The Complexity of Diagnosing High-Altitude Pulmonary Edema: A Case Report and Review of the Differential Diagnosis of Greater Than Expected Hypoxemia at Altitude

Introduction

Travelers to high altitude are at risk of developing high-altitude illness such as acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), or high-altitude cerebral edema (Bärtsch and Swenson, 2013). As altitude increases, the partial pressure of atmospheric oxygen decreases, leading to decreased arterial oxygen saturation and a compensatory increase in ventilation (Hackett and Roach, 2012). In contrast to the vasodilation that can occur in the systemic circulation during hypoxic conditions, the pulmonary circuit vasoconstricts, allowing redistribution of blood away from poorly oxygenated areas of the lungs to better ventilated and more oxygenated areas. This is a normal response that improves systemic oxygen delivery in pathological conditions with localized disease, such as pneumonia and atelectasis. At altitude, however, hypoxic pulmonary vasoconstriction (HPV) is engaged everywhere in the lung to increase pulmonary vascular resistance and pulmonary artery pressure, with a magnitude varying across individuals, species, and time at altitude (Swenson and Bärtsch, 2012). The mechanism of HPV is complex, characterized by contraction of smooth muscle cells within the pulmonary arterioles and venules, and affected by intrinsic and extrinsic modulating factors such as vessel endothelium, chemoreceptors, autonomic nervous system, innervation of the lung, degree of ambient hypoxia, and pulmonary disease. The strength of regional HPV is uniform in most individuals, but in those with documented HAPE susceptibility there is regional variability and uneven vasoconstriction (Bärtsch et al., 2005; Hopkins et al., 2005).

HAPE is traditionally a clinical diagnosis, defined by a cough, shortness of breath, and reduced performance at altitude in an unacclimatized individual as a result of noncardiogenic edema. Clinical presentation typically begins with exertional dyspnea and fatigue out of proportion to others, which progresses to breathlessness at rest, low-grade fever, and blood-tinged frothy sputum (Swenson and Bärtsch, 2012). In unacclimatized persons who acutely ascended to 3600 m, the incidence of HAPE was as high as 1.9% (Ren et al., 2010). HAPE is initially treated with supplemental oxygen, if available, and rest followed by expeditious descent. Recent evidence showed a 95% success rate in treatment of HAPE at moderate altitude with oxygen and rest alone (Yanamandra et al., 2016). In cases when pulmonary edema does not respond to classic intervention, other etiologies must be considered. In this essay, we discuss the workup and management of exaggerated hypoxemia at altitude. We suggest that investigation for underlying cardiopulmonary pathology should be considered when patients do not respond adequately to typical interventions for HAPE, or in patients who develop HAPE, but wish to continue recreating at altitude. We discuss the medical conditions that can contribute to exaggerated hypoxemia at altitude.

Case Presentation

A 58-year-old woman with a history of asthma, hypertension, and breast cancer in remission presented from her home in California (sea level) for an altitude consultation at the University of Colorado Altitude Clinic (1609 m). She had experienced greater than expected hypoxemia at all altitudes and significant exercise intolerance while attempting to summit Mount Kilimanjaro (5895 m) despite taking daily acetazolamide. She started acetazolamide at 125 mg by mouth, twice daily, starting 1 day before her ascent. During ascent, a careful record of her symptoms and oxygen saturations as measured by a finger clip pulse oximeter were kept (Table 1) by her guiding agency.

She began the trip at 914 m, asymptomatic but with an already disproportionally low oxygen saturation of 90%. She maintained oxygen saturation in the upper 80s up to 2794 m on the first night and in the lower 80s up to 3505 m on the second night, but on the third day she began to develop symptoms of exercise intolerance. On further ascent to 4162 m, her oxygen saturation dropped to 73%. Despite her persistent and marked hypoxemia, the group began to ascend the following day with a goal of reaching Lava Tower at 4557 m. During this climb, the patient's hypoxemia acutely worsened, dropping to a saturation of 67% with the onset of tachycardia, nausea, far greater shortness of breath, and exhaustion with progressive fatigue with continued exercise (Table 1). She did not complain of cough or sputum production at this time. With the assistance of the company guides, she increased the frequency of rest breaks and intermittently used supplemental oxygen. She was subsequently given 15 L of oxygen per minute through a nonrebreather mask that initially improved her saturation to 87%, but it quickly dropped to 64% without any improvement in her symptoms despite continued oxygen therapy. It should be noted that her oxygen saturations were checked with a portable finger pulse oximeter oximetry, which become less accurate with decreasing oxygen saturations <80%–85%, and to other conditions unique to altitude that can decrease their reliability (Luks and Swenson, 2011). She attempted administration of albuterol by a metered dose inhaler with no clinical improvement. The guides recorded rales on chest auscultation. Owing to the refractory hypoxemia, she was forced to abandon the climb and was evacuated to the Kilimanjaro base with a presumptive diagnosis of HAPE.

After returning home, she followed up with her primary physician and had a normal complete blood count and basic metabolic panel, eliminating anemia and renal insufficiency as contributing factors, and a normal chest X-ray, although the time elapsed from her attempted climb and her primary care visit is unknown but on the order of many days. She was diagnosed with presumed HAPE given her profound hypoxemia and exercise intolerance at high altitude. She elected to seek further consultation on whether a return to altitude would be feasible. After a brief telephone discussion and review of her case, the Altitude Clinic provider recommended a screening echocardiogram, chest computed tomographic (CT) angiogram of the chest, and pulmonary function tests, which due to logistics, were performed at sea level in California. She was asked to bring the results of these records for her consultation. At the Altitude Clinic in Denver, Colorado, she had a normal cardiopulmonary examination and oxygen saturation at 94% breathing ambient air where >90% has been published as a reference cutoff for normal values (Wolf et al., 2008). There was no evidence of cutaneous telangiectasia. Her worsening clinical status on Kilimanjaro despite her use of supplemental oxygen prompted a further workup for contributing etiologies to her HAPE or possibly another diagnosis than HAPE.

Testing

Her sea level workup in California included a transthoracic stress echocardiogram with bubble protocol that showed a delayed appearance (>5 seconds) of bubbles in the left side of the heart, consistent with the presence of an extracardiac shunt. The echocardiogram also showed an elevated pulmonary artery systolic pressure (PASP) at rest and during exercise, with estimated pressures of 26 mmHg (normal <25) and 46 mmHg (normal <30), respectively. No early bubbles (<1–2 seconds) were demonstrated with or without a Valsalva maneuver, ruling out a patent foramen ovale (PFO) or other interatrial of interventricular communication. Pulmonary function testing revealed normal lung volumes, normal diffusion capacity, and normal air flow rates, all suggesting that any past chemotherapy and/or radiation-induced lung damage from her breast cancer treatment was minor.

Asthma was considered as an etiology, but as the patient did not demonstrate wheezing on chest auscultation and did not respond to albuterol, this was felt to be a less likely etiology. The patient had well-controlled hypertension at baseline, and her echocardiogram did not show evidence of cardiac remodeling or congestive heart failure related to poorly controlled hypertension making acute congestive heart failure or severe hypertension while at high altitude a less likely etiology. CT angiography of the chest, head, and neck showed no evidence of pulmonary arteriovenous malformations (AVMs). The workup indicated that the etiology of her hypoxemia was likely multifactorial, encompassing a component of previously undiagnosed mild pulmonary hypertension and intrapulmonary shunting, contributing to and aggravating the severity of her possible HAPE.

Management and Outcome

An extensive discussion with the patient centered on the risks of returning to altitude given her exaggerated hypoxemia and poor exertional tolerance. Despite these risks, she wished still to enjoy activities at high altitude. Initial management was aimed at advising an ascent rate slow enough to allow adequate acclimatization and addressing while at high altitude possible treatment of her mild pulmonary hypertension at sea level found on the screening echocardiogram. In addition to adopting the recommendations for safe ascent and the use of acetazolamide 125 mg bid as prophylaxis for AMS, she also used tadalafil 10 mg daily during a 6 day climb in the Sierra Nevada (Table 2). She maintained oxygen saturations >80% for the duration of the trip and, perhaps more importantly, reported improved exercise tolerance. However, she did develop facial swelling, a known side effect of tadalafil. During the following year, she returned to Kilimanjaro using acetazolamide 250 mg twice daily and sildenafil 50 mg three times daily, both drugs having known inhibition of HPV. On follow-up, she reported a successful summit of Kilimanjaro with saturation values by pulse oximetry that were maintained >80%.

Discussion

The differential diagnosis of a patient who develops exaggerated shortness of breath with altitude adventure travel is extensive. First a consideration of medical conditions that cause hypoxemia and exertional dyspnea independent of altitude should be addressed as a significant portion of altitude travel involves physical exertion. In addition, an understanding of medical conditions that contribute to clinical deterioration at altitude is advantageous for medical providers who work in high-altitude locales or care for those wishing to go to high altitude. In patients at risk for other medical comorbidities or who fail to respond to standard treatment of HAPE, an extended differential should be entertained and workup is indicated, especially if the patient intends to continue altitude-related work or recreation.

HAPE is one of the rare, but deadly, complications of altitude exposure leading to severe hypoxemia that often requires ultimate descent. The Lake Louise Acute Mountain Sickness Scoring system (Roach et al., 1993) was created to allow physicians, guides, and adventurers alike to qualify their symptoms and guide medical decision-making in austere conditions. Unfortunately, the score system does not include a clinical diagnosis of HAPE. The initial clinical findings common in HAPE such as tachypnea, tachycardia, and decreased exercise tolerance are not sensitive or specific to HAPE alone and many other conditions can meet these criteria (Pennardt, 2013). HAPE must first be considered and intervened upon, as quick identification and treatment is crucial. Initial management of HAPE involves descent. When descent is not feasible, supplemental oxygen to maintain a saturation >90% and portable hyperbaric treatment should be considered (Luks et al., 2010). In the event that descent is not possible, and supplemental oxygen is insufficient, consideration can be made to administer nifedipine. Nifedipine, a nonselective calcium channel blocker has been shown to prevent and treat HAPE in some clinical settings, although response rates vary (Oelz et al., 1992; Deshwal et al., 2012).

Common conditions, however, including pulmonary hypertension, pulmonary embolism, pneumonia, asthma, chronic obstructive pulmonary disease, pneumothorax, diseases associated with respiratory muscle weakness, control of ventilation disorders, congestive heart failure, myocardial infarction, intracardiac shunts, extracardiac shunts, hyperthyroidism, chronic kidney disease, and severe anemia, can all contribute to hypoxemia and exercise intolerance at altitude (Table 3). Although the physical activity associated with adventure travel alone would seem to reduce the risk of venous thrombosis, case reports exist of pulmonary embolism masquerading as HAPE and altitude-associated hypoxia itself appears to increase the risk of thromboembolic events (Brill et al., 2013; Hull et al., 2016; Pandey et al., 2016) due to increase in blood viscosity with polycythemia, dehydration, and periods of forced inactivity with changes in weather or other factors. Pneumonia will also often manifest with clinical signs such as fever, tachycardia, and localized adventitious lung sounds, and can have a similar clinical picture to HAPE. Asthma must also be considered as even patients with well-controlled symptoms at home can decompensate with changes in altitude, exercise, and element exposure (Luks and Swenson, 2007). Identification of other etiologies for refractory hypoxemia has important implications in patients with underlying cardiopulmonary shunts and a predisposition to pulmonary arterial hypertension as a trip to altitude can be particularly risky. For example, PFO is roughly four times more frequent in HAPE-susceptible mountaineers than in those participants resistant to HAPE (Allemann et al., 2006). Whether this applies to everyone with a PFO has not been established. In patients with underlying pulmonary hypertension, ambient hypoxia leads to pulmonary vasoconstriction, which can cause increased pulmonary artery pressure and predispose to HAPE, right heart strain, and acute altitude illness (Luks, 2009).

The workup in these patients can vary, but after a complete history and physical examination, we suggest a complete blood count and metabolic panel, a bubble echocardiogram to evaluate cardiac function, and to look for the presence of an intracardiac or extracardiac shunt or pulmonary hypertension; pulmonary function testing, and CT angiography of the chest to evaluate for structural lung disease, chronic pulmonary embolism, or AVMs. If further medical conditions are identified through this testing, then medical evaluation can proceed as indicated based on the condition. If the patient experiences significant exertional dyspnea, cardiopulmonary exercise testing should be considered, including right heart catheterization and a full echocardiographic cardiac stress test. Ideally, any testing for altitude-related complications should be done at altitude when the patient is symptomatic, in a chamber to simulate altitude, or with hypoxic gas breathing.

In this case report, the patient was found to have underlying pulmonary hypertension with exercise on echocardiography that most likely was exacerbated by HPV at altitude and put her at higher risk of worsening right-to-left shunting phenomenon through her intrapulmonary shunts as detected by the late appearance of bubbles in the left heart chambers. The nature of this type of intrapulmonary shunting by small nonclassical arterial-venous malformations, termed intrapulmonary arterial-venous anastomoses (IPAVA) is understudied. Lovering et al. (2008) have shown that this type of shunting increases with inspired hypoxia and exercise. The presence of pulmonary hypertension and its speculated effect on her poor exercise tolerance and increased intrapulmonary shunting led to a phosphodiesterase (PDE)-5 inhibitor as a rational choice to blunt this effect (Ghofrani et al., 2004; Richalet et al., 2005). Sildenafil, a PDE-5 inhibitor, has been shown to protect against the development of altitude-induced pulmonary hypertension and improve gas exchange (Richalet et al., 2005). It is also notable that although sildenafil had no effect on the arterial oxygen saturation at rest or during exercise, sildenafil did reduce the PASP during exercise and increased maximal workload and cardiac output in a case series of trekkers (Ghofrani et al., 2004). This effect was seen in our patient when she climbed in the Sierra Nevada while taking tadalafil, a longer acting PDE-5 inhibitor. Although her oxygen saturations at corresponding altitudes were not significantly improved compared with her first attempt on Kilimanjaro, she subjectively felt improved and had a higher exercise tolerance. In addition, the patient subsequently took tadalafil and was able to successfully ascend Kilimanjaro on a second attempt.

Ultimately, the patient's hypoxemia was multifactorial, likely resulting from a combination of small anatomical IPAVA shunting and underlying pulmonary hypertension. Her previous chemotherapy and radiation therapy could also have contributed by inducing lung damage, although her normal pulmonary function tests suggest that this influence was likely minor. The use of a PDE-5 inhibitor allowed our patient to successfully ascend Kilimanjaro on a second attempt, maintaining oxygen saturations >80% for the duration.

This case highlights the importance of maintaining a broad differential diagnosis for extreme exercise intolerance in patients who ascend to high-altitude environments, especially with greater than expected hypoxemia. Although HAPE is a common diagnosis, it merely serves as a starting point for further evaluation of medical conditions that can result in extreme hypoxemia at altitude. A consideration of medical conditions that are induced by high-altitude environments as well as an evaluation for conditions exacerbated by altitude exposure is necessary to ensure that patients can enjoy safe recreation in high-altitude environments.