High Altitude Pulmonary Edema Without Appropriate Action Progresses to Right Ventricular Strain: A Case Study

Abstract

Mills, Logan, Chris Harper, Sophie Rozwadowski, and Chris Imray. High altitude pulmonary edema without appropriate action progresses to right ventricular strain: A case study. High Alt Med Biol. 17:228–232, 2016.—A 24-year-old male developed high altitude pulmonary edema (HAPE) after three ascents to 4061 m over 3 days, sleeping each night at 2735 m. He complained of exertional dyspnea, dry cough, chest pain, fever, nausea, vertigo, and a severe frontal headache. Inappropriate continuation of ascent despite symptoms led to functional impairment and forced a return to the valley, but dyspnea persisted in addition to new orthopnea. Hospital admission showed hypoxemia, resting tachycardia, and systemic hypertension. ECG revealed right ventricular strain and a chest X-ray revealed right lower zone infiltrates. This case demonstrates that HAPE can develop in previously unaffected individuals given certain precipitating factors, and that in the presence of HAPE, prolonged exposure to altitude with exercise (or exertion) does not confer acclimatization with protective adaptations and that rest and descent are the appropriate actions. The case additionally demonstrates well-characterized right ventricular involvement.

Introduction

Altitude sickness includes acute mountain sickness (AMS), its more severe end-stage high altitude cerebral edema (HACE), and the distinct entity of high altitude pulmonary edema (HAPE) (Hackett, 1992). These can be characterized by being difficult to diagnose, hard to treat without descent, and have an unpredictable incidence in an altitude-naive population.

HAPE typically presents with a dry cough and reduced performance during days 2–5 at altitude in an unacclimatized individual (Hackett and Roach, 2001; Imray et al., 2011) and is defined according to these symptoms and signs (Hultgren, 1996). HAPE has been shown to be a noncardiogenic edema and appears to be related to excessive pulmonary hypertension, potentially related to a reduced ventilatory response to the hypoxemia of altitude (Bärtsch et al., 2005). As such, risk factors for HAPE include rapid ascent, altitude, overexertion, cold, abnormal cardiopulmonary vasculature, and individual susceptibility (Hackett and Roach, 2001). Treatment, as for all forms of altitude sickness, revolves around reversing hypoxemia. This may be achieved by rest and supplemental oxygen alone, but often descent and hospital therapy are required (Marticorena and Hultgren, 1979; Hackett et al., 1992). Nifedipine, a calcium channel blocker, is a therapy specific to HAPE (Bartsch et al., 1991).

Acclimatization is a key concept in climbing and altitude medicine. It is characterized by incremental increases in altitude over days before an ascent to higher altitude. During acclimatization, cellular, biochemical, and physiological adaptations occur as a result of the hypoxemia of higher altitudes (Grocott et al., 2007). Many studies have shown that pre-exposure, or acclimatization, decreases the incidence of AMS, HACE, and HAPE at higher altitudes (Schneider and Bernasch, 2002; Tsianos et al., 2006; Wagner et al., 2008).

Full written consent has been obtained from the reported individual. Normal ranges for clinical observations were derived from a cohort of climbers who provided informed, written consent and were investigated in accordance with ethical approval gained from the University of Warwick (BSREC REGO-2015-1581).

Case Report

Background

This report describes a physically active 24-year-old Caucasian male who developed HAPE while climbing unacclimatized on Gran Paradiso (4061 m) in Aosta, Italy. Notably, he had summited this mountain twice in previous years without any symptoms of AMS or HAPE or any acclimatization. His lifetime altitude record was 4810 m without any symptoms of AMS or HAPE. His longest previous duration of stay at altitude was 5 days above 2500 m with ascents to 4000 m without acclimatization or symptoms of HAPE in the At-Bashi range, Kyrgyzstan. He had no medical history and no family history of altitude, pulmonary, or cardiac illness.

During this trip he was conducting an AMS research study recruiting volunteers for testing at the Vittore Emanuele II refuge (2735 m) and the summit bergschrund (c. 4000 m). This protocol required the investigator, the subject of this report, to make the 1265 m ascent repeatedly on consecutive days, thus producing the unusual ascent profile seen in Figure 1. Neither acetazolamide nor nifedipine was administered during the trip; paracetamol and NSAIDS were taken as required up to the maximum allowable dose as dictated by symptoms.

FIG. 1.

Ascent profile of the reported individual overlain with his oxygen saturations (dashed line). Printed saturation error bars refer to the one standard deviation ranges reported in Table 1 for a cohort of 47 climbers. The cohort was not remeasured on subsequent days, but for ease of comparison with the reported individual, the reference bars are reproduced identically on ascents 2 and 3.

Night 1 and ascent 1

After an uneventful 800 m ascent from the valley, he slept well on night 1 with no symptoms of AMS. The subsequent morning, he ascended to the summit in 5 hours without experiencing any dyspnea or headache. Interestingly, his oxygen saturations at 4000 m were 75% compared with a 1 SD range in other individuals of 83.4%–94.2% (Table 1). Notably, he carried a load of c. 14 kg containing research equipment that was not a typical summit-climbing load.

Table 1.

Observed Physiological Variables of a Cohort of 48 Climbers

	Mean	1 SD range	n
Oxygen saturation at 2735 m (%)	92.8	88.1–97.5	45
Oxygen saturation at 4000 m (%)	88.8	83.4–94.2	48
Pulse at 2735 m (bpm)	88.9	74.3–103.5	45
Pulse at 4000 m (bpm)	110.3	86.7–133.9	47
Ascent time (hours)	4.73	3.56–5.9	47

Values were measured at 2735 m and after ascent to 4000 m. The majority of climbers spent only one night at the 2735 m refuge. Five of the 47 (11%) climbers had acclimatized with three or more days above 3000 m in the preceding month. The reference range is 1 SD wide.

SD, standard deviation.

Night 2 and ascent 2

At the start of night 2, his oxygen saturations were 90% at 2735 m, which was comparable with that of the observed cohort (88.1%–97.5%; Table 1). During the night, he deteriorated experiencing a frontal headache, fever, vertigo, and poor sleep. In the morning, his oxygen saturations were 80%, considerably outside the normal range of the measured cohort, and he experienced poor appetite and nausea. Despite these symptoms, he reascended and additionally developed dyspnea and exertional chest pain, giving a Lake Louise Score (LLS) of 6 (Roach et al., 1993). Ascent was slower than the first day, limited by respiratory effort, despite a considerably lighter load.

Night 3 and ascent 3

Symptoms of headache, fever, nausea, and vertigo persisted during the third night, giving an LLS of 5. A resting tachycardia was noted with values between 130 and 150 bpm. During ascent 3, the dyspnea and exertional chest pain were considerably worse than during ascent 2, severely reducing ascent rate and ultimately ending the ascent at c. 3900 m. In addition, a dry cough developed. Oxygen saturations at the highest altitude were 72% and central cyanosis was noted. No crackles or rales were heard on auscultation.

Descent

Dyspnea was not present during downhill phases of the descent to the valley, although symptoms of AMS persisted. During the night after ascent 3, at 2000 m, severe orthopnea was experienced and the cough and fever persisted. Oxygen saturations were 85%, again considerably lower than colleagues.

Hospitalization: investigation

Upon admission to hospital in Aosta (583 m) the subsequent day, the patient continued to report exertional dyspnea and orthopnea. On examination, a resting tachycardia (120 bpm), hypertension (155/80), a displaced apex beat, and hypoxemia (92%) were noted; lung examination was normal (Table 2). An ECG showed sinus tachycardia, right axis deviation, and right heart strain (Fig. 2). Blood investigations revealed elevated pro-BNP and high-sensitivity Troponin T (Table 2). Chest radiography showed diffuse consolidation in the right lower zone and a normal heart size (Fig. 3). An echocardiogram after treatment was reported as normal (36 hours after descent).

FIG. 2.

Comparison of ECGs taken at baseline and immediately after descent. ECG during HAPE (right) shows sinus tachycardia, slight right axis deviation, and depressed T waves with full inversion in V1.

FIG. 3.

PA chest radiography the day after ascent 3 showing right lower zone infiltrates and a normal cardiothoracic ratio.

Table 2.

Observations and Laboratory Values Obtained the Day After Ascent 3

	Value	Reference range ^a Baseline value ^b
Admission observations
Blood pressure	155/80	120/80^b
Pulse	120	62^b
Oxygen saturation (%)	92	99^b
Respiratory rate	19	14^b
Temperature (°C)	37.2	36.8^b
Hematology
RBC	5.54	4.5–6^a
HCT	47.7	40–50^a
MCV	86.1	80–96^a
MCH	27.9	26–34^a
WBC	11.2 H	4–10^a
PLT	244	150–450^a
MPV	10.6 H	7.4–10.4^a
Biochemistry
CRP	3.8 H	0–0.5^a
Troponin T	25.28 H	<13.99^a
Pro-BNP	1065 H	<300^a

Reference ranges are as reported by the Aosta laboratory.

Baseline values are given where healthy values preceding the trip are known for the reported individual.

Hospitalization: treatment

The patient was treated with 2 L oxygen through nasal cannulae, 8 mg of intravenous dexamethasone, 2 × 10 mg of oral nifedipine, and a 7-day course of co-amoxiclav. During admission, oxygen saturations improved to 95% and no dyspnea or orthopnea was experienced; sputum color progressed from colorless to green.

Discussion

This case has features some of which are a typical presentation of HAPE in an unacclimatized, experienced climber with the additional potential diagnosis of a lower respiratory tract infection. The case demonstrates the consequences of failing to recognize symptoms and act appropriately.

Precipitants in nonsusceptible individuals

This case is interesting in that the individual had made the same ascent in previous years as he did on day 1 of this trip and he did not experience AMS or HAPE on those occasions. The question, therefore, arises as to what precipitated HAPE during this episode in a nonsusceptible individual. There appear to be three possible explanations.

First, a respiratory tract infection may have played a role in precipitating HAPE. A fever was experienced during nights 2 and 3, green sputum was produced on day 5, white cells and CRP were elevated, and consolidation was noted on chest radiography; however, it has previously been argued that HAPE itself can produce these features including fever without the need for an infective process (Hultgren et al., 1996; Kleger et al., 1996; Hackett and Roach, 2001). Alternatively, a lower respiratory tract infection may have been a complication of HAPE rather than a precipitant.

Second, HAPE may have been caused during this episode by the excessive load carried during ascent 1. Magnitude of effort has previously been reported as a risk factor for HAPE, and would explain why it developed during this ascent and not previously (Ritter et al., 1993; Roach et al., 2000; Major et al., 2012).

Finally, it is possible that HAPE was only experienced on this occasion because during previous trips, descent to the valley has been made on day 2 rather than a subsequent ascent. HAPE developed during night 2, a presentation typical in the literature, and thus would not have had the opportunity to present during previous single night ascents (Stenmark et al., 1999).

Altitude exposure does not always confer acclimatization, adaptation, and protection

Conventional wisdom suggests that continued exposure to and exercise at altitude stimulates adaptive cellular and physiological processes, thus improving symptoms and functional ability (Borowska et al., 2014). Thus one would have expected symptoms to have improved during ascents 2 and 3, as indeed was the reason why the reported individual continued to climb despite symptoms. This case illustrates that once HAPE develops due to exaggerated, and most likely inhomogeneous, pulmonary vasoconstriction, the situation does not improve with continued exposure and, therefore, the only appropriate action is to reverse hypoxemia, which may take the form of descent or supplemental oxygen.

Cardiac involvement

HAPE is known to be an edema of noncardiogenic origin and is distinct from other forms of pulmonary edema, as has been shown by studies demonstrating normal wedge pressure simultaneously with elevated pulmonary artery pressure (PAP) (Maggiorini et al., 2001; Maggiorini and Leon-Velarde, 2003). Despite the absence of left ventricular involvement, the increased PAPs and resistance can cause right ventricular strain. The reported individual experienced orthopnea and angina, and investigation revealed elevated high-sensitivity troponin, pro-BNP, and ECG changes. Although the association between these findings and pathology is well documented in sea-level hospitals, the interpretation of these findings at altitude is complicated. Elevated pro-BNP is considered diagnostic of heart failure in the hospital context. However, studies in vitro and at altitude show that pro-BNP may be elevated as a response to hypoxia without ventricular stretch (Ge et al., 2011; Gao et al., 2013). Similarly, although elevated troponin is often considered indicative of leakage of myocyte contents after ischemia, other reports from altitude suggest that troponins may be elevated in HAPE without overt ischemia (Tanindi and Cemri, 2011; Boos et al., 2013). Therefore, the only findings in this case that truly suggest right ventricular involvement are the ECG changes and the reported orthopnea. ECG changes were first reported in Indian army soldiers in the Himalayas, where ECG changes including T wave inversion were noted within 1–3 days of arriving at altitude, accompanied by considerable exertion (Menon, 1965). Definitive diagnosis would have required pretreatment echocardiogram; the delay until day 2 after symptoms resulted in a normal investigation.

Conclusion

This case illustrates a typical presentation of HAPE with well-characterized respiratory and cardiovascular findings caused by failure to react appropriately to initial symptoms. In addition, it reinforces the point that HAPE is a distinct clinical entity from AMS, caused by specific physiological phenomena, that has a clear start point independent of AMS. As a distinct entity, its development is hard to predict given that precipitants in previously unaffected individuals are hard to identify. Reversal of the distinct pathophysiological features, namely raised PAP in response to hypoxemia, is thus essential for treatment.

Footnotes

Acknowledgments

The authors wish to thank field colleagues for the safe completing of the expedition and the staff at Aosta Oespedale Regionale for care received.

Author Disclosure Statement

No competing financial interests exist.

References

Bartsch

, et al. (1991). Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med, 325:1284–1289.

Bärtsch

, et al. (2005). Physiological aspects of high-altitude pulmonary edema. J Appl Physiol, 98:1101–1110.

Boos

, et al. (2013). Cardiac biomarkers and high altitude pulmonary edema. Int J Cardiol, 167:e65–e66.

Borowska

, Harasim

, and Van Damme-ostapowicz

. (2014). Acute mountain sickness. Arch Physiother Glob Res, 18:19–22.

Gao

, et al. (2013). NT-ProBNP levels are moderately increased in acute high-altitude pulmonary edema. Exp Therap Med, 5:1434–1438.

R-L

, et al. (2011). B-type natriuretic peptide, vascular endothelial growth factor, endothelin-1, and nitric oxide synthase in chronic mountain sickness. Am J Physiol Heart Circ Physiol, 300:H1427–H1433.

Grocott

, Montgomery

, and Vercueil

. (2007). High-altitude physiology and pathophysiology: implications and relevance for intensive care medicine. Crit Care, 11:203.

Hackett

. (1992). The Lake Louise Consensus on the definition and quantification of altitude illness. Adv Biosci, 84:327–330.

Hackett

, et al. (1992). The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med, 13 Suppl 1:S68–S71.

10.

Hackett

, and Roach

. (2001). High-altitude illness. N Engl J Med, 345:107–114.

11.

Hultgren

. (1996). High-altitude pulmonary edema: current concepts. Annu Rev Med, 47:267–284.

12.

Hultgren

, et al. (1996). High-altitude pulmonary edema at a ski resort. Western J Med, 164:222–227.

13.

Imray

, et al. (2011). Acute altitude illnesses. BMJ (Clin Res Ed.), 343:p.d4943.

14.

Kleger

, et al. (1996). Evidence against an increase in capillary permeability in subjects exposed to high altitude. J Appl Physiol (1985), 81:1917–1923.

15.

Maggiorini

, et al. (2001). High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation, 103:2078–2083.

16.

Maggiorini

, and Leon-Velarde

. (2003). High-altitude pulmonary hypertension: a pathophysiological entity to different diseases. Eur Repir J, 22:1019–1025.

17.

Major

, et al. (2012). Peripheral arterial desaturation is further exacerbated by exercise in adolescents with acute mountain sickness. Wilderness Environ Med, 23:15–23.

18.

Marticorena

, and Hultgren

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

19.

Menon

. (1965). High-altitude pulmonary edema: a clinical study. N Engl J Med, 273:66–73.

20.

Ritter

, et al. (1993). Abnormal left ventricular diastolic filling patterns in acute hypoxic pulmonary hypertension at high altitude. Am J Noninvas Cardiol, 7:33–38.

21.

Roach

, et al. (1993). The Lake Louise acute mountain sickness scoring system. In: Hypoxia and Molecular Medicine. Sutton

, Houston

, Coates

, eds. Queen City Printers, Burlington, VT. pp. 272–274.

22.

Roach

, et al. (2000). Exercise exacerbates acute mountain sickness at simulated high altitude. J Appl Physiol (1985), 88:581–585.

23.

Schneider

, and Bernasch

. (2002). Acute mountain sickness: influence of susceptibility, preexposure, and ascent rate. Med Sci Sports Exerc, 34:1886–1891.

24.

Stenmark

, et al. (1999). Hypoxia induces cell-specific changes in gene expression in vascular wall cells: implications for pulmonary hypertension. Adv Exp Med Biol, 474:231–258.

25.

Tanindi

, and Cemri

. (2011). Troponin elevation in conditions other than acute coronary syndromes. Vasc Health Risk Manage, 7:597–603.

26.

Tsianos

, et al. (2006). Factors affecting a climber's ability to ascend Mont Blanc. Eur J Appl Physiol, 96:32–36.

27.

Wagner

, et al. (2008). Mt. Whitney: Determinants of summit success and acute mountain sickness. Med Sci Sports Exerc, 40:1820–1827.