High-Altitude Pregnancy: An Overview of the Research Being Conducted by Dr. Lorna G. Moore and Colleagues

*All figures and graphs seen in this post came directly from a presentation by Dr. Lorna G Moore from the Department of Obstetrics & Gynecology, University of Colorado School of Medicine on September 15, 2021 at Saint Anthony Summit Hospital

It is well known that women living at high altitudes often give birth to infants of lower birth weight than those living at sea level due in part to intrauterine growth restriction (IUGR). However, causes of fetal growth restriction at high altitude are not well understood. Dr. Lorna G Moore and her colleagues have found high altitude (>8,000ft) such as that of Summit County, Colorado provide a natural laboratory for studying the physiological mechanisms sustaining fetal growth and identifying new therapies for treating pregnancy disorders.1 In this article, I will be reviewing their findings on fetal growth and uteroplacental blood flow at high altitude, whether activation of an enzyme called adenosine monophosphate kinase (AMPK) is protective, and whether hypoxia directly or indirectly reduces fetal growth.

A baby’s birth weight is the single greatest predictor of infant mortality. Preterm birth and low birth weight were the second leading causes of infant mortality in 2018 according to the CDC.2 While infants born at high altitude in Colorado have, on average, lower birth weights, multigenerational populations of Andeans and Tibetans are relatively protected from altitude-associated birth-weight reductions. Studies completed over the last 25 years in regions of the world where populations have lived at high altitude for many millennia (i.e., Andeans, Tibetans, and Ethiopians) provide “evidence for genetic adaptation to high altitude” that have been linked to improved  “distribution of blood flow to vital organs and the efficiency of O2 utilization ”.

Uterine artery blood flow is crucial for reproductive success as it provides the necessary blood flow to the placenta and the fetus to meet their metabolic demands. Uterine artery blood flow increases 60-fold at low altitude but has a lesser increase in high-altitude newcomers in Colorado or elsewhere.1 In contrast, a normal pregnancy rise in uterine artery blood flow occurs in Andeans and Tibetans (Ethiopians have not been studied). 

A major factor responsible for increasing uterine artery blood flow is an increase in the diameter of the main uterine artery. Of 63 genes identified as having been acted upon by natural selection, an allele called “TT” for the gene PRKAA1 which codes for the portion of AMPK involved in that enzyme’s activation is more common in Andeans and is associated both with greater uterine artery diameter and increased birth weight at high altitude.1,4 Activation of AMPK causes the uterine artery to dilate, which Dr. Moore and colleagues hypothesized would increase uterine artery blood flow and thereby help maintain birth weight. At low altitude, one of the key factors responsible for raising uterine artery blood is increased production of the vasodilator, nitric oxide (NO), in the uterine artery. Their studies showed that nitric-oxide induced vasodilation fails to occur at high altitude but, interestingly, uterine artery vasodilation in response to AMPK activation is increased, suggesting that “AMPK activation may be compensatory for the lesser NO-induced vasodilation and helps maintain fetal growth”.4 To test this idea, they used a drug called AICAR to activate AMPK in mice that were kept in simulated sea level (SL) or high altitude (HA) conditions during pregnancy. Mice that were given AICAR at high altitude showed an increase in uterine artery diameter, blood flow, and the percent of cardiac output directed to the uterine circulation (UtA flow/cardiac output).1,6

They also found that AICAR restored approximately half of the altitude-associated reduction in fetal weight.1

Their current studies are trying to figure out how a reduction in uterine artery blood flow reduces fetal growth. Their and other persons’ data suggest that lower blood flow is not solely responsible. Since AMPK is not only a vasodilator but also (and best known as) a “metabolic sensor”, Dr Moore and colleagues think that AMPK may be playing a crucial role in linking blood flow to metabolism factors at high altitude. They are planning to continue studies examining the metabolic factors involved in pregnancy and how they act to affect vasoreactivity and fetal growth.1

References

  1. Moore LG. Using studies at high altitude (HA) to identify the causes and ultimately new treatments for pregnancy disorders. lecture presented at the: September 9, 2021. 
  2. Infant mortality. Centers for Disease Control and Prevention. https://www.cdc.gov/reproductivehealth/maternalinfanthealth/infantmortality.htm. Published September 8, 2021. Accessed September 28, 2021. 
  3. Moore LG. Measuring high-altitude adaptation. J Appl Physiol (1985). 2017;123(5):1371-1385. doi:10.1152/japplphysiol.00321.2017
  4. Skeffington KL, Higgins JS, Mahmoud AD, et al. Hypoxia, AMPK activation and uterine artery vasoreactivity. J Physiol. 2016;594(5):1357-1369. doi:10.1113/JP270995
  5. Lorca RA, Lane SL, Bales ES, et al. High Altitude Reduces NO-Dependent Myometrial Artery Vasodilator Response During Pregnancy. Hypertension. 2019;73(6):1319-1326. doi:10.1161/HYPERTENSIONAHA.119.12641
  6. Lane SL, Houck JA, Doyle AS, et al. AMP-activated protein kinase activator AICAR attenuates hypoxia-induced murine fetal growth restriction in part by improving uterine artery blood flow. J Physiol. 2020;598(18):4093-4105. doi:10.1113/JP279341

Zoe Heller is a second year Physician Assistant student from Red Rocks Community College in Arvada, CO. She was born and raised in colorful Colorado and received her undergraduate degree in biological sciences at the University of Colorado Denver. Prior to PA school she worked as a professional research assistant at the Barbara Davis Center and a medical assistant at Denver Endocrinology, Diabetes and Thyroid Center. When she’s not in clinic or studying, you can find her hiking, skiing, or sitting by a campfire at her mountain property “Coolsville” with her husband and two pups, Timber and Willa.

Wound Care at Altitude

Traveling and living at altitude can make many physiologic processes just a little harder. If you have experience in the mountains, you may have noticed that simple cuts and wounds simply take longer to heal than down at sea level. This isn’t your imagination. Wounds can take a significantly longer time to heal while at altitude. This means routine wound care is more important to observe while at altitude.

Normal Wound Healing Process

Wound healing is a well-documented and well-described process. After an injury to the skin, the first step of healing involves creating a blood clot to seal the disrupted vessels. This step involves activation of circulating proteins that promote blood coagulation. Platelets bind together in a strong collection strengthened by coagulation proteins.

The next step of wound healing involves activation of inflammation. While inflammation is generally thought of as a bad thing, it is actually a crucial step in repairing tissues. White blood cells are attracted to the injured area where they can eliminate pathogens that have gotten into the wound. These white blood cells serve other functions as they help to lay down fibrin proteins and activate fibroblasts.

Fibrin and fibroblasts operate in the proliferation stage of wound healing. This stage is when proteins are laid down in the wound to serve as scaffolding for tissues. Blood vessels are then able to heal themselves. Skin cells then start to divide and fill in the area of the wound. After these steps, the collagen that was laid down as a scaffold rearranges itself into a tight matrix that will provide a strong foundation for the healing skin. All in all, the body goes through a few days of inflammation followed by several weeks of regrowing injured tissue.

Changes in Wound Healing at Altitude

Now the question at this point is, how does living at altitude interfere with this whole process? This is an area that is not very well studied, and research is ongoing to discover the impact of altitude on wound healing. What we do know is that wounds tend to take more time healing while at altitude than at sea level. The theory behind this delayed wound healing is due to impaired oxygen delivery at the site of the wound. Individuals with circulation problems like diabetes and arterial stenosis will have similarly delayed healing at wound sites. Furthermore, wounds farthest away from the heart tend to take the longest to heal (think fingers and toes). The coagulation and inflammatory processes will carry on as normal (as these steps don’t require oxygen to function properly); however, proliferation and maturation steps require considerable amounts of oxygen. This can prolong how much time is required in these different steps.

Consequences of Delayed Healing

Prolonged wound healing can lead to some significant consequences. The longer a wound stays open, the greater a chance it has at developing an infection. If a wound becomes infected, it can prolong the healing process even more, lead to more inflammation, result in pain, and even spread of the infection throughout the body. If the maturation phase is interrupted either by an infection or low oxygen state, it can lead to more scar formation and lower tissue strength.

General Wound Care Recommendations

Luckily, the recommendations for caring for a wound do not change while at altitude. It is still important to wash all wounds in clean water. Keep the wound covered with antibiotic jelly such as bacitracin or any over the counter triple-antibiotic ointment. Keep wounds dry and clean and covered with a bandage until it closes. If cuts are deep, they may need to be closed with sutures. Be aware of signs of infection. This would include redness of the wound, warmth, increased pain, purulent discharge, or red streaks radiating away from the wound. While discussing the implications of delayed wound healing at altitude with Dr. Christine Ebert-Santos at Ebert Family Clinic in Frisco, CO, she recommended that sutures closing lacerations remain in for a little longer. For facial lacerations, she recommends leaving them in for 7 days as opposed to the typical 5, and sutures elsewhere can remain in for 10 days. Consult with your regular medical provider if you are concerned with how any wounds are healing.

Sources

Balsa IM, Culp WT. Wound Care. Vet Clin North Am Small Anim Pract. 2015;45(5):1049-1065. doi:10.1016/j.cvsm.2015.04.009

Goodson WH 3rd, Lopez-Sarmiento A, Jensen JA, West J, Granja-Mena L, Chavez-Estrella J. The influence of a brief preoperative illness on postoperative healing. Ann Surg. 1987;205(3):250-255. doi:10.1097/00000658-198703000-00006

Janis JE, Harrison B. Wound healing. Plastic and Reconstructive Surgery. 2016;138. doi:10.1097/prs.0000000000002773

Eric Meiklejohn is a second year Physician Assistant student attending Red Rocks Community College in Arvada, Colorado. He received his undergraduate degree from Colorado State University. Prior to Physician Assistant school, he worked as an EMT both in the Emergency department and on the ambulance. In his free time, he enjoys cooking and spending time with his wife, Nicole, and his dog, Julie.

The Nobel Prize: Hypoxia studies Won in 2019!

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.

A Hike a Day May Keep the Cardiologist Away

Cardiovascular disease is one of the leading causes of death worldwide, with approximately 17.9 million people succumbing to the disease annually (World Health Organization, 2021). In the United States, there is an estimated 18.2 million Americans (20 years and older) with coronary artery disease. Of those, an estimated 655,000 Americans die annually from heart disease. Approximately 805,000 experience myocardial infarction (i.e., heart attack); 605,000 of these are first time heart attacks, and the other 200,000 have experienced at least one in their lifetime (Centers for Disease Control, 2020). Prevention and management of myocardial infarctions is constantly evolving, and new innovations are being developed to minimize the long-term, chronic consequences one may deal with. Interestingly, it is possible that life at higher altitudes, such as in the Rocky Mountains, may provide a natural edge over life at sea level. For example, Summit County, Colorado (avg elevation ~11,113 ft) has a life expectancy of 86.83 years (Stebbins, 2019). On the contrary, Lauderdale County, Mississippi (elevation 668 ft) has a life expectancy of 75.2 years (U.S.News, 2021). When looking at data regarding heart attack deaths, Summit County experiences 7.2 per 100,000 and Lauderdale County has 334.1 per 100,000 (Centers for Disease Control, 2017-2019).

Myocardial infarction is defined by cardiac muscle death that results from prolonged ischemia. The ischemia is typically the result of an atherosclerotic plaque that ruptures and occludes an artery supplying an area of heart muscle. This leads to an imbalance between the oxygen supply and demand in the affected tissue. Additional swelling ensues, occluding microcirculation, which results in more regional ischemia (Montecucco, Carbone, & Schindler, 2016). In addition to the lack of oxygen, cardiac cells overload with calcium, which causes excess contraction, cytoskeleton digestion, excess reactive oxygen species (ROS) formation, DNA fragmentation, and the release of cytochrome C from mitochondria, which signals cellular death (Heusch & Gersh, 2017).

How might altitude play a protective role in such a complicated process? There are many hypotheses out there, and some interesting findings have been discovered in animal models. Mentioned earlier, ROS fragment the DNA within cardiac cells, which is a trigger for cellular death. With the DNA damaged, cellular function ceases. ROS exposure is a normal part of life; they result from the oxygen we breath, which form free radicals (lone oxygen atoms), the pollution in the air, and the alcohol one may consume. Surprisingly, there is a reduction of ROS formation when someone is at a high enough altitude. This leads to the cardiac cell’s ability to form new, healthy cells. This suggests that ROS are like the breaks to a car and reduces the cell’s ability to move forward in the process of cell division. By taking the breaks off, it may be possible to regenerate healthy, functional tissue (Nakada, et al., 2017).

Another issue of myocardial infarction is the process of remodeling and scar tissue formation. Depending on the extent of the damage, remodeling can be detrimental and compromise the heart’s ability to pump blood efficiently. The inflammation that results signals neutrophils to the area to form scar tissue to try and repair the damage. Neutrophils also work to prevent adverse remodeling. The goal in managing heart attacks is to minimize any sort of damage that may result, but if we are too aggressive in this process, we can cause the formation of excess ROS. These ROS play a role in prolonging the lifespan of these neutrophils, allowing them to keep working. If we do not get timely resolution of the neutrophil remodeling, then healing may not be optimized (Montecucco, Carbone, & Schindler, 2016).

One study in rats explored how the heart remodels when exposed to intermittent hypoxia. Over the course of this study, rats were gradually exposed to higher simulated altitudes, and returned to baseline elevations for periods of time. The highest elevation they were exposed to was 8000 m, or the summit of Mt. Everest. They discovered that both right and left ventricles did remodel over the course of the experiment, but the left ventricle experienced significant remodeling only at the highest altitude. They also discovered that the functionality of the left ventricle was maintained. The remodeling was explained by reoxygenation that occurred at normal elevations, which resumed the production of ROS. This mechanism was absent at altitude. There are rare adverse effects of living at high altitude, which include stunted body growth, erythrocythemia (excess red blood cell formation), pulmonary hypertension, and myocardial fibrosis (Papoušek, Sedmera, Neckár, Oštádal, & Kolár, 2020).

It is exciting to explore some of the possible benefits of being and living in higher elevations. Going forward, it will be important to see if there are clinical applications, and if these applications can be administered safely and efficiently. Just like scuba divers being treated for the bends in hyperbaric chambers, what if we can develop a hypobaric chamber for those who experienced a recent heart attack? Is it possible to minimize damage by reducing the amount of oxygen entering the body, and how long would one have to be exposed to such treatment? These are very important questions that need further investigation. For now, the best course of action is to eat healthy, stop smoking, and go for a hike. If you happen to be hiking in Colorado, it may help keep the cardiologist away.

References

Centers for Disease Control. (2017-2019). Interactive Atlas of Heart Disease and Stroke. Retrieved from Centers for Disease Control and Prevention: https://nccd.cdc.gov/DHDSPAtlas/reports.aspx?geographyType=county&state=CO&themeId=8&filterIds=9,2,3,4,7&filterOptions=1,1,1,1,1#report

Centers for Disease Control. (2020, September 8). Heart Disease Facts. Retrieved from Centers for Disease Control and Prevention: https://www.cdc.gov/heartdisease/facts.htm

Heusch, G., & Gersh, B. J. (2017). The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. European Society of Cardiology, 774-784.

Montecucco, F., Carbone, F., & Schindler, T. H. (2016). Pathophysiology of ST-segment elevation myocardial infarction: novel mechanisms and treatments. European Society of Cardiology, 1268-1283.

Nakada, Y., Canseco, D. C., Thet, S., Abdisalaam, S., Asaithamby, A., Santos, C. X., . . . Schiattarella. (2017). Hypoxia induces heart regeneration in adult mice. Nature, 222-226.

Papoušek, F., Sedmera, D., Neckár, J., Oštádal, B., & Kolár, F. (2020). Left ventricular function and remodelling in rats exposed stepwise up to extreme chronic intermittent hypoxia. Respiratory Physiology and Neurobiology.

Stebbins, S. (2019, September 6). 50 counties with high life expectancies: Does yours make the list? Retrieved from USA Today: https://www.usatoday.com/story/money/2019/09/06/the-50-counties-where-people-live-the-longest/40072465/

U.S.News. (2021). Overview of Lauderdale County, MS. Retrieved from U.S.News: https://www.usnews.com/news/healthiest-communities/mississippi/lauderdale-county

World Health Organization. (2021, June 11). Cardiovascular Diseases (CVDs). Retrieved from World Health Organization: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

Tyler Cole is a second year Physician Assistant student at Midwestern University in Glendale, Arizona. He was born and raised in Glendale, and went to The University of Arizona in Tucson, where he earned his bachelor’s in Physiology and Biochemistry in 2013. From there, he went on to serve the city of Tucson as an Emergency Medical Technician for six years. He was also an EMT instructor at Pima Community College for three years. Outside of medicine, Tyler enjoys watching hockey, fishing, traveling, and spending time with his dog, Louie.

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

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.

Nocturnal Hypoxia at High Altitude

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.

High Altitude and Pre-Eclampsia

Human adaptation to hypoxia is an evolutionary change, evidenced by genetic modifications seen in certain populations such as Tibet in Asia, the Andes of the Americas, and Ethiopia in Africa, who thrive at extremely high altitudes. This is done by a process of natural selection, in which those who possess a higher degree of genetic variability are at an advantage over those with limited variability. There was a study that showed statistically similar genotypic and allelic frequencies in sea-level sojourners who undergo acclimatization on the ascent to high altitude and the adapted high altitude natives, particularly in the variants of the genes EDN1 (endothelin 1), ADRB2 (beta-2 adrenergic receptor, surface), ADRB3 (beta-3 adrenergic receptor), eNOS (nitric oxide synthase, endothelial), SCNN1B (sodium channel, non-voltage gated 1 beta subunit), TH (tyrosine hydroxylase) and VEGF (vascular endothelial growth factor) (Tomar et al. 2015).

Pre-eclampsia is the leading worldwide cause of maternal and fetal morbidity and mortality. However, in spite of extensive research, an exact etiology of pre-eclampsia is unknown. The thought is that there may be insufficient adaptation of spiral arterioles or shallow trophoblastic invasion, resulting in reduced uteroplacental blood flow leading to placental hypoxia. In other words, hypoxia may be a contributing factor to pre-eclampsia. This is shown by higher incidences of pre-eclampsia happening in areas of high altitude, along with higher risks of reproductive loss, intrauterine growth restriction, and other pregnancy complications (Zamudio 2007). Therefore, the main question to ask is, can a hypoxia-induced disorder like pre-eclampsia overcome the scarce microenvironment of oxygen deprivation by “acclimatization,” as a rapid form of adaptation?

A study conducted in 2017 evaluated more than 40 genes that are known to be associated with hypoxia for their genetic variability. A total of 36 RNA-seq samples from the amniotic fluid were retrieved from the NCBI. It involved samples of 19 pre-eclamptic preterm births while the controls were from 17 full-term births. The study revealed that the genes that are well-known to be associated with adaptation to high altitude had almost three times higher genetic variability in cases compared to control. In particular, EPAS1 gene showed the highest number of variants, followed by ADAM9 and EGLN1. This suggests there is higher selective pressure on the deprived cells of preeclampsia that leads to a high degree of genetic variability, which reflects their potency to survive the hypoxic microenvironment (Figure 1 and Figure 2).

Furthermore, while cases of preeclampsia were more hypoxic and had the highest number of hypoxic variants, they still had a lower number of adaptive variants (Table 2). This suggests the role of adaptive variants in relieving hypoxic pressure. Interestingly, there was a kind of reciprocal relation between the number of acclimatized variants and the number of hypoxic variants. In the controls, a higher number of acclimatized variants relieved the high pressure and thus resulted in a lower number of hypoxic variants, whereas in preeclamptic cases, the high number of hypoxic variants existed indicating for persistent signal of high selective pressure.

In summary, our human bodies have an incredible ability to shuffle their genes to win newer and better physiological characteristics in extreme conditions such as high altitude and pre-eclampsia. Samples indicate that those who were pre-eclamptic and therefore in hypoxic states, had higher genetic variability than those with normal pregnancies. This shows that the genes strive to alter and change to better fit their environmental conditions driven by the high selective pressure. Although more studies are required to fully understand the mechanisms of genetic variants in high altitude and preeclampsia, identifying these variants can pave the way to new treatment strategies that can help the body to better overcome challenging situations.

References

Ahmed, S. I., Ibrahim, M. E., & Khalil, E. A. (2017). High altitude and pre-eclampsia: Adaptation or protection. Medical Hypotheses, 104, 128-132. doi:10.1016/j.mehy.2017.05.007

Tomar, A., Malhotra, S., & Sarkar, S. (2015). Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives. BMC Genetics, 16(1). doi:10.1186/s12863-015-0268-y

Zamudio, S. (2007). High-altitude hypoxia and preeclampsia. Frontiers in Bioscience, 12(8-12), 2967. doi:10.2741/2286

Esther Kwag is a second-year Physician Assistant student at the Red Rocks Community College, Colorado. Esther was born in Seoul, South Korea and spent her elementary years there until she moved to Colorado and has been living here since. She graduated from the University of Colorado with B.S. Biology with Cum Laude in 2017. Prior to PA school, she worked as a CNA at a physical rehabilitation facility working primarily with post-operative patients who underwent orthopedic surgeries. Interacting with patients and advocating for healthier lifestyle motivated Esther to further pursue her education in medicine. In her free time, she enjoys spending time with family and friends, reading books, and travelling.

Return to High Altitude after Recovery from Coronavirus Disease 2019

Andrew M. Luks and Colin K. Grissom

https://www.colorado.com/activities/colorado-hiking

Prior to COVID-19, I would hike the beautiful mountains of Colorado known as 14ers, a name given to these mountains for being over 14,000 ft. I, like most high-altitude travelers faced the more common concerns associated with hiking such as acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE). With the increase in high-altitude travel, I wondered if there are any new precautions that we should consider before resuming the activities that we love.

The purpose of this article is to highlight the recommendations for patients who wish to return to high-altitude travel after a COVID infection. Not everyone needs an evaluation after a COVID infection. The recommendations noted in this article are based on the duration and severity of the illness of each individual person.

So, who should receive an evaluation before high-altitude travel?

  1. Individuals with symptoms after 2 weeks of a positive COVID-19 test without hospitalization,
  2. Individuals with symptoms after 2 weeks after hospital discharge,
  3. Anyone who required care in the intensive care unit (ICU), and
  4. Anyone who developed myocarditis or thromboembolic events. The recommendations are to undergo pulse oximetry at rest and with activity, spirometry, lung volumes, and diffusion capacity for carbon monoxide(DLCO), chest imaging, electrocardiography (EKG), B-type natriuretic peptide, high sensitivity cardiac troponin (hsTn), and echocardiography.

It is expected that people with lower oxygen levels (hypoxemia) at rest or with exertion in lower elevations will experience greater hypoxemia with ascent to high altitude. It has been shown that ascent to high altitude causes a decrease in barometric pressure leading to a decrease in ambient and inspired partial pressure of oxygen. The decrease in partial pressure of oxygen in alveoli (PaO2) will trigger vasoconstriction of pulmonary arterioles that slows the rate of oxygen diffusion and activates chemoreceptors that increase minute ventilation from hypoxia. However, it is still unclear whether people with low oxygen levels at low elevations are at greater risk for acute altitude illness after ascent. The recommendation is to monitor pulse oximetry after arrival of high altitude.

Individuals with abnormal lung function tests don’t have to avoid high altitude travel as previous studies have shown that patients with COPD with abnormal lung functions tolerate exposure. Furthermore, in people with mild to severe COVID-19 symptoms, the lung mechanic markers such as forced expiratory volume (FEV1), forced vital capacity (FVC) and total lung capacity (TLC) normalize in up to 150 days of infection.  However, if individuals have severe limitations with exercise capacity, they should monitor their oxygen levels with pulse oximetry after ascent. Reduction in exercise capacity is possible after COVID infection and depends on the severity of the illness. Blokland et al., 2020 has shown that previously intubated individuals had a median VO2 max of 15ml/kg per min (average male 35 to 40 and average female 27 and 30), roughly 57% predicted immediately after hospitalization. 

In acute hypoxia, the heart rate increases, which leads to an increase in cardiac output. Individuals with reduced ventricular function from COVID infection do not have to avoid travel. Previous research has shown that individuals with heart failure can tolerate exercise with hypoxia. Moreover, data has shown that individuals with COVID infection maintain preserved left ventricular function and only 3% show a reduced ejection fraction. Individuals with abnormal EKG rhythms and ischemia should be referred to cardiology.  If high sensitivity troponin was abnormally elevated, this would require evaluation for myocarditis with a cardiac MRI. Knight et al., (2020), found that 45% of patients with unexplained elevations of high-sensitivity troponin were found to have myocarditis during hospitalization. It is still unclear how long these abnormalities will last and how it will affect people.

 A concerning finding on ECHO is pulmonary hypertension, as previous research has shown an increased risk in developing HAPE. A study reported that 10% of patients hospitalized for COVID without mechanical ventilation had right ventricular dysfunction for over 2 months. Several studies reported that 7-10% of individuals may have pulmonary hypertension after COVID infection. A vasodilating drug such as nifedipine can be given prophylactically if pulmonary hypertension is unrelated to left heart dysfunction but nifedipine can worsen hypoxemia.

The recommendation for patients who developed myocarditis from a COVID infection is to have an ECHO, Holter monitor, and exercise EKG 3-6 months after illness. Travel can resume after a normal ECHO, no arrhythmias on exercise EKG, and after inflammatory markers (ESR and/or CRP) have normalized. Previous studies suspected that areas with low atmospheric pressures (e.g., high-altitude) that induce hypoxia have increased risk for clot formation. However, this suspicion has never been firmly established; therefore there is no reason to believe that high-altitude will increase the risk for clot formation in individuals who developed an arterial or venous clot from COVID infection.

A few things to consider before planning a high-altitude excursion includes planning to visit areas with access to medical resources or the ability to descend rapidly. If you are new to high altitude, it is recommended to slow the ascent rate. Traveling to high elevations (>4000m) should be avoided until tolerance has developed with moderate elevations (2000-3000m). A more gradual return to physical activity at high altitude is recommended rather than immediate resumption of heavy exertion. As the pandemic subsides and with increase in mountain travel, more research will develop that can better address these risks.

Good news! The Ebert Family Clinic in Frisco, CO provides pulse oximeters for free. So, make sure to visit and grab your pulse oximeter before your next ascent.

Quick Summary of Recommendations

Individuals who require evaluation prior to high-altitude travel:

  1. Individuals who have symptoms after 2 weeks of a positive COVID-19 test without hospitalization
  2. Individuals who have symptoms after 2 weeks after hospital discharge
  3. Any patient who required care in the intensive care unit (ICU)
  4. Any patient who developed myocarditis or thromboembolic events

General recommendations for anyone before high-altitude travel:

  1. Monitor pulse oximetry after arrival of high altitude, and access care or descend if symptoms worsen.
  2. Rest and avoid high-altitude travel for at least 2 weeks after a positive test, and consider a gradually return to physical activity at higher altitudes.
  3. All individuals planning high-altitude travel should be counseled on how to recognize, prevent, and treat the primary forms of acute altitude illness (AMS, HACE, and HAPE)
  4. Limit the extent of planned exertion after ascent and, instead, engage in graded increases in activity that allow the individual to assess performance and avoid overextending themselves.

Reasons to forgo high-altitude travel:

  1. Severely elevated pulmonary artery pressures may be a reason to forego high-altitude travel altogether.
  2. High-altitude travel should likely be avoided while active inflammation is present in myocarditis.
  3. Patients who experienced arterial thromboembolic events due to COVID-19, (e.g. myocardial infarction or stroke) should defer return to high altitude for several months after that event or any associated revascularization procedures.

References:

  1. Andrew M. Luks and Colin K. Grissom. Return to High Altitude After Recovery from Coronavirus Disease 2019. High Altitude Medicine & Biology. http://doi.org/10.1089/ham.2021.0049
  2. Christensen CC, Ryg M, Refvem OK, Skjønsberg OH. Development of severe hypoxaemia in chronic obstructive pulmonary disease patients at 2,438 m (8,000 ft) altitude. Eur Respir J. 2000 Apr;15(4):635-9. doi: 10.1183/09031936.00.15463500. PMID: 10780752.
  3. Blokland IJ, Ilbrink S, Houdijk H, Dijkstra JW, van Bennekom CAM, Fickert R, de Lijster R, Groot FP. Inspanningscapaciteit na beademing vanwege covid-19 [Exercise capacity after mechanical ventilation because of COVID-19: Cardiopulmonary exercise tests in clinical rehabilitation]. Ned Tijdschr Geneeskd. 2020 Oct 29;164:D5253. Dutch. PMID: 33331718.
Image of Jesse Santana, dark brown hair, brown skin, beard and moustache with a stethoscope draped over his white coat, striped, collared shirt and maroon tie.

Jesse Santana is a second-year PA student at Red Rocks Community College in Denver, Colorado. He grew up in Colorado Springs, CO and attended the University of Colorado-Colorado Springs where he earned a bachelor’s in Biology and Psychology. Jesse worked as a Certified Nursing Assistant for two years before pursuing a Master’s in Biomedical Sciences at Regis University in Denver. Shortly after, he coordinated clinical trials in endocrinology and weight loss as a Clinical Research Coordinator at University of Colorado Anschutz Medical Campus. He enjoys hiking Colorado’s 14ers, spending time with family and friends, and camping.

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

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!

Anxiety at Altitude

As I arrived in Denver (5280′), and ultimately Frisco, CO (9000′), the first physical symptom I noticed from the high-altitude environment was dyspnea on exertion. On flat ground I didn’t feel any different than at home in New Jersey, but as soon as I began to climb stairs or hike the beautiful trails in the area, I quickly became winded. I had already read about the common symptoms of high-altitude acclimation and knew this was normal and was on the lookout for headache, nausea, or dizziness. I noticed my resting heart rate was elevated and told myself this was also normal because the low-oxygen environment required my heart to work harder to keep my pulse oxygen levels up. I already owned a pulse oximeter that I had bought during my time working with COVID patients in the Emergency Room on a previous rotation. I checked that within my first week and was initially disappointed that it was averaging around 91%, but soon found out this was also normal, especially since I was still acclimating. My Apple watch trended data over time on my heart rate and I noticed a tremendous difference in my resting HR compared to home.

I landed on May 2nd, 2021 and I think the graphs above make that quite evident. My walking HR was even more noticeably elevated. “The initial cardiovascular response to altitude is characterized by an increase in cardiac output with tachycardia … after a few days of acclimatization, cardiac output returns to normal, but heart rate remains increased”1

My persistently elevated heart rate caused me to feel anxious when hiking or doing other physical activity, and that anxiety in turn raised my heart rate even more. I had experienced PVC’s in the past which occurred only a few times a month, nowhere near the threshold for treatment, and had been reassured they were totally benign. On a hike during my first week in Colorado I experienced a few of these “skipped beats” followed by rapid heart rate and had to talk myself down from the anxiety it caused. This is what prompted me to research the effect of altitude on anxiety. “Adrenergic centers in the medulla are activated in acute hypoxia and augment the adrenergic drive to the organs.”2 It seems as though the body’s compensatory mechanisms to physiological changes can be accompanied by unwanted mental health disturbances. This is especially true for people in the early stages of shifting from low altitude to high altitude. During the adjustment period individuals are most susceptible to new-onset anxiety disorders, but even those living long-term at high altitude are at increased risk of psychiatric ailments.4 In fact, living in high-altitude environments has been associated with serious mental health implications not limited to anxiety disorders, including depression and increased suicidality.4 This has been evidenced by statistically significant changes in PHQ-9 Total Score, PHQ-9 suicidal ideation, and GAD-7 Total Score.4

Sleep disturbances have often been faulted for these increases in anxiety and depression at high altitude, and although I didn’t have any formal sleep studies done while in Colorado, I felt well-rested and didn’t notice a change in my sleep at altitude.3 One hypothesis that could explain these findings and my personal experience, is that hypoxia has an inverse relationship with serotonin.4 Because oxygen is a requirement for the creation of serotonin, living somewhere with decreased oxygen could lead to deficiency. Serotonin has an expansive role in the human body, playing a role in cognition, sleep, mood, digestion and other crucial aspects of life. Low levels of this neurotransmitter have been implicated as a cause for depression and accordingly many of our best antidepressant medications like SSRI’s and SNRI’s work on these pathways. There is also a “chicken or the egg?” argument to be made. Is the anxiety brought on due to hypoxia which in turn causes somatic symptoms like palpitations, shortness of breath, and presyncope; or do these symptoms caused by hypoxia come first, resulting in anxiety and panic attacks? For example, hyperventilation, a well-known provocative factor of panic attacks, is also a response to altitude changes. Hypoxia leads to hypocapnia, which can ultimately lead to respiratory alkalosis.5 Although there are multiple hypotheses for these mental health changes, there does seem to be an agreement in the literature that they do exist.

Luckily, in my experience, my body adjusted over the span of a few weeks. My HR began to trend down towards my normal resting rate in the 70’s and my anxiety levels also dropped. I started doing more challenging hikes, traveling and enjoying the many natural wonders Colorado has to offer. Just being in amazing places like Rocky Mountain National Park and the San Isabel National Forest had a profound impact on my mood as I soaked in the scenery. I took pictures, breathed fresh mountain air and spotted wildlife, which all served to distract me from my worries. The mood-altering benefits of exercise also likely played a role in my increasing happiness. I grew to love the state and as soon as I felt fully adjusted, it was time to go back to New Jersey. Back to sea-level, outrageous humidity and hotter weather.

References:

  1. Naeije R. Physiological adaptation of the cardiovascular system to high altitude. Prog Cardiovasc Dis. 2010 May-Jun;52(6):456-66. doi: 10.1016/j.pcad.2010.03.004. PMID: 20417339.
  2. Richalet JP. Physiological and Clinical Implications of Adrenergic Pathways at High Altitude. Adv Exp Med Biol. 2016;903:343-56. doi: 10.1007/978-1-4899-7678-9_23. PMID: 27343107.
  3. Bian SZ, Zhang L, Jin J, Zhang JH, Li QN, Yu J, Chen JF, Yu SY, Zhao XH, Qin J, Huang L. The onset of sleep disturbances and their associations with anxiety after acute high-altitude exposure at 3700 m. Transl Psychiatry. 2019 Jul 22;9(1):175. doi: 10.1038/s41398-019-0510-x. PMID: 31332159; PMCID: PMC6646382.
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Joseph Albanese is a second-year physician associate (PA) student attending Drexel University in Philadelphia, Pennsylvania. He grew up in Hillsborough, NJ. He got his BA from The Pennsylvania State University as a double major in Psychology and Film Studies. Prior to PA school he worked as a mental health associate in an inpatient psychiatry setting with actively suicidal and homicidal patients. The acuity of the unit he worked on made him appreciate the benefits of talk-therapy, but also the crucial role of medicine in many cases. This led him to apply to PA school. In his free time Joe loves to travel (favorite places include Japan, Iceland, Glacier National Park, and now Colorado). He also enjoys photography, playing sports, and eating new foods.

Information and discussion for visitors and residents in the mountains