
minimum bolus volume and promoting adequate indicator-blood
mixing. As thermodilution calculations are automatically gated to
the indicator’s arrival at the proximal TPSG thermistor (defined as
a rate of temperature change greater than 23.3uC per second at
this sensor) the time required to fill the catheter with saline can, by
definition, be ignored. Of interest, the distal temperature sensor
must detect a magnitude of change greater than 1uC in order to
calculate Tmn.
The distance between the tip of the 7F-MP and the distal TPSG
tip was kept .6 cm at all times, in keeping with previous
validation work which demonstrated that distances .6 cm were
associated with significantly less Tmn variability than distances
,5 cm[10], likely due to improved indicator-blood mixing.
Finally, in keeping with work in the coronary circulation[10]
and in order to quantify the variability of Tmnmeasurements in the
pulmonary circulation, we recorded Tmn in triplicate for each
hemodynamic loading condition in each animal.
Defining Maximal Pulmonary Hyperemia
Attainment of maximal pulmonary hyperemia is fundamental to
reproducible PFR and PIMR assessments. The following vasodi-
lators were administered directly into the segmental pulmonary
artery of 4 animals, in order of increasing duration of action: 1)
adenosine (1 mg/mL) infusions at 10, 100, 200 and 400 mg/kg/
min, for 2–3 mins each, and; 2) papaverine (3 mg/mL) boluses of
3, 6, 12, 24 and 48 mg every 2–4 mins. These agents were chosen
as they have been previously demonstrated to elicit microvascular
hyperemia in the pulmonary[17] and coronary beds[20,21].
Systemic arterial pressures (as recorded by the femoral arterial
pressure monitor), pulmonary arterial pressures (as sensed at the
tip of the 7F-MP and recorded as peak mean PAP during a
respiratory cycle, thus coinciding with expiration)[22], heart rate
(as recorded from the continuous electrocardiography or systemic
arterial pressure monitor) and Tmnwere obtained at baseline and
at maximal steady-state (90–120 secs into infusions, 30–90 secs
after boluses).
Thermodilution-Derived Measurements of PFR Using
TPSG
Thermodilution-derived assessment of blood flow are based
upon the indicator-dilution theory relating flow (Q), intravascular
volume sampled (V) and mean transit-time (Tmn) required for blood
to traverse the sample space[10], as noted in Equation 1.
By definition,
PFR~Qmaximal hyperemia
Qbasal
ðEquation 3Þ
Therefore:
PFR~
Vmax hyperemia
Tmn max hyperemia|Tmn basal
Vbasal
ðEquation 4Þ
As maximal adenosine- and papaverine-induced pulmonary
hyperemia occurs in the absence of change in conduit vessel
diameter in the baboon[17], Vmax hyperemia = Vbasal. Thus, using
either agent to induce hyperemia, thermodilution-derived PFR
(PFRthermo) can be expressed as:
PFRthermo~
Tmn basal
Tmn max hyperemia
ðEquation 5Þ
Using TPSG to measure Tmnand either adenosine 200 mg/kg/
min or papaverine 24 mg to induce maximal pulmonary
hyperemia[17], we thus measured PFRthermo in the intact
pulmonary microvasculature of 11 baboons.
Thermodilution-Derived Measurements of PIMR Using
TPSG
The relationship between flow, pressure (P) and resistance (R),
obeys Ohm’s law:
R~P
Q
ðEquation 6Þ
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Expressing resistance in terms of V and Tmn:
R~P|Tmn
V
ðEquation 7Þ
A TPSG can provide simultaneous pressure and thermodilu-
tion-derived Tmnrecordings. While exact resistance calculations
require knowledge of arterial volume, resistance estimates can be
made using a TPSG only, by calculating a resistance index (RI):
RI~P|Tmn
ðEquation 8Þ
Measurement of the resistance index during maximum microcir-
culatory hyperemia (when, in theory, all available microvessels have
been recruited) provides an estimate of minimum achievable
microvascular resistance. Moreover, by recording pressure and Tmn
distally, the potential effect a hemodynamically significant
proximal artery stenosis may have on this estimate can be
mitigated. Thus, the pulmonary index of microvascular resistance
(PIMR) is defined as follows:
PIMR~Pdistal pulmonary artery|Tmn
ðEquation 9Þ
Using TPSG to measure Tmnand the maximum hyperemic
doses of either adenosine or papaverine to induce maximal
pulmonary hyperemia, we thus measured PIMR in the intact
pulmonary microvasculature of 10 animals.
Effect of Cumulative Microvascular Obstruction on
PFRthermoand PIMR
After establishing the feasibility of measuring PFRthermo and
PIMR measurements using TPSG, increasing amounts of ceramic
microspheres (104, 105and 106particles; diameter 40–120 mm;
Embospheres, Biosphere Medical, Rockland, MA) were adminis-
tered into the segmental artery of 7 baboons. Microsphere sizes
were chosen to obstruct the same caliber vessels as affected by
human PVD (,100 mm)[2], noting that .99.8% of 50 mm
diameter microspheres lodge in the baboon pulmonary circula-
tion[23]. Baseline and maximal adenosine-induced hyperemic
hemodynamics were recorded 60secs after each microsphere
bolus.
Statistical Analysis
All data are presented as mean6SEM. Analysis was performed
using either Prism 4 software (GraphPad Software, San Diego,
California, USA) or the SAS System for Windows version 9 (SAS
Institute, Cary, North Carolina, USA). Two-way ANOVA with
repeated measures was used for comparisons (unless otherwise
stated) with 2-tailed p-values ,0.05 regarded significant. Vari-
ability within a set of measures was calculated using the coefficient
of variability. For microsphere experiments, linear mixed models
were fitted to test for trend in dose response thus allowing for
differing number of observations made between animals and for
repeated measures within each animal.
Results
Effect of Sensor Position on Intravascular Temperature
The measurement of flow using indicator thermodilution
method assumes a constant basal temperature within the vessel
studied, attributing any change in temperature to the indicator per
se. This assumption remains unproven in the pulmonary
circulation, where blood vessels are in close proximity to air.
Using a TPSG pullback maneuver, we found no temperature
gradient across the segmental pulmonary artery interrogated
(0.01060.009, 0.00560.015 and 0.01060.009uC for distal, mid
and proximal segmental pulmonary artery positions, p=0.1).
Therefore, Tmncan be used as a surrogate marker of pulmonary
blood flow in the higher primate model.
Effect of Adenosine on Tmn, Hemodynamics and Cardiac
Rhythm
Adenosine has an established role as coronary hyperemic
agent[20] and was recently shown to induce pulmonary hyperemia
for Doppler sensor guidewire-based PFR assessments in higher
primates[17]. Increasing adenosine infusion rates produced
significant, dose-dependentreductions
0.3660.05, 0.2860.01, 0.2360.03 and 0.2460.02sec for baseline,
10, 100, 200 and 400 mg/kg/min, p,0.0001; maximal effect at
200 mg/kg/min equivalent to 4067% reduction in Tmnv baseline;
Figure 2). Concurrently, adenosine induced systemic hypotension
(10768, 102610, 100610, 8465 and 7864 mmHg for baseline,
100, 200 and 400 mg/kg/min, p=0.0009), without affecting heart
rate (9366, 9269, 9568, 9766 and 9864 beats-per-minute for
baseline, 10, 100, 200 and 400 mg/kg/min, p=0.4) or mean PAP
(1261, 1061, 1364 and 1663 mmHg for baseline, 100, 200 and
400 mg/kg/min, p=0.3). These findings are consistent with
published adenosine pharmacodynamics[17,20].
inTmn
(0.3860.07,
Effect of Papaverine on Tmn, Hemodynamics and Cardiac
Rhythm
Papaverine is a known coronary hyperemic agent[21] and was
recently shown to safely effect pulmonary hyperemia in higher
primates[17]. Increasing papaverine boluses induced dose-depen-
dent reductions in Tmn (0.3960.06, 0.3360.04, 0.2760.06,
0.2860.07 and 0.2560.05 sec for baseline, 3, 6, 12 and 24 mg,
p,0.0001; maximal Tmn reductions of 35613% v baseline;
Figure 3). Doses above 24 mg (up to 48 mg) were poorly tolerated
due to rapid hemodynamic shifts, resulting in disruption of
experimental setup. In addition to its effect on Tmn, papaverine
Figure 2. Adenosine induces dose-dependent reductions in
Tmn, plateauing at $ $200 m mg/kg/min: Tmn– thermodilution-derived
mean transit time; error bars represent SEM.
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significantly increased heart rate (8968, 9066, 9267, 9468 and
10466 beats-per-minute for baseline, 3, 6, 12 and 24 mg,
p,0.0001) without affecting mean systemic pressure (10669,
105612, 107611, 98612 and 104612 mmHg for baseline, 3, 6,
12 and 24 mg, p=0.4) or mean PAP (1961, 1962, 1962, 2063
and 2063 mmHg for baseline, 3, 6, 12 and 24 mg, p=1.0). These
hemodynamic effects are consistent with previously published data
for papaverine[17,24].
Variability of TmnMeasurements
The variability of Tmn measurements was 10.561.8% and
15.662.7% at baseline and during maximal hyperemia, respectively.
PFRthermoin Healthy Primates
PFRthermovalues in the intact pulmonary microvasculature were
calculated (Equation 5) to be 1.5560.12 and 1.5460.12 using
adenosine and papaverine, respectively (p=0.8 using paired t-test
for complementing data sets, comparing both agents).
PIMR in Healthy Primates
To study the effect of pulmonary hyperemia on pulmonary
microvascular resistance estimates, we compared baseline, distally-
measured resistance indices (RIbasal) (Equation 8) with PIMR
(measured at hyperemia; Equation 9). Overall, there was a
statistically significant drop in microvascular resistance at maximal
hyperemia (7.860.7 vs 5.460.4 mmHg.sec for RIbasalvs PIMR,
p,0.0001, two-tailed paired t-test). More specifically, the
reduction in resistance estimates was similar for adenosine-induced
hyperemia (7.861 vs 5.460.6 mmHg.sec, RIbasal vs PIMR,
p=0.003, two-tailed paired t-test) and papaverine-induced
hyperemia (7.760.6 vs 5.460.6 mmHg.sec, RIbasal vs papaver-
ine-derived PIMR, p=0.006, two-tailed paired t-test).
Effect of Progressive Microcirculatory Obstruction on
Thermodilution Derived Pulmonary Hemodynamic
Indices
To study the effect of progressive microcirculatory obstruction
on PFRthermoand PIMR, increasing numbers of microspheres were
administered into the segmental pulmonary artery. Index
calculations were repeated after each bolus, using adenosine to
induce hyperemia.
Cumulative microsphere administration progressively reduced
PFRthermo(1.4160.06, 1.2660.19, 1.1760.07 and 1.0160.03 for
baseline, 104, 105and 106microspheres bolus, p=0.009, Figure 4).
Additionally, progressive microvascular obstruction using mi-
crospheres led to a progressive rise in PIMR (5.760.6, 6.361.0,
6.860.6 and 7.660.6 mmHg.sec for baseline, 104, 105and 106
microspheres bolus, p=0.0048, Figure 5). These changes occurred
in the absence of microsphere effect on resting heart rate (9665,
9666, 9565 and 9666 beats-per-minute for baseline, 104, 105
and 106microspheres bolus, p=0.14), mean systemic artery
pressure (11064, 11664, 10666 and 10766 mmHg, p=0.12) or
mean distal segmental PAP both at maximal hyperemia (2362,
2262, 2262, 2162 mmHg, p=0.43) and at baseline (2062,
2261, 2162 and 2062 mmHg, p=0.85).
Figure 3. Papaverine induces dose-dependent increases in Tmn:
Tmn– thermodilution-derived mean transit time; error bars represent
SEM.
doi:10.1371/journal.pone.0009601.g003
Figure 4. Cumulative microvascular obstruction induces pro-
gressive reductions in PFRthermo: PFRthermo– thermodilution-derived
pulmonary flow reserve. The theoretical minimum value of PFR=1 is
noted by a dashed line as reference; error bars represent SEM.
doi:10.1371/journal.pone.0009601.g004
Figure 5. PIMR tracks progressive pulmonary microvascular
obstruction: PIMR – pulmonary index of microcirculatory resistance;
error bars represent SEM.
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