Effects of Inhaled Nitric Oxide and Oxygen in High-Altitude Pulmonary Edema
Presented in part at the at 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997.
From the VA Medical Center and University of Minnesota, Minneapolis (I.S.A., S.S.C, D.N.C., C.E.M.); High Altitude Medical Research Center, Leh, Ladakh, India (B.A.K.P., K.R.M.R., N.S., S.S.); and the Defense Institute of Physiology and Allied Sciences, Delhi, India (W.S.).
Correspondence to Inder S. Anand, MD, DPhil, FRCP, Professor of Medicine, Department of Cardiology, VA Medical Center 111C, Minneapolis, MN 55417. E-mail anand001{at}maroon.tc.umn.edu
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Abstract |
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Background—High-altitude pulmonary edema (HAPE) is characterized by pulmonary hypertension, increased pulmonary capillary permeability, and hypoxemia. Treatment is limited to descent to lower altitude and administration of oxygen.
Methods and Results—We studied the acute effects of inhaled nitric oxide (NO), 50% oxygen, and a mixture of NO plus 50% oxygen on hemodynamics and gas exchange in 14 patients with HAPE. Each gas mixture was given in random order for 30 minutes followed by 30 minutes washout with room air. All patients had severe HAPE as judged by Lake Louise score (6.4±0.7), PaO2 (35±3.1 mm Hg), and alveolar to arterial oxygen tension difference (AaDO2) (26±3 mm Hg). NO had a selective effect on the pulmonary vasculature and did not alter systemic hemodynamics. Compared with room air, pulmonary vascular resistance fell 36% with NO (P<0.001), 23% with oxygen (P<0.001 versus air, P<0.05 versus NO alone), and 54% with NO plus 50% oxygen (P<0.001 versus air, P<0.005 versus oxygen and versus NO). NO alone improved PaO2 (+14%) and AaDO2 (-31%). Compared with 50% oxygen alone, NO plus 50% oxygen had a greater effect on AaDO2 (-18%) and PaO2 (+21%).
Conclusions—Inhaled NO may have a therapeutic role in the management of HAPE. The combined use of inhaled NO and oxygen has additive effects on pulmonary hemodynamics and even greater effects on gas exchange. These findings indicate that oxygen and NO may act on separate but interactive mechanisms in the pulmonary vasculature.
Key Words: hypoxia • edema • pulmonary heart disease • hypertension • nitric oxide
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Introduction |
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High-altitude pulmonary edema (HAPE) is a life threatening condition1 characterized by pulmonary hypertension, increased pulmonary capillary permeability, and hypoxemia.2 3 4 The mechanisms responsible for the development of HAPE remain incompletely understood. The observation that lowering pulmonary arterial pressure with a vasodilator like nifedipine improves symptoms suggests that pulmonary vasoconstriction plays a role.5 6 The logical treatment of HAPE is to increase alveolar PO2 (PAO2) either by administration of oxygen or by descent to lower altitude. Severe weather and rugged terrain often make immediate descent impossible.
Scherrer et al7 recently reported that inhaled nitric oxide (NO) decreased pulmonary arterial pressure and improved ventilation-perfusion mismatch in HAPE-prone subjects exposed to high altitude. There is evidence that oxygen and NO cause pulmonary vasodilatation through the activation of different K+ channels in the pulmonary artery smooth muscle.8 9 There are, therefore, theoretical grounds for believing that the vasodilatory effects of oxygen and NO could be additive. The present study was designed to explore this hypothesis. To determine the separate and interactive effects of oxygen and inhaled NO, we treated HAPE patients with NO alone, oxygen alone, and NO plus oxygen. Because the investigations were performed in the field, we hoped that the results would also prove of practical help in the treatment of HAPE.
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Methods |
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We studied 14 male soldiers (aged 29±2 years [mean±SEM]) with symptoms of HAPE (Table 1
).
They were transported by helicopter from various locations in the
Western Himalayas to the High Altitude Medical Research Center,
attached to a hospital in Leh (3600 m; barometric pressure, 500
mm Hg), where they were investigated. All were residents of
low-altitude areas and were posted to high-altitude areas on temporary
duty. All gave written informed consent for the study, which was
approved by the institutional review boards of the VA Medical Center,
Minneapolis, University of Minnesota; Defense Institute of Physiology
and Allied Sciences, Delhi, India; and the Director General Armed
Forces Medical Services, India.
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Assessment of HAPE
On arrival in Leh, the clinical severity of HAPE was assessed by
the same observer using the Lake Louise acute mountain sickness (AMS)
scoring system.10 Briefly, patients were assessed
for the presence of 5 symptoms: headache; gastrointestinal upset;
fatigue, weakness, or both; dizziness, lightheadedness, or both; and
difficulty in sleeping. Change in mental status, ataxia, and
peripheral edema were also assessed. Each of these symptoms
and signs were rated between 0 and 3. A score of 0 indicated no
symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe
symptoms. AMS score is the sum of scores of all 8 symptoms and signs. A
chest X-ray was taken and arterial blood gases measured.
Only patients with an AMS score >3, alveolar to arterial
oxygen tension difference (AaDO2)
>10 mm Hg, and evidence of pulmonary edema on chest
x-ray were studied.
Procedures
A 7F thermodilution catheter (Spectramed) was placed in the
pulmonary artery via the right internal jugular vein and an
intra-arterial cannula inserted in the left brachial
artery. Pressures were measured with Statham transducers (Statham
P23Db, Spectramed) linked to a Physio-Control monitoring system
(Physio-Control). All transducers were referenced to midchest level
with patients in supine position. Cardiac output was measured by
thermodilution (Cardiac output computer, model 9520A, Edwards
Laboratories) in triplicate and averaged. Right atrial,
pulmonary arterial, and pulmonary
arterial wedge pressures were measured at end expiration
and averaged over 3 respiratory cycles. A pulse oximeter (Nonin Medical
Inc) attached to a fingertip monitored the oxygen saturation
continuously. Heart rate was measured from the ECG. Derived
hemodynamic variables were calculated according to
standard formulas.11
Arterial and mixed-venous blood gas tension was measured with a blood gas analyzer (ABL 300, Radiometer). Total hemoglobin concentration, hemoglobin oxygen saturation, and methemoglobin levels were measured by A-VOXimeter 100 oximeter (A-VOX Systems, Inc). The partial pressure of alveolar oxygen (PAO2) was calculated from the alveolar gas equation PAO2=PIO2-PACO2/R (where PIO2 is the partial pressure of oxygen at the level of trachea, corrected for humidity and temperature, and R is the expiratory exchange ratio). The calculated AaDO2 and Pao2 were used to assess change in oxygenation.
Administration of Inspired Gases
The effects of 4 different gas mixtures were tested in these
patients. Ambient air (FIO2, 0.21;
PIO2 
90 mm Hg), NO at a concentration
of 15 ppm in air (FIO2, 0.21), oxygen
(FIO2, 0.50), and a mixture of NO (15 ppm) and
oxygen (FIO2, 0.50). A system was designed to
alter NO or oxygen concentrations of the gas mixture independently,
without affecting minute ventilation or airway pressure. Briefly,
patients were asked to breathe spontaneously through a snugly fitted
face mask coupled to a 1-way inspiratory valve. Humidified room air
from a compressor was delivered, at flow rates 2 to 3 times the
patient's minute ventilation, to the inspiratory valve via a T tube
connector. The other end of the T tube was connected to a 6-ft-long,
1.5-in-wide corrugated tube to vent expiratory gases to the outside. An
in-line oxygen analyzer (MiniOX I, Catalyst Research) was used
to control the FIO2 delivered. NO (Puritan
Bennett) was supplied in a concentration of 2200 ppm and was delivered
using a sensitive direct reading flowmeter (0 to 300 mL/min,
Cole-Parmer Instrument Co). The concentration of inhaled NO was
monitored just proximal to the face mask with a commercially available
NO monitor using electrochemical detectors (NOxBOX, Bedfont
Scientific); it was maintained at 15 ppm. High flow rates of gas
mixtures helped to avoid formation of nitrogen dioxide and prevent
rebreathing.
Study Design
After recording baseline measurements on room air, the
effects of NO (15 ppm in room air;
FIO2, 0.21), oxygen
(FIO2, 0.50), and a mixture of NO and
oxygen (NO 15 ppm ; FIO2, 0.50) were tested. To
exclude the cumulative effects of these gases, the inhalation of each
gas mixture was followed by a period of breathing room air. Moreover,
the sequence of administration of gases was randomized. The effects of
4 different treatment conditions were tested in each patient: room air
and the 3 different gas mixtures. Each treatment lasted 30 minutes,
and measurements were performed in the last 10 minutes, when the
hemodynamic and gas exchange variables were stable.
Between treatments, a 30-minute period of exposure to room air was
introduced as a "washout period," at the end of which
hemodynamic and gas exchange measurements were
repeated. Thus, a total of 7 measurements were made on each patient: 4
on room air and 3 on the gas mixtures. In 2 patients, blood gas
measurements could not be recorded because of equipment failure. In
these patients, only hemodynamic data were available.
At the end of the study, which lasted 4 hours, patients were treated
in the routine manner with supplemental oxygen (35% oxygen by face
mask) until symptoms and signs of HAPE had completely resolved.
Patients were then transported to low altitude. No complications
occurred during the study.
Statistical Analysis
The data are expressed as the mean±SEM. To evaluate for the
individual effects of each of the gases studied (NO, oxygen, and NO
plus oxygen), a paired, 2-tailed Student's t test
comparison was made between measurements on room air immediately
preceding the treatment period and the measurements obtained after
exposure to each gas. Because of the crossover nature of the study
protocol, the data were then analyzed for any possible
carryover or period effects on the variables measured. This
analysis was performed by a 1-way ANOVA for repeated measures.
No significant effects were noted (P=0.4 for carryover,
P=0.7 for period), confirming that after exposure to each of
the gases, all variables returned to baseline values when subjects
were placed back on room air. In addition, and also by 1-way ANOVA,
there were no significant differences between the measurements obtained
on room air after each treatment period (P=0.4). This
allowed us to make comparisons between the responses observed with each
of the gases studied. The measurements obtained during the room air
periods were averaged for each subject and compared with the data
obtained during treatment with each of the gases under study by 1-way
ANOVA for repeated measures. Contrasts between the least square means
observed during each treatment period were obtained by Scheffé's
method, so as to identify significant differences between the
treatments. To investigate for any possible interactive effects between
NO and oxygen when given combined, a test for interaction was performed
as described by Cochran and Cox.12 An 
value
of 0.05 was used as a cutoff for statistical significance. All
analyses were performed using the SAS statistical package (SAS
Institute).
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Results |
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All patients in this study had moderate to severe HAPE as judged by their AMS scores (mean 6.4±0.7), radiographic evidence of pulmonary edema, and significant arterial hypoxemia (Table 1
). Hemodynamic measurements confirmed
the presence of pulmonary arterial hypertension,
with normal pulmonary capillary wedge pressures and normal
systemic hemodynamics. (Table 2, measurements on room air). Blood gas
analysis revealed severe hypoxemia and increased
AaDO2. Pulmonary artery
pressure correlated inversely with arterial oxygen
saturation (SaO2)
(r=-0.47, P<0.01) and arterial
oxygen tension (r=-0.34, P=0.017), and
directly with AaDO2
(r=0.30, P=0.04).
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Effect of Inhaled NO
Inhalation of NO at 15 ppm caused a prompt reduction in
pulmonary artery pressure by a mean of 11.1±1.5 mm Hg
(P<0.001) and in pulmonary vascular resistance by
36% (P<0.001). The mean
PaO2,
PaCO2, and
SaO2 increased slightly (all
P<0.01). A decrease in
AaDO2 was also noted
(P<0.01). Because PAO2
was virtually unchanged, the decrease in
AaDO2 may be interpreted as
indicating a relative decrease in intrapulmonary shunting. The
decrease in pulmonary artery pressure correlated with the
decrease in AaDO2 (r=0.59,
P=0.028). Inhalation of NO had no effects on systemic
hemodynamics; cardiac output and systemic vascular
resistance remained unchanged (P>0.5 for both). The heart
rate did not change, but respiratory rate decreased by 6.5%
(P<0.05). On cessation of NO inhalation and return to
breathing room air, all the hemodynamic and gas
exchange variables returned to baseline values. Throughout the
study, the methemoglobin level in the blood never exceeded 2%.
Effect of Breathing Oxygen
Oxygen inhalation caused a significant decrease in
pulmonary artery pressure (10.6±1.2 mm Hg,
P<0.001), which was similar to that seen after inhalation
of NO (P=0.49 for the difference between treatments, Figure 1). In contrast to NO, however, oxygen
produced a decrease in cardiac output (11.4%, P=0.003).
Therefore, the calculated pulmonary vascular resistance fell by
a smaller amount after inhalation of oxygen than after inhalation of NO
(23% versus 36%, P=0.02 for the difference between
treatments, Figure 1). In addition, treatment with oxygen increased
systemic vascular resistance by 14.7% (P<0.001) and
decreased heart rate by 11.8% (P<0.001). The respiratory
rate decreased by 9.4% (P=0.002), but this decrease was
comparable to that seen with NO (P=0.6 for the difference
between treatments). As expected, oxygen increased
PaO2 and
SaO2 to a greater extent than
inhalation of NO (P<0.001 for both differences between
treatments, Figure 1). Again, all variables returned to baseline
values after resumption of breathing room air.
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Effect of Breathing NO Combined With Oxygen
The combination of NO and oxygen produced a decrease in
pulmonary artery pressure and pulmonary vascular
resistance that was greater than that seen with NO or oxygen alone
(P<0.0001 for differences between treatments, Figure 1).
The effect of the combination was simply additive and not interactive,
ie, the effect due to the joint action of both gases was not greater
than the sum of the effect of each gas considered separately
(P=0.11 for interaction). The responses seen in systemic
hemodynamics were similar to those seen after treatment
with oxygen: cardiac output fell and systemic vascular resistance
increased; both effects were not significantly different
(P>0.5) from those seen with oxygen alone. With respect to
gas exchange, whereas NO caused only a small increase in
PaO2, combined treatment with NO and
oxygen increased PaO2 considerably
more than with oxygen alone (P<0.0001 versus oxygen, Figure 1, P<0.001 for interactive effect of combination). The
combined treatment decreased AaDO2
from that seen after treatment with oxygen alone (P<0.001
versus oxygen alone).
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Discussion |
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In this study, we report the first use of inhaled NO at a high altitude in patients who were severely ill with HAPE. We found that inhaled NO improved arterial oxygenation and diminished pulmonary arterial pressure in patients with profound hypoxemia, moderately severe pulmonary hypertension, and overtly symptomatic pulmonary edema. Although treatment with either inhaled NO or oxygen acutely improved oxygenation and lowered pulmonary artery pressure, the use of inhaled NO and oxygen together caused an additive effect on pulmonary hemodynamics and an even greater effect on gas exchange.
In contrast to other vasodilator agents that have been used at high altitude,5 6 13 inhaled NO improved ventilation-perfusion mismatch and decreased venous admixture, as documented by a decrease in AaDO2, both on room air and at 50% FIO2. This may be attributed to the fact that inhaled NO selectively vasodilates only those portions of the pulmonary vasculature that are ventilated, resulting in more optimally matched ventilation and perfusion. This study, therefore, extends observations of previous investigators, who also demonstrated decrease in pulmonary artery pressure (by Doppler echocardiography) and improvement in ventilation-perfusion mismatch with inhaled NO (40 ppm) on ventilation-perfusion scans.7 There are, however, a number of significant differences between the 2 studies. The previous study was done on HAPE-prone subjects in the controlled environment of a laboratory at high altitude. Only 10 of the 18 subjects developed radiographic evidence of pulmonary edema, and even in those, the AaDO2 was only modestly increased (15±4 mm Hg). We investigated severely ill patients who had developed HAPE during routine activities at high altitude and obtained hemodynamic and gas exchange data using invasive monitoring. This study, therefore, underscores the feasibility of using inhaled NO in the setting of a field hospital. Moreover, a lower dose of NO was used (15 ppm) and the effects of inhaled NO, oxygen, and their combination were compared. The interpretation of this data is that ventilation and perfusion were better matched in the presence of NO and oxygen than with either of these 2 gases alone.
The observation that NO and oxygen interact to improve oxygenation and decrease pulmonary arterial pressure suggests that these 2 gases act on separate but complementary mechanisms to cause pulmonary vasodilation at high altitude. Normally, the pulmonary vasculature is able to sense a decrease in oxygen tension and respond with vasoconstriction (because of inactivation of oxygen sensitive potassium (K+) channels in pulmonary artery smooth muscle cells).14 15 Both oxygen and NO cause pulmonary vasodilation, at least in part, through activation of K+ channels. The additive effects of NO and oxygen, when given together, may derive from activation of different K+ channels. Oxygen appears to activate predominantly the voltage-dependent K+ channels,9 whereas NO activates a Ca-sensitive K+ (KCa++) channel.8 9 16 Thus, while both NO and oxygen are capable of independently causing significant pulmonary vasodilatation and subsequent increases in oxygenation, their additive effects may be more profound than their respective effects alone.
The greater-than-additive effects of NO and oxygen on gas exchange are not surprising. Inhaled NO, when given alone, improves oxygenation presumably by increasing blood flow through the well ventilated parts of the lungs that are exposed to room air. With combined NO and oxygen, not only is blood flow to the ventilated parts of the lung expected to be greater, the lung is also exposed to a much higher oxygen tension. Therefore, the improvement in gas exchange parameters with the combined use of NO and oxygen are greater than the additive effects of the individual gases.
In summary, this represents the first report of the use of inhaled NO in acutely ill patients with HAPE at altitude. We demonstrate that both NO and oxygen cause an acute decrease in pulmonary artery pressure, intrapulmonary shunting, and improvement in oxygenation. There appears to be an additive effect on pulmonary hemodynamics and an even greater effect on gas exchange when both oxygen and NO are delivered simultaneously. Although further study is necessary to determine the potential long-term benefits or adverse sequelae associated with NO use, this study suggests that there may be significant benefits for patients who are acutely ill with high-altitude pulmonary edema. Finally, this report may provide some insight into the mechanism whereby NO and oxygen improve gas exchange in an hypoxic hypobaric atmosphere.
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Acknowledgments |
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We are indebted to Dr A.P.J. Abdul Kalam, Scientific Advisor to the Defense Minister, Government of India, and Head, Defense Research and Development Organization, for helping to initiate this project; to Lt Gen D. Raghunath, Director General Armed Forces Medical Services, for permission to study these patients; to the Indian Air Force for air-lifting our equipment; to Dr Shepard of A-VOX Systems, Inc, San Antonio, Tex, for the loan of the A-VOXimeter 100 oximeter; to Nonin Medical Inc, Plymouth, Minn, for loan of a pulse oximeter; to staff of the hospital for all their help. This work was supported by VA Research Funds, Minnesota Medical Foundation (Ao-152–96), and the Defense Research and Development Organization, Ministry of Defense, Government of India.
Received May 15, 1998; revision received August 5, 1998; accepted August 13, 1998.
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oxygen. Both NO and oxygen caused an acute decrease in
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simultaneously. Inhaled NO may have a therapeutic role in
the management of HAPE.
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