(Circulation. 1996;93:266-271.)
© 1996 American Heart Association, Inc.
Articles |
Role of Nitric Oxide in the Local Regulation of Pulmonary Vascular Resistance in Humans
From the Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Correspondence to Christopher J. Cooper, MD, Department of Medicine, Cardiovascular Division, Medical College of Ohio, 3000 Arlington Ave, Toledo, OH 43699.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Endothelium-derived nitric oxide (NO) may be an important mediator of vascular resistance in the pulmonary circulation. We tested the hypotheses that in conscious adults the endothelium, through NO production, is important in maintaining basal pulmonary vascular resistance and that it can increase NO production further in response to receptor-mediated stimulation, leading to further vasodilation.
Methods and Results Pulmonary arterial resistance vessel function was studied within the distribution of a segmental lower lobe pulmonary artery in eight conscious adults 37 to 76 years old who were undergoing cardiac catheterization. Segmental blood flow was determined with use of a Doppler-tip guide wire and quantitative angiography. Drugs were administered locally within the segmental artery through an infusion catheter. NG-Monomethyl-L-arginine (L-NMMA) was used as a specific inhibitor of NO production, whereas acetylcholine (ACh) was used to test receptor-mediated vasodilation. To demonstrate that vasodilation to ACh was NO dependent, ACh response was tested alone, in the presence of L-NMMA, and in the presence of a control constrictor phenylephrine. Basal pulmonary vascular resistance was NO dependent because L-NMMA infusion resulted in a dose-dependent decrease in local flow velocity (P<.005), with flow decreasing 33% at the highest dose of L-NMMA. ACh infusion resulted in a dose-dependent increase in flow velocity (P=.001). The ACh response was at least in part NO dependent because it was diminished by the presence of L-NMMA (P<.05). The effect of L-NMMA on the ACh response was not due to nonspecific preconstriction because L-NMMA diminished the ACh response significantly more than did the endothelium-independent constrictor phenylephrine (P<.05) despite comparable preconstriction.
Conclusions In healthy conscious adults, (1) normal basal pulmonary resistance is maintained in part by continuous local production of NO and (2) the local NO production is responsive to receptor-mediated stimulation, leading to further vasodilation, and can be tested with ACh.
Key Words: endothelium • acetylcholine • nitric oxide • endothelium-derived factors • lung
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Pulmonary resistance vessels perform several important functions, including maintenance of low pressure and resistance at rest and during physiological increases in flow. Loss of these normal functions may result in the development of pulmonary hypertension. The mechanisms responsible for the regulation of pulmonary vascular resistance in conscious adults are not clearly understood.
Recent advances in vascular biology have broadened our understanding of the importance of the local relation between the endothelium and the vascular smooth muscle. This interaction is mediated by paracrine compounds such as endothelium-derived relaxing factor, one of which is NO or a related NO compound.1 NO is synthesized from L-arginine by the enzyme NO synthase. This enzyme can be competitively inhibited by L-NMMA.2 In pulmonary arterial preparations, inhibition of NO production with L-NMMA enhances hypoxic contraction,3 4 5 6 enhances contraction to vasoconstrictors,6 7 and can increase baseline pulmonary arterial pressure.4 5 8
Recently, NO dependence of basal pulmonary resistance was described in children.9 In adults, intravenous administration of L-NMMA increased pulmonary vascular resistance.10 This observation in adults was potentially confounded by a large increase in systemic resistance and a decrease in cardiac output. We developed a method to safely study resistance regulation within a single pulmonary arterial segment in conscious adults without affecting systemic hemodynamics. The purpose of the present study was to determine the role of the endothelium, operating through NO synthase, in directly regulating basal pulmonary vascular resistance and to determine the ability of the endothelium to modify resistance in response to pharmacological stimuli in conscious adults. Also, we sought to determine whether the pulmonary vasodilator response to ACh was NO dependent in vivo in humans.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Population
The study population consisted of eight patients (six men and two women) referred to the cardiac catheterization laboratory for diagnostic angiography. The average age was 59 years (range, 37 to 76 years). Patients with a history of tobacco use, lung disease, congestive heart failure, or congenital heart disease or with abnormal pulmonary arterial or pulmonary capillary wedge pressures were excluded. All participants had normal pulmonary and systemic hemodynamics (Table 1
). The most
frequent indication for catheterization was for
evaluation of chest pain. Coronary artery disease was
present in five subjects (62%), two subjects had noncardiac chest
pain, and one patient underwent catheterization for
evaluation of syncope.
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Study Protocol
Written informed consent was obtained from
patients before the
catheterization procedure in accordance with guidelines
established by the Committee for the Protection of Human Subjects. All
vasoactive medications, including nitrates, ß-blockers, calcium
channel blockers, and converting enzyme inhibitors,
were withheld beginning the day before the
catheterization.
After completion of the diagnostic
catheterization, all patients received 10 000 IU IV
heparin. A 7F or an 8F multipurpose angioplasty guiding catheter was
placed in the left lower pulmonary artery over a standard
0.035-in guide wire. A 1.0-mm infusion catheter (Cook
Cardiovascular) was advanced through the guiding
catheter into the proximal portion of the straight segment of a lower
lobe segmental pulmonary artery. This catheter occupies 
6%
of the luminal area of the vessel in which it is positioned. A
Doppler-tip 0.014- or 0.018-in Flow-wire (Cardiometrics)
was positioned through the infusion catheter, just distal to the tip of
the infusion catheter within the straight portion of the segmental
pulmonary artery. Doppler velocity was continuously
monitored with the Cardiomap system (Cardiometrics).
Study drugs were
serially administered into the segmental
pulmonary artery through the infusion catheter at a flow rate
of 0.8 mL/min per infusate according to the following protocol: (1)
control infusion of 5% dextrose for 3 minutes; (2) serial 3-minute
infusions of ACh with final estimated intra-arterial
concentrations of 10-8, 10-7,
10-6, and 10-5 mol/L; (3) 
10 minute
recontrol infusion (5% dextrose); (4) serial 3-minute infusions of
phenylephrine with final estimated concentrations of
10-7 and 10-6 mol/L; (5) concurrent 3-minute
infusions of 10-7 mol/L phenylephrine and
10-5 mol/L ACh; (6) 10 minute recontrol infusion (5%
dextrose); (7) serial 4-minute infusions of L-NMMA with final estimated
concentrations of 3x10-5 and
6x10-5
mol/L; and (8) concurrent 3-minute infusions of 6x10-5
mol/L L-NMMA and 10-5 mol/L ACh. These concentrations were
based on an estimated flow of 250 mL/min in the basalar segmental
artery. One patient did not receive L-NMMA, and in one patient flow
velocities during delivery of 10-8,
10-7, and 10-6 mol/L ACh were not
recorded. ACh was obtained from Iolab Pharmaceuticals;
phenylephrine was obtained from American Regent
Laboratories, Inc; and L-NMMA was obtained from
Calbiochem-Novabiochem.
Heart rate, blood pressure, pulmonary artery pressure, and ECG were continuously monitored, with recordings taken at the end of each infusion protocol. Selective pulmonary angiography was performed at the end of each infusion with nonionic contrast (Omnipaque). Camera angulation was adjusted to minimize vessel overlap.
Analysis
Pulmonary Flow Velocity
Pulmonary
arterial segmental flow velocities
were determined with a 12-MHz piezoelectric ultrasound transducer
mounted on the tip of a 0.014-in guide wire. These Doppler velocity
signals were processed with a real-time spectrum analyzer
using on-line fast Fourier transform. The signal was displayed as
continuous spectral velocity envelope (Cardiometrics) and was
recorded onto VHS tape. Peak instantaneous velocities were
analyzed, with the formula (average peak velocity)/2 used to
calculate mean velocity in cm/s.11 The velocity signals
for 10 sinus beats were averaged. This method has previously been
validated ex vivo and demonstrates excellent linear correlation to
volumetric flow with R2 values between .98 and
1.000.11 12
Quantitative Pulmonary
Angiography
Angiographic images were projected on a
cine-projector. Vessel diameters were analyzed with
electronic digital calipers in accordance with a previously validated
technique for analysis of vessel diameter during vasomotor
function testing.13 These measurement were made in a
straight segment of pulmonary artery 5 mm distal to the tip of
the Doppler wire, which is the site of Doppler signal
acquisition. These diameter measurements were measured during the same
phase of the cardiac cycle for each condition. Three determinations
were made at sequential sites separated by 0.5 mm. These were repeated
for four consecutive cine frames for a total of 12 determinations per
condition. Measurements were calibrated to the known external diameter
of the non–contrast-filled guiding catheter.
Statistical Analysis
The primary end points in this study,
flow velocities, were used
as an index of resistance vessel function. Vessel diameter at the site
of Doppler velocity sampling was obtained to ensure that changes in
flow velocity were not attributable to changes in vessel diameter.
Similarly, pulmonary arterial and systemic
pressures were obtained to demonstrate that changes in flow velocity
were not due to changes in transpulmonary pressure.
Directional changes within subjects between conditions were
assessed.
Repeated-measures ANOVA was used to analyze the separate dose-response curves for L-NMMA and ACh. The immediately preceding recontrol values were used as the baseline for these experiments. Paired t tests were used to compare two sample continuous data with Scheffé's F test used when multiple posthoc comparisons were performed. Statistical significance was defined as a two-sided value of P<.05. The data are expressed as mean±SD except as indicated.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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The effect of L-NMMA on basal flow velocity was evaluated in six patients. L-NMMA infusion resulted in a consistent dose-dependent decrease in flow velocity (Fig 1
)
(P<.005). Flow velocity decreased 33% at the highest dose
of L-NMMA. The decrease in flow velocity could not be attributed to
conduit vessel dilation at the site of Doppler signal acquisition
because conduit vessel diameter did not change (Table 2).
Similarly, the fall in flow velocity could not be
attributed to change in pulmonary arterial pressure
because it remained constant (Table 2).
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The effect of ACh on local pulmonary flow was evaluated
in seven patients. ACh infusion resulted in a dose-dependent
increase in flow velocity (Fig 2) (P=.001).
Flow velocity increased 119% with the highest dose of ACh. The
increase in flow velocity could not be attributed to vasoconstriction
of the conduit artery at the site of Doppler flow analysis
because this diameter did not change (Table 3).
Similarly, the increase in flow velocity could not be attributed to
increase in pulmonary arterial pressure because it
remained unchanged (Table 3).
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The effect of 10-5 mol/L ACh infusion alone, in the
presence of L-NMMA, and in the presence of phenylephrine
was evaluated in seven patients. ACh (10-5 mol/L)
increased flow velocity from 5.4±1.6 to 12.4±4.8 cm/s
(
velocity,
7.0 cm/s). ACh increased flow velocity during L-NMMA infusion from
3.7±1.5 to 8.3±4.1 cm/s (velocity, 4.6 cm/s). The presence
of
L-NMMA thus decreased the magnitude of the increase in flow velocity to
ACh 34% compared with the control ACh infusion (P<.05). To
determine whether preconstriction with L-NMMA alone had an effect on
the flow-velocity response to ACh, the response to ACh was
determined in the presence of an
endothelium-independent vasoconstrictor,
phenylephrine. The flow velocities obtained with L-NMMA
(7.4±2.9 cm/s) and phenylephrine (7.8±3.5 cm/s) before
concomitant ACh infusions were equivalent (P=.61). L-NMMA
decreased the magnitude of the increase in flow velocity to ACh
significantly more than phenylephrine (P<.05,
Fig 3). The lower flow-velocity values obtained with
ACh plus L-NMMA infusion compared with ACh plus
phenylephrine were not due to conduit vessel dilation at
the site of Doppler velocity analysis because these values
were not different (3.75±1.03 and 3.77±1.14 mm, respectively)
and the
values could not be attributed to change in pulmonary
arterial pressure. Thus, L-NMMA appears to decrease the
magnitude of the response to ACh regardless of the baseline flow
velocity.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the present study, we demonstrated for the first time that in conscious adults, local NO production is an important mechanism regulating basal pulmonary vascular resistance and that NO production can be augmented, leading to further reductions in local resistance. Also, we demonstrated that in vivo, receptor-mediated dilation of the human pulmonary resistance vessels with ACh appears to be at least in part NO dependent. Selective infusions within a single pulmonary artery were used to avoid the confounding effects of alterations in cardiac output, systemic pressure, and associated reflex changes. Resistance vessel function was tested because clinical pulmonary vascular disease is largely a disease of the resistance vessels.
NO appears to be important in regulating basal
pulmonary resistance in adults. Withdrawal of NO synthase
activity with infusion of a competitive inhibitor, L-NMMA,
resulted in resistance vessel constriction that was manifested by a
decrease in regional pulmonary blood flow velocity (Fig 1
). The
magnitude of the effect suggests that NO production is
important in maintaining basal flow and the normal low resistance state
in conscious adults. This is consistent with a previous
observation in children administered L-NMMA locally9 and
extends an observation made in normal adult volunteers administered
L-NMMA systemically.10 Together, these findings support a
role for NO in maintaining the normal low resistance state of the
pulmonary vasculature throughout life.
Prior studies in animals have yielded conflicting information on the role of NO production in regulating basal pulmonary tone. In many preparations, inhibition of NO production with L-arginine analogues5 8 14 15 16 17 18 19 or inhibition of guanylate cyclase with methylene blue20 21 led to an increase in basal pulmonary resistance or tone, supporting a role for NO in regulating basal resistance. In other preparations, little or no effect has been seen on basal tone.6 22 23 24 This discrepancy may reflect differences between species.10 In some preparations where no effect was seen on basal tone, additional preconstriction with hypoxia6 23 or direct-acting smooth muscle constrictors6 22 24 accentuated NO production and led to an increase in pulmonary tone with subsequent NO inhibition. It may be that differences in experimental design or differences between species contribute to these divergent observations on the role of NO in determining basal pulmonary resistance.
In humans, NO production is responsive to and can be
augmented by receptor-mediated stimulation, leading to further
vasodilation. We demonstrated that NO is important in regulating
changes in pulmonary blood flow to receptor-mediated
stimulus with ACh in humans. Graded administration of ACh within a
segmental pulmonary artery resulted in a dose-dependent
increase in flow velocity (Fig 2). Coadministration of L-NMMA
during
ACh infusion diminished the magnitude of the increase in flow velocity,
suggesting that in vivo, the effect of ACh on pulmonary
resistance is at least in part mediated through NO synthase activity.
The incomplete inhibitory effect of L-NMMA on the ACh
response may be explained by the relatively weak inhibitory
effect of L-NMMA,2 the relatively low doses of L-NMMA
administered (chosen to avoid systemic effects), partial agonist
activity of L-NMMA,25 or additional actions of ACh. These
findings suggest that NO production can increase in response to
receptor-mediated stimulation and that this capacity of the
pulmonary resistance vessel to further vasodilate can be tested
with ACh in vivo in humans.
The effect of L-NMMA on the ACh response does not appear to be
due to an effect of nonspecific preconstriction. To demonstrate
that the inhibitory effect of L-NMMA on flow-velocity
response to ACh was not due to a nonspecific effect of preconstriction,
the increase in flow velocity was compared between ACh in the presence
of L-NMMA and ACh in the presence of the direct-acting smooth
muscle cell constrictor phenylephrine. A similar amount of
preconstriction was achieved with phenylephrine and with
L-NMMA. L-NMMA, however, diminished the increase in flow velocity in
response to ACh infusion more completely than phenylephrine
(Fig 3) despite the similar amount of preconstriction. Thus,
the
inhibitory effect of L-NMMA on ACh is not due to a
nonspecific constrictor effect but is more likely due to its specific
inhibitory effect on NO synthase activity.
Prior studies largely support the hypothesis that ACh-induced pulmonary vasodilation is at least in part mediated by endothelial production of NO. In human pulmonary arterial rings,26 the ACh vasodilator response is endothelium dependent because it is abolished by removal of the endothelium. Also, many studies in animals suggest that the endothelium-dependent ACh response is at least in part mediated by NO because it can be diminished by inhibition of NO production with L-arginine analogues,3 5 14 15 16 22 by inhibition of guanylate cyclase with methylene blue,3 20 22 or by the use of other proposed inhibitors of endothelium-derived relaxing factor.27 28 In two studies, the ACh response was not attenuated by inhibition of NO production with L-NMMA6 or by inhibition of guanylate cyclase with methylene blue,21 suggesting that differences may exist between species or that experimental conditions may influence this interaction. Overall, a majority of the published data support an endothelium-dependent and a NO-dependent nature of the ACh response in the pulmonary circulation.
ACh has been used previously in humans to study vasodilator function of the pulmonary vascular resistance bed. ACh has a long history of use as an agent for testing pulmonary vascular regulation in humans with pulmonary vascular disease.29 30 More recently, with an increased appreciation of the role of the endothelium in regulating the response to ACh in vitro, this agent has been used in vivo in humans to test endothelial dysfunction as a mechanism for the development of pulmonary vascular disease. As such, this agent has been used to test endothelium-dependent responses in the resistance vessels of adults31 and children9 32 and in pulmonary conduit vessels of adults.33 With ACh, abnormalities of endothelium-dependent vasodilator function have been described in the resistance vessels of children with congenital heart disease32 and in the conduit vessels of adults with congestive heart failure.33 Our current findings are the first to confirm that ACh, given locally in vivo in humans, tests NO-dependent, endothelium-mediated vasodilator mechanisms in the resistance vessels within the pulmonary bed.
L-NMMA was used as a specific inhibitor of NO production whose action is presumed to be on endothelial production of NO within the vasculature. L-NMMA was used in the present study as a specific inhibitor of NO synthase activity. This use of L-NMMA to selectively inhibit NO synthase activity is supported by experimental data from several studies that demonstrate the specific nature of L-NMMA in inhibiting endothelium-dependent vasorelaxation and NO release to a variety of stimuli. This effect of L-NMMA is stereospecific because it is not seen with D-L-NMMA.6 Furthermore, L-NMMA does not effect endothelium-independent relaxation in vitro5 34 35 and can be inhibited by removal of the endothelium,3 34 suggesting that the effects of L-NMMA on vascular tone are endothelium dependent.
Use of selective infusions within a segmental pulmonary artery allow the study of local pulmonary blood flow regulation in the absence of confounding reflex changes. The local administration of low doses of agonists and antagonists in this study avoided confounding changes in systemic or pulmonary hemodynamics. Flow changes were thus isolated from pressure changes, allowing directional changes in flow velocity to be used as a surrogate for directional changes in resistance. In the present study and in previous studies,9 32 local infusions at doses that avoid systemic effects have thus permitted the sensitive assessment of pulmonary vasomotor control in vivo in humans. When vasoactive substances, used to test pulmonary vasomotor regulation, are administered intravenously into the general circulation, large changes in systemic hemodynamics generally occur. L-NMMA, given to normal volunteers in such a fashion, was noted to cause changes in systemic resistance before changes in pulmonary resistance were noted.10 Also, L-NMMA significantly increased systemic pressure at relatively low doses, but pulmonary pressure never increased, even at the highest dose of L-NMMA in this cohort. This lack of effect of intravenously administered substances on pulmonary arterial pressure and resistance may be attributable to the confounding effects of changes in flow through the pulmonary bed from direct or reflex changes in cardiac output. These difficulties appear to be overcome by studying local resistance regulation using low doses of drug that do not alter systemic hemodynamics.
A limitation of the present study is that it only describes one system of pulmonary vascular regulation—NO production. It is likely that other local endothelium-dependent and -independent mechanisms, including prostacyclin36 37 and endothelin36 38 formation, are important in the regulation of pulmonary vascular resistance. Also, interactions between these mechanisms and NO production36 may be important. The methodology described in the present study may be useful in assessing the role of these mechanisms in regulating pulmonary resistance in vivo in humans.
In summary, NO production, presumably through endothelial cell release of NO or a related NO species, appears to be an important regulator of pulmonary resistance in conscious adults with clinically normal pulmonary status. NO production appears to function in maintaining the basal low resistance state and is capable of further decreasing resistance in response to receptor-mediated stimulation. This ability of the NO pathway to respond to receptor-mediated stimulation can be tested with acetylcholine. The magnitude of these effects suggest that NO production may be one of the major determinants of pulmonary resistance in the conscious adult with clinically normal pulmonary vasculature.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by a National Institutes of Health (NIH) Program Project Grant in Vascular Biology and Medicine (HL-48743). Dr Creager is a recipient of a NIH Academic Award in Systemic and Pulmonary Vascular Medicine (HL-02663). Dr Selwyn is a recipient of a MacArthur Foundation Award. Dr Anderson is a clinical fellow of the Alberta Heritage Foundation for Medical Research. Dr Ganz is a recipient of an NIH Research Career Development Award (KO4-HL-02566).
Received July 25, 1994; revision received August 7, 1995; accepted August 29, 1995.
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X. Lu, X. Guo, C. Linares, and G. S. Kassab A new method to denude the endothelium without damage to media: structural, functional, and biomechanical validation Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1889 - H1894. [Abstract] [Full Text] [PDF]
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S. J. Hutchison, R. E. Sievers, B.-Q. Zhu, Y.-P. Sun, D. J. Stewart, W. W. Parmley, and K. Chatterjee Secondhand Tobacco Smoke Impairs Rabbit Pulmonary Artery Endothelium-Dependent Relaxation Chest, December 1, 2001; 120(6): 2004 - 2012. [Abstract] [Full Text] [PDF]
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F. T. KANEKO, A. C. ARROLIGA, R. A. DWEIK, S. A. COMHAIR, D. LASKOWSKI, R. OPPEDISANO, M. J. THOMASSEN, and S. C. ERZURUM Biochemical Reaction Products of Nitric Oxide as Quantitative Markers of Primary Pulmonary Hypertension Am. J. Respir. Crit. Care Med., September 1, 1998; 158(3): 917 - 923. [Abstract] [Full Text] [PDF]
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K. Bando, P. Vijay, M. W. Turrentine, T. G. Sharp, L. J. Means, G. J. Ensing, B. J. Lalone, Y. Sekine, L. Szekely, and J. W. Brown Dilutional And Modified Ultrafiltration Reduces Pulmonary Hypertension After Operations For Congenital Heart Disease: A Prospective Randomized Study J. Thorac. Cardiovasc. Surg., March 1, 1998; 115(3): 517 - 527. [Abstract] [Full Text]
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