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Acclimation, Child Growth & Development, Health, High Altitude, Medicine

Beneficial Effects of Chronic Hypoxia

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Living in Summit County, Colorado has its perks – residents are within a 20 to 40 minute drive to five world class ski resorts, and some of the most beautiful Rocky Mountain trail systems are accessible right out our back door. With the endless opportunities drawing residents outdoors to partake in physical activity, it comes as no surprise that Summit County is considered one of the healthiest communities in the country. However, there may be more than meets the eye when it comes to explaining this, as it also has something to do with the thin air.

As a Summit County native, you have likely heard the term “hypoxia” or “hypoxemia” mentioned a time or two. So what does this mean? Simply put, these words describe the physiological condition that occurs when there is a deficiency in the amount of oxygen in the blood, resulting in decreased oxygen supply to the body’s tissues. When this occurs in the acute setting, it may result in symptoms such as headache, fatigue, nausea, and vomiting. These are common symptoms experienced by those with altitude illness, also known as acute mountain sickness. While these symptoms can cause extreme discomfort and may put a huge damper on a mountain vacation, they are not usually life threatening. However, in a small number of people, development of more serious conditions such as a high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE) can occur. The treatment for all conditions related to altitude illness is oxygen, whether via return to lower elevations or by a portable oxygen concentrator that allows you to stay where you are. While altitude illness generally affects those who rapidly travel from sea level to our elevation, it has also been known to affect residents returning home to altitude, usually after a period of two or more weeks away. In a very small subset it can occur after a period of only a day or two. This generally occurs in those with a preexisting illness, where altitude exacerbates the condition.

While the acute effects of altitude can clearly have detrimental effects on one’s physical well-being, there is emerging research demonstrating that chronic hypoxia may actually come with several health benefits. Long time Summit County business owner and community pediatrician, Dr. Chris Ebert-Santos of Ebert Family Clinic in Frisco, has spent quite some time studying the effects of chronic high-altitude exposure, and recently attended and presented at the Chronic Hypoxia Symposium in La Paz, Bolivia, the highest capital city in the world.

It is important to first understand the adaptations that occur in our bodies as a result of long-term hypoxia. The ability to maintain oxygen balance is essential to our survival.

So how do those of us living in a place where each breath we take contains about ⅓ fewer oxygen molecules survive?

Simply put, we beef up our ability to transport oxygen throughout our body. To do this, our bodies, specifically the kidneys, lungs and brain increase their production of a hormone called erythropoietin, commonly known as EPO. This hormone signals the body to increase its production of red blood cells in the bone marrow. Red blood cells contain oxygen binding hemoglobin proteins that deliver oxygen to the body’s tissues. Thus, more red blood cells equal more oxygen-carrying capacity. In addition to increasing the ability to carry oxygen, our bodies also adapt on a cellular level by increasing the efficiency of energy-producing biochemical pathways, and by decreasing the use of oxygen consuming processes2. Furthermore, the response to chronic hypoxia stimulates the production of growth factors in the body that work to improve vascularization2, thus, increased ability for oxygenated blood to reach its destination. 

So, how can these things offer health benefit?

To start, it appears that adaptation to continuous hypoxia has cardio-protective effects, conferring defense against lethal myocardial injury caused by acute ischemia (lack of blood flow) and the subsequent injury caused by return of blood to the affected area3. The exact mechanism of how this occurs is not well understood, but it seems that heart tissue adapts to be better able to tolerate episodes of ischemia, making it more resistant to damage that could otherwise be done by decreased blood flow that occurs during what is commonly known as a heart attack. This same principle applied to ischemic brain damage when tested in rat subjects. Compared to their normoxic counterparts, rats pre-conditioned with hypoxia sustained less ischemic brain changes when subjected to carotid artery occlusion, suggesting neuroprotective effects of chronic hypoxia exposure4.

Additionally, it appears that altitude-adapted individuals may be better equipped to combat a pathological process known as endothelial dysfunction5. This process is a driving force in the development of atherosclerotic, coronary, and cerebrovascular artery disease. Altitude induces relative vasodilation of the body’s blood vessels compared to lowlanders2. A relaxing molecule known as nitric oxide, or NO, assists with causing this dilation, and in turn the resultant dilated blood vessels produce more of this compound5. The molecule has protective effects on the inner linings of blood vessels and helps to decrease the production of pro-inflammatory cytokines that damage the endothelium5. This damage is what kickstarts the cascade that leads to atherosclerosis in our arteries. Thus, a constant state of hypoxia-induced vasodilation may in fact decrease one’s risk of developing occlusive vascular disease. 

The topics mentioned above highlight a few of the proposed mechanisms by which chronic hypoxia may be beneficial to our health. However, do keep in mind that there are potential detrimental effects, including an increased incidence of pulmonary hypertension as well as exacerbation of preexisting conditions such as COPD, structural heart defects and sleep apnea, to name a few6. Research regarding the effects of chronic hypoxia on the human body is ongoing, and given its significance to those of us living at elevations of 9,000 feet and above, it is important to be aware of the impact our physical environment has on our health. Dr. Ebert-Santos is avidly involved in organizations dedicated to better understanding the health impacts of chronic hypoxia, and has several current research projects of her own that may help us to further understand the underlying science.

Kayla Gray is a medical student at Rocky Vista University in Parker, CO. She grew up in Breckenridge, CO, and spent her third year pediatric clinical rotation with Dr. Chris at Ebert Family Clinic. She plans to specialize in emergency medicine, and hopes to one day end up practicing again in a mountain community. She is an avid skier, backpacker, and traveler, and plans to incorporate global medicine into her future practice.

Citations

  1. Theodore, A. (2018). Oxygenation and mechanisms for hypoxemia. In G. Finlay (Ed.), UpToDate. Retrieved May 2, 2019, from https://www-uptodate-com.proxy.rvu.edu/ contents/oxygenation-and-mechanisms-of-hypoxemia?search=hypoxia&source=search_ result&selectedTitle=1~150&usage_type= default&display_rank=1#H467959
  2. Michiels C. (2004). Physiological and pathological responses to hypoxia. The American journal of pathology, 164(6), 1875–1882. doi:10.1016/S0002-9440(10)63747-9. Retrieved May 2, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1615763/ 
  3. Kolar, F. (2019). Molecular mechanism underlying the cardioprotective effects conferred by adaptation to chronic continuous and intermittent hypoxia. 7th Chronic Hypoxia Symposium Abstracts. pg 4. Retrieved May 2, 2019. http://zuniv.net/symposium7/Abstracts7CHS.pdf
  4. Das, K., Biradar, M. (2019). Unilateral common carotid artery occlusion and brain histopathology in rats pre-conditioned with sub chronic hypoxia. 7th Chronic Hypoxia Symposium Abstracts. pg 5. Retrieved May 2, 2019. http://zuniv.net/symposium7/Abstracts7CHS.pdf
  5. Gerstein, W. (2019). Endothelial dysfunction at high altitude. 7th Chronic Hypoxia Symposium Abstracts. pg 11. Retrieved May 7, 2019. http://zuniv.net/symposium7/Abstracts7CHS.pdf
  6. Hypoxemia. Cleveland Clinic. Updated March 7, 2018. Retrieved May 9, 2019. https://my.clevelandclinic.org/health/diseases/17727-hypoxemia
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, Health, High Altitude, Medicine, Mountaineering

How to Stay Healthy During Your Holidays at High Altitude

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Acute Altitude Illness affects about 7.4% of travelers to mountain resort areas, including Frisco, Colorado which sits at an altitude of about 2800 meters. Dr. Kendrick Adnan, MD, MSPH is an emergency medicine physician associated with Vail Health. Dr. Adnan often sees visitors to Vail and other popular ski and vacation areas in Summit County that are experiencing Acute Altitude Illness. I sat down with Dr. Adnan, and we discussed the treatment of Acute Altitude Illness as well as signs, symptoms, risk factors, and prevention of Acute Altitude Illness.

What causes Acute Altitude Illness?

  • Acute Altitude Illness develops when the body responds to hypoxia, a low level of oxygen in the blood. Areas of high altitude have a lower concentration of oxygen in the air than lower altitudes, which makes your body work harder to put oxygen in your blood. Your body responds to the lower oxygen concentration by increasing how often and how deeply you breathe. This causes a decrease in carbon dioxide and increase in tpH in the blood. Your heart, lungs, blood vessels, and kidneys all respond to the low pH in your blood, which can cause the signs and symptoms of Acute Altitude Illness.
  • Some people will experience severe forms of Acute Altitude Illness called High-Altitude Pulmonary Edema or High-Altitude Cerebral Edema. These are life-threatening conditions that can cause death in both adults and children if not treated promptly by a medical professional.

What are the signs and symptoms of Acute Altitude Illness in adults?

  • Headache
  • Nausea
  • Vomiting
  • Decreased appetite
  • Fatigue
  • Shortness of breath on exertion
  • Decreased exercise tolerance
  • Chest tightness
  • Hypoxia

What are the signs and symptoms of Acute Altitude Illness in children?

  • Fussiness
  • Poor feeding
  • Pale or blue-tinged skin
  • Sleeping too much or too little

What is the treatment for Acute Altitude Illness (AAI)?

The best treatment for AAI is supplemental oxygen through a nasal cannula and descent to a lower elevation. You will need to visit a healthcare provider, clinic, or hospital to get supplemental oxygen if your oxygen level drops below 89%. Visitors to high-altitude areas may be hesitant to abandon their vacation plans in order to descend to a lower altitude. A healthcare provider may be able to prescribe medications to help you recover from AAI. However, if your low oxygen level does not improve with supplemental oxygen and medication, it is important to descend to an area of lower altitude.

Studies show that acetazolamide, dexamethasone, and tadalafil are medications that can potentially treat Acute Altitude Illness and/or High-Altitude Pulmonary Edema. A healthcare provider may prescribe these medications for you if appropriate.

What increases the chance that I will experience Acute Altitude Illness?

  • Traveling by airplane from low altitude to high altitude.
  • Being a resident of low altitude
  • Past episode of Acute Altitude Illness
  • Physical exertion at high altitude, especially in colder temperatures

What can be done to prevent Acute Altitude Illness and High-Altitude Pulmonary Edema?

  • A slower ascent will decrease your risk of AAI. Dr. Adnan recommends spending the night in Denver after air travel if you are planning to visit a high-altitude area.
  • Avoid strenuous exercise like skiing, hiking, and mountain biking for 48-72 hours after arrival to a high-altitude area.
  • Buy a pulse oximeter to check your oxygen level. A level above 89% is normal at high-altitude and does not require treatment.
  • Ask your healthcare provider about taking Diamox (acetazolamide) for 2-3 days before you arrive at a high-altitude destination. You will need a prescription for this medication.
  • Avoid medications that decrease your respiratory rate like opiates, sleeping medications, benzodiazepines, and barbiturates.

References

Schafermeyer, R. W. DynaMed. Acute Altitude Illnesses. EBSCO Information Services. https://www.dynamed.com/condition/acute-altitude-illnesses. Accessed November 19, 2021. Simancas-Racines D, Arevalo-Rodriguez I, Osorio D, Franco JVA, Xu Y, Hidalgo R. Interventions for treating acute high altitude illness. Cochrane Database of Systematic Reviews 2018, Issue 6. Art. No.: CD009567. DOI: 10.1002/14651858.CD009567.pub2. Accessed 03 November 2021.

Sasha Scott is a physician assistant student at Drexel University in Philadelphia, PA. She is originally from Indianapolis, IN and attended Purdue University for undergrad. Sasha enjoys running, cross stitching, cooking, and exploring Philadelphia when she is not studying!

Genetics, Health, High Altitude, Medicine

Carotid Body Tumors at High Altitude

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Carotid body tumors (CBTs) are more common at higher altitudes. It also has been proposed that altitude can play a role in the genetic mutations that cause CBTs to form in the inherited types of CBTs. How might altitude affect the genetics of CBT formation?

The carotid body is a peripheral nervous system sense organ. It is located bilaterally at the bifurcation of the common carotid artery, between the internal and external carotid arteries. The carotid body helps maintain physiologic homeostasis with the help of its sensory chemoreceptors. These sensory chemoreceptors “detect changes in the quality in the composition of arterial blood flow, such as pH, CO2, temperature, and partial pressure of arterial oxygen” (Forbes & Menezes, 2021). The carotid body therefore responds to states of hypoxia, hypercapnia and acidosis.

Carotid body tumors (CBTs) are rare paragangliomas of the head and neck. Sporadic, familial and hyperplastic are the 3 different forms of CBTs.  The hyperplastic form is most prevalent in patients who are in chronic hypoxic states. Chronic hypoxic states are seen in patients with COPD or cyanotic heart disease. However, chronic hypoxic states are also seen in people who live at high altitude. The only known risk factors for developing a carotid body tumor include chronic hypoxia and genetic predisposition. The only treatment for CBTs is surgery, which is a very challenging surgery due to the complex location of CBTs by a main vessel, the carotid artery.

This is an image of an MRI showing carotid body tumors (Burgess et al., 2017)

Risk for CBT’s are related to different altitudes. Prasad et al. (2019) stated the prevalence of CBTs were increased at altitudes exceeding 2000 feet of above sea level where as Chaaban (2021) states CBTs are more common in people living at altitudes exceeding 5000 feet above sea level.  The big question becomes why are CBTs more prevalent at altitude? Forbes & Menezes (2021) found that the Carotid body plays a role in the acclimation to high altitude in regards to ventilation, respiratory rate and oxygen levels. At increasing altitudes, there is less oxygen in the air. This leads to a hypoxic state and causes the respiratory rate to increase. The Carotid body itself is responsible for detecting the low oxygen level at high altitude and then increasing the respiratory rate. There may be a chronic hypoxic state as acclimation to high altitude occurs. There also may be a defect in oxygen sensing by the carotid body, which worsened by moderately high altitudes (Astrom et al., 2003). Hyperplasia of the glomus cells of the Carotid body occurs due to the chronic hypoxia and cellular proliferation can occur due to the defect in oxygen sensing. Hyperplasia and cellular proliferation can then lead to tumor formation. It is even found that patients with multiple tumors, like having bilateral CBT’s (as pictured on the MRI imaging) at first time of diagnosis live at higher altitudes, with longer duration of high altitude residence. (Astrom et al., 2003).

CBTs are rare and some surgeons may only see a few CBTs in their career. According to two ENT surgeons in Lakewood, Colorado at a Level I Trauma center, they have encountered many more CBTs in Colorado in their career than in other places at lower altitude. Peter McGuire, MD has been practicing in Colorado for over 5 years as an ENT surgeon. He has encountered about 5-10 CBTs since being in Colorado (P. McGuire, MD, personal communication, November 9, 2021). He states he has only encountered two at lower altitude. When talking to Erin Roark, FNP, who practices alongside ENT surgeon Christopher Mawn, MD, in the 10 years they have been working together in Colorado they have encountered about 15-20 CBTs. (E. Roark, FNP, personal communication, November 10, 2021).

There is evidence that altitude can affect gene mutations. “It has been proposed that environmental hypoxia modulates genetic predisposition to CBP” (Praasad et al., 2019). It has been found that CBTs that develop at high altitudes have been associated with the penetrance, expressivity, and population genetics of what are considered inherited CBTs. Again, cellular proliferation can occur when there is a defect in oxygen sensing by the carotid body and this defect in oxygen sensing can be worsened by moderately high altitudes. This causes cellular proliferation, increased number of actively dividing cells and increased likelihood of an alteration of the DNA sequence (Astrom et al., 2003). An alteration of the DNA sequence is also called a second-hit somatic mutation. “Therefore, living at higher altitudes is expected to facilitate the development of independent tumor foci that develop clonally following the second-hit mutation” (Astrom et al., 2003).

Many questions remain regarding the increased prevalence of CBT’s at altitude. Research is needed to determine if an existent CBT grows when the patient moves from an area of low altitude to an area of high altitude. Genetic studies looking for underlying predispositions to these tumors and other conditions related to altitude will continue to be fundamental.

For more another article related to genetics and altitude see blog entry from December 2019 on aural atresia.

References

Astrom, K., Cohen, J. E., Willett-Brozick, J. E., Aston, C. E., & Baysal, B. E. (2003). Altitude is a phenotypic modifier in hereditary paraganglioma type 1: Evidence for an oxygen-sensing defect. Human Genetics, 113(3), pp. 228-237. https://doi.org/10.1007/s00439-003-0969-6.

Burgess, A., Calderon, M., Jafif-Cojab, M., Jorge, D., & Balanza, R. (2017). Bilateral carotid body tumor resection in a female patient. International Journal of Surgery Case Reports, 41, 387-391. https://doi.org/10.1016/j.ijscr.2017.11.019

Chaaban, M.R. (2021). Carotid body tumors. Medscape. Retrieved November 7, 2021 from https://emedicine.medscape.com/article/1575155-overview#a8.

Forbes, J. & Menezes, R. (2021). Anatomy, head and neck, carotid bodies. StatPearls Publishing. Retrieved November 7, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK562237/.

Pacheco-Ojeda, L. A., MD. (2017). Carotid body tumors: Surgical experience in 215 cases. Journal of Cranio-Maxillo-Facial Surgery, 45(9), pp. 1472-1477. https://doi.org/10.1016/j.jcms.2017.06.007.

Prasad S., Paties C., Pantalone M., et al. (2019). Carotid body and vagal paragangliomas: Epidemiology, genetics, clinicopathological features, imaging, and surgical management. In: Mariani-Costantini R. (Ed.), Paraganglioma: A Multidisciplinary Approach (ch. 5). Brisbane (AU): Codon Publications. doi: 10.15586/paraganglioma.2019.ch5. Retrieved November 7th, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK543230/.

Katelyn Guagenti is a FNP student at the University of Cincinnati. She graduates December 10, 2021. She lives in Lakewood, CO and she plans to work with Dr. Christopher Mawn and Dr. Peter McGuire at Aspen Ridge ENT clinic after graduation. In her free time she likes to do CrossFit, hike, ski, snowmobile, and any other activity that involves hanging out with her Husband, Vincent, and dog, Judd. Most of all she loves to go to Grand Lake, CO, her favorite place here in beautiful CO. 

Acclimation, Altitude Science, Health, High Altitude, Hyperbaric Therapy, Medicine, Surgery, Technology

Wound Healing at High Altitude: Hyperbaric Therapy, A Patient’s firsthand experience with post-surgical wound healing in Summit County

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The nuances of wound healing at high altitude is a topic that has already been explored on this platform (see Eric Meiklejohn’s “Wound Care at Altitude”). Identifying the impact that impaired oxygen delivery can have on healing time, tissue regeneration, and infection rates offers great insight into the roles health care providers can assume to support our high-altitude patients. For this interview, I was able to speak directly with  a Summit County resident who had firsthand experience with these processes.

I’ve heard a bit about your experiences with wound healing at high altitudes I will ask some preliminary questions,. This entire experience was more of a marathon than a sprint. How long have you been living at this altitude, and how old were you at the time of your procedure? I’d lived at high altitude for over twenty-six years before I was diagnosed with breast cancer. I was Fifty-three when I had my surgery. I was in great shape, exercising regularly, and eating really well.

Tell me about your procedure: Well, the initial procedure was in January 2018 down in Denver. I had a bilateral mastectomy done to remove the cancerous tissue, and bilateral expanders were inserted during that surgery so that down the line I could have implants placed. Within the first week we started noticing some necrotic changes to my incisions, and that they were not healing well. The expanders were inflated with air, and it was thought that my traveling back to high altitude from Denver could have increased the pressure inside them.  By the end of week one I went back in to see my doctor, who deflated my expanders pretty significantly.

Have you ever been diagnosed with a medical condition that could affect wound healing, such as Diabetes or Hypertension? No. Breast Cancer was my first real medical diagnosis.

Had you ever had surgery while living at this altitude before? And if so, what was the outcome? Yes, I’d had surgery for an umbilical hernia and that went very well. No complications at all, everything healed just fine. I’d also had tendon damage in my right hand after a fall, and I recovered really well after that surgery at this same altitude.

Regarding healing after your mastectomies, describe the anticipated wound healing time and wound care directions. The time estimate for  recovery was four weeks. I was to rest for two weeks, increase activity slightly for the second two weeks with minimal physical therapy, then by the end of that fourth week the projection was that I would be mostly recovered. I was given strict precautions against heavy lifting, restricting arm movements, and not driving. For wound care I was doing daily dressing changes, not submerging the area in water, and applying Silvadene cream twice daily.

Following the removal of the expanders, what was the rest of the healing process like? Over the next two months I cared for my wounds at home. They were open and oozing, and over time the daily dressing changes and medication applications became quite taxing, both physically and emotionally. It took a lot out of me, and really interfered with my day-to-day life…not to mention the pain. On March 9th, 2018 I underwent an incision revision and resection procedure for the necrotic tissue. At that point my breast tissue had manifested itself as far as which parts were healthy and which would die, so they went in and resected the areas that were not viable. On the left side I lost most of the top surface of the breast, including the entire nipple area. Two weeks after that, I had a [chemo therapy] port placed in my arm  so I could begin treatments, but that incision also had a difficult time healing. That eventually led to a one month delay in my chemo therapy.

In March and April the incisions on the right breast eventually healed, but because of all the tissue loss and necrosis on the left side those wounds did not heal. There was still a lot of drainage from that breast and it was mostly still open so I had to keep the bandage on. By early May (after this wound had been open for 5 straight months) my doctor and I started seeing more signs of infection to that breast, so around May 12th of 2018 he called me in for an emergency procedure and I had the expander completely removed from my left breast. I continued chemo and eventually that left side began to heal in the absence of the expander.

During this time, from March until I finished chemo in August, the port site never healed. The whole reason behind having the port placed was so it could heal over and I could go back to a normal life between chemo sessions. But instead I walked around with a bandage for those six months because my port site remained open. I had Her2 positive cancer, so after my six months of chemo I needed to continue taking Herceptin for one additional year. I opted to have the port removed after six months and had an IV placed every three weeks for my treatments. It was very hard on my veins, but I felt I had no choice.

In late August, with the port out and the left expander out, the last of my open wounds really started healing. I started looking at what I could do to help my tissue heal even better- my thought was that when this is all done and I am all well healed I would like to have my expanders placed and inflated again, but I don’t want to have to go backwards through this process. I did all this research, and that’s where I learned about hyperbaric therapy. That changed everything for me.

What did you learn about Hyperbaric therapy, and what was your experience with it? I did a lot of independent research online and came up with two options that I wanted to discuss with my doctor. The first was a topical option for applying oxygen directly to the wound, which was a very complicated and involved process -and the second was hyperbaric therapy.

I discussed this with my oncologist who was very familiar with hyperbaric chamber treatment centers in Denver, and who wrote me a referral to be evaluated at the one in Presbyterian St. Luke’s Medical Center. I was evaluated by their team, showed them all the photos I had been taking throughout this entire ordeal, and they seemed hopeful that they would be able to help me. I really wish I’d gone there sooner.

My plan was to use this to help me recuperate a little bit so I could give the expander one more shot on the left side. After having the left expander placed, the second phase of my plan was to get another course of hyperbaric therapy to aid in recovering from that procedure. It was eventually prescribed and accepted by insurance, who approved 27 hyperbaric sessions following my surgery.

I underwent the left expander placement in February of 2019, observed the same restrictions, and had identical at-home wound care as my initial surgery in January 2018, but with the addition of hyperbaric therapy my results were night and day. The day after surgery I started hyperbaric, and in so much less pain. I was off all pain medications within 48hours. I was able to get out, walk, function in my daily life, and the tissue healed really well. It was amazing! I felt great, had tons of energy, and it was just a completely different experience. It was nothing short of miraculous.

What was your hyperbaric chamber treatment like? It was five days a week in Denver. Being there was for me a huge learning experience. There were people there being treated for diabetic wounds, hearing loss, adjunct therapy for various types of cancer, joint and tendon disease, tissue necrosis, concussions, head trauma, and so many other things. I hadn’t known that this therapy could be utilized in all these different areas.

After your successful left expander placement, how was your transition to breast implants? Months after the left expander was reinserted, I did transition to breast implants (summer 2019) but even then, I insisted on post operative hyperbaric therapy. I was only approved for ten sessions that time, but the results were the same. Rapid healing time, noticeable decrease in pain after starting therapy, and the ability to function throughout the day. Of all the factors that played a role in this process for you, what variable would you most want to adjust? Honestly, I just wish I’d started hyperbaric therapy sooner. If there was a way to get providers who work with high altitude dwellers to recommend hyperbaric treatment as a part of their primary or secondary treatment course, that’s the one thing I would change.Well, I am very happy to know that despite the difficulty you experienced in this process, you are now three years post op, well healed, and satisfied with your results. Thank you again for sharing your story. My pleasure. If my sharing can help someone else find hyperbaric therapy or open them up to alternative methods of treatment sooner so as not to have to experience what I went through in those first few months, then it was all worth it.

Janell Malcolm is a second year Physician Assistant student in the Red Rocks PA Program in Arvada, Co. A Jamaica native, she loves the ocean, tropical fruit, and 100 degree weather. You will likely find her spending her free time with family or reading/re-reading Jane Eyre. Her personal and career goals are geared towards providing adequate medical care to underserved communities. Special interests post graduation: Labor & Delivery, General Surgery.

Acclimation, Altitude Science, Health, High Altitude, Medicine

The Nobel Prize: Hypoxia studies Won in 2019!

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The Nobel prizes are announced this month. Alfred Nobel invented dynamite in 1866. Within 30 years, Nobel made a large fortune from his invention. He demonstrated his passion for literature and science by creating a yearly prize to discoveries most beneficial to humankind. The five prize categories include physics, chemistry, medicine (physiology), literature and peace. The Nobel prize nominations are made by university professors, national assemblies, state governments, and international courts. The prize is awarded yearly to individuals who have discovered a new paradigm or a paradigm shift within their field. The prize recipients are declared on the first Monday of October of every year and the award is presented by the Nobel assembly on November 10th, the anniversary of Alfred Nobel’s death. The Nobel prize consists of a gold medal, a diploma of recognition of achievement, and a cash prize in the amount of $1 million U.S. dollars. 

There is no limit to the number of nominations that can be made or the number of times that an individual can be nominated. There were 400 candidates nominated in the field of medicine in 2019, all of which inspired, challenged, and demonstrated greatness in their field. In 2019 the Nobel Prize in Medicine honored three scientists for their discovery of the human body’s ability to adapt to low oxygen environments. 

Hypoxia is a state of which oxygen supply is insufficient for normal life functions, experienced by the human body at high altitude. Tissues and cells require a range of oxygen in order to survive. Oxygen is required by mitochondria, in all cells, to convert food into useable energy. “Otto Warburg, the recipient of the 1931 Nobel Prize in Physiology or Medicine, revealed that this conversion is an enzymatic process.” At low oxygen environments, as experienced at high altitude, the body must adapt in order to maintain basic cellular function. There are several mechanisms in the human body that increase oxygen concentration including breathing rate, regulated by the carotid body, increased heart rate, stimulated by the vagus nerve, and increased production of red blood cells (RBCs)  through the bone marrow, regulated by the kidney. 

The carotid body is a chemoreceptor near the carotid artery that detects oxygen, carbon dioxide and pH levels in the blood. At low oxygen, the carotid body relays an afferent (ingoing) signal to the the brain via the glossopharyngeal nerve. The medullary center in the brain then sends an efferent (outgoing) signal that increases the respiratory rate to maximize oxygen delivery to the brain. The carotid sinus is a baroreceptor near the aorta of the heart which senses changes in pressure. As pressure increases in the atmosphere, experienced at high altitude, the carotid sinus sends a signal along the vagus nerve to the brain which then increases the heart rate. “The 1938 Nobel Prize in Physiology or Medicine was awarded to Corneille Heymans for discoveries showing how blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain.”

At low oxygen environments, the kidney increases production of erythropoietin, which stimulates RBC generation in the bone marrow,  called erythropoiesis, resulting in higher oxygen delivery to the brain and skeletal muscles needed at high altitude. Erythropoiesis was discovered in the early 20th century, however oxygen’s role in the process was not completely understood. The cell’s ability to sense and adapt to oxygen availability was discovered and explained by three scientists, William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza. 

2019 Nobel Prize, Physiology: 

Thanks to the work of Dr. Gregg L. Semenza and Sir Peter J. Ratcliffe, we now understand that the oxygen sensing mechanism that stimulates erythropoieten is present in all tissues, not just the kidney. Semenza conducted research on liver cells using gene-modified mice and found that a specific protein binds to an individual gene (the EPO gene), dependent upon oxygen availability. Semenza named the binding protein the Hypoxia-Inducible-Factor (HIF). The HIF protein was found to compose two transcription factors, HIF-1alpha and ARNT. In 1995, Semenza published his findings of the HIF protein. His work explained that when the body is at high oxygen environments, there is very little HIF-1alpha present within cells. At high oxygen availability, HIF-1alpha is rapidly degraded by a proteasome within cells. The degradation is signaled by a protein called ubiquitin which binds to HIF-1alpha at high oxygen, flagging HIF-1alpha for degradation by the proteasome. This process was recognized by the 2004 Nobel Prize in Chemistry, Aaron Ciechanover, Avram Hershko and Irwin Rose. 

The mechanism by which ubiquitin binds, causing the degradation of HIF-1alpha at high oxygen environments was explained by the work of William Kaelin, Jr. who conducted research on von Hippel-Lidau’s (VHL) disease. The VHL gene mutation causes an increased risk of cancer. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer and was involved in controlling responses to hypoxia. VHL is part of a complex that labels proteins with ubiquitin. Ratcliffe discovered the physical interaction of the VHL gene with HIF-1alpha, causing degradation of the HIF-1alpha at normal oxygen levels. 

At hypoxic environments, HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4). 


At hypoxic environments, HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4).

Kaelin and Ratcliffe’s research identified how oxygen levels regulate the interaction between VHL and HIF-1alpha. Their work demonstrated that at normal oxygen levels, hydroxyl groups are added to specific positions within HIF-1alpha, causing modification of the protein and allowing VHL to recognize and bind to HIF-1alpha, leading to degradation of the protein complex.  At high altitude, cells produce a greater amount of the HIF-1alpha protein which binds to the EPO gene, up-regulating the production of erythropoietin hormone, stimulating RBC production. Together, Semenza, Kaelin, and Ratcliffe explained the oxygen sensing mechanism.

Acclimation, Altitude Science, Child Growth & Development, Doc Talk, Health, High Altitude, Neonatal

Doc Talk: Pregnancy at Altitude & What You Need to Know, an Interview with Dr. Javier Gutierrez, MD (OB/GYN)

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A man with gray hair in blue hospital scrubs and a white surgical mask hanging tied from his neck smiles widely with bright teeth showing
Dr. Javier Gutierrez

Dr. Gutierrez is originally from Mexico City and attended medical school at Universidad La Salle Medical School. He completed his residency at the University of Miami School of Medicine, Jackson Memorial Hospital and has been Board Certified by the American Board of Obstetrics and Gynecology since 1986. He worked in Mexico City with his father who is also an OBGYN before moving to Summit County in 1998. He says that he dealt with pregnancy at altitude even in Mexico City as a young doctor but now has become even more experienced while practicing at St. Anthony Summit Hospital in Summit County, Colorado. In his career he has delivered more than 7,000 babies.

Gutierrez estimates that about 3% of his patients are visitors to Summit County. Most of these patients are not at full term in their pregnancy and present in the ER with signs of premature labor due to dehydration. Usually, these patients are stabilized and sent to Denver for definitive treatment given St. Anthony Summit Hospital only has a Level 1 nursery (basic newborn care).

The most common conditions that he sees occurring in pregnant women at altitude are pregnancy-induced hypertension (PIH), intrauterine growth restriction (IUGR), and small for gestational age (SGA). Because of this, he says that the main difference of observing pregnancy at altitude is more frequent ultrasounds to monitor the growth of the baby. Luckily, most pregnant women at altitude are very fit and healthy because of the active lifestyle that Summit County encourages. However, some women also have a difficult time restricting their activity level enough to maintain proper growth of the baby. The recommended maximum heart rate during pregnancy is 80% of your maximum heart rate, which can be hard to not exceed in an active pregnant female living at altitude.

Nevertheless, the risk of high altitude pulmonary edema (HAPE), high altitude cerebral edema (HACE), and sleep problems are about the same as in pregnant women not living at altitude. In general, pregnant women past 24 weeks have difficulty sleeping no matter where they live. In addition, if you know you are at high risk for developing HAPE or have a history of HAPE you are just as likely to develop HAPE during your pregnancy as you are not pregnant.

Sleeping with oxygen is recommended and has many benefits for all individuals living at altitude, pregnant women included. However, it likely wouldn’t decrease the number of SGA babies because of the activity level of most individuals as mentioned earlier. A woman’s body increases blood volume, red blood cell count, respiratory rate, and vasodilates blood vessels to accommodate for the growing fetus. This in turn allows the body to compensate well and usually maintain normal oxygen saturation levels at altitude.  But Dr. Gutierrez feels eventually it will be recommended for everyone to sleep with oxygen, most people just don’t want to.

Especially with dehydration, he has seen very high red blood cell concentrations. However, these individuals usually only need rehydration and do not suffer any complications. He has not seen a drastic increase in the number of blood clots in pregnant females at altitude even though they are likely at higher risk. But if a pregnant female who is dehydrated and recently traveled to altitude presents with shortness of breath, he definitely puts HAPE and pulmonary embolism (PE) higher on his list of possible diagnoses than he would not at sea level.

An important and simple recommendation is increasing their fluid intake. At altitude you have more insensible water loss and are likely more physically active, which in turn can lead to faster dehydration causing premature labor. Luckily this complication is easily managed with adequate fluid intake. In addition, if you know you are at high risk for developing HAPE it is recommended that you do not travel to altitude, especially later in your pregnancy.

The baby lives in a hypoxic environment in the womb anyway so there are no known advantages to living at altitude while being pregnant, other than the active and healthy lifestyle Summit County promotes.

One of the most challenging cases Dr. Gutierrez has treated was severe maternal respiratory distress during early third trimester due to HAPE. The most definitive treatment was to transport her to a lower altitude, however, they had to stabilize the mother enough to be able to transfer her and her baby. In addition, Summit County does not have a high level nursery to take care of a very premature baby even if they were able to deliver the baby safely to take stress off the mother’s body. He said it was a delicate balance trying to determine what was best and safest for both the mother and the baby.

Bailie Holst is a second-year Physician Assistant student at Red Rocks Community College in Arvada, CO. Bailie was born in Longmont, Colorado and spent her life in Northern Colorado until moving to Minneapolis, Minnesota for her undergraduate studies at the University of Minnesota. She also spent her life traveling throughout the country competing in gymnastics competitions and eventually earning a full-ride athletic scholarship for gymnastics to the University of Minnesota. She finished her gymnastics career and graduated with a Bachelor’s degree in Physiology in 2017. Prior to PA school she worked as a medical assistant in a sports medicine and rehabilitation office in Colorado for two years. In her free time, Bailie now enjoys golfing, traveling, spending time with family, and playing with her brand-new puppy.

Acclimation, Altitude Science, Doc Talk, Genetics, Health, High Altitude, Medicine

Nocturnal Hypoxia at High Altitude

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The long-awaited results for the Ebert Family Clinic study on sleep at altitude were analyzed in collaboration with Colorado Sleep Institute (CSI). Christine Ebert-Santos, MD, MPS and Tara Taylor, FNP organized and conducted the Overnight Pulse Oximeter Study In Healthy Adults at three elevations, with the support of the local mountain community and the American Embassy in La Paz, Bolivia. The purpose of the study was to evaluate nocturnal oxygen saturation levels in populations living at 3800 m (12,467′), 2800 m (9,186′) and 2500 m (8,202′) and determine treatment recommendations for central apnea and hypoxia. Volunteers were recruited by the clinic from residents in the community and current patients, and by the American Embassy nurse practitioner Annette Blakelee. Informed consent was obtained by the clinic staff and providers. Each participant completed a health questionnaire on length of residence at altitude, medical history and possible symptoms related to higher elevations. Blood pressure, height, weight, and BMI were measured and documented at enrollment. Patients enrolled in study sites for routine care had past Hb/Hct added to the questionnaire. The device (pulse oximeter) was dispensed to the participants with instructions for use. The participants wore the device at night during sleep before returning it to the research staff at the clinic. The results were downloaded from a USB device, recorded onto a spreadsheet, and analyzed by a statistician. If the results were concerning for hypoxia, (<89% for over 20% of the study), participants were asked to repeat the test, completely off any substance (e.g., drugs, alcohol). The study also accounted for factors such as years at altitude and percent of life at altitude to assess potential adaptations to the environment and subsequently, changes in oxygen saturation levels. The goal of the study is to inform providers and residents which symptoms are related to altitude or sleep disorders and recommend treatment that will allow them to feel better and be more active, as well as reduce complications from hypoxia, such as pulmonary and systemic hypertension, fatigue, and daytime drowsiness.

Results of the study concluded that years at altitude, percent of life at altitude, gender, and age do not explain the variance of adaptation to altitude, as measured by time <88% oxygen saturation (SpO2) in these data. The only factor statistically significant in adaptation to altitude was body mass index (BMI). This data provides direction for future studies.

P>0.05 is non-significant. This suggests that there is something else besides percent of the life spent at altitude that explains the level of adaptation participants are experiencing.

Overlapping fit lines (colored) and range estimates (gray) means that the groups are not different. Thus gender cannot explain the difference in adaptation responses.

 Tara Taylor FNP had the primary role of reviewing and discussing sleep study results with individuals participating in this study. Tara has worked at the Ebert Family Clinic for over 3 years as a family practitioner, before which she was an intensive care nurse for adults and children for 14 years. She is passionate about sleep issues that occur at high altitude. Tara states that “the most interesting finding was that normal, healthy adults without any comorbidities who are of normal weight and do not have any other medical conditions, had basal oxygen levels <90%, and most had 88-89% basal oxygen. We did see some drops to 85-87% oxygen saturation (SpO2) overnight without any apnea. We checked the length of time spent in different ranges. I found that healthy adults were spending more time below 90% SpO2 than anticipated. We used the index per hour, which gave us a preliminary idea of how many times oxygen increases and decreases.” Based on the results, patients would be notified on any follow up that was needed.

The new Colorado Sleep Institute (CSI) in Frisco will allow patients to receive comprehensive care with more accurate results than can be found at a lower elevation clinic. Dr. Mark Hickey, MD, Board Certified Specialist in Sleep Medicine, and Dr. Ellen Stothard reviewed and interpreted the data collected by Ebert Family Clinic. Dr. Stothard is currently the Research and Development Director at the Colorado Sleep Institute. Her passion lies in conducting sleep research, collecting relevant data, and readily communicating findings, as she believes that good sleep is fundamental for a healthy lifestyle. Dr. Stothard discussed the difference between central versus obstructive sleep apnea and a highly prevalent process called treatment emergent central sleep apnea (TECSA), which is the persistence of central sleep apnea during treatment for obstructive sleep apnea. According to Dr. Stothard, “TECSA is seen when one is treated for obstructive sleep apnea with the continuous positive airway pressure (CPAP), causing a disruption to the central sensing mechanism, resulting in central sleep apnea. Following this phenomenon, patients with obstructive sleep apnea believe that they are resistant to treatment when the CPAP doesn’t improve their symptoms.” These patterns are actually central events which can be helped with decreasing pressure of the CPAP and readjusting air flow. Essentially, CPAP settings should be adjusted based on altitude and elevation, as this is a huge factor influencing nocturnal oxygen saturation levels.

Dr. Stothard has worked with numerous patients receiving CPAP treatment including those at lower altitudes. Since opening her clinic at high altitude, the providers at CSI have noticed that patients tend to feel more fatigue, reporting less relief from treatment with CPAP. Symptoms the patients are experiencing require an individualized approach. “Sleep medicine is so unique,” states Dr. Stothard  “and you have to take the time to tailor the treatment and titrate it to perfection to match the patient’s physiology, tolerance for the air, and whether they wear a nasal mask or full-face mask. We spend a lot of time on those specific things in our clinic.”

Dr. Stothard discussed the influence altitude has on conditions such as obesity, explaining that “BMI is a known risk factor for sleep apnea. Someone with a higher BMI will have a different physiology due to its effect on airway collapsibility. Recommendations to reduce sleep apnea are to maintain a healthy weight, which can improve the success of treatment.” Dr. Stothard also spoke about the role of physical therapy in sleep hygiene and how it can help improve sleep, especially in people who have traumatic brain injuries. “Understanding the way sleep facilitates recovery and repair of the body is crucial” and physical therapists can help bridge that gap. Sleep not only allows for the body to restore and re-energize, but also allows for the toxins to be cleansed out from the brain. Moreover, “while we sleep, there is an increase in the interstitial space in the brain allowing the cerebrospinal fluid to flush out chemicals, such as adenosine.” Excess retention of adenosine can cause sleepiness and grogginess acutely, while chronically, it can cause inflammation, fibrosis, and organ damage.

The Overnight Pulse Oximeter Study In Healthy Adults gives us some interesting preliminary information. The CSI and Ebert Family Clinic will be collaborating on future studies to help us understand sleep at altitude in greater depth. For more information on the high prevalence of central apnea at altitude at all ages and the importance of using oxygen at night for residents 50 and older, see previous blog posts on sleep and interviews with local providers Dr. Craig Perrinjaquet and Dr. Peter Lemis.

Arti Kandalam is a second-year physician assistant student at the Red Rocks Community College Physician Assistant Program in Arvada, CO. Arti was born and raised in Sugar Land, TX and lived there until graduating high school. She then moved to Austin, TX to attend the University of Texas in pursuit of her Bachelors in English degree. Shortly after, she obtained her Masters in Biomedical Sciences at the University of Houston in Victoria. She moved back to Sugar Land, TX, where she worked as a Medical Assistant and Scribe at Texas Pain Centers for 4 years. In her free time, Arti enjoys dancing/teaching Bollywood choreography, biking, and hiking.

Acclimation, Altitude Science, Genetics, Health, High Altitude, Medicine, Neonatal

Maternal Intermittent Hypoxia and the Effect on Adult Respiratory Control and the Gut Microbiome in Male Offspring

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On Friday, June 4th, I had the pleasure of attending the, online, Fifth Annual Center for Physiological Genomics of Low Oxygen (CPLGO) Summit. There were many great presentations that I had the opportunity to watch, including the presentation of Dr. Christine Ebert-Santos’ study looking at nighttime pulse oximetry in participants living at high altitude for longer than one year. The presentation this post will discuss is about research conducted at the University of Florida by Dr. Tracy Baker, PhD. This presentation was particularly of interest because it looks at hypoxia in relationship to Obstructive Sleep Apnea (OSA). OSA occurs when patency of the upper airway is compromised and air is inhibited from passing, leading to hypopnea and obstructive apneas1. Hypopnea are episodes of greater than 30% decrease in air flow that lasts ≥ 10 seconds with continued respiratory effort1. Obstructive apnea is a total stop in airflow that lasts ≥ 10 seconds with chest and abdominal efforts to continue breathing1. Patients with OSA have a higher apnea-hypopnea index (AHI) at altitude than at sea level, meaning that their time with decreased oxygenation while sleeping is increased at higher altitude2. Additionally, patients living at altitude with mild or moderate sleep apnea may have a false negative sleep apnea result when having a sleep study performed at sea level, which means that patients who have OSA at altitude will not show signs of sleep apnea at sea level, therefore missing the diagnosis on sleep study2.

Currently, it is understood that the effects of hypoxia secondary to sleep apnea takes a toll on the body over time. Patients often experience snoring and daytime sleepiness in addition to other symptoms or changes to the body that may not be as easily recognizable, such as living in an increased inflammatory state1,3. Further, it is well known that an adverse maternal environment during pregnancy can lead to long term fetal complications3. Combining these two concepts, Dr. Baker wanted to further investigate the adverse effects of hypoxia due to maternal sleep apnea to get a better understanding of the subsequent consequences this deprived oxygen state has on mothers and their offspring. The hypothesis of this study was: Intermittent hypoxia during pregnancy has detrimental and long-lasting consequences on offspring neural function.

To test this hypothesis, Dr. Baker and her team exposed pregnant rats to intermittent hypoxia during days 10-21 of gestation. OSA was modeled from hypoxia episodes, but not the sleep fragmentation that accompanies the disease. It is understood that both components of sleep apnea, hypoxia and sleep fragmentation, would have their own influence on the offspring. The rats were put into a chamber and delivered 15 episodes of hypoxia per hour, as people can experience up to 10-20 episodes of apnea per hour during pregnancy, in increments of 90 seconds with 90 seconds of normoxia in between. During hypoxic episodes, oxygen levels were brought down to 10% and oxygen saturation was reliably reduced to 85% with adequate re-saturation during episodes of normoxia. Control rats were exposed to normoxia, 21% oxygen “on and off”, to control for and take into consideration confounding factors such as air flow within the chamber. While in labor, the rats were then removed from the chamber to give birth in a normal environment. The baby rats, or pups, were never exposed to hypoxia after they were born. Lastly, the pups were followed into adulthood to monitor for long term effects.3

Next, data from the gestational induced hypoxia (GIH) offspring and the control rat offspring (GNX) was compared. The GIH offspring showed no evidence for obesity and no difference in the volume of fat pads from shortly after birth to 12 weeks, as they had the same trajectory as the GNX offspring. There was also no difference between gestational length, number of pups, pup retrieval time, or pup survival between the two groups. To evaluate effects of gestational hypoxia on breathing, the adult offspring were placed in a plethysmography chamber. A plethysmography chamber measures changes in volume in the body to assess how much air is in the lungs when breathing. The rats were given one-hour to acclimate in the chamber and ventilation was then measured over the following three hours. Of the two groups, male GIH offspring had a significantly increased number of spontaneous apneas per hour compared to male and female GNX offspring and female GIH offspring, who had no change in the number of apneic episodes. Apneic episodes are defined as a pause in breathing that lasts longer than the duration of two breaths. Spontaneous apneic episodes are episodes of apnea with no apparent trigger on plethysmography signal. Approximately 60% of GIH male offspring had spontaneous apnea out of the 95% confidence interval, suggesting gestational intermittent hypoxia altered the phenotype in the male offspring. Again, this was not a congruent finding in GIH females.3

An additional factor to be considered in this scenario is respiratory plasticity, which is the body’s ability to help animals adapt to life changing circumstances, such as hypoxia and sleep apnea. A body’s ability to have respiratory plasticity is suggestive of a healthy neural system because breathing is an automatic and rhythmic function of the brain stem. Ultimately, the respiratory system you are born with is not the one you will die with. Recurrent central apnea can promote respiratory plasticity. Dr. Baker’s team further investigated whether the GIH rats had an altered adaptive response to conditions that alter the body’s natural response to breathing, which in this case is recurrent central apnea. Her team mechanically ventilated adult offspring that were vagalized, paralyzed, and urethane anesthetized to study neural control of breathing independent from the process of ventilation, and data was recorded via phrenic neurograms. A neural apnea was caused by lowering PaCO2 levels lower than the level for breathing and was then stopped by raising PaCO2 back to baseline levels. Recurrent neural apneas triggered plasticity mechanisms to make it harder to elicit the next apnea. Data showed adult male GIH offspring have impaired responses to recurrent reductions in respiratory neural activity and did not express plasticity following a triggered central apnea episode. Like prior results, female GIH offspring did not have this same neural plasticity impairment as the males, showing no elevations in spontaneous apnea and intact compensatory plasticity triggered by central apneas.3

Further, adult offspring were assessed for increased inflammation. To no surprise, GIH males had increased basal neuroinflammation. Although both male and female GIH offspring had increased inflammatory markers, the females were able to suppress the inflammation by an unknown mechanism that the male GIH offspring could not. Adult offspring of GIH and GNX groups were exposed to bacterial lipopolysaccharide (LPS), which confirmed that the GIH males mounted a greater inflammatory response compared to the other offspring, suggesting these males have an altered inflammation response. In the central nervous system (CNS), microglia are innate immune cells that can produce inflammatory cytokines and comprise 5-10% of CNS cells. Dr. Baker’s team pharmacologically depleted these cells in the adult offspring by administering the drug PLX3397 for seven days. This resulted in a stark reduction of microglia by 86%. The GIH male offspring with depleted microglia were able to regain compensatory plasticity triggered by recurrent central apneas. Three days after stopping PX3397, the microglia came back and expanded. When the microglia repopulated, there was restoration of the impaired plasticity phenotype in GIH males.3

To get a better understanding of what could be driving the persistent microglial inflammation in the GIH males, the gut-brain-axis was assessed. In human literature, it is suggested that sleep apnea is associated with gut dysbiosis. Investigating this link, feces was collected from the rats which showed diversity in the bacterial species present in GIH males compared to GIH females and both sexes of the GNX group. Dr. Mangalam looked at the GI bacteria shift and determined the gut microbiomes were comprised of two main phyla of bacteria, Bacteroidetes and Firmicutes. GIH males had increased Bacteroidetes and decreased Firmicutes compared to the other offspring. Initially unsure of this significance, Dr. Mangalam deduced that the decreased bacteria in the GIH male microbiome produce a short string fatty acid called butyrate. Once produced, this fatty acid stimulates the release of neuropeptides and serotonin, which are up taken by the portal vein. From there, butyrate enters the blood circulation and crosses the blood brain barrier (BBB), stimulating active receptors on the vagus nerve. Butyrate supports plasticity in the brain and reduces inflammation.3

This leads to the final question: can the neural plasticity deficit be rescued by decreasing neuroinflammation by supplementing male GIH offspring with butyrate? GIH male rats were supplemented with eight doses of 2mg/kg of Tributyrin over 22 days, which is converted into butyrate3. Upon creating central apnea in the GIH males treated with Tributyrin, it was found that their respiratory plasticity was fully rescued3. So, what does this mean?

Simply, this means gestational intermittent hypoxia has sex-specific, long-lasting effects on adult offspring physiology. This is shown by: 1) gut dysbiosis in male offspring, 2) increased central apneas during sleep with impaired respiratory plasticity, 3) enhanced basal inflammation of microglia in male offspring with increased inflammatory response upon provocation, and 4) microglial depletion or butyrate supplementation repaired deficits in respiratory plasticity.3

The research conducted by Dr. Baker’s team opens additional research opportunities regarding effects of hypoxia on vulnerable populations, such as pregnant mothers and their offspring. The findings from this study can be retested and built upon as research continues to be done. Although this research was not conducted at altitude, it is still interesting and pertinent to the altitude community, as hypoxia and OSA are common problems at altitude. This study contributes important knowledge to the science and medical community; however, more research will need to be done to confirm and fully understand the adverse effects of hypoxia during pregnancy. Further, more information is needed to understand how effects of gestational hypoxia can be applied to populations experiencing hypoxia secondary to living at altitude in a low oxygen environment.

References:

  1. Guilleminault C, Zupancic M. Sleep Disorders Medicine. Third Edition. Philadelphia, PA. Saunders. 2017. pp: 319-339.
  2. Patz D, Spoon M, Corbin R, et al. The effect of altitude descent on obstructive sleep apnea. CHEST. 2006; 130(6): 1744-1750. Doi: https://doi.org/10.1378/chest.130.6.1744
  3. Baker T. CoBAD: Maternal Intermittent Hypoxia and the Effect on Adult Respiratory Control and the Gut Microbiome in Male Offspring. Oral presentation at: the Fifth Annual Center for Physiological Genomics of Low Oxygen (CPLGO) Summit; June 4th, 2021; online.

Amanda Smith is a second year PA student at Drexel University in Philadelphia, Pennsylvania. Amanda was raised in the “sweetest place on Earth”, Hershey, Pennsylvania. She obtained her B.S. in Health Science with a double minor in Creative Writing and Community Health at Hofstra University on Long Island. Between obtaining her undergraduate and graduate degrees, Amanda worked as an Emergency Department scribe, pediatric nurse aide, and as a lead research coordinator in Neurosurgery/Neuro-Oncology at the Penn State Hershey Neuroscience Institute. Amanda loves to travel and was able to incorporate her love for traveling and medicine by traveling across the country for clinical rotations, rotating at sites in New York, California, Pennsylvania, and Colorado, with her next destination in Alaska!

Accessibility, Acclimation, Altitude Science, Athletic Training, Backcountry, Backpacking, Diabetes, Health, High Altitude, Medicine, Mountaineering

A Summation of Wilderness Medical Society Clinical Practice Guidelines for Diabetes Management

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According to recent research, nearly thirty million individuals in the United states have been diagnosed with diabetes. Due to this higher rate of prevalence, more people are aware of the basic information surrounding a diabetic diagnosis.  However, there are common misconceptions surrounding the average diabetic patient, with most information focused on the more common form of diabetes, type 2. Although the majority of diabetic patients in the United states do have type 2 diabetes, an estimated 5 to 10% of people with diabetes actually have type 1. Type 1 diabetes is an autoimmune disease in which the body’s own immune system destroys the cells in the pancreas that make insulin. Insulin is a very important hormone that enables sugar to enter the bloodstream in order for it to be used by the cells for energy, as well as stored for later use. Unlike type 2 diabetes, there is no cure for type 1 diabetes and the treatment options are limited; the only management for this form of diabetes is insulin therapy. The most common therapeutic regimens for type 1 diabetes includes constant monitoring of blood sugars using a glucometer or continuous glucose device. These devices combined with either syringes, preloaded insulin pens, and/or an insulin pump are the means to survival for type 1 diabetics. However, there have been many advancements in the ways physicians are able to help their type 1 diabetics control and manage their disease.  Because of this, type 1 diabetics are able to live their lives with far less complications.  When desired, type 1 diabetics are able to compete at high levels of activity and complete amazing feats, such as wilderness activities.

It is inspiring to know how type 1 diabetics are still able to perform in high intensity activities such as ultramarathons, ironmen/ironwomen, as well as professional sports, to name a few.  However, with such strenuous activity, it is important to note that diabetes control is more challenging.  Of note, it cannot be stressed enough, that baseline diabetic control is already challenging in itself.  By adding the addition of a strenuous environment and activity, diabetes control becomes more difficult as it is multifactorial.

To help address this issue, the Wilderness Medical Society (WMS) worked to form clinical practice guidelines for wilderness athletes with diabetes. The WMS gathered a group of experts in wilderness medicine endocrinology, primary care, and emergency medicine to compose these guidelines.  These guidelines are outlined for both type 1 and 2 diabetics who participate in mild-vigorous intensity events in wilderness environment with reduced medical access and altitudes greater than or equal to 8250ft; the objective to help individuals with diabetes better plan and execute their wilderness goals. The foundation summarizes their recommendations into pre-trip preparation, including a list of essential items to bring when on your wilderness trip, potential effects of high altitude on blood glucose control and diabetes management, and an organized algorithm to treat hyperglycemia and ketosis in the backcountry.

Effects of High Altitude on Diabetes Management:

At baseline, the various types of exercise activities are broken into aerobic, anaerobic, and high intensity exercise. Each type of exercise utilizes the energy stored in our bodies, in the form of sugar. In a healthy person without any comorbidities, during aerobic activities, glucose uptake into the large muscle groups is increased due to the increase in energy expenditure. To keep glucose higher during this form of exercise, insulin secretion is reduced. Simultaneously, other hormones such as adrenaline, cortisol, and glucagon are released into the system to promote further glucose release from processes such as gluconeogenesis and glycogenolysis.

Again, the body is utilizing its resource of glucose to move to the larger muscle groups to keep them moving and active. During anerobic and high intensity exercise, the same process occurs, but since these forms of exercise tend to be in short bursts, insulin levels tend to rise particularly in the post workout period.  This helps to diminish the effects of the counterregulatory hormones and keep blood sugar levels stable. If the athlete is unable to properly regulate insulin secretions during these various forms of exercise, then it is likely that he/she will experience frequent episodes of hyperglycemia. Also, due to the increase in insulin sensitivity in muscles post workouts lasting >60 min, hypoglycemia can also ensue.

In general, the WMS and other research demonstrates brief episodes of high intensity exercise are linked to hyperglycemia for diabetics. On the other hand, longer duration aerobic exercise will cause hypoglycemia. Unfortunately, due to the complex intricacies of glycemic control during exercise, in addition to the individuality of each patient and the multiple variables involved in each wilderness expedition (temperature, altitude, duration, etc.), the definitive guidance for adjustment of daily insulin continues to need refinement. This is why the WMS recommends extensive pre-trip planning with the various tools, research, and supplies that will be needed when planning any form of wilderness adventure.

Pre-trip Prep:

Like all endeavors, preparation is key in order to be better equipped to deal with the majority of future scenarios.  Planning is especially important when going on a wilderness expedition. Preparation becomes even more important with the diagnosis of diabetes. The WMS outlines the specific recommendations that should be included as a diabetic wilderness athlete. For example, pre-trip prep should generally include: (1) a medical screening, (2) research of the endeavor and how it may affect glucose management, and lastly (3) essential diabetes-specific medical supplies and backups.

Additionally, according to the American diabetes association, persons with diabetes should discuss with their primary care provider and or endocrinologist before a strenuous wilderness activity. This follow up ensures that athletes are up to date on their screenings, health maintenance labs, and prescriptions needed for therapy. Due to the various ways that diabetes can affect the body, the WMS also recommends that if a patient has cardiovascular involvement, retinopathy, neuropathy, or nephropathy, there should be a more extensive risk assessment by the provider. Although these complications are less commonly seen in high intensity wilderness athletes, adequate histories should be taken to avoid adverse circumstances.

As discussed earlier, altitude accompanied with increased strenuous exercise demands also has various effects on blood glucose management. As it pertains to altitude and blood sugar management in type 1 diabetes, multiple studies have shown an increase in insulin requirements at altitudes above 4000m (13,123′). At this time, researchers are unsure if this finding is due to the effects of acute mountain sickness or hypobaric hypoxia. Therefore, wilderness athletes with diabetes should be aware of the insulin resistance increase at these extreme altitudes.  In conjunction with altitude changes, as previously noted, the type of exercise will also play a role in insulin control.  Aerobic exercise for longer than 60 minutes can cause a hypoglycemic episode in type 1 diabetics due to the increased muscle sensitization to insulin. Therefore, at altitudes 4000m or above, wilderness athletes will be in a mixed long duration anaerobic/aerobic exercise. With the combination of these factors, there is a counter regulation effect, and the athlete becomes both more sensitive to insulin due to increase duration of exercise and less sensitive due to altitude demands. In order to better predict the effects of altitude combined with exercise, the WMS recommends close monitoring on shorter trips to recognize their specific glycemic trends prior to an extreme high-altitude expedition, as well as increased close monitoring of glucose management during their high-altitude endeavors.

Table 1: Environmental Effects on Diabetes, Imported from WMS

Lastly, in preparation of a high-altitude excursion, there are recommended items that should be packed for daily management of glucose, in addition to back up items to ensure athletes with diabetes aren’t left in a dangerous situation. Fortunately, the WMS was able to create a well-organized table on the recommended supplies.

Table 2: Medical Kit Preparation, Imported from WMS

Treatment of ketoacidosis or HHS:

To be properly prepared, an athlete should complete his/her own research on how changes of altitude and exercise can affect blood glucose management.  This includes complete pre-trip preparation and packing.  Once cleared, a diabetic athlete can finally head out on the high-altitude adventure. In case of emergency, a diabetic should be aware of the proper steps if he/she were to experience diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), or even acute mountain sickness (AMS). Hyperglycemia is described as a blood glucose greater than 250 mg/dL and without adequate treatment can lead to either DKA or HHS. Type 1 diabetics are more likely to go into DKA, while type 2 diabetics are more inclined to present in HHS. One of the most important indicators if a person were to be in DKA are ketones in blood or urine. This is why it is very important to make sure a wilderness athlete carries ketone strips in his/her emergency medical pack. Typically, if a patient finds ketones in their urine after using a ketone strip, then he/she is educated to seek emergent medical attention. When on a wilderness adventure, this can be a difficult task to accomplish. This is why the WMS also developed a flowchart in order to manage hyperglycemia and DKA without medical support. Refer to table 3 for their flowchart.

Table 3: Algorithm for management of hyperglycemia and ketosis in the backcountry. EDD, estimated daily dose, PO, oral intake, Imported from WMS

One issue that diabetics have when dealing with high-altitude is differentiating hypoglycemia and hyperglycemia side effects from AMS. The most reliable differentiating factor is increased blood sugar readings correlating with symptoms. WMS states that either a continuous glucose monitor or increased finger sticks for a higher frequency of blood sugar readings is important to determine if a person with diabetes is experiencing blood sugar complications of AMS. When discussing treatment of AMS in diabetics, the same methods are used as are recommended for a non-diabetic individual: Acetazolamide and dexamethasone in initial medical management. In regard to diabetes, it is important to discuss the potential additional side effects. Acetazolamide can worsen dehydration and acidosis if used at the wrong time. Dexamethasone is known to worsen blood glucose control. Both are still useful in acute mountain sickness but must be weighed against causing worsened complications.

Conclusion:

When participating in a wilderness adventure, individuals with diabetes will be prone to more medical side effects. Changes in altitude, along with the level of activity are known to affect diabetic control, so proper preparation prior to departure is required in order to ensure the health and safety of a diabetic wilderness athlete.  After being cleared by a medical professional and obtaining proper information, diabetics can plan to complete a wilderness adventure similar to that of a healthy individual with no comorbidities.  However, it is common for diabetics to experience hyperglycemia with high intensity activities and an increase in altitude. Therefore, diabetics (particularly type 1 diabetics), should be prepared with extra insulin to counteract elevated glucose levels. Alternatively, if a diabetic were to be at higher altitude with a longer duration of aerobic or anaerobic exercise, then he/she may be prone to hypoglycemia — lower blood sugar levels.  In either case, individuals with diabetes will need to monitor blood sugar levels more closely.  The WMS provides diabetics with an outline of recommended supplies that may be needed in the wilderness.  The outline also suggests for diabetics to bring ketone strips, as this is the most accurate measurement to determine if a diabetic is in DKA or HHS.  The ultimate goal of the WMS is to ensure the health and safety of diabetic athletes. Diabetes is a difficult disease to manage but becomes even more challenging when partaking in a wilderness adventure.

(All tables and figures imported from WMS)

References:

de Mol P, de Vries ST, de Koning EJ, Gans RO, Tack CJ, Bilo HJ. Increased insulin requirements during exercise at very high altitude in type 1 diabetes. Diabetes Care. 2011;34(3):591-595. doi:10.2337/dc10-2015

VanBaak KD, Nally LM, Finigan RT, et al. Wilderness Medical Society Clinical Practice Guidelines for Diabetes Management. Wilderness Environ Med. 2019;30(4S):S121-S140. doi:10.1016/j.wem.2019.10.003

Jonathan Edmunds is a second-year physician assistant student at RRCC PA Program in Arvada Colorado. Jonathan is a Colorado native, born and raised in Littleton, CO. He attended Colorado State University in Fort Collins, CO where he competed in Track and Field as a long jump/triple jumper, as well as earned his bachelor’s Biological Sciences. During his junior year in college, he was diagnosed with Type 1 diabetes and quickly became an advocate the support of diabetes education. After graduating in 2015, he focused his medical career aspirations on becoming a PA. He volunteered at Banner Fort Collins Medical Center and work at Bonfils Blood Center as a phlebotomist for 2 years before applying to PA school. In his free time, he enjoys coaching track and field at Littleton high school his alma mater, doing all things outdoors, and cozying up to his three “Irish” chihuahuas at home.