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Can I Ever Go Back Up To High Altitude Again? – Recurrence Risk of HAPE & HARPE

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by Taylor Kligerman, PA-S

Can I ever return to high altitude? Do I need to move down to a lower elevation?

Disease processes often differ at high altitudes. Some conditions have only been known to occur at high elevations. Most of the resources cited in this blog refer to ‘high altitude’ being at or above 2,500 meters or 8,200 feet.

Ebert Family Clinic in Frisco, Colorado is at 9,075 ft. Many areas in the immediate vicinity are over 10,000′, with some patients living above 11,000′. Two of the more common conditions seen in patients at Ebert Family Clinic are high altitude pulmonary edema (HAPE) and high altitude resident pulmonary edema (HARPE), similar conditions that affect slightly different populations in this region of the Colorado Rocky Mountains.

In “classic” HAPE, a visitor may come from a low-altitude area to Frisco on a trip to ski with friends. On the first or second day, the person notices a nagging cough. They might wonder if they caught a virus on the plane ride to Denver. The cough is usually followed by shortness of breath that begins to make daily tasks overwhelmingly difficult. One of the dangerous aspects of HAPE is a gradual onset leading patients to believe their symptoms are caused by something else. A similar phenomenon is seen in re-entry HAPE, where a resident of a high altitude location travels to low altitude for a trip and upon return experiences these same symptoms [1].

In HARPE, a person living and working here in Frisco may be getting ill or slowly recovering from a viral illness and notices a worsening cough and fatigue. These cases are even more insidious, going unrecognized, and so treatment is sought very late. Dr. Christine Ebert-Santos and her team at Ebert Family Clinic hypothesize that while residents have adequately acclimated to the high-altitude environment, the additional lowering of blood oxygen due to a respiratory illness with inflammation may be the inciting event in these cases.

In both cases, symptoms are difficult to confidently identify as a serious illness versus an upper respiratory infection, or simply difficulty adjusting to altitude. For this reason, Dr. Chris recommends that everyone staying overnight at high altitude obtain a pulse oximeter. Many people became familiar with the use of these instruments during the COVID-19 pandemic. The pulse oximeter measures what percent of your blood is carrying oxygen. At high altitude, a healthy level of oxygenation is typically ≥90%. This is an easy way to both identify potential HAPE/HARPE, as well as reassure patients they are safely coping with the high-altitude environment [2].

HAPE and HARPE are both a direct result of hypobaric hypoxia, a lack of oxygen availability at altitude due to decreased atmospheric pressures. At certain levels of hypoxia, we observe a breakdown in the walls between blood vessels and the structures in lungs responsible for oxygenating blood. The process is still not totally understood, but some causes of this breakdown include an inadequate increase in breathing rates, reduced blood delivered to the lungs, reduced fluid being cleared from the lungs, and excessive constriction of blood vessels throughout the body. These processes cause fluid accumulation throughout the lungs in the areas responsible for gas exchange making it harder to oxygenate the blood [3].

We do know that genetics play a significant role in a person’s risk of developing HAPE/HARPE. Studies have proposed many different genes that may contribute, but research has not, so far, given healthcare providers a clear picture of which patients are most at-risk. Studies have shown that those at higher risk of pulmonary hypertension (high blood pressure in the blood vessels of your lungs), are more likely to develop HAPE [4]. This includes some types of congenital heart defects [5,6]. High blood pressures in the lungs reach a tipping point and appear to be the first event in this process. However, while elevated blood pressures in the lungs are essential for HAPE/HARPE, this by itself, does not cause the condition. The other ingredient necessary for HAPE/HARPE to develop is uneven tightening of the blood vessels in the lungs. When blood vessels are constricted locally, the blood flow is shifted mainly to the more open vessels, and this is where we primarily see fluid leakage. As the blood-oxygen barrier is broken down in these areas, we may also see hemorrhage in the air sacs of the lungs [3].

One observation healthcare providers and scientists have observed is that HAPE/HARPE can be rapidly reversed by either descending from altitude or using supplemental oxygen. Both strategies increase the availability of oxygen in the lungs, reducing the pressure on the lungs’ blood vessels by vasodilation, quickly improving the integrity of the blood-oxygen barrier.

In a preliminary review of over 100 cases of emergency room patients in Frisco diagnosed with hypoxemia (low blood oxygen content) Dr. Chris and her team have begun to see trends that suggest the availability of at-home oxygen markedly reduces the risk of a trip to the hospital. This demonstrates that patients with both at-home pulse oximeters and supplemental oxygen have the capability to notice possible symptoms of HAPE, assess their blood oxygen content, and apply supplemental oxygen if needed. This stops the development of HAPE/HARPE before damage is done in the lungs. In the case of many of our patients, these at-home supplies prevent emergencies and allow patients time to schedule an appointment with their primary care provider to better evaluate symptoms.

Additionally, Dr. Chris and her team have observed that patients with histories of asthma, cancer, pneumonia, and previous HAPE/HARPE are often better educated and alert to these early signs of hypoxia and begin treatment earlier on in the course of HAPE/HARPE, reducing the relative incidence identified by medical facilities. There are many reasons to seek emergent care such as low oxygen with a fever. Patients with other existing diseases causing chronically low oxygen such as chronic lung disease may not be appropriately treated with  supplemental oxygen, although this is a very small portion of the population. Discussions with healthcare providers on the appropriate prevention plan for each patient will help educate and prevent emergency care visits in both residents and visitors.

A young child with short brown hair and glasses with dark, round frames wears a nasal canula for oxygen.

Studies of larger populations have yet to be published. A review of the case reports in smaller populations suggests that the previously estimated recurrence rate of 60-80% is exaggerated. This is a significant finding as healthcare providers have relied on this recurrence rate to make recommendations to their patients who have been diagnosed with HAPE. A review of 21 cases of children in Colorado diagnosed with HAPE reported that 42% experienced at least one recurrence [7]. This study was conducted by voluntary completion of a survey by the patients (or their families) which could lead to significant participation bias affecting the results. Patients more impacted by HAPE are more likely to complete these surveys. Another study looking at three cases of gradual re-ascent following an uncomplicated HAPE diagnosis showed no evidence of recurrence. The paper also suggested there may be some remodeling of the lung anatomy after an episode of HAPE that helps protect a patient from reoccurrence [8]. Similar suggestions of remodeling have been proposed through evidence of altitude being a protective factor in preventing death as demonstrated by fatality reports from COVID-19[9].

Without larger studies and selection of participants to eliminate other variables like preexisting diseases, we are left to speculate on the true rate of reoccurrence based on the limited information we have. Strategies to reduce the risk of HAPE/HARPE such as access to supplemental oxygen, pulse oximeters, and prescription medications [10] are the best way to prevent HAPE/HARPE. Research should also continue to seek evidence of individuals most at risk for developing HAPE/HARPE [11].

A woman with reddish-brown, straight hair just below her shoulders, wears a white coat over a mustard-colored shirt, smiling.

Taylor Kligerman is a third-year medical student at Rocky Vista University with plans to complete a residency in emergency medicine. She was born and raised in Flossmoor, IL, and became interested in medicine following her first medical mission trip to Gonaïves, Haiti in 2010. Taylor has extensive experience in wilderness and remote emergency medicine. Before starting medical school, she was certified as a wilderness EMT and gained experience in remote areas of Canada and Western North Carolina on whitewater expeditions and as a volunteer with local search and rescue. Her personal interests include camping, skiing, and all paddle sports.

References

  1. Ucrós S, Aparicio C, Castro-Rodriguez JA, Ivy D. High altitude pulmonary edema in children: A systematic review. Pediatr Pulmonol. 2023;58(4):1059-1067. doi:10.1002/ppul.26294
  2. Deweber K, Scorza K. Return to activity at altitude after high-altitude illness. Sports Health. 2010;2(4):291-300. doi:10.1177/1941738110373065
  3. Bärtsch P. High altitude pulmonary edema. Med Sci Sports Exerc. 1999;31(1 Suppl):S23-S27. doi:10.1097/00005768-199901001-00004
  4. Eichstaedt C, Benjamin N, Grünig E. Genetics of pulmonary hypertension and high-altitude pulmonary edema. J Appl Physiol. 2020;128:1432
  5. Das BB, Wolfe RR, Chan K, Larsen GL, Reeves JT, Ivy D. High-Altitude Pulmonary Edema in Children with Underlying Cardiopulmonary Disorders and Pulmonary Hypertension Living at Altitude. Arch Pediatr Adolesc Med. 2004;158(12):1170–1176. doi:10.1001/archpedi.158.12.1170
  6. Liptzin DR, Abman SH, Giesenhagen A, Ivy DD. An Approach to Children with Pulmonary Edema at High Altitude. High Alt Med Biol. 2018;19(1):91-98. doi:10.1089/ham.2017.0096
  7. Kelly TD, Meier M, Weinman JP, Ivy D, Brinton JT, Liptzin DR. High-Altitude Pulmonary Edema in Colorado Children: A Cross-Sectional Survey and Retrospective Review. High Alt Med Biol. 2022;23(2):119-124. doi:10.1089/ham.2021.0121
  8. Litch JA, Bishop RA. Reascent following resolution of high altitude pulmonary edema (HAPE). High Alt Med Biol. 2001;2(1):53-55. doi:10.1089/152702901750067927
  9. Gerken J, Zapata D, Kuivinen D, Zapata I. Comorbidities, sociodemographic factors, and determinants of health on COVID-19 fatalities in the United States. Front Public Health. 2022;10:993662. Published 2022 Nov 3. doi:10.3389/fpubh.2022.993662
  10. Luks A, Swenson E, Bärtsch P. Acute high-altitude sickness. European Respiratory Review. 2017;26: 160096; DOI: 10.1183/16000617.0096-2016
  11. Dehnert C, Grünig E, Mereles D, von Lennep N, Bärtsch P. Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude. European Respiratory Journal 2005;25(3):545-551; DOI: 10.1183/09031936.05.00070404
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What is Acute Mountain Sickness?

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Acute mountain sickness (AMS) is a condition that can occur when individuals ascend to high altitudes rapidly, typically above 2,500 meters (8,200 feet). The symptoms of AMS are due to the body’s struggle to adapt to the decreased oxygen levels at higher elevations. More specifically, the symptoms are caused by cerebral vasodilation that occurs in response to hypoxia, in an attempt to maintain cerebral perfusion.1

The typical symptoms of AMS include headache, nausea, vomiting, anorexia, and fatigue. In children the symptoms are less specific including increased fussiness, crying, poor feeding, disrupted sleep, and vomiting. Symptom onset is usually 6-12 hours after arrival to altitude but this can vary.

AMS affects children, adults, males and females equally, with a slight increased incidence in females. It is difficult to believe, but physical fitness does not offer protection against AMS. However, people who are obese, live at low elevation, or undergo intense activities upon arrival to elevation are at increased risk.1

Treatments for Acute Mountain Sickness

Descending

Descending and decreasing altitude is a vital treatment for people with severe symptoms of AMS. By decreasing altitude there will be more oxygen in the air and symptoms will not be as severe..2 

Oxygen

Since the main cause of AMS is hypoxia, oxygen supplementation is an effective treatment when descent is not wanted or possible. Supplemental oxygen even at .5L to 1L per hour can be effective in reducing symptoms.1  It can be prescribed for short periods of time or to be used only during sleep  In the central Colorado Rockies, this may be a practical solution for “out of towners” who have traveled up to the town of Leadville (10,158’/3096m) for vacation, but in an austere environment supplemental oxygen may not be a reasonable treatment option. There should be symptomatic improvement within one hour.

Acetazolamide

Acetazolamide is a carbonic anhydrase inhibitor which causes increased secretion of sodium, potassium, bicarb, and water. This mechanism of actions lends beneficial to the treatment of AMS because it decreases the carbonic anhydrase in the brain. 3There is evidence to support the use of acetazolamide in the prevention of AMS, but minimal evidence pointing towards it’s role in treatment. Dosing is inconsistent but is usually prescribed at 125-250mg BID.

Hyperbaric Therapy

Many people consider hyperbaric chambers to be large structures in hospitals, however there are portable and lightweight hyperbaric chambers that can be used in austere environments or during expeditions. The mechanism of action of hyperbaric therapy is a simulated decrease in elevation, of approximately 2500 meters. These chambers will remove symptoms within approximately one hour of use but symptoms are likely to return. They are useful in the field but not frequently required in a hospital setting.1

Lynde Tucker is a third year medical student who grew up in Lake Tahoe California, and moved to Colorado for medical school. She is grateful for the opportunity to be back living in the mountains and working in a mountain community.

References

  1. https://www.uptodate.com/contents/acute-mountain-sickness-and-high-altitude-cerebral-edema?search=acute%20mountain%20sickness&source=search_result&selectedTitle=1~15&usage_type=default&display_rank=1#H35
  2. https://my.clevelandclinic.org/health/diseases/15111-altitude-sickness
  3. https://www.uptodate.com/contents/acetazolamide-drug-information?search=acetazolamide%20altitude&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2#F129759
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High Altitude Sleep Disorders … A Thing of the Past?

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The fundamentals of vitality include food, water, air, shelter, and sleep. Sleep, though often underappreciated, can influence our physical and mental  health,  complex and easily impacted by outside factors. Living at a  high altitude may be wonderful but what is gained in beauty and adventure, is compromised with  reduced quality sleep. With increasing elevation comes more nighttime awakenings,  brief arousals, nocturnal hypoxemia, and periodic breathing. Light  sleep increases and slow-wave and REM sleep decrease.

The current gold standard for diagnosis of suspected sleep disorders includes polysomnography:  seven or more streams of data at a hospital or sleep center. The SleepImage  System allows for more flexibility with children, adolescents, and adults. Currently,  Dr. Chris Ebert-Santos of Ebert Family Clinic in Frisco, Colorado, USA (9000′) is using this technology primarily to assess some of the most common  forms of Sleep Breathing Disorders and secondly, to analyze the percentage of oxygen  desaturation of her patients while in their homes. 

The SleepImage System measures several variables that construct a summary for each  individual. Sleep quality is generated using Sleep Quality Index (SQI) biomarkers. Pathology  markers measure sleep duration, efficiency, and latency. Central Sleep Apnea (CSA) and Obstructive Sleep Apnea (OSA) are assessed together as Sleep Apnea Hypoxia Index (sAHI). Periodic and fragmented sleep pathology are reported and can be used to assess disease  management long-term. 

Recently, the clinic analyzed Patient X’s sleeping patterns without and with  supplemental oxygen. The theory: adding a steady flow of oxygen to the  nightly sleep regimen reduced the total amount of time desaturating and severity of sleep  breathing disorders. On the night preceding treatment, Patient X experienced an SQI of 17  (expected >55) and efficiency at 95% (expected >85%) for overall sleep quality. Sleep  opportunity demonstrated a 0h:02m latency (expected <30m), and duration of 5h:47m (expected  7-9h); sAHI was marked as severe for both 4% and 3% desaturation with values at 34 and 61,  respectively (severe= >30.0 in adults). Fragmented sleep was at 55% (expected <15%) and  periodicity at 22% (expected <2%). Lastly, Patient X spent 25% of his night’s sleep under 90%  SpO2, 18% under 88% Spo2, and 4% under 80% SpO2. Ideally, a healthy night’s sleep should  aim to remain above 90% SpO2 for the majority of the time in bed. 

When oxygen supplementation was introduced, improvements were observed. Sleep quality  showed a slight change, SQI increased to 31 (previously 17, expected >55), and efficiency  decreased to 87% (previously 95%; expected >85%) while remaining at a target value. Sleep  opportunity showed a slight increase during latency to 0h:12m while remaining within the  expected value of <30mins; duration jumped to 8h:14m but that could be attributed to an early  bedtime. Fragmented sleep remained in the severe range but decreased by 5%; periodicity improved to 0%, removing it from both the severe and moderate range. The most notable  improvement was observed with sAHI, both the 3% and 4% desaturation categories improved to the moderate range with values of 9 and 14, respectively. Time under 90% SpO2 also improved  to only 4% throughout the night and 0% below 88% SpO2. 

Since data is collected while patients sleep, skewed results from the placebo effect can be  reduced or eliminated. Increased duration could be attributed to longer time in bed, as mentioned  above, and should be examined more in-depth longitudinally. Latency for sleep increased with  oxygen treatment but that could be attributed to discomfort from the nasal cannula or greater  tiredness one day over the other. Similarly, latency should be examined longitudinally.

The results seen with this patient are common in our population.  Many people report they slept significantly better their first night on oxygen. Many patients studied on and off oxygen show the same dramatic decrease in their sleep apnea index. The gold standard for treating sleep apnea involves a mask to increase the pressure in the airway and prevent the collapse and narrowing that occurs during relaxation and sleep.  Does the supplemental 2 liters per minute of oxygen cause enough increased airway pressure to prevent airway narrowing? Supplemental oxygen would not be considered for an intervention or treatment in other locations where sleep studies are conducted because they are not usually showing significant hypoxia. Does the improvement in oxygen, even if it is the difference between oxygen saturations in the high 80’s and low 90’s increasing to the mid 90’s affect the balance of oxygen and carbon dioxide in a way that changes the incidence of apnea and drive to breathe during sleep?

Long-term, this easy-to-use SleepImage System can assess sleep disorders  across all age groups and contribute to long-term management for many people living at altitude. Oxygen, a simple intervention that is widely available and relatively inexpensive, requiring no special visits to fit and adjust, has the potential to  improve symptoms and sleep greatly. 

References

  • Introduction to SleepImage https://sleepimage.com/wp-content/uploads/Introduction-to-SleepImage.pdf
  • Diagnosis and treatment of obstructive sleep apnea in adult https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714700/
  • Sleep and Breathing at High Altitude https://pubmed.ncbi.nlm.nih.gov/11898114/#:~:text=Sleep%20at%20high%20altitude%2 0is,REM%20sleep%20have%20been%20demonstrated.measure

Ashley Cevallos is a second-year Physician Assistant student at Red Rocks Community College in Arvada, CO. She received her undergraduate degree from  University of Maryland, Baltimore County. Before PA school, she worked as a vestibular technician and research coordinator for Johns Hopkins department of Otolaryngology. She was born in Ecuador and raised in Maryland. In her free time, she enjoys hiking, yoga, discovering new plants/animals and picnics. 

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Living With High Altitude Pulmonary Hypertension: An Interview with Karen Terrell

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by Jennifer Wolfe, NP-S

During my last week of a clinical rotation at Ebert Family Clinic in Frisco, Colorado, at 9000 feet, I was thrilled to have the opportunity to interview high altitude resident Karen Terrell with physician Dr. Chris Ebert-Santos.  During this time, we were able to discuss high altitude pulmonary hypertension, also known as NAPH. This is a condition that Karen has been living with since 2015.  NAPH is condition that can affect people that live above 8,200 feet, more than 140 million people live at this altitude worldwide, including the population of Summit County, where the town of Frisco, Colorado is. Pulmonary hypertension is a group of disorders that will typically be diagnosed during a heart catheterization measuring the mean arterial pressure of the right side of the heart.  These disorders are broken down into five groups. High altitude pulmonary hypertension is in group three. The primary symptoms that people first notice is extreme fatigue, difficulty getting air upon exertion, and difficulty engaging in their normal exercise routines.

How long have you lived in Summit County [Colorado], and where did you move from originally?

Karen: I grew up in Nebraska, I moved to New York City as soon as I was old enough to leave home.  I went to Boulder for school, and then moved to Denver for work.  I went to an Outward-Bound Experience, and I fell in love with this area.  I have lived in Summit County over 37 years. My kids were born and raised here; they are now in their 30s.

What are some of the things that you love to do in area?

Karen: I downhill ski, I uphill ski, and I cross country ski.  Mountain biking is my passion. I downhill bike, that is where you take the gondola to the top of the mountain and then ride your bike down.

When did you start to have symptoms?

Karen: 2015

What were the symptoms that you noticed first?

Karen: Extreme fatigue and erratic pulse, with or without exertion.  By the end of a run, I would be so exhausted that I was practically crawling home.

Do have to go on oxygen at any point?

Karen: In 2018 I started using oxygen at night. I still use oxygen at night.  In 2020 I started riding and skiing with portable oxygen. When my oxygen columns fail, so do I. It was also during this time I began to work on nasal breathing night and day.  I have been doing research on the importance of nasal breathing and retraining the body on how to take in oxygen.  Practicing nasal breathing is especially important when you are using a nasal cannula to get oxygen when you are being active.

An image of the OxyGo FIT portable oxygen concentrator with specifications.
https://oxygo.life/oxygo-fit

Dr. Chris Ebert-Santos:  The standard is “if you’re 50 and you’ve lived here 10 years and you want to live here for another 10 years you should be sleeping on oxygen.”

Between 2015 and 2018 did you have any other symptoms or worsening concerns?

Karen: In 2017 I applied for life insurance.  I was denied as I had what I now know is chronic proteinuria. The nephrologist was perplexed as to why someone who is as active as I am and takes no medication is having this condition.  The insurance company essentially told me that they would not touch me with a 10-foot pole.  This was the “canary in the mine” that made me think something was not right. In 2018, I had a cardiac ablation. The cardiac ablation corrected the erratic heart rate and relieved my extreme fatigue. However, it did nothing for my oxygen saturation.

You mentioned in 2020 that you started to ski and ride your bike with portable oxygen.  Did something happen in 2020, besides COVID?

Karen: You know, with everything that I have going on health wise I have been so cautious that I have not ever had COVID. In 2020, I was at an office visit with my PA. I mentioned that biking and skiing at higher elevation with exertion, that I felt flattened and near-dead.  My pulse oximeter showed oxygen saturation of low 70’s. My PA freaked out and thought I had Pulmonary Hypertension (as opposed to HAPH) and sent me to a Denver Pulmonary specialist.

What did the pulmonary specialist tell you?

Karen: When I went to the pulmonary specialist, they said my oxygen numbers were fine at Denver’s elevation. The Pulmonologist advised moving to lower elevation but said there is no knowing how low until I experiment.  I have lived in Summit County and raised my children here; my children still live here.  Moving was not an option. I started riding and skiing with portable oxygen. When 02 columns fail, so do I. I do have periodic episodes of extreme joint pain resulting from excessive stress/time at desk (10-hr days).  However, I try to eliminate the pain by remaining active using oxygen when I need it. If I don’t use oxygen to sleep, I feel half dead the next day and it is difficult to wake up the next day.  I worry about the long-term effects of the hypoxia, however I continue to monitor.  I am hoping to see more research done in the area of high-altitude pulmonary hypertension. 

Jennifer Wolfe is in her final semester of Nurse Practitioner school at Georgetown University. She was born and raised in Missouri and attended The University of Missouri where she graduated with a bachelor’s degree in psychology. After attending Mizzou she married her husband who was active duty in the US Navy. They traveled to many bases and had two boys before calling Denver their home in 2011.  Jennifer received her BSN from Denver College of Nursing. Jennifer has spent 7 years as a nurse in the emergency department of several level II trauma centers before starting at Georgetown as a part of the Family Nurse Practitioner program.  Jennifer enjoys spending her free time with her family and their three dogs.  

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HAFE: High-Altitude Flatus Expulsion

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Often, at high altitude we hear complaints of gas pain and increased flatus in our infant population. Parents often wonder, are we doing something wrong? Is my child reacting to breastmilk, or showing an intolerance to certain foods?  Actually there is another explanation for increased flatus and gas pain in the high-altitude region of Colorado. 

The term HAFE was coined by Dr. Paul Auerbach and Dr. York Miller and published in the Western Journal of Medicine in 1981. Their discovery began In the summer of 1980, when the two doctors were hiking in the San Juan Mountains of Colorado on a quest to summit three 14ers. During their ascent they noticed that something didn’t smell right! As the pair continued to emit noxious fumes, they began to put their scientific brains to work and discovered HAFE. The symptoms include an increase in frequency and volume of flatus, or in other terms an increase in toots! We all have familiarity in watching our bag of potato chips blow up when reaching altitude or our water bottle expanding as we head into the mountains. This reaction is due to a decrease in barometric pressure. Based on Boyle’s law, decreased barometric pressure causes the intestinal gas volume to expand, thus causing HAFE (Skinner & Rawal, 2019).

A graphic illustrating how Boyle's law works: the pressure of a gas increases as its volume decreases.

To my surprise, a gas bubble the size of a walnut in Denver, Colorado (5280 ft) would be the size of a grapefruit in the mountain region of Summit County, CO (8000+ ft)! Trapped gas is known to lead to discomfort and pain. The use of simethicone may have merit in mitigating the effects of HAFE. Simethicone works by changing the surface tension of gas bubbles, allowing easier elimination of gas. This medication, while benign, can be found over the counter and does not appear to be absorbed by the GI tract (Ingold, C. J., & Akhondi, H., 2022). 

While this phenomenon may not be as debilitating as high-altitude pulmonary edema (HAPE), it deserves recognition, as it can cause a significant inconvenience and discomfort to those it inflicts. As the Radiolab podcast explained in their episode The Flight Before Christmas , expelled gas in a plane or car when driving up to the mountains can be embarrassing. While HAFE can be inconvenient, it is a benign condition and a matter of pressure changes rather than a disease or pathological process. We would love to talk more about HAFE at Ebert Family Clinic if you have any questions or concerns!

A bald eagle flies over a misty settled into the valley against the blue-green pine forest of a mountain.
A bald eagle flies toward its nest atop a bare lodgepole pine.

As always, stay happy, safe, and healthy 😊

Taylor Hollingsworth is finishing her final semester as a family nurse practitioner (FNP) student at Georgetown University. Originally from the east coast, Taylor plans to start her FNP career in North Carolina close to family. She has a passion for pediatric and family wellness and has worked as a pediatric intensive care unit nurse for 6 years! In her free time, Taylor loves to hike, fly fish, run, and spend time with her fiancé Logan. 

References

Auerbach, P. & Miller, Y. (1981). High altitude flatus expulsion. The Western Journal of Medicine, 134(2), 173-174.

Chemistry Learner. (2023). Boyle’s Law. https://www.chemistrylearner.com/boyles-law.html

Ingold, C. J., & Akhondi, H. (2022). Simethicone. StatPearls Publishing. 

McKnight, T. (2023). The Flight Before Christmas [Audio podcast]. Radiolab. https://radiolab.org/episodes/flight-christmas

Skinner, R. B., & Rawal, A. R. (2019). EMS flight barotrauma. StatPearls Publishing. 

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Are Epigenetics the Bridge to Permanent Physiologic Adaptations in Organisms Living at High Altitude?

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Epigenetics slide from speaker at Hypoxia conference in La Paz Bolivia, 2022

The CDC defines epigenetics as “the study of how your behaviors and environment can cause changes that affect the way your genes work… epigenetic changes are reversible and do not change your DNA sequence, but they can change how your body reads a sequence.”1 Examples of epigenetic changes include methylation, histone modifications, and non-coding RNAs. Researchers have postulated the involvement of epigenetics in an organism’s adaptations to hypoxic high-altitude environments. After looking into this topic, I questioned if epigenetics may be the bridge to the permanent physiologic alterations in organisms living at high altitudes. 

Hypoxia Inducible Factor-1 (HIF-1) is a nuclear transcription factor activated in hypoxia states, and regulates several oxygen-related genes. The role of epigenetics, specifically methylation of HIF-1 in the expression of the erythropoietin gene, in states of hypoxia was researched. Erythropoietin was chosen due to it being a widely known protein that stimulates erythropoiesis in states of hypoxia. It was confirmed that HIF-1 binds to a HIF-1 binding site (HBS) on the erythropoietin enhancer and will induce transcription of erythropoietin.2 CpG methylation in the HBS interferes with HIF-1 binding, thus inhibiting the activation of transcription of erythropoietin.2  They also found that there were several other oxygen-related genes that were susceptible to similar epigenetic changes.2 Another study investigating HIF-1 and its binding to HIF-1 response element (HRE) upstream to a target gene confirmed the potential for epigenetic changes, specifically methylation. They found that this HIF-1 binding site has a CpG dinucleotide, making it inherently susceptible to methylation.3 To clarify, the most notable epigenetic change is the methylation of cytosine located 5’ to guanine, known as CpG dinucleotides.3 Again, they reported that methylation of the CpG island in the HIF-1 binding site upstream of the target gene, erythropoietin, was negatively correlated with its expression.3 

Furthermore, research on epigenetic changes in rats exposed to long and short-term intermittent hypoxic environments and their room air recovery treatments suggests there is a long-term effect in rats exposed to long-term intermittent hypoxia.4  Rats were exposed to short-term (10 days) and long-term (30 days) intermittent hypoxia resembling obstructive sleep apnea oxygen profiles.4 The short-term hypoxic rats treated for 10 days at room air reversed their altered carotid body reflexes including hypertension, irregular breathing, and increased sympathetic tone. While the long-term hypoxia rats treated for 30 days at room air did not have a reversal of altered carotid body reflexes.4 There were similar results in reactive oxygen species (ROS) and antioxidant enzyme (AOE) levels. The long-term hypoxia rats had increased levels of ROS and decreased AOEs in their recovery periods compared to the short-term hypoxia rats.4 

Erythropoietin is not the only oxygen-related gene that is affected. For example, a study looked at the methylation profiles of Tibetan and Yorkshire pigs under high-altitude hypoxia. IGF1R and AKT3 were two notable differentially methylated genes found to have high expression and low methylation levels in Tibetan pigs that suggest a role in adaptation to hypoxic environments.5 Both genes are responsible for cell proliferation and survival.5 Tibetan pigs are known to have become physiologically adapted to their high-altitude hypoxic environment over generations and epigenetic changes were verified in the genome-wide sequence ran in this study.5 This study alludes that epigenetics is not only a bridge but may be a part of the permanent physiologically selected adaptations to ensure survival at high altitudes.

In conclusion, research demonstrates a variety of epigenetic changes that are taking place in these high-altitude hypoxic environments. The research suggests that they may likely be tissue-specific as well. There are definite knowledge gaps in the exact roles that epigenetics may play in hypoxic environments and gene expression. There is room for more research and identifying alterations to epigenetics to improve human physiologic adaptations to hypoxia. 

References 

1. Centers for Disease Control and Prevention. What is Epigenetics. https://www.cdc.gov/genomics/disease/epigenetics.htm. Accessed December 30th, 2022.

2. Wenger, R.H., Kvietikova, I., Rolfs, A., Camenisch, G. and Gassmann, M. (1998), Oxygen-regulated erythropoietin gene expression is dependent on a CpG methylation-free hypoxia-inducible factor-1 DNA-binding site. European Journal of Biochemistry, 253: 771-777. https://doi.org/10.1046/j.1432-1327.1998.2530771.x

3. Yin H, Blanchard KL. DNA methylation represses the expression of the human erythropoietin gene by two different mechanisms [published correction appears in Blood 2000 Feb 15;95(4):1137]. Blood. 2000;95(1):111-119.

4. Nanduri J, Semenza GL, Prabhakar NR. Epigenetic changes by DNA methylation in chronic and intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol. 2017;313(6):L1096-L1100. doi:10.1152/ajplung.00325.2017

5. Zhang B, Ban D, Gou X, et al. Genome-wide DNA methylation profiles in Tibetan and Yorkshire pigs under high-altitude hypoxia. J Anim Sci Biotechnol. 2019;10:25. Published 2019 Feb 5. doi:10.1186/s40104-019-0316-y

A woman in a white coat with long, dark, straight hair below her shoulders smiles.

Emily Paz is a third-year medical student at Rocky Vista University College of Osteopathic Medicine and is looking forward to pursuing a career in orthopedics. She is from the central coast of California and earned her Bachelor of Science degree in General Biology from the University of California San Diego. She worked in an emergency department as an EMT after her undergraduate education which reaffirmed her passion and curiosity for medicine. In her free time, she enjoys snowboarding, practicing Muay Thai, cooking, and spending time with family and friends.

Acclimation, Altitude Science, Athletic Training, Backcountry, Health, High Altitude, High Altitude Training & Fitness, Huts, Hyperbaric Therapy, Mountaineering, Sleep at Altitude

Sleep at High Altitude

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Have you thought of what it would be like living in the mountains year-round? Medical professionals find it is important to look at what living at high elevations can do to the human body. One activity heavily affected is sleep. As mentioned in previous blog posts, visitors often have trouble falling asleep, staying asleep, and feeling rested in the morning. A recent study published in Physiological Reports measured the effects of sleeping patterns at high elevation. The participants experienced a simulated elevation inside a hyperbaric chamber. This mimicked sleeping at elevations of 3000 meters (9,842 feet) and 4050 meters (13,287 ft) for one night and then sleeping at sea level for several nights to establish a baseline for the research participants. Participants exercised for 3 hours in the hyperbaric chamber allowing researchers to observe how the lower oxygen concentrations affected their ability to perform strenuous tasks. The group that slept in a simulated 4050 meter environment had an increased heart rate that was 28% higher and an oxygen saturation 15% lower than the 3000 meter participants. When comparing sleep itself, the group at 4050 meters had 50% more awakening events throughout each night. This goes along with previous research on this blog that states that people who sleep at high altitude complain of insomnia and frequent awakening when first arriving at high elevation.

These numbers increase even more dramatically when compared to participants at sea level. Related symptoms reported during this study showed the incidence of acute mountain sickness occurred in 10% of the participants at a simulated 3000 meters, increasing to 90% at 4050 meters. As mentioned, the average heart rate increases and oxygen saturation decreases as the elevation increases. The baseline heart rate at sea level was 62 beats per minute, increasing to 80 at 3000 meters and 93 at 4050 meters. Ideally health care providers aim to oxygenate vital organs by keeping the oxygen saturation level between 92-100%. The lower the oxygen level the harder it is to keep organs properly profused. Age, health status, and place of residence are taken into consideration when examining study reports. Oxygen saturation at sea level was 98% decreasing to 92% at 3000 meters and 84% at 4050 meters.

As mentioned in a previous post by Dr. Neale Lange, sleeping at high altitudes can be hard due to the frequent awakenings and nocturnal hypoxia caused by the low oxygen levels at higher elevation. This study reiterates these findings with the results of the average oxygen saturation at 3000 meters being around 92%. Dr. Lange also found that sleep apnea was often more prominent and had more negative effects on the human body in environments that were lower in oxygen. This study agrees with that statement finding that people with sleep apnea had twice the hourly awakenings compared to those at higher elevation that did not have sleep apnea. Dr. Lange also pointed out that the contribution of hypobaric atmosphere to symptoms at altitude as opposed to pure hypoxemia is unknown. Frisco, Colorado is at an elevation of 2800 meters. Ongoing research at Ebert Family Clinic including residents and visitors along with laboratory studies such as this one can guide decisions about interventions and treatment to improve sleep and help us enjoy our time in the mountains.

References

  1. Figueiredo PS, Sils IV, Staab JE, Fulco CS, Muza SR, Beidleman BA. Acute mountain sickness and sleep disturbances differentially influence cognition and mood during rapid ascent to 3000 and 4050 m. Physiological Reports. 2022;10(3). doi:10.14814/phy2.15175
  2. Blog post: HOW DO YOU DEFINE A GOOD NIGHT’S SLEEP?:AN INTRODUCTION TO THE SLEEPIMAGE RING, AN INTERVIEW WITH DR. NEALE LANGE

Casey Weibel is a 2nd year student at Drexel University, born and raised in Pittsburgh, Pennsylvania. He went to Gannon University for his undergrad and got a degree in biology.  Before PA school, Casey was an EMT.  He enjoys hiking and kayaking and is a big sports fan. 

Acclimation, Altitude Science, Doc Talk, Health, High Altitude, Sleep at Altitude

How do you define a good night’s sleep? : An Introduction to the SleepImage Ring, An Interview with Dr. Neale Lange

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Dr. Neale Lange is a leader in sleep medicine who started his medical training in South Africa and now practices Pulmonary and Sleep Medicine for UCHealth in Denver.

Sleep plays a crucial role in cognitive behavior and physical well-being but is often times taken for granted. As Dr. Neale Lange puts it, many people have been taught or trained to devalue sleep in an effort to maximize the time awake to study, get caught up on work, or complete other tasks1. However, research over the years has demonstrated that the toll sleep deprivation plays on the body is significant. Sleep deprivation can lead to impairment in memory, cognition, and emotion, and can lead to chronic medical conditions such as diabetes, heart disease and cancer2. It is also thought that sleep deprivation and hypoxemia are associated with white matter disease in the brain and deep slow wave sleep, is what fixes it4.

Furthermore, Dr. Lange states that sleeping at altitude carries its own risks. Sleeping at altitude, where there is less oxygen in the air, can cause overall poor sleep quality, increased awakenings, frequent arousals, marked nocturnal hypoxia and periodic breathing.. Additionally, sleeping at altitude can negatively impact our sleep architecture, increasing the amount of light sleep and decreasing the amount of deep slow-wave and REM sleep which plays a key role in memory creation, retention and emotional control and personal behavior3.

In hopes to defining a person’s sleep at altitude, Dr. Lange started a sleep lab in Summit County at St. Anthony Summit Hospital, which, as he put it, “opened a can of worms” when he saw how sick and complicated patients sleep apnea cases were. Time and time again, he saw that when patients who were struggling with sleep apnea were given 2L of supplemental oxygen by nasal cannula, the apnea improved. Additionally, those patients with sleep apnea who descended around 4,000 ft to Denver have improved saturations but may still have sleep apnea. His facility study included baseline tests at two hours without oxygen and then two hours with oxygen while a person slept. He found that although the apnea improved in many, improvements in sleep itself did not always follow.

This left him with the question of: How do we measure “good sleep?” Well, as he states, it is not that simple. Though the obvious answer may be to turn to medications to determine good sleep, this can be misleading. Medications have an amnestic effect on people because when they wake up in the morning, if their memory is blank, they feel that they have had a good night’s rest. But in reality, this is subjective. The true data collected during sleep is objective, so to answer his question of measuring sleep, he turns to a tool of cardiopulmonary coupling (CPC). This tool, called a SleepImage Ring, looks similar to an Apple Watch and is worn around a patient’s finger throughout the night. Using Bluetooth technology, data is collected and transferred through a smartphone for analysis, providing the patient with a vast amount of data about their sleep.

The SleepImage System is the only FDA approved medical grade technology with the simplicity of a consumer device on the market for use in both children and adults. It is intended for use by a healthcare professional to establish a patient’s sleep quality and aid in evaluation and clinical diagnosis of sleep disorders and sleep disordered breathing, or SDB. It uses CPC technology which is “based on calculations and spectral analysis of cardiovascular- and respiratory data” collected during sleep using continuous “normal sinus rhythm ECG- or PLETH (Plethysmogram from a PPG sensor) signal as the only input requirement.” The output metrics from the SleepImage System include “sleep duration (SD), total sleep time (TST), wake after sleep onset (WASO) and sleep quality (SQI) and sleep disordered breathing (SDB) related output metrics that include an Oxygen Desaturation Index (ODI), an Apnea Hypopnea Index (sAHI), a Respiratory Disturbance Index (sRDI), Central Sleep Apnea Index and the Sleep Apnea Indicator (SAI) that is derived from Cyclic Variation in Heart Rate (CVHR)6. With a PLETH signal including saturations, the SDB data conforms with the American Academy of Sleep Medicine AHI scoring and severity definitions.” Additionally, we can determine how long a patient spends in various sleep stages, including stable, unstable and REM sleep, determine apnea events, and autonomic nervous system activity. The data is generated and presented on the SleepImage Quality Report (shown below). The ring and report are designed as such where you can do individualized, precise sleep medicine. It is true when Dr. Lange says “the devil is in the details” referring to the vast amount of information that can be analyzed from this device during one night of sleep.

Currently, the gold standard to monitoring and diagnosing sleep disorders is polysomnography, also known as a sleep study, which records certain body functions as you sleep to determine brain activity, oxygen, heart rate, breathing, as well as eye and leg movements5. It can detect types of sleep apnea; however, this comprehensive test is typically done during an overnight stay in a hospital or other sleep center, which presents a disadvantage. The disadvantage to polysomnography is that it takes people out of their natural sleeping environment, is costly, and time consuming, which deter a large portion of people from partaking in sleep studies.

Dr. Neale Lange explains that this device can change the way we look at our sleep and may provide better insight into a person’s sleep on a greater scale due to the ease of wearing the device over multiple nights, compared to spending one night in a sleep lab for a study. A study done on 65,000 users indicated that there is added benefit to multi-night testing as compared to single night testing. Testing for sleep apnea on only one night has been shown to vary from night to night, indicating that single night testing potentially misclassifies 20% of people7. This device provides the ease of multi-night testing for patients, which is a significant advantage and increases accurate diagnosis of sleep disordered breathing. To Dr. Lange, “it is about individualized patient care” and evaluating “the person sitting in front of [him]” which makes this device so valuable. Dr. Lange states that, “living at altitude is a particular challenge, and if people are thinking ahead,” instead of wondering, “how long do I want to live at altitude,” a better question would be, “how can I invest in brain wellness.”

In summary, sleep deprivation, especially at altitude, is an important focus that people should not overlook. At Ebert Family Clinic in Frisco, one of the most important questions asked is, “how did you (or your child) sleep last night?” Now, with the SleepImage Ring, we can objectively evaluate our patient’s sleep which can aid in the diagnosis and management of various conditions.

References

  1. South African Dental Association. (2021, November 25). The sleep disorder spectrum: Mouth breathing to Osa – Dr Neale Lange (WEB126). YouTube. Retrieved December 5, 2021, from https://www.youtube.com/watch?v=agZruGNfFNI
  2. Irish, L. A., Kline, C. E., Gunn, H. E., Buysse, D. J., & Hall, M. H. (2015). The role of sleep hygiene in promoting public health: A review of empirical evidence. Sleep medicine reviews, 22, 23–36. https://doi.org/10.1016/j.smrv.2014.10.001
  3. Wickramasinghe, H., & Anholm, J. D. (1999). Sleep and Breathing at High Altitude. Sleep & breathing = Schlaf & Atmung, 3(3), 89–102. https://doi.org/10.1007/s11325-999-0089-1
  4. Voldsbekk, I., Groote, I., Zak, N., Roelfs, D., Geier, O., Due-Tønnessen, P., Løkken, L. L., Strømstad, M., Blakstvedt, T. Y., Kuiper, Y. S., Elvsåshagen, T., Westlye, L. T., Bjørnerud, A., & Maximov, I. I. (2021). Sleep and sleep deprivation differentially alter white matter microstructure: A mixed model design utilizing advanced diffusion modelling. NeuroImage, 226, 117540. https://doi.org/10.1016/j.neuroimage.2020.117540
  5. Mayo Foundation for Medical Education and Research. (2020, December 1). Polysomnography (Sleep Study). Mayo Clinic. Retrieved December 25, 2021, from https://www.mayoclinic.org/tests-procedures/polysomnography/about/pac-20394877#:~:text=Polysomnography%2C%20also%20called%20a%20sleep,leg%20movements%20during%20the%20study.
  6. MyCardio LLC. (2021, November 24). Introduction to sleepimage®. Retrieved December 10, 2021, from https://sleepimage.com/wp-content/uploads/Introduction-to-SleepImage.pdf
  7. Lechat, B., Naik, G., Reynolds, A., Aishah, A., Scott, H., Loffler, K. A., Vakulin, A., Escourrou, P., McEvoy, R. D., Adams, R. J., Catcheside, P. G., & Eckert, D. J. (2021). Multi-night Prevalence, Variability, and Diagnostic Misclassification of Obstructive Sleep Apnea. American journal of respiratory and critical care medicine, 10.1164/rccm.202107-1761OC. Advance online publication. https://doi.org/10.1164/rccm.202107-1761OC

Catherine Atkinson is a second-year Physician Assistant student at Red Rocks Community College in Arvada, CO. She was born and raised in Colorado where she has lived her entire life. She received her undergraduate degree in integrative physiology from The University of Colorado- Boulder. Prior to PA school, she was an ophthalmic technician at Colorado Retina Associates. In her free time, she loves cooking, skiing, playing golf and spending time with her family and friends.