Managing High-Altitude Pulmonary Edema with Oxygen Alone: Results of a Randomized Controlled Trial

Abstract

Yanamandra, Uday, Velu Nair, Surinderpal Singh, Amul Gupta, Deepak Mulajkar, Sushma Yanamandra, Konchok Norgais, Ruchira Mukherjee, Vikrant Singh, Srinivasa A. Bhattachar, Sagarika Patyal, and Rajan Grewal. High-altitude pulmonary edema management: Is anything other than oxygen required? Results of a randomized controlled trial. High Alt Med Biol. 17:294–299, 2016.—Treatment strategies for management of high-altitude pulmonary edema (HAPE) are mainly based on the observational studies with only two randomized controlled trials, thus the practice is very heterogeneous and individualized as per the choice of treating physician. To compare the response to different modalities of therapy in patients with HAPE in a randomized controlled manner. We conducted an open-label, randomized noninferiority trial to compare three modalities of therapy (Therapy 1: supplemental O₂ with oral dexamethasone 8 mg q8 hours [n = 42], Therapy 2: supplemental O₂ with sustained release oral nifedipine 20 mg q8 hours [n = 41], and Therapy 3: only supplemental O₂ [n = 50]). Bed rest was mandated in all patients. The study was conducted in a cohort of previously healthy young lowlander males at an altitude of 3500 m. Baseline characteristics of the patients were comparable in the study arms. Complete response was defined as clinical and radiological resolution of features of HAPE, no oxygen dependency, a normal 6-minute walk test (6MWT) on 2 consecutive days, and normal two-dimensional echocardiography. Results were compared by analysis of variance using SPSS version 16.0. There was no statistical difference in duration of therapy to complete response between the three groups (Therapy 1: 8.1 ± 4.0 days, Therapy 2: 6.7 ± 3.9 days, Therapy 3: 6.8 ± 3.2 days; p = 0.15). There were no deaths in any of the groups. We conclude that oxygen and bed rest alone are adequate therapy for HAPE and that adjuvant pharmacotherapy with either dexamethasone or nifedipine does not hasten recovery.

Introduction

Increasingly, people are moving to high altitude for work or tourism, sometimes to altitudes more than 4500 m. Every year, the beauty and recreational opportunities of the mountains attract millions of visitors from lowland to high-altitude destinations worldwide. These sojourns to high-altitude (HA) can be accompanied by a spectrum of health problems known as high-altitude illnesses (HAI).

High-altitude pulmonary edema (HAPE) is only second to acute mountain sickness (AMS) in its prevalence among all HAI. The management of HAPE varies between institutions and even between physicians within the same institution. The Wilderness Medical Society (WMS) guidelines published in 2014 (Luks et al., 2014) recommend strategies for prevention and treatment of HAPE, primarily based on observational studies of trekkers and mountaineers with only two small randomized controlled trials (RCTs) published to date (Anand et al., 1998; Deshwal et al., 2012). There are very few studies on management of HAPE in situations outside trekking/mountaineering circumstances (Marticorena and Hultgren, 1979; Zafren et al., 1996; Anand et al., 1998). Long-term deployments for occupational reasons (mining, military deployment, porters, railroad workers, etc.) pose different challenges from mountaineering and trekking with respect to the availability of therapies, a higher incidence of re-entry HAPE, and precipitating factors such as unaccustomed exertion or infection in this subset. It is also not always possible to have every individual with HAPE descend as per the WMS 2014 guidelines due to occupational requirements, costs, and inclement weather conditions (Luks et al., 2010). Descent may not be an easy option and drugs may not always be available, but oxygen alone may be sufficient. Given the very limited data in this area, we conducted an open-label RCT in a cohort of young males at an altitude of 3500 m.

Aim and Objective

To study the noninferiority of supplemental oxygen given as the only therapy versus supplemental oxygen with the addition of one of two pharmacological agents (dexamethasone and nifedipine) in two separate therapeutic arms. The primary endpoint of the study was a response to therapy. A secondary endpoint was all-cause mortality or the need to descend for further care.

Patients and Methods

Methodology

The study design was an open-label, randomized controlled noninferiority trial conducted over a period of 1.5 years at a single secondary-level hospital situated at 3500 m in the Himalayas of Northern India. The patients included only previously healthy lowlander young males. They underwent medical evaluation (detailed history, complete blood count [CBC], liver and renal chemistries and lipid profile, chest radiography, physical examination, and history of any comorbidities) before induction to high altitude and also at periodic intervals (CBC and physical examination) after induction to HA (Day 1–7 and monthly thereafter). All individuals were acclimatized within 6 days on reaching 3500 m either by road or air. Thereafter, they undertook a staged ascent to the target altitude of occupation/deployment. Institutional ethics committee approval was obtained, and the study adhered to all guidelines mandated by the Declaration of Helsinki.

Patients

All cases of HAPE irrespective of severity presenting to the study center were admitted. After providing informed consent, the patients were either included or excluded from the study as per the selection criteria listed in Table 1. Patients in this study were restricted to those not having been above 4000 m. Patients were selected by alphabetic randomization, in which all individuals with given first names starting from A to I were randomized to therapy 1, J to R were randomized to therapy 2, and S to Z were randomized to therapy 3. Patients were subjected to a standardized evaluation both at admission and then at regular intervals thereafter, as shown in Table 2.

Table 1.

Selection Criteria for the Patients

Inclusion criteria	Exclusion criteria
• Lowlanders	• Highlanders (Ladakhi/Tibetan ethnicity/born in HA)
• Newly diagnosed HAPE cases	• HAI (HAPE, AMS, and HACE) in the last 6 months
• No known comorbidities	• On treatment with pharmacological agents before randomization.
• Previously healthy subjects	• Presence of simultaneous HACE

AMS, acute mountain sickness; HA, high-altitude; HACE, high-altitude cerebral edema; HAI, high-altitude illnesses; HAPE, high-altitude pulmonary edema.

Table 2.

Investigations Panel for the Patients Included in the Study

Baseline investigations	Follow-up investigations
• Baseline peripheral saturation (SpO₂) by pulse oximetry	• Four hourly SpO₂
• Clinical parameters	• Four hourly clinical parameters
–Pulse	• Chest X-ray—Day 1, 3, 5, 7, 10
–Blood pressure (BP)	• 6MWT daily after day 3 of admission or SpO2 > 92% (without supplemental O₂), whichever is earlier
–Respiratory rate (R/R)	• Two-dimensional echocardiography—at discharge
–Temperature
• Chest X-ray—PA view
• Radiological scoring by
–Vock's scoring^a
• Baseline 2D echocardiography

Vock et al. (1991).

2D, two dimensional; 6MWT, 6-minute walk test; PA, posterior–anterior; SpO₂, oxygen saturation as measured by pulse oximetry.

Standard chest radiography or chest X-rays (CXRs) were performed using floor-mounted projection radiography (nondigital equipment of 60 kV, 75 mAs exposure time, and film source distance of 6 feet) on day 1, 3, 5, 7, and 10 (frequency was increased if clinically indicated). Standing posterior–anterior (PA) radiographs at end inspiration were done routinely, but portable bedside supine antero-posterior views were obtained in patients not able to stand upright without help, n = 4). All CXRs were independently assessed by radiologists blinded to the study and reviewed by the primary author (not blinded to the study). The CXR was used to confirm the diagnosis of HAPE, grade its severity based on Vock's scoring criteria (Vock et al., 1991), provide alternative diagnosis, and to use subsequently during follow-up as a criterion for the remission of HAPE (if positive at diagnosis). Patients who met the Lake Louise criteria for HAPE (defined as the presence of at least two pulmonary signs among rales or wheezing in at least one lung field, central cyanosis, tachypnea, tachycardia, and two pulmonary symptoms among cough, dyspnea at rest, weakness or decreased exercise performance, chest tightness or congestion) were screened for the study and the diagnosis of HAPE was further confirmed by a positive CXR (Sutton et al., 1992). Patients with a negative CXR were excluded from analysis.

Echocardiography was performed using the Phillips^™ HD7 Diagnostic Ultra Scanner system. Pulmonary artery systolic pressure (PASP) was estimated using the tricuspid regurgitation (TR) velocity. The TR signal was assessed in inspiration, in a right ventricular two-chamber view or a subcostal view ensuring that a continuous wave Doppler signal parallel to the TR jet could be obtained. The right atrial pressure was estimated indirectly assessing inferior vena cava collapse in a subcostal view (Rudski et al., 2010). The measurement of PASP was possible only in 82% of the patients (with no statistical difference between the therapeutic groups), either due to a poor window or severe tachypnea/tachycardia.

Because co-occurrence of HAPE/high-altitude cerebral edema (HACE) is not uncommon, patients with simultaneous high-altitude cerebral edema (HACE) were excluded as the management includes steroid administration.

Baseline characteristics of the patients were compared. All patients were brought to medical attention within a period of 30–60 minutes from symptom onset and after randomization. They were initially treated with supplemental oxygen and respective pharmacotherapy (based on the randomization) with subsequent transfer to the study center under medical attention while remaining on supplemental oxygen while in route. The median time to transfer the patient was 3.4 hours, with a wide variability (30 minutes to 6.4 hours) depending on the terrain and mode of transport. There was no statistically significant difference between the groups in the time to transfer. Patients were further managed at the study center at 3500 m. No patients warranted evacuation to sea level or lower altitude due to clinical worsening. Bed rest was mandatory for all the patients until clinical improvement. The response criteria were predefined and the duration of response in days was compared between the three groups. All clinical events, if any during this period, were recorded.

Study arms

Therapy 1: Oxygen with dexamethasone

Patients were managed with supplemental oxygen and were given oral dexamethasone 8 mg q8 hours until documentation of response/remission as per the predefined criteria outlined below.

Therapy 2: Oxygen with nifedipine

Patients were managed with supplemental oxygen and were given nifedipine 20 mg sustained release q8 hours until documentation of response/remission as per the predefined criteria outlined below.

Therapy 3: Oxygen therapy

Patients were managed with supplemental oxygen provided by a Venturi mask with an oxygen flow rate of 8–10 L/min and F_IO₂ of 0.5 for the first 24 hours or until a stable oxygen saturation as measured by pulse oximetry (SpO₂) off supplemental oxygen (>92% for 15 minutes), whichever came sooner. Following this, the oxygen flow rate was decreased to 4–6 L/min with F_IO₂ of 0.3–0.4 until the subsidence of clinical signs (chest auscultatory findings of rales, wheeze, and crepitations, tachypnea, tachycardia, and cyanosis if present at baseline). Subsequently, the oxygen flow rate was maintained at 2 L/min by oxygen concentrator with F_IO₂ of 0.27 for at least 12 hours in a day until documentation of complete response. F_IO₂ was based on the flowmeters attached to Venturi devices (although the actual F_IO₂ may vary in the hypobaric environment and was not objectively measured).

Patients were subjected to strict bed rest (no movement outside bed even for daily routines) for the first 24 hours or stable SpO₂ off supplemental oxygen (above 92% for 15 minutes), whichever was later. Thereafter, patients were allowed use the bathroom (∼50 m) on subsidence of clinical signs (as above). Patients were allowed to do activities of daily living only after normalization of their 6-minute walk test (6MWT—described below). Treating physicians were at liberty to add any further therapy and medications in cases of clinical worsening or send the patient to lower altitude (sea level), but these patients were then excluded from the study.

Outcome measures

The mean duration of therapy to complete response was calculated from the day of symptom onset to when the patient achieved a complete response. A complete response was defined as clinical and radiological resolution of features of HAPE, no oxygen dependency (defined as SpO₂ on ambient air >92% for more than 2 hours), a 6MWT distance >500 m (ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories, 2002) on 2 consecutive days, and two-dimensional echocardiography being normal (defined for this study as PASP <35 mm and a documented fall from the PASP at diagnosis). Adverse events were defined as the need for descent to sea level due to clinical worsening despite best available therapy at 3500 m or death from any cause.

Statistical analysis

The data were analyzed using SPSS version 16.0, the results are presented as mean ± standard deviation, and a p-value of <0.05 was accepted as significant. The results were compared by analysis of variance.

Results

Of the patients admitted with HAPE during the study period, 246 patients with HAPE were screened for inclusion in the study and 150 were randomized (Fig. 1).

FIG. 1.

Consort diagram and management in the therapeutic groups of the study.

The patients in all three arms were comparable with no statistical differences in mean age, severity of HAPE (as identified by baseline SpO₂ and Vock's radiological score), duration of high-altitude stay, the altitude at which patient developed HAPE, the mean change in altitude from the place of occurrence to the study center, and baseline mean arterial blood pressure. The baseline characteristics of the three groups are presented in Table 3. Among the study patients, 13.5% (n = 18) had an oral temperature more than 98.9°F/99.9°F (6 a.m./4 p.m., respectively) during the first 24 hours of presentation. Careful physical examination and symptoms described by the patients did not suggest infection. Also, all patients had subsidence of fever without antibiotics or specific therapy for fever, and had no other localizing signs to suggest infection. The incidence of fever at presentation or within the first 24 hours was not different between the three groups.

Table 3.

Comparison of the Parameters in All Three Therapeutic Modalities

	Dexamethasone+O₂					Nifidepine+O₂					O₂ alone
	Mean	Median	SD	Min.	Max.	Mean	Median	SD	Min.	Max.	Mean	Median	SD	Min.	Max.	p
Age (years)	32.86	33.50	7.10	21.00	48.00	32.95	33.00	7.08	21.00	52.00	33.28	31.00	9.16	21.00	56.00	0.96
SpO₂ (%)	66.40	66.00	14.07	33.00	87.00	63.27	65.00	12.04	28.00	86.00	64.98	66.00	11.41	40.00	84.00	0.52
Vock's score	12.33	13.50	3.87	4.00	16.00	12.44	12.00	3.74	2.00	16.00	12.12	12.00	3.31	4.00	16.00	0.91
HA stay (weeks)^a	7.53	6.80	4.56	0.28	20.00	7.17	6.50	4.48	0.42	22.00	7.55	6.85	5.19	0.54	22.00	0.92
Heart rate (per minute)	106.07	107.00	13.75	85.00	142.00	108.73	107.00	12.04	86.00	144.00	107.02	106.00	11.41	88.00	132.00	0.61
Respiratory rate (per minute)	30.07	30.00	4.56	18.00	36.00	29.85	30.00	5.40	20.00	44.00	27.86	29.50	6.66	10.00	38.00	0.12
Altitude of HAPE occurrence (m)	3480.95	3500.00	165.14	3100.00	3800.00	3548.10	3548.00	182.49	3100.00	3810.00	3511.44	3500.00	155.27	3100.00	3800.00	0.19
Change in altitude for therapy (m)^b	19.05	0.00	165.14	−300.00	400.00	−48.10	−48.00	182.49	−310.00	400.00	−11.44	0.00	155.27	−300.00	400.00	0.19
Time for complete response (d)	8.12	7.00	4.03	4.00	12.00	6.71	6.00	3.95	4.00	12.00	6.82	6.00	3.24	4.00	11.00	0.15

HA stay: continuous stay at HA without return to sea level from the time of induction to 3500 m (further changes in altitude beyond 3500 m not taken into account for duration of stay calculation).

Change in altitude for therapy = altitude of study center − altitude of HAPE occurrence.

SD, standard deviation.

The mean systolic pulmonary artery pressures at rest (using TR gradient and right atrial pressure) were elevated in the patients at diagnosis (mean −44 ± 2 mmHg) with no significant difference in the different arms (p = 0.842). The pressures at the time of discharge were significantly lower (mean −26 ± 3 mmHg; p = 0.02), but there was no significant difference between the groups (p = 0.74).

There were no deaths in any of the three groups. The mean duration of time to response was not significantly different among the three groups with a p-value of 0.15 (Table 3).

Discussion

HAPE can be life threatening in the absence of timely management. Current management strategies are those recommended in the WMS 2014 guidelines, which are derived mainly from observational studies, case series, and expert opinion. There are only two small randomized treatment studies (Anand et al., 1998; Deshwal et al., 2012; Luks et al., 2014), only one of which used nifedipine as we did (Deshwal et al.), while the other used inhaled nitric oxide (Anand et al.), a very expensive therapy. The major strength of our study is that it is the only RCT to compare these three practical and relatively inexpensive therapeutic modalities in the management of HAPE. Patients in this study were restricted to those who developed HAPE at an altitude no greater than 4000 m. There was no statistical difference in the time to response between the therapeutic arms. There was a nonstatistically significant trend toward a longer recovery time in the patients treated with dexamethasone.

Diagnosis of HAPE in this study protocol was based both on Lake Louise criteria and chest radiography consistent with pulmonary edema (Sutton et al., 1992). The clinical criteria (Lake Louise) were used to allow comparison between the studies (Sutton et al., 1992; Deshwal et al., 2012). In this study, seven patients had a lack of CXR findings, but screened positive for HAPE by Lake Louise criteria. All these seven patients responded well to therapy directed toward HAPE, but they were excluded from analysis owing to the lack of a diagnostic CXR. Four of these patients had opacities diagnosed on a later chest computerized tomography (CT) scan. The presence of fever in 13.5% of our patients with no localization of possible infection or requiring specific therapy is considered a part of the clinical spectrum of HAPE. A detailed screening for infection by microbiological assays and serological/molecular markers to conclusively prove the absence of infection was not carried out as part of the study owing to resource constraints.

There is a lack of clarity on therapeutic modalities such as defining bed rest, dose/duration of supplemental oxygen, duration of pharmacotherapy, and outcome measures. In the absence of standard guidelines, most of the criteria used in this study were primarily designed to standardize the study protocol and to decrease interobserver variability of outcome parameters. They were based on the local experience of the authors over the last few years in combination with the best available literature, and were study specific.

Descent is the primary and best therapy for HAPE. As descent to low altitude is not always possible, the WMS guidelines suggest at least a 1000 m descent with minimal exertion. Supplemental oxygen and portable hyperbaric chambers are particularly important in circumstances where descent is not possible as in our settings. Several authors have studied the role of supplemental oxygen without any pharmacological treatment. Zafren et al. published a series of 58 cases of HAPE, of which 25 patients were managed at moderate altitude with bed rest and supplemental oxygen. These 25 patients were re-examined on the next day after treatment, and SpO₂ had increased by 10 percent, while the heart rate and respiratory rate had decreased, and patients had nearly recovered. However, the major limitation of this study was its observational nature and lack of comparison to any other treatment (Zafren et al., 1996). Marticorena and Hultgren (1979) demonstrated the response to bed rest alone without any supplemental oxygen in a case series of HAPE. Both these studies did not use descent and had faster responses. The plausible explanation for a longer time to complete response in our study, compared to these studies, in all three arms (ranging from 4 to 12 days with a median of 7 days) could mainly be explained by the rigorously defined complete response we chose to use, which was not done in other studies.

Nifedipine is recommended in the absence of supplemental oxygen and descent. A single nonrandomized nonblinded study by Oelz et al. involving six patients at 4559 m studied the effect of nifedipine as an adjunctive agent (Oelz et al., 1989). They concluded that despite continuing exertion, these patients showed clinical improvement with nifedipine in the absence of descent or provision of supplemental oxygen. In contrast, a study by Deshwal et al. comparing the efficacy of nifedipine to placebo in patients managed with descent to a lower altitude (1370 m) and supplemental oxygen failed to show any statistically significant benefit of nifedipine. The lack of information in this article about comparison of baseline and outcome parameters between groups, as well as the method of randomization, precludes a critical evaluation of these data. Also, no other studies have validated this finding. Although the study by Deshwal et al. was conducted in a similar setting to our study, there are some important differences. Primarily, their main therapy was descent to lower altitude (1370 m), whereas all patients in our study were managed at 3500 m. Second, the major cause of HAPE in their study was insufficient acclimatization (85 of 110) in contrast to the unaccustomed exertion some in our study undertook at high altitude (96 of 140). This could also explain the delayed onset of HAPE from the time of induction being higher in our study. In our study, the mean duration of response was lowest in the nifedipine arm (6.5 ± 3.9 days) with no statistical difference between the supplemental oxygen alone (6.8 ± 3.2 days). All patients in the nifedipine arm achieved a response and did not need any additional treatment.

Dexamethasone has a grade 2C recommendation for treatment of HAPE as per the WMS guidelines 2014 Update (Luks et al., 2014). It is postulated that dexamethasone acts by decreasing pulmonary inflammation and enhancing epithelial ion-transport mechanisms involved in alveolar fluid reabsorption (Urner et al., 2012), which may explain the improved maximum exercise capacity in HAPE-susceptible individuals prophylactically treated with dexamethasone (Siebenmann et al., 2011). Despite these physiological studies demonstrating its role in HAPE prevention, there are no clinical studies showing its benefit in proven HAPE except for reports and case series (Jones et al., 2013). We thus included dexamethasone 8 mg q8 hours as one of our treatment options. All patients in the dexamethasone arm showed a response and did not need any additional treatment, although the response to therapy was slightly slower (8.3 ± 4.3 days). Also, there are no guidelines on the exact dosing of dexamethasone in patients with proven HAPE (Luks et al., 2014). The dose used in this study was higher than other studies for prevention of HAPE (8 mg q12 hours).

The major limitations of our study were the lack of a placebo group, treating physicians not blinded to the treatment groups, the small change in altitude (∼500 m) in transfer to the treatment center, the development of HAPE after adequate acclimatization, and studying only previously healthy males. We did not study patients with HAPE occurring at altitudes >4000 m, and thus, extension of our findings to this group of patients must be considered uncertain. The study was not designed to study the precipitating factors for HAPE in previously acclimatized individuals, the exact duration of onset of HAPE at a given altitude, and the role of exertion in the causation of HAPE. Inclusion of only males was primarily owing to the primary cohort from which the subjects were drawn. Only previously healthy individuals with no comorbidities were included so as to study the treatment on HAPE without the confounding that other health problems would add. Thus, we cannot make extension of our findings to those with comorbidities, the elderly, or children. In addition, our study has limited applicability in the setting of trekking and mountaineering and other types of hypoxic exposure in remote areas where supplemental oxygen may not be available, since oxygen was provided to all patients.

Conclusion

We conclude that oxygen alone is adequate therapy for HAPE and that adjuvant pharmacotherapy with either nifedipine or dexamethasone does not hasten recovery.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Anand

, Prasad

, Chugh

, Rao

, Cornfield

, Milla

, et al. (1998). Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema. Circulation, 98:2441–2445.

ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. (2002). ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med, 166:111–117.

Deshwal

, Iqbal

, and Basnet

. (2012). Nifedipine for the treatment of high altitude pulmonary edema. Wilderness Environ Med, 23:7–10.

Jones

, Stokes

, McKenzie

, Nilles

, and Stoddard

. (2013). Management of high altitude pulmonary edema in the Himalaya: A review of 56 cases presenting at Pheriche medical aid post (4240 m). Wilderness Environ Med, 24:32–36.

Luks

, McIntosh

, Grissom

, Auerbach

, Rodway

, Schoene

, et al. (2010). Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness. Wilderness Environ Med, 21:146–155.

Luks

, McIntosh

, Grissom

, Auerbach

, Rodway

, Schoene

, et al. (2014). Wilderness Medical Society practice guidelines for the prevention and treatment of acute altitude illness: 2014 Update. Wilderness Environ Med, 25(4 Suppl):S4–S14.

Marticorena

, and Hultgren

. (1979). Evaluation of therapeutic methods in high altitude pulmonary edema. Am J Cardiol, 43:307–312.

Oelz

, Maggiorini

, Ritter

, Waber

, Jenni

, Vock

, et al. (1989). Nifedipine for high altitude pulmonary oedema. Lancet, 2:1241–1244.

Rudski

, Lai

, Afilalo

, Hua

, Handschumacher

, Chandrasekaran

, et al. (2010). Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr, 23:685–713;quiz 86–88.

10.

Siebenmann

, Bloch

, Lundby

, Nussbamer-Ochsner

, Schoeb

, and Maggiorini

. (2011). Dexamethasone improves maximal exercise capacity of individuals susceptible to high altitude pulmonary edema at 4559 m. High Alt Med Biol, 12:169–177.

11.

Sutton

, Coates

, Houston

, edrs. (1992). The Lake Louise Consensus on the Definition and Quantification of Altitude Illness. Queen City Printers, Burlington, VT.

12.

Urner

, Herrmann

, Booy

, Roth-Z' Graggen

, Maggiorini

, and Beck-Schimmer

. (2012). Effect of hypoxia and dexamethasone on inflammation and ion transporter function in pulmonary cells. Clin Exp Immunol, 169:119–128.

13.

Vock

, Brutsche

, Nanzer

, and Bartsch

. (1991). Variable radiomorphologic data of high altitude pulmonary edema. Features from 60 patients. Chest, 100:1306–1311.

14.

Zafren

, Reeves

, and Schoene

. (1996). Treatment of high-altitude pulmonary edema by bed rest and supplemental oxygen. Wilderness Environ Med, 7:127–132.