Unraveling the Mechanism of High Altitude Pulmonary Edema

INTRODUCTION

ALL IMPORTANT MEDICAL SCIENCE begins witha clinical observation. Astute investigators

then document the abnormal clinical manifes-tations and pathophysiologic responses, atwhich time the detective work begins. Thereare few better examples of this process thanhigh altitude pulmonary edema (HAPE).

Over the last four decades, clinical observa-tions have led to physiologic documentationand, as technology advanced, cellular, molecu-lar, biochemical, and genetic biology attackedclinical problems with vigor. Although HAPEaffects a small number of people, very few clin-

ical entities have been so thoroughly unrav-eled. There are still a number of unansweredquestions regarding its pathophysiology, but itis a particular tribute to medical research thatso much is understood about HAPE.

This paper will not devote itself to the clini-cal presentation and treatment of HAPE norfully describe prominent earlier investigatorswho set the groundwork for future work. It willrather spend more time on the journey of thelatter two decades, which have confirmed thefindings of early investigators while progress-ing boldly into more recent levels of technol-ogy. It will then set a course for future investi-gators to put the final questions to rest.

HIGH ALTITUDE MEDICINE & BIOLOGYVolume 5, Number 2, 2004© Mary Ann Liebert, Inc.

Unraveling the Mechanism of High Altitude Pulmonary Edema

ROBERT B. SCHOENE

ABSTRACT

Schoene, Robert B. Unraveling the mechanism of high altitude pulmonary edema. High Alt. Med.& Biol. 5:125–135, 2004.—During the last decade, major advances in the understanding of themechanism of high altitude pulmonary edema (HAPE) have supplemented the landmark workdone in the previous 30 years. A brief review of the earlier studies will be described, which willthen be followed by a more complete treatise on the subsequent research, which has elucidatedthe role of accentuated pulmonary hypertension in the development of HAPE. Vasoactive me-diators, such as nitric oxide (NO) and endothelin-1, have played a major role in this under-standing and have led to preventive and therapeutic interventions. Additionally, the role of thealveolar epithelium and the Na–K ATPase pump in alveolar fluid clearance has also more re-cently been understood. Direction for future work will be given as well.

Key Words: pulmonary hypertension; endothelin-1; nitric oxide; alveolar fluid clearance; ac-climatization

Clinical Professor of Medicine, University of California, San Diego School of Medicine, and Program Director, In-ternal Medicine Residency, UCSD Medical Center, San Diego, California.

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FOUNDATION

HAPE is characterized by the extravasationof fluid from the intra- to extravascular spacein the lung. It occurs in otherwise healthy people without known cardiac or pulmonarydisease. Its clinical manifestations mimic anyform of alveolar-filling process, such as pneu-monia, cardiogenic edema, or other forms ofnoncardiogenic pulmonary edema. In fact, itwas thought to be congestive heart failure or pneumonia in its early clinical descriptionsgoing back to the late 19th century and into theearly 20th century (Mosso, 1898; Ravenhill,1913). By the mid-20th century, South Ameri-can clinicians were reporting cases of HAPEthat they thought were noncardiogenic formsof pulmonary edema (Hurtado, 1955; Lizar-raga and Soroche, 1955; Vega, 1955; Alzamora-Castro et al., 1961). The first descriptions in theEnglish literature were by Hultgren andSpickard (1960) and Houston (1960), with fol-low-up by Hultgren, Spickard, and Lopez in1962 (Hultgren et al., 1962). These papers con-centrated on clinical observation and the sus-picion that HAPE was a noncardiogenic formof pulmonary edema, which piqued the inter-est of investigators about the role of the pul-monary vasculature in HAPE. Questions aroseabout the hemodynamic response of this vas-cular bed and the site and mechanism of theleak. Before we speculate on what happenswhen the edema fluid is in the alveolus, let usfirst look at the vasculature from which thefluid leaks and we will find a rich and com-plex series of events.

THE PULMONARY VASCULATURE

Pulmonary vascular vasoreactivity and theendothelium go hand in hand. Many of the biochemical mediators of vasoreactivity are ac-tually produced in the endothelium, and theendothelium itself acts as a barrier to fluid ex-travasation into the extravascular space. Thenext sections will deal with an update on therole of pulmonary hypertension in the devel-opment of HAPE, its vasoactive mediators, andthe endothelium itself as a fragile barrier tofluid leak.

Pulmonary vasoreactivity

Accentuated pulmonary hypertension haslong been thought to be a major culprit in thepredisposition to HAPE. Both invasive (Fred etal., 1962; Hultgren, 1964; Roy et al., 1969; Hult-gren et al., 1971; Kobayashi et al., 1987) andnoninvasive echocardiography (Kawashima etal., 1989; Yagi et al., 1990; Hackett et al., 1992;Vachiery et al., 1995; Swenson et al., 2002) haveshown a strong relationship to the devel-opment of HAPE in individuals with eithermild resting normoxic pulmonary hyperten-sion and/or accentuated pulmonary vascularresponse to hypoxia and/or exercise. More re-cent studies have substantiated the ability toidentify HAPE-susceptible individuals by us-ing stress Doppler echocardiography (Gruniget al., 2000; see Fig. 1), as well as the close cor-relation in the same individuals between inva-sive and noninvasive (echocardiographic) mea-surements done at both low and high altitude(Allemann et al., 2000). Agents used to preventthis pressure rise (such as the calcium channelblocker nifedipine; Bartsch et al., 1991) or treatit or direct vasodilators, such as nitric oxide(NO) (Scherrer et al., 1996; Anand et al., 1998;Maggiorini et al., 1999), have prevented the development of HAPE in HAPE-susceptible individuals (nifedipine) and have improvedgas exchange in those already stricken withHAPE (NO).

Pulmonary hypertension alone may not beenough to result in the development of HAPE.Sartori et al. (2000) compared individuals whowere predisposed to a brisk hypoxic pul-monary vasoconstrictive response after suffer-ing transient hypoxic pulmonary hypertensionduring the perinatal period to a group of con-trols and to a group of HAPE-susceptiblemountaineers. Although both the HAPE-sus-ceptible individuals and the patient group de-veloped comparable degrees of pulmonary hy-pertension, none of them developed clinicalHAPE, while 8 of the 14 HAPE-susceptible in-dividuals did. This study suggests that otherfactors are necessary to develop the full-blownclinical picture.

A search for vasoactive mediators that maybe responsible for an accentuated HPVR hasled to some insight. Thromboxane B2 was

HIGH ALTITUDE PULMONARY EDEMA 127

found in bronchoalveolar lavage (BAL) fluid ofindividuals with HAPE (Schoene et al., 1986,1988). Endothelin-1, a potent pulmonary vaso-constrictor, was either increased or had de-creased clearance in individuals with HAPE(Sartori et al., 1999b; see Fig. 2), while aug-mented activation of sympathetic tone wasgreater in HAPE-susceptible individuals (Du-plain et al., 1999). The endothelin-1 associationis at best controversial, since other investiga-

tors did not see an increase (Bartsch et al., 2001).Furthermore, since hypoxia is a potent stimu-lus for endothelin-1 synthesis (Goerre et al.,1995), it is likely that the difference found inthe Sartori and Bartsch studies may have to dowith the fact that the SaO2% in the Sartori studyin the HAPE-susceptibles was 10% lower.

The pulmonary vasculature is also elegantlybalanced with means by which to vasodilate aswell as vasoconstrict. An imbalance of these re-

FIG. 1. A. Pulmonary artery systolic pressure (PASP) response as measured by Doppler echocardiography to pro-longed hypoxia in control (solid circles) and HAPE-susceptible subjects (solid diamonds) showing higher pressuresin HAPE-susceptible subjects. B. Time course of PASP during normoxic supine bicycle exercise in same subjects(Grunig et al., 2000). The data are strikingly similar to the invasive studies from the 1960s and 1970s as noted in thetext. (From Grunig et al., 2000)

A

B

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sponses can, therefore, lead to clinical illness.As mentioned before, NO plays a major role inpulmonary vasodilatation. For instance, in a ratmodel of HAPE, mortality was reduced from39.5% to 6.2% with the administration of NO(Omura et al., 2000). Furthermore, an indi-vidual’s inherent characteristic of producingand/or clearing NO may play an importantrole in the predisposition to HAPE. Duplain et al. (2000) found a reduced level of exhaledNO, suggesting that a defect in pulmonary ep-ithelial NO synthesis may contribute to an ex-aggerated HPVR and thus to HAPE in somesubjects (Fig. 3). A further study by Busch et al.(2001) found that, when exposed to hypoxia,mountaineers susceptible to HAPE had a de-creased level of NO exhalation compared tocontrols, which suggests an inherently lowerNO synthesis or increased clearance, resultingin less pulmonary vasodilatation and higherpulmonary artery pressures (Fig. 4). Thesefindings were supported further by the studyby Swenson et al. (2002).

Understanding of the mediators of vasocon-striction and vasorelaxation has important im-plications for prevention and therapy. As wasmentioned, nifedipine was used to mitigate theaccentuated HPVR in HAPE-susceptible indi-viduals in a field study on the summit of MonteRosa and was found to be successful in pre-venting HAPE. This study has led to the capa-bility of preventing HAPE in individuals who

are susceptible to it who still desire to go tohigh altitude. The use of NO is obviously im-practical in the field, but other substances offerpotential hope. Examples of such interventionsinclude L-arginine, an over-the-counter sup-plement, which is a precursor to NO that mayaugment pulmonary vasodilatation. A greatdeal of interest is being shown in the use ofsildenafil, a phosphodiesterase-V inhibitor that

FIG. 2. Arterial oxygen saturation (%), endothelin-1 (pg/mL), and pulmonary artery pressure (mmHg) in 16 moun-taineers prone to HAPE (open bars) and 16 control subjects resistant to HAPE (dark bars) when exposed to 4459 maltitude. (From Sartori et al., 1999)

FIG. 3. The effects of high altitude exposure on exhaledpulmonary nitric oxide (NO) in 13 HAPE-susceptible sub-jects who developed pulmonary edema (open squares),15 HAPE-susceptible subjects who did not develop pul-monary edema (closed squares), and 24 control subjects(open circles). (From Duplain et al., 2000)

Hours at high altitude(4559 m)

Exh

aled

nitr

ic o

xide

(pm

ol/s

ec)

1230

50

70

24 36 48


also leads to pulmonary vascular relaxation onboth the pulmonary arteriolar and the pul-monary venular side (Kleinsasser et al., 2001;Lodato, 2001; Zhao et al., 2001). An equally “en-joyable” remedy might lie in red wine, whichsuppresses endothelin-1 gene expression aswell as having antioxidative properties, both ofwhich may be helpful in ameliorating thepropensity for HAPE (Schafer and Bauersachs,2002). Such innovative therapy should lead toan enthusiastic number of subjects going tohigh altitude for more than just the enjoymentof the view.

The endothelium as a barrier

The pulmonary endothelium is a fragile bar-rier that is susceptible to both mechanical stressand inflammation. Increased physical pres-sures can lead to stretching of the endothelium,creating gaps that are open to both proteins andred blood cells, such as is well known in con-gestive heart failure, while inflammation canlead to a similar outcome by an insult to thisfragile monolayer of cells. Two major contro-versies have been discussed with respect toHAPE over the last two decades or more. First,is inflammation necessary to make the endo-thelium more susceptible to leak from highpressures and/or is it the primary culprit in

HAPE? Second, are high pressures adequatealone to result in the extravascular leak offluid?

This discussion began when leukotriene B4concentrations were found to be very high inBAL fluid in subjects acutely ill with HAPE(Schoene et al., 1986, 1988), while levels ofleukotriene E4, a stable metabolite of the in-flammatory arachidonic acid cascade, werefound to be high in individuals with HAPE, butnot in controls at a moderate-altitude ski resort(Kaminsky et al., 1996). Since these studieswere done in individuals already sick withHAPE, it was difficult to know whether the in-flammation was an inciting factor or merely apost facto phenomenon in response to the pro-tein leak. A number of years after the initiallavage studies, one of the original investigatorsrepeated the study, but with a different design.Swenson et al. (2002) did both low and high al-titude BAL studies in HAPE-susceptible indi-viduals. Upon acute ascent and early signs ofHAPE, he lavaged subjects and found higherpulmonary artery pressures and high levels ofprotein, but no evidence of inflammatory me-diators (Fig. 5). In another study there was noevidence of an increase in urinary leukotrieneE4 in HAPE-susceptible individuals exposed tohypoxia (Bartsch et al., 2000). These studieswere a logical follow-up to the earlier ones and

FIG. 4. Effects of prolonged hypoxia (12% oxygen) on pulmonary NO excretion rates in HAPE-susceptible subjects(open columns, n � 9) and control subjects (solid columns, n � 9). Data are given as percentage of normoxic baselinevalues. (From Busch et al., 2001)

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gave strong evidence for a lack of inflamma-tion as a necessary comorbid factor in the de-velopment of HAPE.

Further efforts to look for inflammatory mediators during exposure to hypoxia have led to the investigation of vascular endothelialgrowth factors specific to the pulmonary vas-culature in individuals susceptible to HAPE.The exposure to high altitude in both normalsubjects and HAPE-susceptibles (Walter et al.,2001) has led to results with no elevation ofVEGF, making the role of the substance in thedevelopment of HAPE unlikely.

The site of the fluid leak in the lung still re-mains unclear. If one assumes that an increasein hydrostatic pressures is necessary to cause

the leak, then the precapillary arteriole, the pul-monary capillary, and the pulmonary venulesremain the leading and only contenders. Thedetermination of the site relies on where the in-creased pressures are seen. If HPVR is uniformat the precapillary level, then the precapillaryarteriole would be the primary location forleak. If, on the other hand, there is hetero-geneity to this vasoconstriction, then the pre-capillary arteriole and the pulmonary capillarywhere the constricted blood flow could be di-verted are both possible sites. However, hy-poxic pulmonary venoconstriction is wellknown to occur and was predicted to be a ma-jor cause in the increase in pulmonary capillarypressure that leads to pulmonary edema asearly as 1960 by Hultgren and Spickard in theirdescription of HAPE in South America (Hult-gren and Spickard, 1960). Hultgren stated,“Pulmonary venous constriction induced byhypoxia may be the fundamental causativemechanism. This would result in elevation ofpulmonary capillary pressure without eleva-tion of left ventricular diastolic pressure.” Sub-sequent studies investigated the hemodynam-ics of hypoxic pulmonary venoconstriction(Hakim et al., 1983; Hakim, 1988; Audi et al.,1991; Hillier et al., 1997), and a recent study byMaggiorini et al. (2001) used the rapid occlu-sion technique during pulmonary catheteriza-tion in control and HAPE-susceptible subjectsat high altitude and found evidence of in-creased pulmonary capillary pressures in theHAPE-susceptible subjects without signs of leftventricular dysfunction.

Furthermore, more evidence is accumulatingthat HPVR is heterogeneous, which, in addi-tion to the evidence of pulmonary venocon-striction, would still leave two sites of leak, thepulmonary capillary and the precapillary arte-riole. Not only does HPVR appear to be patchy,but it may be even more so in HAPE-suscepti-ble individuals (Viswanathan et al., 1979; Elseret al., 1998). Using SPECT scanning, investiga-tors found more homogeneous flow in HAPE-resistant subjects who were exposed to 5 h ofbreathing 11% oxygen. The HAPE-susceptiblesubjects had much more heterogeneity of flow.Using anesthetized supine pigs and infusion ofmicrospheres during different levels of hy-poxia, Hlastala et al. (in press) showed great

FIG. 5. Three panels showing pulmonary artery systolicpressure (mmHg), bronchoalveolar lavage (BAL) redblood cells (�106 �L, and BAL albumin (mg/dL) at lowaltitude and high altitude (4559 m) in HAPE-resistant(light column), HAPE-susceptible but well subjects (mid-dle column), and HAPE-susceptible subjects with HAPE.(From Swenson et al., 2002)


heterogeneity in the distribution of perfusion,which was related in part to the heterogeneityof the baseline ventilation–perfusion matching.These studies thus lend strong evidence to het-erogeneous HPVR in the mammalian lung, de-grees of which, because of areas of accentuatedintravascular pressures, may predispose cer-tain individuals to HAPE.

If increased pressures are distributed in apatchy fashion throughout the lung vascula-ture, how can we be assured that these pres-sures can lead to endothelial leak? The conceptof stress-induced failure of pulmonary capil-lary endothelium has been recently reviewed(West and Mathieu-Costello, 1998, 1999; West,2000) and is defined as an increase of intravas-cular hydrostatic pressure that “stretches” theendothelial lining, baring the basement mem-brane and leading to leak of fluid into the ex-travascular space. The reviews were based on previous studies by these same authors(Tsukimoto et al., 1991; West et al., 1991, 1993; West and Mathieu-Costello, 1992a, 1992b, 1993,1995). This body of research showed that acuteelevation of hydrostatic pressures in the mi-crovasculature to the levels of 40 mmHg in ananimal model can lead to stress failure of theendothelium (Fig. 6), but pressures as low as

20 mm Hg can result in early interstitial edema(Maggiorini, 2002). Clearly, depending on thedegree of failure, abnormally elevated levels ofprotein, including high molecular weight pro-teins, can extravasate into the extravascularspace, and if the stress is great enough and thegaps large enough, red blood cells may also bepresent in this space.

We thus have strong evidence that increasedpressures in the pulmonary microvasculatureplay a major role in the development of HAPE.These sites include the pulmonary capillaryand the precapillary arteriole. Furthermore,there is much greater understanding of boththe mediators of the vasoconstriction and theindividual variability, which is probably ge-netically conveyed, that will lead to suscepti-bility to HAPE.

THE ALVEOLAR EPITHELIUM ANDFLUID HOMEOSTASIS

The role of fluid in the extravascular spacein the lung in health and disease depends notonly on its accumulation, but also on the effi-ciency of its rate of clearance from the alveolarand interstitial spaces and subsequent lym-

FIG. 6. Number of breaks per millimeter of endothelial and epithelial boundary length plotted against capillarytransmural pressure in the rabbit pulmonary vasculature. The number of breaks rises precipitously after 24 mmHg.These pressures are consistent with pressures experienced at high altitude or during maximal exercise. (From Westand Mathieu-Costello, 1999.)

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phatic drainage. Thus, the role of alveolar fluidclearance (AFC) in HAPE has received in-creasing attention over the last few years andwas recently reviewed (Hoschele and Mair-baurl, 2003). The mechanism of clearance oc-curs at the alveolar epithelial cell barrier and isan active process utilizing Na,K-ATPase. Dadaet al. (2003) demonstrated recently a time-de-pendent decrease of Na,K-ATPase activity inepithelial cells exposed to hypoxia (Fig. 7). Inthis elegant study, which has numerous impli-cations for clinical situations, hypoxia alsocaused an increase in mitochondrial reactiveoxygen species (ROS) levels that was subse-quently inhibited by antioxidants. The anti-oxidants also prevented the hypoxia-mediateddecrease in Na,K-ATPase activity and accu-mulation of protein at the basolateral mem-brane. This study thus suggests two importantmechanisms contributing to impaired clear-ance of alveolar fluid.

This study comes on the shoulders of earlierones that looked at epithelial Na channel pro-tein (ENaC) as a marker for fluid clearance. Using mesoepithelial potential difference mea-surements that are amiloride sensitive, investi-gators found that HAPE-prone individualsmay have lower ENaC (Sartori et al., 1999b).Mice partially deficient in ENaC also showedgreater lung water accumulation when ex-posed to hypoxia (Lepori et al., 1999). A healthy

and normal epithelial barrier appears neces-sary for removal of and recovery from alveolaredema. A number of other studies showed thatthe impairment induced by hypoxia in ani-mal models was reversed by returning them to normoxia (Matthay and Wiener-Kronish,1990; Planes et al., 1996, 1997; Mairbaurl et al.,1997).

The site of the alveolar epithelium thus pro-vides another locus where prophylactic or ther-apeutic intervention can be investigated. In thislight, Sartori et al. (2002) used a �-agonist, sal-meterol, that facilitates alveolar fluid clearancethrough the Na,K-ATPase pump in HAPE-sus-ceptible individuals and found that the risk ofHAPE was much lower on the �-agonist. Sal-meterol may also lower pulmonary artery pres-sures and decrease inflammation, two mecha-nisms that may lead to HAPE, but theseconfounding factors need to be elucidated at alater date.

GENETIC FACTORS

Given that there is great heterogeneity in bi-ologic response in humans, it is conceivablethat some characteristics are controlled by genepolymorphisms that regulate the response ofvarious mediators. For instance, the accentu-ated HPVR in HAPE-susceptible individuals

FIG. 7. Hypoxia decreases NA,K-ATPase activity in endothelial cells exposed to severe hypoxia, 1.5% O2, for 15, 30,or 60 min. (From Dada et al., 2003)


may have similar gene signaling as in patientswho develop familial pulmonary arterial hy-pertension, who have a gene mutation thoughtto lead to the inexorable process in this disease.Furthermore, genes that regulate NO or en-dothelin-1 synthesis may be up- or downregu-lated in a way that predisposes these people topulmonary hypertension. In fact, Droma et al.(2002) found a positive association of endothe-lial nitric oxide synthase gene polymorphismsand HAPE. Their findings suggest that theremay be an impaired synthesis of NO that car-ries with it a genetic marker that may predictsusceptibility to HAPE, but much more workis necessary to extend and confirm these in-triguing findings.

In another study looking at vasomotor reac-tivity to hypoxia in the lung, Hanaoka et al.(2000) showed that HAPE-susceptible individ-uals had increased pulmonary artery pressuresduring hypoxia compared to control subjects,with a greater cephalad redistribution of bloodflow in a subgroup with human leukocyte anti-gen (HLA-DR6) alleles that were not present inHAPE-resistant subjects. Attempts to look atangiotensin-converting enzyme genes withvarious alleles have also been undertaken in anattempt to understand vasoreactivity in fluidbalance, but Dehnert et al. (2002) found no as-sociation between the ACE I/D gene polymor-phisms in HAPE-susceptible subjects.

Like the attempt to identify alterations ingene makeup in many clinical entities, so thegenetic survey studies with some physiologicbasis in HAPE will also go on for many yearsto come. The identification of gene alterationscan lead either to direct gene therapy and/orto identification of individuals susceptible toHAPE. It will then be some time before practi-cal application of such investigations can cometo fruition, but in its embryonic phase it is ex-citing to think of the possibilities.

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Address reprint requests to:Robert B. Schoene, MD

Program DirectorInternal Medicine Residency

University of CaliforniaSan Diego Medical Center

200 West Arbor DriveSan Diego, CA 92103

E-mail: [email protected]

Received December 1, 2003; accepted in finalform February 25, 2004

Documents

Unraveling the Mechanism of High Altitude Pulmonary Edema