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Departments of Medicine and Radiology, University of Bern, Inselspital, CH-3010 Bern; Department of Medicine, Kantonsspital, CH-7000 Chur, Switzerland; Departments of Sports Medicine and Hematology, University of Heidelberg, D-69115 Heidelberg, Germany; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, Tennessee 37232-6602
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Kleger, Gian-Reto, Peter Bärtsch, Peter Vock, Bernhard
Heilig, L. Jackson Roberts II, and Peter E. Ballmer. Evidence against an increase in capillary permeability in subjects exposed to
high altitude. J. Appl. Physiol.
81(5): 1917-1923, 1996.
A potential pathogenetic cofactor for the
development of acute mountain sickness and high-altitude pulmonary
edema is an increase in capillary permeability, which could occur as a
result of an inflammatory reaction and/or free radical-mediated
injury to the lung. We measured the systemic albumin escape by
intravenously injecting 5 µCi of 125I-labeled albumin and the
plasma concentrations of cytokines, F2-isoprostanes (products of lipid
peroxidation), and acute-phase proteins in 24 subjects exposed to 4,559 m. Ten subjects developed acute mountain sickness, and four subjects
developed high-altitude pulmonary edema. The transcapillary escape
rate of albumin was 6.9 ± 2.0%/h (SD) at low (550 m) and 6.3 ± 1.9%/h at high (4,559 m) altitude (P = 0.23; n = 24). The subjects with
high-altitude pulmonary edema had a modest but insignificant increase
in the transcapillary escape rate of albumin (4.6 ± 1.9%/h at low
vs. 5.7 ± 1.9%/h at high altitude;
P = 0.42;
n = 4). Plasma concentrations of
fibrinogen, 
1-acid
glycoprotein, C-reactive protein, and interleukin-6 were unchanged in
the early phases and significantly increased by the end of the
observation period in the subjects with high-altitude pulmonary edema,
whereas tumor necrosis factor- and
F2-isoprostanes did not change at
all. This suggests that the inflammatory reaction was rather a
consequence than a causative factor of high-altitude pulmonary edema.
In summary, these data argue against a dominant role for increased
systemic capillary permeability in the development of acute mountain
sickness and high-altitude pulmonary edema.
vascular permeability; high-altitude pulmonary edema; acute
mountain sickness; free radicals; F2-isoprostanes
INTRODUCTION HIGH-ALTITUDE PULMONARY EDEMA (HAPE) is a
noncardiogenic pulmonary edema that may occur during the first days of
acute exposure to high altitude (19). HAPE is associated with an
increase in leakage of both fluid and proteins into the alveolar space
(34, 35) and enhanced hypoxic pulmonary vasoconstriction (20). It is
not clear, however, whether the increased leakage of fluid and proteins
is a cause or a consequence of HAPE. In contrast, a causative role for
high pulmonary arterial pressure in the development of HAPE has been
suggested by many workers. In this regard, pulmonary arterial
hypertension has been shown to precede HAPE formation (5), and lowering
pulmonary arterial pressure by various drugs is associated with
short-term improvement of pulmonary gas exchange (15, 33), long-term
clinical improvement (29), and prevention of HAPE (5).
The transcapillary escape rate (TER) of albumin is a measure of the
systemic capillary permeability (1, 2, 30) and was reported to be
elevated in subjects exposed to high altitude irrespective of the
presence of acute mountain sickness (AMS) or HAPE (8, 16). Coates
et al. (8) demonstrated a modest but insignificant increase in the TER
in healthy subjects exposed to an altitude of 4,300 m in a
pressure chamber. In a recent study, Hansen et al. (16) measured the
TER in healthy volunteers flown to 4,350 m and reported a significant
increase in the TER.
Previous studies that investigated the influence of high altitude on
the TER did not include subjects susceptible to HAPE and did not
explore potential pathogenetic factors (e.g., various inflammatory
cytokines and free radical mediated-injury) that could cause an
increase in systemic capillary permeability (3, 11, 12, 23, 25). We
were particularly interested in exploring the hypothesis that free
radical injury to the lung may play a role in the development of HAPE.
This was based on the fact that a release of tumor necrosis factor
(TNF) can occur in settings of diminished tissue oxygenation and that
TNF can cause enhanced hypoxic pulmonary vasoconstriction, generation
of free radicals, and pulmonary edema (9, 14, 21, 22, 32). We
investigated this hypothesis by determining whether exposure to high
altitude caused an increase in TNF release and
F2-isoprostane formation. F2-isoprostanes are
prostaglandin-like products of lipid peroxidation, and quantification
of F2-isoprostanes has proven to
be a reliable and sensitive marker of free radical-mediated injury in
vivo (26-28). We therefore investigated whether high-altitude
exposure in HAPE-resistant and HAPE-susceptible subjects was associated
with an increase in TER, altered levels of acute-phase proteins and
various plasma cytokines, or enhanced formation of
F2-isoprostanes, an indicator of
free radical-mediated injury.
METHODS Subjects and study
design. Twenty-four healthy subjects with former
exposure to high altitude (>4,000 m) were prospectively studied.
Eight of the subjects had a history of at least one documented episode
of HAPE, and two had a history of AMS. All subjects were studied in the
metabolic unit of the University Hospital of Bern, Switzerland (550 m;
baseline) and 3-4 wk later at a mountain hut in the Swiss-Italian
Alps (Capanna Margherita, 4,559 m). They started their active ascent on
foot at an altitude of 3,200 m and reached 3,611 m on the first day.
After an overnight stay, they continued the ascent to 4,559 m and
remained at this altitude for ~40 h, which included two overnight
stays.
The clinical investigations and determinations of the plasma
concentrations of various cytokines, acute-phase proteins, and F2-isoprostanes were performed at
baseline (i.e., time point
pre-ascent), within 2-3 h after arrival at 4,559 m (time point HA-1d), in the morning
after the first night (time point
HA-2d), and after the second night at 4,559 m before
departure (time point HA-3d). The TER was measured at time points
pre-ascent and HA-2d,
and chest radiography was performed at time points
pre-ascent and HA-3d or when clinical signs of HAPE were present.
The study protocol was approved by the Ethical Committee of the
University of Bern, and written informed consent was obtained from the
subjects before they participated in the study.
Measurement of TER of albumin. The TER
was measured according to the method described previously (1-3).
The subjects received 60 mg of potassium iodide orally starting the day
before the investigation and for 14 days thereafter to block
125I uptake by the thyroid gland.
After an overnight fast, 5 µCi of
125I-labeled albumin
(Sari-125-A-2, Sorin Biomedica, Saluggia, Italy) were injected
intravenously, and blood samples were drawn from an opposite cubital
vein at 10-min intervals over a period of 60 min. Radioactivity was
counted in 2-ml plasma samples on a gamma counter (1260 Multigamma II,
Wallac, Turku, Finland) and expressed as counts per
minute. Usually, albumin escape is expressed as a monoexponential
function because albumin molecules escape from the intravascular
compartment proportionally to the plasma albumin. However, the linear
and monoexponential curves of the decrease in counts over the first 60 min after an intravenous injection were not different, as described
earlier (1). Therefore, the TER of albumin was calculated from the
linear regression line of the decrease in plasma radioactivity over 60 min, according to the formula (1, 3, 31) TER (in %/h) = ( Determination of plasma protein
concentrations. Plasma protein concentrations were
measured at all time points (i.e., pre-ascent to HA-3d). Plasma albumin
concentration was determined with bromcresol purple (10) on a Hitachi
717 autoanalyzer (Wako Pure Chemical Industries, Osaka, Japan);
transferrin, Determination of plasma cytokine
concentrations. Interleukin (IL)-6, IL-1
× 60 × 100)/y, where is the slope and y is the intercept of
the linear regression.
1-acid
glycoprotein, and prealbumin were determined by nephelometry (Behring,
Marburg, Germany); and C-reactive protein (CRP) was determined by
turbidimetry. Plasma fibrinogen concentration was measured according to
the method of Clauss (7).
, IL-2,
soluble IL-2 receptor, TNF-, and TNF- receptor P-60 plasma
concentrations were measured with commercial assays (Quantikine, RD
Research and Diagnostics System, Minneapolis, MN).
0.05.
RESULTS
Clinical examinations. Fourteen of the twenty-four subjects (58%) suffered from AMS and four developed HAPE (17%). The AMS scores of all subjects are summarized in Table 1. HAPE was diagnosed on day HA-2d in one subject and on day HA-3d in the other three. Two of the subjects with AMS departed after the determinations at time point HA-2d because of progressive symptoms of mountain sickness.
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Three subjects with AMS received dexamethasone after and one before the determination of the TER. They were included in the final calculation because omitting them did not change the results. All subjects with HAPE showed a rapid improvement of symptoms after treatment with supplemental oxygen and oral nifedipine (20 mg every 6 h). For safety reasons, the two subjects with the most severe HAPE were flown out by helicopter to 1,600 m where they recovered completely within a few hours.
In Table 2, the results of the arterial blood gas analyses are summarized in the three groups, i.e., in subjects without AMS or HAPE (AMS/HAPE), with AMS, and with HAPE.
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TERs and plasma concentrations of
albumin. Figure 1 shows a
typical curve of the decline in plasma radioactivity, demonstrating the
linear decrease over the first 60 min (1). In Fig.
2, the TERs of albumin are shown for the
three groups. The TER was 6.9 ± 2.0%/h at low and 6.3 ± 1.9%/h at high altitude in all subjects (P = 0.23;
n = 24). TER was 7.5 ± 1.2 and 7.1 ± 1.8%/h (P = 0.61) in the group
without AMS/HAPE and 7.3 ± 2.2 and 5.8 ± 1.9%/h
(P = 0.07) in the group with AMS. The
subjects suffering from HAPE showed a modest increase in TER (from 4.6 ± 1.9 to 5.7 ± 1.9%/h), but this difference was not
significant (P = 0.42). When the
albumin escape was expressed as an absolute albumin outflux (in g/h or mg · kg body
weight
1 · h1),
again there was a modest but insignificant increase in the subjects
with HAPE (5.47 ± 2.2 to 6.95 ± 3.24 g/h;
P = 0.43).
Plasma albumin concentrations were within the normal range and showed
no change over time among the three groups (data not shown). The degree
of AMS as demonstrated by the Lake Louise score on day
HA-2d did not correlate with the values of TER (Fig.
3).
Plasma protein and cytokine
concentrations. The time courses of changes in plasma
fibrinogen and 1-acid
glycoprotein concentrations are given in Table
3. Fibrinogen
(P values are given in Table 3) and
1-acid glycoprotein plasma
concentrations increased significantly in the HAPE subjects at
time point HA-3d but did not increase in the other subjects.
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In Table 4, the plasma concentrations of prealbumin and transferrin are summarized. The slight decrease in the plasma concentration of the two proteins was not significant.
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Figure 4 summarizes the relationship
between the time courses of the plasma concentrations of both IL-6 and
CRP. Subjects without AMS/HAPE and with AMS showed no significant
changes in the plasma concentrations of IL-6 and CRP. In contrast,
subjects with HAPE exhibited a significant increase in plasma
concentrations of IL-6 at time point
HA-2d and of both IL-6 and CRP at time
point HA-3d (Fig. 4).
) and
interleukin-6 (IL-6; 
). HA-1d, within 2-3 h after arrival at
high altitude; HA-3d, after 2nd night at high altitude before
departure. No changes occurred in subjects without AMS/HAPE or with
AMS. In contrast, subjects with HAPE showed a significant increase in
IL-6 at time point HA-2d, succeeded by
a significant increase in both IL-6 and CRP plasma concentrations at
time point HA-3d.
The plasma concentrations of IL-1, soluble IL-2 receptor, and
TNF- receptor P-60 exhibited a wide scatter without any significant changes among the groups or at the different time points. IL-2 plasma
concentrations were below the level of detection. In contrast, mean
TNF- plasma concentrations were unexpectedly high at baseline in the
subjects without AMS/HAPE (see Table 5).
However, this can be attributed to the fact that two subjects had
sustained plasma concentrations that were above normal throughout the
entire observation period. Differences at high altitude among the
groups were, however, not significant after correction for baseline
values by analyzing differences between measurements obtained at
baseline and high altitude.
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DISCUSSION
In the present study, exposure to 4,559 m had no apparent effect on systemic capillary permeability irrespective of AMS. Subjects with HAPE exhibited a slight, albeit nonsignificant, increase in TER. The observed acute-phase reaction in HAPE subjects, reflected by an increase in the plasma concentrations of IL-6 and CRP, is most likely a consequence rather than a cause of HAPE because it occurred at a time point after the subjects had developed HAPE.
In contrast to earlier studies (8, 16), we have not found an increase
in the TER of albumin measured by intravenously injecting radiolabeled
albumin into the 24 subjects exposed to 4,559 m. Whereas the average
TER of subjects without AMS/HAPE and those with AMS remained virtually
unchanged, the small number of subjects
(n = 4) who developed HAPE exhibited a
modest increase in TER, but this was not significant. In a recent
study, Hansen et al. (16) demonstrated a small increase in TER in
subjects flown to an altitude of 4,350 m. The values of TER in their
subjects, however, were relatively low at sea level (4.8%/h) and
increased to only 6.7%/h at high altitude. The latter value would
still be close to the normal range of values of TER that Ballmer and colleagues (1, 2) and Parving and Gyntelberg
(30) have reported. The power analysis in our study indicated a
statistical power > 95%, assuming an absolute increase in TER by
2.5%/h (e.g., from 5 to 7.5%/h) and an error of 5%. Taking
sample size and variability into account, this calculation suggests
that the increase in TER observed by Hansen et al. (16) might be due to
an error because they examined only 12 subjects, of whom 3 were
excluded from the final analysis. Moreover, Hansen et al.
compared subjects treated with either a placebo or a
calcium-channel blocker (i.e., isradipine). Interestingly, four of the
six subjects on the calcium-channel blocker treatment exhibited an
increase in TER, whereas only two of the subjects on the placebo showed
an increase in TER. Although clearly speculative, one might argue that
isradipine itself had an influence on TER. Because calcium-channel
blockers are known to give rise to edema formation (24), presumably by
causing an increase in systemic vascular permeability, this might well produce an increase in TER.
In the present study, three of the four subjects suffering from HAPE showed small insignificant increases in the TER of albumin (see Fig. 2). In the fourth subject in whom the TER did not increase, clear radiographic evidence of beginning HAPE was present when the last measurement of TER was obtained. This may suggest that increased capillary permeability is not an essential requirement for the development of HAPE. However, measurement of TER is only a reflection of global capillary permeability and cannot mirror organ-specific changes. Moreover, the lymphatic return may redistribute substantial amounts of extravasated 125I-labeled albumin very rapidly. Also, the evidence of the present data is limited by the small number of subjects studied. With a larger number of subjects and more precise methods, e.g., early bronchoalveolar lavage, a minute capillary leak in the lungs might have been detected. Nevertheless, the observation in one subject with HAPE and unchanged TER would mitigate against a dominant causative role for increased capillary permeability in the pathogenesis of HAPE.
A potential shortcoming of the present study might be the overall limited sensitivity of the method used for measuring capillary permeability. Comparisons with the previous investigations by Ballmer and colleagues (1, 2) and Parving and Gyntelberg (30) demonstrate somewhat higher values of TER in the present study, with a larger scatter of data that can be attributed to unexpected and unexplained higher values in women (8.3 ± 2.0 vs. 6.3 ± 1.7%/h in men; P = 0.02) and possibly the younger age of the present subjects (average age 10 yr lower). Variability of TER data was similar at both altitudes, and the interindividual coefficient of variation in repeated measurements over a few hours was shown by Rossing et al. (31) to be 8.5% and over 1 yr only 14%. For these reasons and because several studies using the same method were able to demonstrate increases in TER, e.g., by >50% after injecting recombinant human IL-2 into melanoma patients (3) or by even 100% within a few hours of cardiac surgery or 300% in patients with septic shock (13), we do not think that methodological problems are responsible for the present negative findings. As pointed out before, a minor generalized capillary leak, however, cannot be excluded with our data.
Our data, which do not support a hypothesis that exposure to hypobaric hypoxia causes an increase in systemic TER, are in accordance with various in vivo findings in the literature. Homik et al. (18) investigated the differential effects of hypoxia and microvascular pressure in an in vivo preparation of dog lungs and demonstrated unequivocally that an increase in microvascular pressure was the only important pathogenetic factor causing edema formation in that model, irrespective of the inspired oxygen concentration. Moreover, Henriksen and Kok-Jensen (17) investigated patients with low oxygen tensions due to chronic obstructive pulmonary disease and found identical values of TER when compared with healthy subjects. On the other hand, there is evidence from animal studies that both normo- and hypobaric hypoxia increase pulmonary transvascular protein leakage (36). Thus rats exposed to a barometric pressure resembling 14,500 feet or to a fractional inspired oxygen concentration of 15% exhibited significant increases in protein leakage as measured by tagged albumin. The discrepancies between those findings and ours remain unexplained. Possible explanations may be differences between species and different sensitivities of the methods used, as suggested by Stelzner et al. (36).
Possible mechanisms to explain an increase in capillary permeability in
AMS/HAPE would be an acute inflammatory reaction and/or oxidant
injury. The data we obtained, however, do not support either of these
as playing a causative role in AMS or HAPE. First, the plasma
concentrations of the proinflammatory cytokines IL-1 and IL-2 did
not increase in either group of subjects. However, we cannot rule out
that early changes may have occurred that cannot be detected by a
global measurement of the plasma concentrations. The increase in plasma
concentrations of IL-6 and CRP in the subjects with HAPE occurred after
the onset of HAPE (Fig. 4), suggesting that these were not causative in
the development of HAPE. The observation with regard to CRP and the
development of HAPE confirms similar data obtained from a study carried
out previously at the same location (4). In regard to the possibility
of a free radical-mediated injury to the lung, we had considered a
hypothesis whereby a release of TNF might induce an oxidant injury to
the lung. However, we did not find any increase in the plasma
concentration of F2-isoprostanes, nor was there any correlation between the plasma concentration of TNF
and the occurrence of AMS or HAPE. As a group, higher levels of TNF
were actually found in the subjects who did not experience either AMS
or HAPE, primarily because of unusually sustained high levels in two
individuals. However, compared with the initial baseline values
measured, no significant increases were found at the later time points
in any of the groups.
On the surface, our findings may seem inconsistent with the findings of Schoene and colleagues (34, 35), who reported cellular infiltration, i.e., macrophages and high levels of high-molecular proteins, and inflammatory mediators, e.g., leukotriene B4, in the bronchoalveolar lavage fluid of subjects suffering from HAPE. However, because of the design of that study, those data appear to have been obtained during more severe and advanced stages of HAPE. Therefore, the inflammatory reaction may have been a consequence rather than a cause of HAPE.
In summary, exposure to high altitude, irrespective of AMS, does not cause a significant systemic capillary leak. However, we cannot exclude minute changes in systemic or even moderate increases in local pulmonary capillary permeability because the measurement of TER by injecting 125I-labeled albumin may not reflect organ-specific capillary permeability. Moreover, a solid conclusion in regard to HAPE cannot be drawn from our data because of the small number of subjects with HAPE. The observed increases in the plasma concentrations of inflammatory reactants, at the time point when some subjects had already developed HAPE, suggest that this may be a consequence rather than a cause of HAPE. Collectively, however, our data do not support the notion that exposure to high altitude causes a major alteration in capillary permeability. Rather, results from this and previous studies (5, 15, 29, 33) suggest that altered pulmonary hemodynamics is likely the primary causative factor involved in the pathogenesis of AMS/HAPE.
ACKNOWLEDGEMENTS
We thank the volunteers for their cooperation; Max Ballmer of the Swiss Alpine Club (Sektion Basel) for help in the recruitment of the volunteers; the Sezione Varallo del Club Alpino Italiano and the nurses of the Department of Medicine, University of Bern, Switzerland, for providing the facilities at the Capanna Regina Margherita and at the hospital; Dr. R. Mini, Department of Medical Radiation Physics, Inselspital, Bern, for assistance with the handling of radioactive substances in the field; the Swiss Army for providing and transporting the mobile X-ray unit; Franziska Keller for doing the chest radiographs; and Sylvia Schütz-Hofmann and Meral Turgay for expert technical assistance.
FOOTNOTES
Address for reprint requests: P. E. Ballmer, Dept. of Medicine, Univ. of Bern, Inselspital, CH-3010 Bern, Switzerland (E-mail: ballmer{at}insel.unibe.ch).
Received 10 November 1995; accepted in final form 25 June 1996.
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