Altitude Sickness: Is it the Altitude or Are You Just Out of Shape?

Written by : Samantha Mazzeo, DO

Edited by: Wesley Chan, MD

Good news! It’s most likely the altitude. But why do we feel so winded at higher altitudes? What is different in the atmosphere? What does the human body do to acclimate? How can we treat or better yet, prevent illness from occurring?

In the recent Wilderness Journal Club meeting on December 1st, 2020, we discussed the updated 2019 Wilderness Medical Society guidelines for prevention and treatment of High Altitude Illness as well as two articles on possible future therapies.[1]

The physiology behind High Altitude Ascent

Our bodies have a fascinating ability to acclimate to their surroundings. Yet sometimes, our bodies face difficulty adjusting to a new environment, leading to illness. So, how does the body react when we travel to higher altitudes?

As air expands, the pressure and density of the air molecules decrease. At higher altitudes, the air is less dense and thus there are fewer gas molecules. This includes oxygen. This concept leads to the basic explanation of high altitude pathophysiology: hypobaric hypoxia (latin roots for the win!) which means, low-pressure system with low-oxygen.

Let us take a quick trip down memory lane and return to one of my personal favorite subjects, inorganic chemistry, and consult our good friend John Dalton. Dalton explains the Law of Partial Pressures, which states the total pressure of all gases within a system is equal to the sum of the partial pressures of each gas.

In terms of physiology, the partial pressure of oxygen is the driving force for the diffusion of oxygen throughout the body. At sea level, there is a larger gradient of oxygen between inspired air and bodily tissues. However at higher altitudes, there is a lower atmospheric pressure as well as less inspired oxygen (Figure 1). As a result, the pressure gradient is lower and less oxygen is available, ultimately leading to less oxygen absorbed into the bodily tissues and a lower oxygen saturation. In turn, the lower oxygen in the blood stimulates the peripheral chemoreceptors located in the carotid and aortic bodies, which triggers increased minute ventilation. This hypoxic ventilatory response (HVR) leads to increased oxygen consumption and increased alveolar O2, thus creating a larger gradient for diffusion. However as a result, more carbon dioxide is exhaled out, leading to a respiratory alkalosis. Our bodies acclimate by creating a compensatory metabolic acidosis by increasing bicarbonate excretion in the urine.

Figure 1 [2 , 3]

Clinical Presentations of Altitude Illness Sickness

So, is it the altitude or are you out of shape? Turns out, HVR is primarily influenced by genetics and can vary widely among individuals.[4] However, some external factors can influence HVR, such as substances that can either stimulate (i.e. coca, caffeine) or depress (i.e. alcohol, poor sleep patterns) the respiratory response. A preliminary study on the relationship between HVR and exercise-induced arterial hypoxemia found that resting acute hypoxic ventilatory response (AHVR) is not related to exercise-induced arterial hypoxemia during maximal exercise in men or women.[5] Studies to date do not suggest an active relationship between cardiovascular fitness and the HVR seen at high altitudes. Of note, competitive athletes utilize high altitude to theoretically maximize their athletic performance. Three different models are practiced which describe where an athlete lives and trains. They include the training models live high + train high (LH+TH), live high + train low (LH+TL), and live low + train high (LL+TH).[6] Although to date, definitive evidence supporting these strategies are limited and inconclusive.

High Altitude Illness (HAI) is the term used to encompass the cerebral and pulmonary syndromes that occur following ascent to a high altitude. HAI generally occurs when ascending to 2500m (8200ft), although it can occur as low as 2000m (6500ft). Even so, there’s no definitive cut off where altitude sickness does (or does not) occur. Acute Mountain Sickness (AMS) and High Altitude Cerebral Edema (HACE) are two cerebral syndromes that fall within the same spectrum of pathophysiology, representing different severities. High Altitude Pulmonary Edema (HAPE) refers to the pulmonary syndrome experienced by patients ascending to high altitude.

AMS is defined as headache plus one or more of the following symptoms: nausea, vomiting, fatigue, or dizziness. AMS can be classified into mild, moderate, or severe based on the Lake Louise AMS Score.[9] HACE develops when AMS includes additional signs, such as ataxia, severe lethargy, altered mental status, or encephalopathy.

HAPE typically develops 2-4 days following ascent. Symptoms include nonproductive cough, dyspnea on exertion, tachycardia, tachypnea, fever, and inspiratory crackles. As HAPE progresses, dyspnea at rest will occur, cough may start to contain blood or pink frothy sputum, and oxygen saturation will be lower than expected for the altitude.

AMS/HACE and HAPE occur as a result of extravascular fluid accumulation, though the pathophysiology is not fully understood. In patients with severe AMS or HACE, cerebral edema can be seen on imaging as well as at autopsy. MR imaging in these patients shows reversible vasogenic edema and suggests there is increased permeability of the blood brain barrier. [7] As a result, brain swelling occurs. Similarly, hypoxemia also causes disruption of the alveolar-capillary barrier in the lungs. This results in fluid, cells, and large proteins to spill into the alveolar space, increasing the pulmonary pressure. In severe cases, basement membranes are disrupted, leading to alveolar hemorrhage.

It is important to note that many other conditions may present similarly to HAI and deciphering between the diagnoses may be difficult. Differential diagnoses may include carbon monoxide poisoning, dehydration, exhaustion, heat illness, hypoglycemia, hypothermia, hyponatremia, electrolyte imbalances, and pneumonia. Additionally, altered mental status from hypoxemia versus HACE may be difficult to differentiate.

Prevention and Treatment of HAI

As with most diseases, the best approach to managing a disease is to prevent it from occurring. For both AMS/HACE and HAPE, gradual ascent is the top recommendation for prevention.[1] Gradual ascent is defined as an average ascent rate of 500 meters per day, to allow for acclimatization. However, with the convenience of air travel, most people can fly directly to their destination within hours, and often don’t have extra days to spare for acclimatization. Therefore, when travelers are looking for an alternative, more convenient option, nifedipine and acetazolamide are recommended as first-line pharmacological therapy for prevention of HAPE and AMS/HACE, respectively. Nifedipine is a vasodilator, effective against pulmonary hypertension. Acetazolamide is a diuretic and works by inhibiting carbonic anhydrase in the renal tubules, increasing bicarbonate excretion. Increasing excretion of bicarbonate creates a compensatory metabolic acidosis to counteract the respiratory alkalosis that initially occurs from the HVR. This compensation process occurs naturally during acclimatization, however, acetazolamide accelerates this physiological process in preparation for ascent and decreasing occurrence of HAI.

Figure 2 [8]

Other agents that may be effective for AMS/HACE include dexamethasone and ibuprofen. Dexamethasone is the next agent recommended if a patient cannot tolerate acetazolamide.[1] Occasionally, it is given with acetazolamide to travelers that are ascending rapidly and are required to immediately perform physical work (i.e. military, rescue teams, etc.). Dexamethasone has many uses. In AMS/HACE, it is presumed to decrease cerebral edema through multiple pathways.[9] However, it is important to note that dexamethasone does not aid in acclimatization, and if discontinued prematurely, there is a risk of sudden onset of AMS symptoms. Other agents that may be effective for HAPE include tadalafil and dexamethasone. They are considered if a traveler has contraindications to taking nifedipine.

Figure 3 [9]

First-line treatment for AMS/HACE and HAPE is straightforward – descend and supplemental oxygen. Travel down to lower altitude should immediately occur once severe HAI develops. For non-severe HAI, a traveler may cease ascent and remain at a constant altitude until symptoms resolve before resuming ascent. Descent is the most effective treatment for severe HAI and is most likely to result in resolution of symptoms. Supplemental oxygen should also be administered, if available, especially if descent cannot immediately occur. Other options may aid in the treatment of HAI, such as portable hyperbaric chambers, though they should not delay descent. Medications that can be administered for AMS/HACE include acetazolamide and dexamethasone, while treatments for HAPE include nifedipine, tadalafil/sildenafil, and CPAP/EPAP. If both HACE and HAPE are suspected in a patient, dexamethasone and nifedipine are both recommended. Though to reiterate, descent is the FIRST course of action and should not be delayed.

Table 1. Summary of HAI Treatment and Prevention

Sleeping in a Hypoxic Environment: A Preventative Strategy?

In 2014, Dehnert et al. investigated how sleeping in a hypoxic environment may play a role in preventing AMS in high altitude travelers.[10] They performed a placebo-controlled, randomized double-blind study with 76 healthy male subjects between ages 18-50 years. Subjects were randomized to sleep in tents that were either 21% oxygen (sea level) or 14-15% oxygen (3043m altitude) for a total of 14 days. Four days following, subjects were exposed to an environment with 12% oxygen, representing 4500m elevation and evaluated for AMS symptoms. Unfortunately, technical issues hindered the goals of the study and the treatment group was not exposed to the initial FiO2 of 14-15%. Instead, 21 of the 37 subjects in the treatment group reached an oxygen environment sufficient for acclimatization (>2200m), with a represented altitude of 2600m, on average. There was a statistically significant difference between AMS-C scores (a subscore of the Environmental Symptom Questionnaire) as well as Lake Louise scores, with lower scores (less symptoms) seen in the group that has slept at a lower oxygen level.[11] This data is preliminary and one of the first studies of its kind, thus more data is needed to further assess if this preventative strategy is effective. Additional areas to investigate may include how long the acclimatization effects last and the height of altitude exposure it protects against.

The Role of the Coca Plant

Four out of the top five highest cities in the world are located in South America. In order of height, they are La Paz (Bolivia), Cuzco (Peru), Sucre (Bolivia), and Quito (Ecuador), all of which are within the Andes Mountains and were part of the Incan empire (1200s-1500s). For centuries, Incan cultures have acknowledged the coca plant as a remedy for HAI.[10] Archaeology evidence has estimated the cultivation of coca to have occurred as early as 1900 BC, while evidence of coca chewing via carbon dating of mummies is estimated to have occurred as far back as 1000 BC.

altitude sickness

Given its rich history and the desire to take a “natural” remedy over a pharmaceutical, the coca plant has become widely used for its proposed effect on preventing and treating AMS. By the 1800s, the coca plant had made its way to Europe and North America, gaining popularity from an article written by an Italian neurologist, Dr. Paolo Mantegazza, who proposed the plant was capable of reducing fatigue, enhancing mood, and supporting sexual activity. Sigmund Freud further substantiated the benefits of the plant during his lifetime.

Over the past 50 years, multiple studies have been published investigating the effects of the coca plant on altitude sickness. Most evidence on the effect of coca on HAI is inconclusive to date, since most studies are difficult to compare due to a variety of study designs, subject populations, and study endpoints.[12] Ultimately, more research is needed before large medical societies can recommend it as a management strategy.

*Top Tips to Remember*

1. Knowledge is power! (and keeps you safe) → learn about altitude sickness and how to minimize the risk of developing symptoms. Share this knowledge with friends, family, and patients
2. Know your limits and listen to your body → we often push ourselves to extremes, but if someone traveling to high altitude starts to develop symptoms or feels unwell, slow down and reevaluate the situation.
3. Descend & use oxygen → once symptoms start to develop or worsen, the first piece of effective management is to treat the symptoms (with oxygen) and knock out the source of illness (descend from high altitude)

Hikes at high altitude are exciting and challenging but are certainly not without risk. Understanding the pathophysiology of HAI and treatment options will help prepare physicians to recognize and treat these conditions. My favorite experience at high altitude was a hike up Vinicunca (also known as Rainbow Mountain), a hike from 14,000 to 17,000 feet. I struggled at times on my way to the top (luckily no cerebral or pulmonary syndromes), but the views at the end were certainly worth it!

Travel smart, be safe, educate your patients, and embark on adventures!

Wesley Chan

EM/IM Resident Class of 2024

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Altitude Sickness: Is it the Altitude or Are You Just Out of Shape?

Published by Wesley Chan on February 18, 2021February 18, 2021

The physiology behind High Altitude Ascent