Vol. 280, Issue 4, H1875-H1881, April 2001
Helium inhalation enhances vasodilator effect of
inhaled nitric oxide on pulmonary vessels in hypoxic dogs
Masaki
Nie1,
Hirosuke
Kobayashi2,
Motoaki
Sugawara3,
Tomoyuki
Tomita2,
Kuniyoshi
Ohara1, and
Hirokuni
Yoshimura1
1 Department of Thoracic and Cardiovascular Surgery and
2 Department of Medicine, Kitasato University, Kitasato 1-15-1,
Sagamihara, Kanagawa 228-8555; and 3 Department of
Cardiovascular Sciences, Tokyo Women's Medical University, Tokyo
162-8666, Japan
 |
ABSTRACT |
There are theoretical and
experimental indications that the presence of He as a balance gas
markedly increase the diffusion velocity of other gases contained in a
gas mixture. We allowed dogs with pulmonary vasoconstriction induced by
hypoxia to inhale a mixture of 5 parts per million (ppm) of nitric
oxide (NO) and O2 balanced with He (NO in He) instead of
N2 (NO in N2). The dilating effect of NO in He
and NO in N2 on the pulmonary artery was evaluated by
determining conventional pulmonary hemodynamic parameters, mean
pulmonary artery (PA) pressure (MPAP), and pulmonary vascular resistance indexed to body surface area (PVRI), pulmonary impedance (Z), and the recently developed hemodynamic index,
time-corrected wave intensity (WI). The main findings in this study
were as follows: 1) hypoxia increased MPAP, PVRI,
Z at 0 Hz (Z0), Z at the
first harmonics, characteristic impedance (Zc),
the reflection coefficient (
), and the first peak of WI;
2) NO in N2 reduced Z0
and ; and 3) NO in He reduced the first peak of WI and
reduced Z0 and more than NO in
N2. The enhanced vasodilatory effect of NO in He might be
associated with facilitated diffusion of NO diluted in the gas mixture
with He. In conclusion, increased efficacy of NO in He offers the
possibility to reduce the inhaled NO concentration.
diffusion; pulmonary hypertension; impedance; wave
intensity
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INTRODUCTION |
INHALATION OF OXYGEN
BALANCED with He instead of N2 was used to treat
asthma patients (2, 13, 16). O2 and He
mixtures have lower density than mixtures of O2 and
N2 and reduce turbulence in the flow due to their low
Reynolds numbers (20). However, He-O2
viscosity is actually greater than that of air. Therefore, inhalation
of He-O2 might be disadvantageous in lungs with intact airways, because its greater viscosity compared with air should require
more driving pressure (and hence more effort) to achieve streamlined
flow through small airways (7).
There are also theoretical and experimental indications that a mixture
of two (17) or more (5, 6) gases interferes with their diffusion velocities, and that the presence of He as a
balance gas markedly increases the diffusion velocity of other diluted
gases in a mixture. Therefore, inhalation of He mixtures might be
beneficial in gas transport even in lungs with an intact airway,
because diffusional transport is important in peripheral airways and alveoli.
Because inhaled nitric oxide (NO) dilates constricted pulmonary vessels
and reduces pulmonary artery (PA) pressure without inducing systemic
hypotension (10, 27), NO inhalation is widely used to
treat patients with pulmonary hypertension (23, 29). We
hypothesized that inhalation of NO in He enhances the diffusional transport of NO in peripheral airways and alveoli and therefore enhances the vasodilator effect of inhaled NO on constricted pulmonary vessels during hypoxia. It has been reported that inhaled NO only partially reverses hypoxic pulmonary vasoconstriction in dogs (30) in contrast to sheep (3, 10, 28, 32) and
humans (9). Therefore, to investigate the facilitated
diffusion of NO in the presence of He, we used intact dogs and allowed
the dogs with pulmonary vasoconstriction induced by hypoxia to inhale a
mixture of 5 parts per million (ppm) NO and O2 balanced
with He (NO in He).
The specific question we attempted to answer in this study was whether
NO in He improves pulmonary hemodynamics more than NO inhalation
balanced with N2 (NO in N2) in our intact
animal model.
Dilating effects on the pulmonary arteries were evaluated by
1) conventional pulmonary hemodynamic parameters: mean
pulmonary artery pressure (MPAP), and pulmonary vascular resistance
indexed to body surface area (PVRI); 2) pulmonary impedance
analysis; and 3) a recently developed hemodynamic index,
time-corrected wave intensity (WI) (24).
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MATERIALS AND METHODS |
Animals and measurements.
Eight Beagle dogs weighing 12.0-22.0 kg were anesthetized with
intravenous pentobarbital sodium (35 mg/kg). Anesthesia was maintained
by continuous intravenous infusion of pentobarbital sodium (4 mg · kg
1 · h1), and muscles
were paralyzed with pancuronium (0.1 mg/kg) every 2 h. Animal care
was performed in accordance with the guidelines of the Animal Care
Committee of Kitasato University, and the conduct of this study
conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.
The animals were intubated and mechanically ventilated at 25 breaths/min and tidal volume of 12 ml/kg with positive end-expiratory pressure maintained at 3 cmH2O. Core body temperature was
maintained at 37-39°C with an external heater. A 5.5-Fr
thermodilution PA catheter (model P575-EH, Abbott; Chicago, IL) was
inserted via the left femoral vein. MPAP and central venous
pressure were measured through the catheter. A catheter with
catheter-tip blood pressure and velocity microsensors (model SVPC-664A;
Millar Instruments; Houston, TX) was introduced via the right femoral
vein. With the use of a fluoroscope, we confirmed that the catheter tip
was located in left main PA and that microsensors (35 mm from the
catheter tip) and the thermodilution PA catheter were located at just
downstream of the PA valve. Because the thermodilution PA catheter was
located and kept in the main PA, we could not measure the pulmonary
capillary wedge pressure. Therefore, we used PA end-diastolic pressure
(PAEP) as an estimate of left atrial pressure (LAP). In a preliminary study, we confirmed that LAP was stable throughout the study during hypoxia as well as normoxia, and PAEP was identical to LAP at normoxia,
but PAEP was significantly higher than LAP at hypoxia. Pressures were
measured (in mmHg) at normoxia, PAEP = 5.3 ± 0.2 (means ± SE; n = 8), and LAP = 5.2 ± 0.2; at
hypoxia in N2, PAEP = 13.1 ± 0.4, and LAP = 5.2 ± 0.4; at hypoxia in He, PAEP = 12.4 ± 0.2, and
LAP = 5.2 ± 0.2; at hypoxia in 5 ppm NO in N2,
PAEP = 10.7 ± 0.5, and LAP = 5.3 ± 0.4; at 5 ppm
NO during hypoxia with He, PAEP = 9.0 ± 0.4, and LAP = 5.3 ± 0.3. Therefore, we used PAEP at normoxia as an estimate of
LAP throughout the study. The pressure and flow velocity signals of the
catheter-tipped microsensors were fed via a pressure amplifier (model
AP-621G, Nihonkoden; Tokyo, Japan) and a flow amplifier
(700-1,500, Narco Bio-Systems) into a computer (PowerBook
2400c/180, Macintosh; Cupertino, CA) by using a 16-bit
analog-to-digital transformer (model MP100A, Biopac Systems) at a
sampling interval of 2 ms (500 Hz). The filter characteristics of the
3-dB cutoff frequency were 20 Hz of the one-pole Batterworth type for
the pressure sensor and 30 Hz of the two-pole Batterworth type for the
flow sensor. Electrocardiogram signals were also fed into the computer.
An arterial catheter was placed in the femoral artery to measure mean
systemic arterial pressure (MSAP) and to obtain arterial blood samples.
Blood samples for mixed venous blood analysis were obtained through the
PA catheter. The PO2,
PCO2, and pH values of blood were measured at
37°C with an automated blood gas analyzer (model ABL505, Radiometer;
Copenhagen, Denmark) and were corrected for body temperature measured
via the PA catheter. We calculated cardiac output by Fick's principle
by dividing the minute oxygen consumption rate (expired volume per
minute times the difference between the oxygen fraction in inspired gas
and mixed expired gas) by the difference between the oxygen content of
arterial and mixed venous blood. Blood gas content was calculated by
using a standard formula (19). In a preliminary study, the
cardiac output values obtained by Fick's principle were found not to
differ from those obtained by the thermodilution method. The cardiac output values from Fick's principle in means ± SE by
n = 8 and those from thermodilution were the following
(in l/min): 3.6 ± 0.5 and 3.1 ± 0.0 at normoxia, 2.0 ± 0.3 and 2.1 ± 0.1 at hypoxia, 2.0 ± 0.3 and 2.1 ± 0.1 at hypoxia in N2, 1.9 ± 0.2 and 2.2 ± 0.2 at hypoxia in He, 1.1 ± 0.1 and 2.8 ± 0.1 at hypoxia in 5 ppm NO in N2, and 2.5 ± 0.5 and 2.7 ± 0.0 at
hypoxia in 5 ppm NO in He, respectively. The cardiac output values were
indexed to body surface area (CI). The body surface area (in
m2) for dogs was calculated by using the standard formula:
body wt (kg)
× 0.1, and PVRI was calculated as
(MPAP 
PAEP) × 79.92 CI.
The inspiratory oxygen fraction, FIO2, was
adjusted to 0.21 during normoxia and to 0.08-0.11 during hypoxia
to adjust arterial PO2 (PaO2)
to ~30 mmHg. The gas mixtures were produced by using three mass flow
controllers (model 1259C, MKS; Andover, MA), one each for pure
O2, N2, and He, respectively. The
O2, N2, and He were of research level purity
(>99.999%). The O2 fraction was continuously monitored
with an oxygen sensor (model OMD-100, Aika; Tokyo, Japan), and the He
fraction was monitored with an He sensor (model XP-314, Shin Cosmos
Denki; Osaka, Japan). The NO gas was supplied from a nitrogen-balanced
800 ppm NO gas cylinder (Takachiho Chemicals; Tokyo, Japan) to the
inlet arm of the ventilator at a flow rate of ~60-140 ml/min via
a microflowmeter (RK1150, Kofloc; Tokyo, Japan). The NO2
level was measured with an electrochemical sensor (NOxBOX II, Bedfont
Scientific; Kent, UK), and it was found to be 0.6 ppm in 800 ppm NO in
N2 gas. The mean NO concentration in the inspired gas was
continuously monitored with a chemiluminescence NO-NOx
analyzer (model ECL-88US, Yanako; Kyoto, Japan) and adjusted to 5 ppm.
Because the response of chemiluminescence NO-NOx analyzer is not rapid enough to detect the fluctuation of NO level during inspiration, we introduced CO2 gas instead of 800 ppm NO in
N2 to the inlet arm of the ventilator at a flow rate of 60 ml/min to examine the fluctuation of introduced gas, and we measured the CO2 concentration with the use of a high-response
capnography (Respina 1H26, San-ei; Tochigi, Japan). As a result, the
CO2 concentration peaked in early expiration phase and
returned to the plateau level during the late expiration and whole
inspiration phase, indicating stable NO concentration during
inspiration in this study.
The concentration of inhaled NO, 5 ppm, was chosen on the basis of a
preliminary dose-response study of inhaled NO level and MPAP during
hypoxia. Inhalation of 5 ppm NO in He decreased MPAP to the lowest
plateau level, which was lower than the MPAP level that inhalation of
40 ppm NO in N2 could achieve.
The study protocol sequence consisted of the following eight steps:
1) normoxia, 2) hypoxia, 3) NO during
hypoxia, 4) NO during hypoxia with He,
5) NO during hypoxia with N2, 6)
hypoxia with N2, 7) hypoxia with He, and
8) normoxia with N2.
After an interval time for stabilization of MPAP at each step (from 15 to 30 min), MPAP, cardiac output, MSAP, and core body temperature were
measured, and arterial and mixed venous blood samples were drawn.
Meanwhile, expired gas was collected in a gastight Tedler bag for 5 min, and pulmonary artery pressure and flow velocity were measured with
the catheter-tipped microsensors for 10 s, eliminating the effect
of breathing on the measurements by stopping the ventilator in end expiration.
Impedance analysis.
The impedance was calculated from the pressure (P) wave and bulk flow
(Q) wave, which was obtained by multiplying instantaneous flow velocity
(U wave) by the effective cross-sectional area of the main
pulmonary artery. The effective cross-sectional area was obtained by
dividing cardiac output per minute by an integral of the U
wave for 1 min.
The impedance analysis was carried out according to a standard
algorithm (18) with the use of a wave analysis program
(Igor Pro version 3.1, Wavemetrics; Lake Oswego, OR). Briefly, a
Hamming window was applied to each bin of data files composed of 4,096 points to reduce side-lobe leakage. Fast Fourier transform was then
performed, and the PA input impedance
[Zin(
j)] was calculated as a
function of frequency () by using the formula
Zin(j) = P(j)/Q(j), and its modulus and phase were
obtained at every P wave and Q wave until 15 Hz, which had amplitudes
>2% of pressure and flow pulse amplitudes. The
Zin(j) spectra calculated were then corrected for the phase responses of the PA pressure and flow
transducers and amplifiers.
An impedance at 0 Hz (Z0), which represents
total PVRI, was derived from the PA impedance spectra. An impedance at
the first harmonics (Z1) was also derived. The
characteristic PA impedance (Zc) was calculated
from the PA input impedance modulus spectra as the mean of the
magnitude of Zin(j), between 2 and
15 Hz, and the reflection coefficient () was calculated as
Time-corrected WI.
Pressure and flow signals on the time domain were measured when
ventilation was stopped in end expiration. The flow velocity signals
were time shifted 6-12 ms to adjust the time delay of the flow
velocity signals compared with the pressure waves. We performed
three-point numerical differentiation of the pressure and flow waves
and calculated WI as
where dP/dt is the first derivative of pressure
development over time and dU/dt is the change in
flow velocity over time.
Statistical analysis.
Values are expressed as means ± SE unless otherwise stated. To
confirm stability throughout the experimental steps, Student's paired
t-test was applied to the following steps: 1)
normoxia and normoxia with N2, steps 1 and
8; 2) hypoxia and hypoxia with N2,
steps 2 and 6; and 3) NO during
hypoxia and NO during hypoxia with N2, steps 3 and 5. Because there were no statistical differences in any of the parameters between the corresponding experimental steps,
the corresponding data for normoxia and normoxia with N2, hypoxia and hypoxia with N2, and NO during hypoxia and NO
during hypoxia with N2 were averaged and shown as normoxia,
N2-hypoxia, and NO in N2. The data of
He-hypoxia were also shown to indicate that no significant effect of He
was detected by Student's paired t-test compared with
N2-hypoxia. Whenever ANOVA for repeated measures detected
significant differences among the data during normoxia, N2-hypoxia, with NO in N2, and with NO in He,
the data for the specific effects of 1) hypoxia, comparing
normoxia with N2-hypoxia, 2) NO in
N2, comparing N2-hypoxia with NO in
N2, and 3) "NO in He," comparing NO in
N2 with NO in He, were evaluated by using Student's paired
t-test with the Bonferroni correction as a post hoc test.
| |
RESULTS |
Conventional hemodynamic parameters and blood gas analysis.
Heart rate did not change during hypoxia (see Table
1). MPAP significantly increased during
hypoxia, and NO inhalation in He significantly reduced MPAP compared
with NO inhalation in N2. PVRI increased during hypoxia and
remained at a similar level during NO inhalation in N2 and
NO inhalation in He. CI significantly decreased during hypoxia, but it
did not change both at NO inhalation in N2 and NO
inhalation in He. PaO2 decreased during hypoxia but remained at a similar level at all experimental steps during
hypoxia. PaCO2 remained constant throughout the
experiment. The hemodynamic and blood gas data of
N2-hypoxia did not differ from those of He-hypoxia.
Impedance analysis.
Z0 significantly increased during hypoxia and
significantly decreased after NO inhalation (see Table
2). It decreased further after NO
inhalation in He. Zc significantly increased
during hypoxia but did not change either after NO inhalation in
N2 or after NO inhalation in He. significantly
increased during hypoxia, and decreased significantly after NO
inhalation in N2. It decreased further after NO inhalation
in He.
Time-corrected WI.
WI had two positive peaks (see Table 3
and Fig. 1 for examples). During
hypoxia, the first peak was increased due to increased dP/dt
and dU/dt, and negative waves were occasionally
observed between the first and second peaks. NO inhalation in
N2 did not decrease the first peak significantly, but NO
inhalation in He reduced the first peak significantly due to decreased
dP/dt and dU/dt. The second positive
peak did not change during any of the experimental steps.
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Fig. 1.
Pressure (P), flow velocity (U), and the time-corrected
wave intensity (WI). WI had two positive peaks. During hypoxia, the
first peak was increased due to increased first derivative of pressure
development over time (dP/dt) and change in flow velocity
over time (dU/dt), and negative waves were
occasionally observed between the first and second peaks. Nitric oxide
(NO) inhalation in N2 decreased the first peak due to
decreased dP/dt and dU/dt, and
negative waves were decreased. NO inhalation with He further decreased
the first peak (see Table 3) and negative waves.
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| |
DISCUSSION |
Main findings.
This study had three main findings: 1) hypoxia increased
MPAP, PVRI, Z0, Zc,
Z1, , and the first peak of WI and decreased CI; 2) NO inhalation in N2 reduced
Z0 and ; and 3) NO inhalation in
He reduced MPAP and the first peak of WI significantly and further
decreased Z0 and .
Conventional hemodynamic parameters and blood gas analysis.
Hypoxia increased MPAP and PVRI, despite decreased CI, indicating the
presence of hypoxic pulmonary vasoconstriction. Because cardiac output,
heart rate, and blood gas values did not change significantly during
hypoxia, with or without NO inhalation in N2 or He, we were
able to evaluate the effects of NO in N2 and NO in He on
MPAP and PVRI as well as other hemodynamic parameters, impedance
parameters, and the time-corrected WI uninfluenced by cardiac output
level, heart rate, and blood gases. At the same oxygenation level, a
similar cardiac output and heart rate should be sufficient for oxygen
delivery to the tissues.
Compared with NO in N2, MPAP decreased significantly after
NO inhalation in He, indicating a greater vasodilator effect of NO in
He. It is likely that NO delivery to the periphery of the lungs was
facilitated by He more than by N2. As Frostell et al. (10) reported, NO inhalation had no effect on the systemic
circulation, and its effects were confined to the pulmonary circulation.
Impedance analysis.
A considerable change in Z0 has been reported
(25) during hypoxia, whereas it was reported that hypoxic
pulmonary vasoconstriction was associated with insignificant changes in
pulmonary vascular impedance (8, 15).
In our study, hypoxia was found to increase Z0,
Z1, Zc, and , and NO
inhalation decreased Z0 and , indicating
improvement in resistance and vascular impedance matching by inhalation
of NO. NO in He further decreased Z0 and ,
indicating a greater improvement in resistance and impedance matching.
The vasodilator effect of 40 ppm of NO has been reported
(31) to be preserved during exposure of cats to anoxia,
and it completely reversed the severe pulmonary vasoconstriction.
Maggiorini et al. (15) reported that inhalation of 150 ppm
of NO reversed Z0 and Z1
at hypoxia. All of this evidence suggests that the vasodilator effect of NO attenuates hypoxic pulmonary vasoconstriction and that this effect is facilitated in the presence of He.
Time-corrected WI.
The WI is positive for forward traveling (compression and expansion)
waves and negative for backward traveling (reflected compression and
expansion) waves (24). In our study, WI had two positive
peaks in the pulmonary artery, the same as in the systemic circulation.
The initial peak was located in early ejection phase. A compression
wave traveling from the right ventricle during early ejection accounts
for the acceleration of blood flow and pressure rise in the pulmonary
artery. The initial peak, which represents the intensity of a forward
traveling compression wave, would be expected to vary with the
contractile state of the right ventricle and with its afterload, as
shown in the left ventricle (11). During hypoxia, the
increased pulse wave speed, as shown by the increase in
Zc, and the increased afterload were expected to
decrease the first peak of WI, but hypoxia increased WI by increasing
dP/dt and dU/dt, indicating the major
contribution by increased contractile performance of the right
ventricle. It is possible that sympathetic nerve stimulation
(4) and inotropic substances secreted at hypoxia, such as
epinephrine, enhance right ventricular contractility, increasing the
rates of pressure and flow changes in the pulmonary artery.
NO in He decreased the initial peak significantly. The decrease in the
initial peak is attributed to the decreased demand for right
ventricular contractility to maintain cardiac output, likely due to
decreased afterload, i.e., the vasodilator effect of inhaled NO.
However, it may also be attributable to the inhibitory effect of
inhaled NO on the right ventricular contractility. This possibility
should be further investigated by evaluating right ventricular performance.
Between the first peak and second peak, i.e., during the sustained
middle phase of ejection, WI was zero in normoxia and during hypoxia
with NO inhalation, indicating that blood flow continues in the absence
of significant net wavefront travel and implying that right ventricular
shortening matched pulmonary artery outflow. The momentum of the
flowing blood dominated right ventricular ejection with little wave
energy flux being transmitted from the ejecting heart to the ejected blood.
Negative waves were occasionally observed during hypoxia, indicating
backward waves, i.e., reflection waves. Backward waves did not have
sharp peaks but consisted of several broad peaks, indicating several
reflection sites in pulmonary arterial vessels during hypoxia. Inhaled
NO is reported to uniformly dilate vessels, from large pulmonary
arterial vessels to peripheral vessels, ensuring uniform blood flow due
to reduced reflection waves.
The second peak occurred during the late ejection phase. Analysis of WI
has shown that the heart itself stops blood flow in the aorta during
late ejection phase before closure of the aortic valve by generating
forward expansion waves traveling in the aorta from the left ventricle
toward the periphery (12, 21, 22). The same as in the
systemic circulation, the second peak in the pulmonary artery in late
ejection phase indicates that the right ventricle also stops blood flow
in the pulmonary artery by generating forward expansion waves traveling
in the pulmonary artery from the right ventricle toward the peripheral
vessels. Hypoxia and NO inhalation did not alter the magnitude of the
second peak, because NO inhalation decreased the magnitude of the
negative dP/dt at the second peak, but it did increase the
magnitude of the negative dU/dt.
NO inhalation with He.
Inhalation of NO in He improved pulmonary hemodynamics more than
inhalation of NO in N2, although this vasodilatory effect was partial (66% decrease in the increase in PVRI by NO in He during
hypoxia, in contrast to 28% decrease by NO in N2) and less than that at normoxia (i.e., 100% recovery). This result was similar to the report by Romand et al. (30) of NO inhalation in a
canine model with hypoxic pulmonary vasoconstriction, suggesting that NO and hypoxia act on the vasoconstriction response via different reactions and/or different receptors in dogs. Regional
electrophysiological diversity among pulmonary vascular smooth muscle
cells is reported (1) to be a major determinant of
segmental differences in vascular reactivity to hypoxia and NO.
Therapeutic use of a He-O2 mixture was first described by
Barach (2). To the extent that gas flow through obstructed
airways is turbulent, inhalation of lower density gas may preserve
laminar flow at high flow rates by reducing the Reynolds number
(20), thereby reducing airway resistance. In addition,
because the pressure drop during turbulent flow in large airways is
proportional to 
u2, where is the density
and u is the flow velocity of a gas mixture in the airway, a
gas mixture with lower density decreases the pressure drop. An 80:20
He-O2 mixture, Heliox, has a density one-third that of air.
However, gas velocity rapidly decreases beyond the third-generation
central airways in the normal bronchial tree, because airway
cross-sectional area increases, and thus the resistive pressure drop
for laminar flow in the peripheral airways is independent of gas
density. The viscosity of the He-O2 mixture is actually greater than that of air. Therefore, it has been considered that inhalation of 80% He-20% O2 should be useful only in
those conditions in which a decrease in gas density is beneficial; such
a decrease permits greater flow for the same driving pressure when air
flow is turbulent. This occurs only where flow is rapid or where
irregularities in the lumen of air passages cause eddy currents
(7). Therefore, the administration of He-O2
mixture would not be beneficial for oxygen transport in the lungs
without airway narrowing, and inhalation of He-O2 might be
disadvantageous because its greater viscosity compared with air should
require more driving pressure to achieve laminar flow through small
airways (7). A possible reduction in airway resistance in
this study may not have been a major cause of the improved hemodynamics
because the lungs are intact and the ventilation rate was kept constant
throughout the experiment, irrespective of the level of resistance.
The characteristics of diffusion involving two species of gas, called
binary diffusion (17), have been reported to be quite different from diffusion of one component, and the characteristics of
diffusion involving more than three species of gas, multicomponent diffusion, have also be reported to be different from diffusion of two
(5). This notion has also been verified experimentally (6). On the basis of the blood gas data in this study, it
is likely that transport of O2 and CO2 was not
facilitated by He. In contrast, on the basis of the hemodynamic data,
it is suggested that He facilitated the diffusion velocity of NO,
possibly due to the diluted amount of NO in the gas mixture. However,
it should be noted that there is no direct evidence of facilitated NO
diffusion in this study, and the mechanism of the enhanced vasodilatory effect of NO in He needs to be further investigated.
NO inhalation is widely used to treat patients with pulmonary
vasoconstriction, including patients with primary pulmonary hypertension (23), persistent pulmonary hypertension of
the newborn (29), postoperative pulmonary vasoconstriction
complicating congenital heart defects (26), and limited
scleroderma with isolated pulmonary hypertension (33). The
observed decrease in MPAP during NO inhalation in He may be easily
obtained by an increased NO concentration in N2. However,
it is recommended that the concentration of inhaled NO be as low as
possible (34), because NO combines with O2 to
produce NO2, and may damage pulmonary tissue. To comply
with the demand to minimize the inhaled dose of NO, breath-by-breath
delivery of spikes of concentrated gas has been proposed to lower its
concentration (14). NO inhalation balanced with He is
another potential tool for enhancing the vasodilator effect of NO on
pulmonary vessels or for reducing the NO concentration while
maintaining adequate pulmonary vasodilation. Although 90% of He in
inspired gas is an unrealistic proportion for clinical applications, NO
in He may be applied to patients with pulmonary hypertension without
respiratory failure, in whom N2 can be replaced with He in
a sufficient proportion of the inspired air. In conclusion, administration of NO in He improved pulmonary hemodynamics more than NO
in N2.
| |
ACKNOWLEDGEMENTS |
The authors thank Dr. Warren M. Zapol of the Department of
Anaesthesia and Critical Care, Massachusetts General Hospital, Harvard
Medical School, for collaboration on basic and clinical research on
both the acute respiratory distress syndrome and NO. The authors also
thank Yoshihiko Masaki, Shigenobu Nakayama, and Minoru Hirose for
technical support and Shizuo Hanya for suggesting the use of NO in He.
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FOOTNOTES |
This study was supported by Ministry of Education, Science, Sports, and
Culture of Japan Research Grants 08045069 and 09470285.
Address for reprint requests and other correspondence: H. Kobayashi, Dept. of Medicine, Kitasato Univ. School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan (E-mail: hiro{at}kitasato-u.ac.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 2 June 2000; accepted in final form 5 December 2000.
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