High-Altitude Pulmonary Edema Is Initially Caused by an
Increase in Capillary Pressure
Marco Maggiorini, MD; Christian Mélot, MD; Sebastien Pierre, MD; Fredi Pfeiffer, PhD;
Ilona Greve, MS; Claudio Sartori, MD; Mattia Lepori, MD; Markus Hauser, MD;
Urs Scherrer, MD; Robert Naeije, MD
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Background—High-altitude pulmonary edema (HAPE) is characterized by severe pulmonary hypertension and bronchoalveolar lavage fluid changes indicative of inflammation. It is not known, however, whether the primary event is an
increase in pressure or an increase in permeability of the pulmonary capillaries.
Methods and Results—We studied pulmonary hemodynamics, including capillary pressure determined by the occlusion
method, and capillary permeability evaluated by the pulmonary transvascular escape of 67Ga-labeled transferrin, in 16
subjects with a previous HAPE and in 14 control subjects, first at low altitude (490 m) and then within the first 48 hours
of ascent to a high-altitude laboratory (4559 m). The HAPE-susceptible subjects, compared with the control subjects,
had an enhanced pulmonary vasoreactivity to inspiratory hypoxia at low altitude and higher mean pulmonary artery
pressures (37⫾2 versus 26⫾1 mm Hg, P⬍0.001) and pulmonary capillary pressures (19⫾1 versus 13⫾1 mm Hg,
P⬍0.001) at high altitude. Nine of the susceptible subjects developed HAPE. All of them had a pulmonary capillary
pressure ⬎19 mm Hg (range 20 to 26 mm Hg), whereas all 7 susceptible subjects without HAPE had a pulmonary
capillary pressure ⬍19 mm Hg (range 14 to 18 mm Hg). The pulmonary transcapillary escape of radiolabeled transferrin
increased slightly from low to high altitude in the HAPE-susceptible subjects but remained within the limits of normal
and did not differ significantly from the control subjects.
Conclusions—HAPE is initially caused by an increase in pulmonary capillary pressure. (Circulation. 2001;103:20782083.)
Key Words: edema 䡲 lung 䡲 capillaries
H
igh-altitude pulmonary edema (HAPE) is a lifethreatening complication of rapid ascents to altitudes
higher than 2500 m.1 Exactly what causes HAPE remains
unknown. Patients with HAPE have an increase in pulmonary
artery pressures and normal left atrial pressure2–7 and enhanced pulmonary vasoreactivity to hypoxia8 –10 and are
improved by pharmacological interventions that decrease
pulmonary artery pressures.11–14 These observations are in
keeping with the hypothesis that HAPE is caused by a stress
failure of the pulmonary capillaries related to inhomogeneous
hypoxic vasoconstriction and overperfusion.15 The bronchoalveolar lavage fluid in patients with HAPE, however, has
been shown to be rich in high-molecular-weight proteins,
cells, and markers of inflammation,16 suggesting increased
capillary permeability as a primary event. We therefore
designed the present study, which aimed at direct measurements of both pressure and permeability of the pulmonary
capillaries in the early stages of HAPE.
Methods
Subjects and Study Design
Thirty nonacclimatized mountaineers, 7 women and 23 men 23 to 60
years old, were included in the study, which was approved by the
Ethics Committee of the University Hospital of Zürich. Sixteen had
a history of ⱖ1 episodes of HAPE.
All the subjects underwent a right heart catheterization with
pulmonary hemodynamic measurements, including pulmonary capillary pressure, and a measurement of pulmonary capillary permeability as estimated by the transvascular escape of 67Ga-labeled
transferrin, at the University Hospital of Zürich (altitude 490 m). The
pulmonary hemodynamic measurements were repeated after 10
minutes of breathing an inspired oxygen fraction (FIO2) of 0.12 to
produce a decrease in arterial partial pressure of O2 (PaO2) to values
normally recorded at an altitude of ⬇4500 m.
Thereafter, within 2 to 3 weeks, all the subjects ascended in ⬍24
hours from Alagna Valsesia (1130 m) to a research laboratory on
Monte Rosa, the Regina Margherita hut (4559 m), with an overnight
stay at the Gnifetti hut (3611 m). After a first night at 4559 m, the
subjects underwent another measurement of pulmonary capillary
permeability and a right heart catheterization with pulmonary hemo-
Received November 13, 2000; revision received January 17, 2001; accepted January 23, 2001.
From the Medical Intensive Care Unit of the Department of Internal Medicine (M.M., I.G.), the Division of Nuclear Medicine (F.P.) and the Department
of Radiology (M.H.), UniversitätsSpital, Zürich, and the Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne (C.S.,
M.L., U.S.), Switzerland; and the Departments of Intensive Care and Physiology (S.P., C.M., R.N.), Erasme University Hospital, Brussels, Belgium.
Correspondence to Professor Dr. med. M. Maggiorini, Medizinische Intensivstation, UniversitätsSpital Zürich, Rämistrasse 100, CH-8091 Zürich,
Switzerland. E-mail [email protected]
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
2078
Maggiorini et al
High-Altitude Pulmonary Edema
2079
Figure 1. Chest x-ray film at low (A) and
high (B) altitude of a representative subject
with early HAPE.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
dynamic measurements. Pulmonary hemodynamic measurements
were repeated after 10 minutes by breathing an FIO2 of 0.33 to
increase PaO2 to values normally recorded at low altitude. One of the
subjects was investigated only at high altitude.
Assessment of HAPE
HAPE was clinically suspected in the presence of dry cough,
dyspnea and/or orthopnea, tachypnea (⬎25 breaths per minute), or
central cyanosis and if rales and/or wheezes were present on chest
auscultation. Posteroanterior chest radiographs were taken with a
mobile unit (TRS, Siemens) with a fixed target-to-film distance of
140 cm at 95 kV and 3 to 6 mA/s. At the Capanna Regina
Margherita, HAPE was diagnosed if the x-ray film showed clear
signs of interstitial and/or alveolar edema compared with the chest
radiograph taken at low altitude (Figure 1). Thereafter, chest radiographs were coded and analyzed according to previously described
criteria17 by a radiologist who was unaware of the subjects’ clinical
history. Briefly, with the mediastinum used as the vertical axis and
the hila as the horizontal axis, 4 lung areas were assessed separately
for the presence of edema. Normal parenchyma was given a score of
0; areas with questionable pathological findings, 1; areas with ⬍50%
interstitial infiltration, 2; areas of ⬎50% nonconfluent interstitial
infiltration, 3; and areas with alveolar, patchy confluent infiltrates, 4.
Any chest radiograph with ⱖ1 lung quadrant with a score of 2 was
considered positive for HAPE.
Right Heart Catheterization
Right heart catheterization was performed with a standard thermodilution balloon-tipped pulmonary artery catheter (131H-7F Baxter)
inserted via an internal jugular vein. To enhance the safety of the
procedure, the internal jugular vein was first located with an
ultrasound Doppler device (SonoGuide2, Darbomed AG). Thereafter, the pulmonary artery catheter was floated under constant
pressure-wave monitoring into the pulmonary artery for the measurement of mean pulmonary artery pressure (Ppa), pulmonary artery
occluded pressure (wedge pressure, Ppao), pulmonary capillary
pressure (Pc), and right atrial pressure and for mixed-venous blood
sampling. A small polyethylene catheter (Vygon) was inserted into a
radial artery or a femoral artery to measure systemic arterial pressure
and for arterial blood sampling. Pulmonary and systemic artery
pressures were measured with transducers (Homedica AG) connected to a hemodynamic and ECG monitoring system (Sirecust 404,
Siemens). The pressure transducers were zero-referenced at midchest, and vascular pressures were measured at end expiration. Heart
rate was determined by a continuously monitored ECG. Cardiac
output (Q̇) was measured by thermodilution with 10-mL injections of
5% cold dextrose in water (8°C to 10°C) and a computer (Vigilance,
Baxter), and was calculated as the mean of 3 to 5 determinations.
Determination of the Pulmonary
Capillary Pressure
The vascular pressure signals were sampled at 200 Hz with an
analog-to-digital converter (RTI 800, Analog Devices) and stored on
a personal computer. Pulmonary capillary pressure was computed in
triplicate from the pulmonary artery pressure-decay curve obtained
after rapid inflation of the balloon of the pulmonary artery catheter18
(Figure 2). For each of the Pc measurements, the subjects were asked
to stop breathing at the end of a normal tidal volume for a period of
8 seconds. The pressure-decay curve was fitted by an exponential
equation on the basis of a least-squares analysis applied to a set of
data between 0.2 and 2.0 seconds after the occlusion, adjusted to
Ppao, and extrapolated back toward time 0⫹150 ms with a purposemade software.
Assessment of the Pulmonary Capillary Leak
Pulmonary capillary permeability was assessed with a noninvasive
measurement of the transvascular protein flux in the lung as initially
reported in humans by Gorin et al19 and adapted by Raijmakers et
al.20 Red blood cells were labeled in vitro with 99mTc (300 ␮Ci, 11
␮Bq; physical half-life 6 hours) after injection of sodium pyrophospate (DRN 4342 TechneScan PYP, Mallinckrodt). Transferrin was
labeled in vivo with intravenous injection of [67Ga]gallium citrate
(100 ␮Ci, 4 ␮Bq; physical half-life 78 hours).20 67Ga radioactivity
was measured in 1-minute frames (time points 0 to 60) with 2 mobile
scintillation detection probes (2⫻2-in sodium iodine crystal) placed
on the midclavicular line over the right (fourth intercostal space) and
the left (second intercostal space) lung. Measurements obtained at
Figure 2. Pressure-decay curves for determination of Pc in 3
representative subjects at high altitude: a control subject, a
HAPE-susceptible subject with no edema (non-HAPE), and a
subject with HAPE. Calculated Pcs were 13, 15, and 26 mm Hg,
respectively.
2080
Circulation
April 24, 2001
the Scheffé test. Regression coefficients were calculated with a
least-squares regression analysis. A value of P⬍0.05 was considered
statistically significant. The values are expressed as mean⫾SEM.
Results
Measurements at Low Altitude
The control subjects and the HAPE-susceptible subjects had
similar values for blood gases and hemodynamics, and a
normal PLI, in normoxia (Table).
Hypoxia decreased arterial PO2 (PaO2) and arterial PCO2
(PaCO2), increased Ppa, Pc, and Q̇, and did not change Ppao.
The HAPE-susceptible subjects had a higher Ppa and a lower
Q̇ than the control subjects in hypoxia. As shown in Figure 4,
hypoxia increased Ppa more in the susceptible subjects who
later developed the condition on the mountain than in the 2
other groups, whereas the difference in hypoxia-induced
increase in Pc was of borderline significance (P⫽0.08).
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Figure 3. PLI measurements obtained in representative subject
with HAPE shown in Figure 1. For explanation, see text. Mean
PLI was 6.8⫻10⫺3/min at low altitude and 10.4⫻10⫺3/min at
high altitude.
these sites were routed separately to a PC for online analysis (Target
System Electronics GmbH) and storage. Radial artery blood samples
(1.5 mL) were obtained at times 5, 8, 11, 15, 20, 25, 30, 40, 50, and
60 minutes for determination of radioactivity (Cobra II gamma
counter, Canberra Packard). With windows of 20% centered around
each peak, 99mTc and 67Ga were measured at 140 and 184 keV,
respectively, and corrected for background radioactivity, physical
half-life, and spillover of 67Ga into the 99mTc window. For each blood
sample, a time-matched count rate over the lung was taken and the
radioactivity ratio was calculated: radioactivity ratio ⫽ (67Galung/
99m
Tclung)/(67Gablood/99mTcblood). The pulmonary leak index (PLI) was
calculated as the slope of the increase of the radioactivity ratio over
time divided by the intercept (Figure 3). The values for both lungs
were averaged.
To demonstrate the sensitivity of this method for detecting a
pulmonary capillary leak, we studied 8 patients (17 to 72 years old)
during early adult respiratory distress syndrome (ARDS) who were
admitted to the Medical Intensive Care Unit of the Department of
Internal Medicine of the University Hospital in Zurich. All these
patients were mechanically ventilated and had pulmonary artery
catheters inserted by the physician in care for diagnostic and
therapeutic purposes.
Gas Administration and Monitoring
The subjects breathed the hypoxic and the hyperoxic gas mixtures
wearing a tight face mask connected by a 2-way low-resistance valve
and a 30-L reservoir bag to calibrated 10-L tanks containing 12% and
33% oxygen in pure nitrogen, respectively (PanGas). At both
altitudes, FIO2, minute ventilation, end-tidal CO2 concentration, and
hemoglobin O2 saturation were continuously monitored with a
device that automatically adjusts for changes in atmospheric pressure
and temperature (Capnomac Ultima, Datex). Arterial blood samples
were taken from the arterial catheter and immediately analyzed with
an automated analyzer (model 278, Ciba-Corning Diagnostics).
Statistical Analysis
The statistical analysis was performed with the StatView software
package.21 A 2-way repeated-measures ANOVA was used to compare differences between low and high altitude and the 2 subject
groups. Differences between the subjects who developed HAPE,
those who did not, and the control subjects were analyzed by 1-factor
ANOVA. When the F ratio of the ANOVA reached a level of
P⬍0.05, comparisons between the subject groups were made with
Measurements at High Altitude
Twelve to 36 hours after arrival at the highest altitude, none
of the control subjects, but 9 of the 16 HAPE-susceptible
subjects developed clinical and radiographic evidence of
pulmonary edema (radiographic score 7.0⫾0.6, range 4 to 10)
(Table). The radiographic score was already diagnostic of
HAPE (scores 2 to 10, mean 6.2) in 4 of these 9 subjects at
the time of investigation. The radiographic score became
abnormally high in the other 5 subjects during the following
night.
Altitude decreased PaO2 and PaCO2. The altitude-induced
decrease in PaO2 was more pronounced in HAPE-susceptible
subjects than in control subjects. The HAPE-susceptible
subjects with HAPE had a PaO2 of 37⫾2 mm Hg versus a
PaO2 of 43⫾2 mm Hg in HAPE-susceptible subjects who did
not develop HAPE (P⫽0.03). PaCO2 was not different in the
subgroups.
Altitude increased Q̇, Ppa, Pc, and Ppao. The latter change
was slight and significant in the HAPE-susceptible subjects
only. Altitude-induced increases in Ppa and Pc were more
pronounced in the HAPE-susceptible subjects than in the
control subjects. Representative pressure-decay curves
(Ppa⫺Ppao) obtained in a control subject, a HAPEsusceptible subject without HAPE, and a subject with HAPE
are shown in Figure 2. Altitude-induced increases were most
important in the subjects who developed HAPE with a Ppa
⬎35 mm Hg and a Pc ⬎19 mm Hg (Figure 5). Pc was
correlated to Ppa (r2⫽0.76, P⬍0.001) and, as shown in
Figure 6, to PaO2 and to the radiographic score.
The PLI remained within normal limits in all subjects.
There was no difference between the PLIs of the HAPEsusceptible subjects who developed edema, those who did
not, and the control subjects (F of the ANOVA⫽1.95,
P⫽0.16) (Figure 7). The PLI increased slightly in both
HAPE-susceptible subjects who did not develop HAPE
(8.5⫾0.5 to 11.9⫾0.9⫻10⫺3/min, P⫽0.02) and in those who
developed HAPE (8.2⫾0.6 to 11.7⫾1.4⫻10⫺3/min, P⫽0.04),
but not in control subjects (10.0⫾0.5 to 9.3⫾0.8⫻10⫺3/min,
P⫽0.32) (F of the ANOVA⫽5.34, P⫽0.03). In patients with
ARDS, the PLI was definitely higher (Figure 7).
Maggiorini et al
High-Altitude Pulmonary Edema
2081
Arterial Blood Gases, Pulmonary Hemodynamics, and PLI in Control Subjects and
High-Altitude Pulmonary Edema–Susceptible Subjects at Low and High Altitude
Low Altitude (490 m)
High Altitude (4559 m)
Baseline
Hypoxia
Baseline
Hyperoxia
Control
14
14
14
14
HAPE-susceptible
15
15
16
16
No. of subjects
PaO2, mm Hg
Control
92⫾2
38⫾1†
45⫾1†‡
90⫾2‡§
HAPE-susceptible
92⫾4
39⫾2†
40⫾1*†
76⫾3*†‡§
Control
34⫾1
32⫾1†
27⫾1†‡
31⫾1†§
HAPE-susceptible
37⫾1
33⫾1†
27⫾1†‡
30⫾1†‡§
Control
3.3⫾0.1
4.5⫾0.2†
3.7⫾0.2‡
3.2⫾0.1‡
HAPE-susceptible
3.1⫾0.2
3.8⫾0.3*†
3.7⫾0.1†
3.2⫾0.2‡§
Control
14⫾1
22⫾1†
26⫾1†‡
22⫾1†§
HAPE-susceptible
16⫾1
27⫾2*†
38⫾2*†‡
31⫾2*†‡§
10⫾1
12⫾1†
13⫾1†
12⫾1†
9⫾1
13⫾1†
19⫾1*†‡
16⫾1*†‡§
Control
8⫾1
9⫾1
10⫾1
9⫾1
HAPE-susceptible
7⫾1
8⫾1
10⫾1†
9⫾1
PaCO2, mm Hg
Q̇, L 䡠 min⫺1 䡠 m⫺2
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Ppa, mm Hg
Pc, mm Hg
Control
HAPE-susceptible
Ppao, mm Hg
Pulmonary leak index, 10⫺3/min
Control
HAPE-susceptible
10.0⫾0.5
9.3⫾0.8
8.4⫾0.5
11.8⫾0.9†
Mean values are given as mean⫾SEM.
Pⱕ0.05 *vs control, †vs low-altitude baseline, ‡vs low-altitude hypoxia, §vs high-altitude baseline.
With supplemental O2, PaO2 and PaCO2 increased and Ppa
and Q̇ decreased, but there was a decrease in Pc in the
HAPE-susceptible subjects only.
Discussion
The main finding of the present study is that early HAPE is
characterized by an increase in pulmonary capillary pressure,
Figure 4. Individual Ppa and Pc in 14 control subjects and 15
HAPE-susceptible subjects while breathing 12% oxygen for 10
minutes at low altitude. Non-HAPE indicates HAPE-susceptible
subjects without HAPE. Horizontal bars show means. **P⬍0.01
vs control subjects.
whereas capillary permeability as assessed by the transvascular escape of radiolabeled transferrin remains within the
limits of normal.
HAPE generally occurs in circumstances not easily compatible with invasive studies. Direct measurements of pulmonary vascular pressures by right heart catheterization, however, have been reported previously in a total of 20 patients
with HAPE.2–7 In these patients, Ppa was on average 42
Figure 5. Individual Ppa and Pc in 14 control subjects and in 16
HAPE-susceptible subjects at high altitude. Horizontal bars
show means. *P⬍0.05, **P⬍0.01 vs control; †P⬍0.01 vs
non-HAPE.
2082
Circulation
April 24, 2001
Figure 6. Correlations between pulmonary capillary pressure and PaO2, and
radiographic score at high altitude.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
mm Hg but ranged from 13 to 113 mm Hg. This variability
may be explained by variable altitude of occurrence, frequent
evacuation to lower altitude at time of diagnosis, and treatments with diuretics and/or oxygen. Conversely, left atrial
pressure as assessed by occluded (or wedge) Ppa was consistently low or normal.2–7 The present results show that
severe pulmonary hypertension with a normal left atrial
pressure is a constant finding in untreated HAPE. They also
confirm that pulmonary hypertension tends to be severe, with
mean pulmonary artery pressure often ⬎30 to 40 mm Hg in
asymptomatic HAPE-susceptible subjects,8 and mild, with
mean pulmonary artery pressure most often between 20 and
30 mm Hg, in normal subjects with good tolerance to high
altitude.22,23 In addition, our results are in keeping with
previous reports of variably enhanced pulmonary vasoreactivity to hypobaric hypoxia in HAPE-susceptible subjects8 –10
and with studies showing an only partial reversibility of Ppa
with supplemental oxygen breathing after a few hours of
hypoxia.22,23
Figure 7. PLI in 14 control subjects and 16 HAPE-susceptible
(HAPE-s) subjects at high altitude and in 8 patients with ARDS.
Non-HAPE indicates HAPE-susceptible subjects who did not
develop HAPE. **P⬍0.01 vs control, †P⬍0.01 vs non-HAPE,
‡P⬍0.01 vs HAPE. Horizontal bars show means.
The present study is the first to report Pc determinations in
normal volunteers. At low altitude, the values were compatible with a normal longitudinal distribution of pulmonary
vascular resistance in all the subjects.18 Pulmonary capillary
pressures increased at altitude but were on average 6 mm Hg
higher in the HAPE-susceptible subjects than in the control
subjects. In addition, there was a threshold of 19 mm Hg for
Pc, above which pulmonary edema developed. This threshold
value for edema formation is in keeping with previous
experimental observations in dogs of a PO2-independent
critical capillary pressure of 17 to 24 mm Hg, above which
lungs continuously gain weight.24 Why oxygen breathing
only partially reversed altitude-induced increase in Pc is not
clear but could be explained by early remodeling of small
pulmonary venules.
There are 2 different explanations for increased Pc in
HAPE-susceptible subjects. The first relies on inhomogeneous hypoxic vasoconstriction causing regional overperfusion of capillaries,1 leading to stress failure.15 It is difficult,
however, to conceive that the tip of the pulmonary catheter
always went to pulmonary arteries perfusing edematous lung
regions. The second relies on hypoxic constriction occurring
either at the smallest arterioles or at the venules, or both.
Occlusion studies on isolated dog lungs have shown that the
venous component of hypoxic pulmonary vasoconstriction
may amount to 20% of the total increase in pulmonary
vascular resistance.25 The capillary-venous segment, as determined by arterial occlusion, has been estimated, on the
basis of comparisons with direct micropuncture pressure
measurements, to include not only the capillaries but also
small arterioles, up to 100 to 150 ␮m in diameter.26 One study
suggested that these smallest arterioles leak in the presence of
markedly increased Ppa.27 As previously suggested,13 a hypoxic pulmonary venous constriction might offer a more
satisfactory explanation for increased Pc in HAPE.
The 67Ga-labeled transferrin protein transport ratio has
been reported to be a sensitive and specific marker of acute
lung injury that discriminates between cardiogenic pulmonary edema and ARDS.20 In the present study, 67Ga PLIs were
within the normal range at low and high altitude and were not
Maggiorini et al
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
different between those subjects who developed HAPE and
those who did not. There was, however, a slight but significant tendency of the capillary leak index to increase from low
to high altitude in the HAPE-susceptible subjects. This may
be explained by an early transcapillary leak of protein due to
very high capillary pressures. Early inflammatory changes
cannot be excluded either. In addition, because hemoptysis
occurs in HAPE,1 it is also possible that the pulmonary
capillary leak index in our subjects with HAPE would have
underestimated capillary permeability changes because of
passage of tagged red blood cells into the alveolar space.
The absence of a major increase in pulmonary capillary
leak index in HAPE seems to contrast with reported increases
in protein and inflammatory mediators in bronchoalveolar
lavage fluid in subjects with HAPE.16 These measurements,
however, were obtained in subjects at a later stage of HAPE
than in the present study. Conversely, elevated concentrations
of markers of inflammation have also been reported in
bronchoalveolar lavage fluid of patients with pulmonary
edema secondary to left heart failure.28 A likely scenario
therefore may be that markedly increased capillary pressures
(possibly with focal areas of stress failure) lead to secondary
inflammatory changes.
In summary, we found that subjects with early HAPE have
pulmonary capillary pressures ⬎19 mm Hg and a 67Ga PLI
within the normal range, suggesting that HAPE is initially a
hydrostatic-type pulmonary edema.
Acknowledgments
This study was supported by grants from the EMDO Foundation, the
Olga-Mayenfisch Foundation, and the Hermann-Kurz Foundation,
Zürich, Switzerland; the Crivelli Foundation, Lugano, Switzerland;
the Placide Nicod Foundation, Lausanne, Switzerland; the Swiss
National Research Foundation; the International Olympic Committee, United States; the Swiss and Belgian divisions of Baxter; Vygon,
Ecouen, France; and the Fonds de la Recherche Scientifique Médicale, Belgium (3.4517.95). We are most grateful to all the hut
keepers and the Sezione Varallo of the Italian Alpine Club for
providing the facilities at the Regina Margherita hut. We thank H.
Boeschenstein-Manner for preparing the manuscript.
References
1. Hultgren HN. High-altitude pulmonary edema: current concepts. Annu
Rev Med. 1996;47:267–284.
2. Fred HL, Schmith AM, Bates T, et al. Acute pulmonary edema of altitude.
Circulation. 1962;25:929 –937.
3. Penaloza D, Sime F. Circulatory dynamics during high altitude pulmonary edema. Am J Cardiol. 1969;23:369 –378.
4. Roy BS, Guleria JS, Khanna PK, et al. Haemodynamic studies in high
altitude pulmonary edema. Br Heart J. 1969;31:52–58.
High-Altitude Pulmonary Edema
2083
5. Kobayashi T, Koyama S, Kubo K, et al. Clinical features of patients with
high altitude pulmonary edema in Japan. Chest. 1987;92:814 – 821.
6. Koitzumi T, Kawashima A, Kubo K, et al. Radiographic and hemodynamic changes during recovery from high altitude pulmonary edema.
Intern Med. 1994;33:525–528.
7. Hultgren NH, Lopez CE, Lundberg E, et al. Physiologic studies of
pulmonary edema at high altitude. Circulation. 1964;29:393– 408.
8. Hultgren HN, Grover RF, Hartley LH. Abnormal circulatory responses to
high altitude in subjects with a previous history of high-altitude pulmonary edema. Circulation. 1971;44:759 –770.
9. Viswanathan R, Jain SK, Subramanian S, et al. Pulmonary edema of high
altitude, II: clinical, aerohemodynamic and biochemical studies in a group
with history of pulmonary edema of high altitude. Am Rev Respir Dis.
1969;100:334 –349.
10. Kawashima A, Kubo K, Kobayashi T, et al. Hemodynamic responses to
acute hypoxia, hypobaria, and exercise in subjects susceptible to high
altitude pulmonary edema. J Appl Physiol. 1989;67:1982–1989.
11. Oelz O, Maggiorini M, Ritter M, et al. Nifedipine for high altitude
pulmonary oedema. Lancet. 1989;2:1241–1244.
12. Bärtsch P, Maggiorini M, Ritter M, et al. Prevention of high altitude
pulmonary edema by nifedipine. N Engl J Med. 1991;325:1284 –1289.
13. Hackett PH, Roach RC, Hartig GS, et al. The effect of vasodilators on
pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med. 1992;13(suppl 1):S68 –S71.
14. Scherrer U, Vollenweider L, Delabays A, et al. Inhaled nitric oxide for
high altitude pulmonary edema. N Engl J Med. 1996;334:624 – 629.
15. West J, Colice G, Lee Y, et al. Pathogenesis of high-altitude pulmonary
oedema: direct evidence of stress failure of pulmonary capillaries. Eur
Respir J. 1995;8:523–529.
16. Schoene RB, Swenson ER, Pizzo CJ, et al. The lung at high altitude:
bronchoalveolar lavage in acute mountain sickness and pulmonary
edema. J Appl Physiol. 1988;64:2605–2613.
17. Vock P, Fretz C, Franciolli M, et al. High altitude pulmonary edema:
findings at high altitude chest radiography and physical examination.
Radiology. 1989;170:661– 666.
18. Cope DK, Grimbert F, Downey JM, et al. Pulmonary capillary pressure:
a review. Crit Care Med. 1992;20:1043–1056.
19. Gorin AB, Kohler J, DeNardo G. Noninvasive measurement of pulmonary
transvascular protein flux in normal man. J Clin Invest. 1980;66:869–877.
20. Raijmakers PG, Groeneveld AB, Teule GJ, et al. Diagnostic value of the
gallium-67 pulmonary leak index in pulmonary edema. J Nucl Med.
1996;37:1316 –1322.
21. Haycook K, Roth J, Gagnon J, et al. StatView: The Ultimate Integrated
Data Analysis and Presentation System.. . . 4.02 ed. Berkeley, Calif:
Abacus Concepts, Inc; 1993.
22. Kronenberg RG, Safar P, Wright F, et al. Pulmonary artery pressure and
alveolar gas exchange in men during acclimatization to 12,470 ft. J Clin
Invest. 1971;50:827– 837.
23. Groves BM, Reeves JT, Sutton JR, et al. Operation Everest II: elevated
high altitude pulmonary resistance unresponsive to oxygen. J Appl
Physiol. 1987;63:521–530.
24. Homik LA, Bshouty Z, Light RB, et al. Effect of alveolar hypoxia on pulmonary
fluid filtration in in situ dog lungs. J Appl Physiol. 1988;65:46–52.
25. Audi SH, Dawson CA, Rickaby AA, et al. Localisation of the sites of
pulmonary vasomotion by use of arterial and venous occlusion. J Appl
Physiol. 1991;70:2126 –2136.
26. Hakim TS, Kelly S. Occlusion pressures vs. micropipette pressures in the
pulmonary circulation. J Appl Physiol. 1989;67:1277–1285.
27. Whayne TF Jr, Severinghaus JW. Experimental hypoxic pulmonary
edema in the rat. J Appl Physiol. 1968;25:729 –732.
28. Schutte H, Lohmeyer J, Rosseau S, et al. Bronchoalveolar and systemic
cytokine profiles in patients with ARDS, severe pneumonia and cardiogenic pulmonary oedema. Eur Respir J. 1996;9:1858 –1867.
High-Altitude Pulmonary Edema Is Initially Caused by an Increase in Capillary Pressure
Marco Maggiorini, Christian Mélot, Sebastien Pierre, Fredi Pfeiffer, Ilona Greve, Claudio Sartori, Mattia
Lepori, Markus Hauser, Urs Scherrer and Robert Naeije
Circulation. 2001;103:2078-2083
doi: 10.1161/01.CIR.103.16.2078
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World
Wide Web at:
http://circ.ahajournals.org/content/103/16/2078
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once
the online version of the published article for which permission is being requested is located, click Request Permissions in
the middle column of the Web page under Services. Further information about this process is available in thePermissions
and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/