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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

High Altitude and Pre-Eclampsia

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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.

Acclimation, Altitude Science, Athletic Training, Backcountry, Backpacking, COVID-19, Health, High Altitude, High Altitude Training & Fitness, Mountaineering, Pandemic

Return to High Altitude after Recovery from Coronavirus Disease 2019

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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.

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!

Acclimation, Altitude Science, Health, High Altitude, Mental Health, Mountaineering

Anxiety at Altitude

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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.
  4. Kious BM, Bakian A, Zhao J, Mickey B, Guille C, Renshaw P, Sen S. Altitude and risk of depression and anxiety: findings from the intern health study. Int Rev Psychiatry. 2019 Nov-Dec;31(7-8):637-645. doi: 10.1080/09540261.2019.1586324. Epub 2019 May 14. PMID: 31084447.
  5. Roth WT, Gomolla A, Meuret AE, Alpers GW, Handke EM, Wilhelm FH. High altitudes, anxiety, and panic attacks: is there a relationship? Depress Anxiety. 2002;16(2):51-8. doi: 10.1002/da.10059. PMID: 12219335.

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.

Altitude Science, Exposure, Health, High Altitude, Mountaineering

Nail Abnormalities at High Altitude

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With summer just around the corner, more people will be hitting the mountains for some high altitude hikes and 14ers. There have been numerous anecdotal findings of mountaineers with changes to their fingernails after ascending the world’s tallest peaks, with the most common abnormalities being Mees’ lines, Muehrcke’s lines, and Beau’s lines. While the peaks in Colorado do not compare to those of the Himalayas, there is always a chance, albeit very low, that you may notice some changes to your nails after a high altitude expedition.

Both Mees’ lines and Muehrcke’s lines are types of leukonychia, which means “white nails”. Mees’ lines present as a single horizontal white band, sometimes multiple, located in the nail plate and are non-blanching. Throughout history, Mees’ lines have been associated with drug toxicity, such as from arsenic or thallium.4 Additionally, there are many systemic diseases that have been associated with Mees’ lines in which the body is experiencing high amounts of stress, such as with myocardial infarction, sickle cell crisis, and tuberculosis.4

Mee’s lines

One case report, “Mees’ lines in high altitude mountaineering”,  by Avinash Aujayeb details how a 27-year old man developed Mees’ lines after he traversed high altitudes in the Pakistani Karakorum range, attempting to scale a summit of 7031 meters.1 He acclimated to altitude at a camp located at 4000 meters,  and stayed for a total of 21 days. No medications were used for acclimatization. In his attempt to reach the summit, he became extremely fatigued and hypothermic, and turned around at 6900 meters. Upon return to sea level, he lost about 17 pounds of weight. Six weeks after his expedition, he developed non-blanching horizontal white lines on his nails, consistent with Mees’ lines. The lines eventually moved distally and completely disappeared. While the paper does not go on to hypothesize the cause of this man’s development of Mees’ lines, it seems reasonable that they appeared due to the stress the man endured as evidenced by his need to turn around early from fatigue and hypothermia, and likely hypoxia given the extreme altitude.

Muehrcke’s lines present as a pair of horizontal white bands located in the nailbed, the skin beneath the nail plate, making them blanchable (unlike Mee’s lines which are located within the nail itself). Muehrcke’s lines usually present on the 2nd, 3rd and 4th fingers, and typically spare the thumb. Historically, these lines are most associated with hypoalbuminemia as seen in a protein-losing condition of the kidney called nephrotic syndrome.4 They have also been found in disease states of systemic immunosuppression, such as in HIV, where the metabolism of the body is stressed and has decreased ability to make proteins. 4

Muehrcke’s lines

The discovery of Muehrcke’s lines was first published in the British Medical Journal in 1956 by Robert C. Muehrcke.4  In the paper, he details a study in which he compared 750 adult patients and healthy volunteers who had normal serum albumin against 65 patients known to have chronic hypoalbuminemia.  He saw that the pair of white horizontal lines were only in those with the chronic hypoalbuminemia, most specifically those with a serum albumin below 2.2 g/dL.4 Once these patients were treated and their albumin concentrations increased, the lines disappeared after a few weeks. He thought the findings suggested that Muehrcke’s lines were from an albumin deficiency due to poor nutrition.

In a letter to the editor of High Altitude Medicine and Biology, authors Windsor, Hart, and Rodway describe the presence of Muehrcke’s lines on Mount Everest after a 38 year old with no significant medical history noticed their appearance a few weeks after he had returned to sea level.3 There were two parallel horizontal lines under the nails of his 2nd, 3rd, 4th, and 5th digits, sparing the overlying nail. They believe the development of these nail findings were indeed from hypoalbuminemia , however do not believe it was from a nutritional deficiency as Muehrcke first described, because the climber had been healthy throughout his expedition and he maintained good nutrition.3 They attribute the findings to peripheral edema, which is a common finding in high altitude mountaineers. With this edema, fluid levels in the tissues increase. The authors believe this may have inhibited the growth of the nailbed, which then resumed with return to sea level.

Another nail finding from high altitude mountaineering is called Beau’s lines, which are an indented groove across the span of the nail horizontally, beginning at the base of the lunula. The lines result when nail formation is temporarily halted during episodes of stress, and usually present several weeks after the stressful incident.2 They are generally caused by local trauma to the nail, extreme temperatures, and toxicity from chemotherapy.4

Beau’s lines

There was a prospective study completed by authors Bellis and Nickol in High Altitude Medicine and Biology where the study participants were completing a research expedition in eastern Nepal in April and May of 2003.2 The maximum altitude reached varied from 5,142 to 6,476 meters and the length of stay of each individual also varied. The study found Beau’s lines developed in 1 out of 56 participants at 4 weeks, however by 8 weeks, 17 out of the 52 (or 33%) developed Beau’s lines. The authors hypothesized that the changes were possibly due to the hypoxic as well as hypobaric environment which could diminish the activity of the nail matrix. However, they did acknowledge the fact that there were other factors that could have resulted in the Beau’s lines, such as extreme cold conditions and possible injuries to the fingers due to the nature of the work of the researchers. No participants reported frostbite or any damage to the hand, however at night temperatures dropped as low as negative 20 degrees Celsius.

Clubbed fingers

These nail abnormaltities are less likely to be found during expeditions within the United States unless hiking in Alaska, which has Denali, the tallest peak in the US at 20,310 meters. Outside of Alaska, the tallest peak is Mount Whitney in California, which pales in comparison at 14,505 meters. Most of the case reports completed on these nail findings were from several week-long expeditions in the Himalayas. However, condition you may already be aware of is clubbing of the fingers. This presents as a bulbous enlargement of the fingertips caused by chronic hypoxia. During my five-week visit here, I have anecdotally heard from two different Summit County residents that they have many healthy and young friends with clubbed fingers. Unfortunately, I was unable to find any research on the prevalence of clubbed fingers among individuals living at high elevations, but I believe it is something that deserves to be looked into deeper. 

References

  1. Aujayeb, A. (2019). Mees’ lines in high altitude mountaineering. BMJ Case Reports, 12(3), 1. doi:10.1136/bcr-2019-229644
  • Bellis, F., & Nickol, A. (2005). Everest Nails: A prospective study on the incidence OF Beau’s lines after time spent at high altitude. High Altitude Medicine & Biology, 6(2), 178-180. doi:10.1089/ham.2005.6.178
  • Windsor, J. S., Hart, N., & Rodway, G. W. (2009). Muehrcke’s lines on Mt. Everest. High Altitude Medicine & Biology,10(1), 87-88. doi:10.1089/ham.2008.1079
  • Zaiac, M. N., & Walker, A. (2013). Nail abnormalities associated with systemic pathologies. Clinics in Dermatology,31(5), 627-649. doi:10.1016/j.clindermatol.2013.06.018

Makenna Schmidgall is a second-year physician assistant student at the Midwestern University Physician Assistant Program in Glendale, Arizona. She grew up in Gilbert, AZ, but left her desert home to attend New York University in the Big Apple where she earned a bachelor’s degree in Global Public Health/Biology. During her junior year of college, she began working as an ER scribe in multiple emergency departments of the Mount Sinai Health System in New York, NY. She enjoys gardening, hiking and playing with her new Labrador retriever puppy “Piper”.  

Acclimation, Altitude Science, COVID-19, Health, High Altitude, Pandemic, Technology

HAST: the High Altitude Simulation Test

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Maybe you are planning to ski or hike a 14er. Taking a leap of faith and moving out of the city and into the mountains. Or maybe it’s just taking a flight in a pressurized airplane cabin. Maybe you just spent 10 days in the hospital with rib fractures and are now anxious to return home to 9000 feet in elevation. You could be an individual that is worried you will miss out on that incredible work retreat to a beautiful mountain sanctuary due to your apprehension about your Chronic Obstructive Pulmonary Disease COPD.

Wouldn’t it be nice to know how you would respond to altitude prior to reaching your destination, so you could be better prepared?   

There is such a test. It is called HAST: High Altitude Simulation Testing. This test can simulate 8000 feet in elevation, in the safety of a doctor’s office at lower elevations.  HAST is a diagnostic test that can effectively calculate an individual’s supplemental oxygen needs prior to traveling to high altitude. The California Thoracic Society recommends that individuals diagnosed with severe airway disease, cystic fibrosis, neuromuscular disease, kyphoscoliosis, individuals who have been hospitalized for acute respiratory illness within the last 6 weeks, individuals with previous air travel intolerance, COPD, or cerebral vascular disease would benefit from a HAST prior to traveling to altitude (Corby-DeMaagd, 2020).

This test is performed by obtaining a patient’s blood pressure, heart rate/rhythm, and oxygen saturation at baseline. Once baseline vitals are complete the patient is monitored while breathing in a mixture of gases containing approximately 15.1% oxygen, simulating the FiO2 at an elevation of 8,000 feet. A patient;s oxygen saturation levels can be recorded by an arterial line (large IV in the wrist) monitoring the patient’s arterial blood gasses, or by an oxygen monitor attached to the patient’s finger or on a nasal cannula. This allows the physician to screen for hypoxia, arrhythmias, or other significant symptoms. If the patient becomes symptomatic, the oxygen levels are reassessed while providing the patient with supplemental oxygen to identify exactly how much oxygen would be needed to keep the patient comfortable at a higher altitude.  This test on average takes 2 hours to complete (Corby-DeMaagd, 2020).  

According to Mark Fleming, the supervisor of the Pulmonary Physiology Services at National Jewish Health in Denver, Colorado, for an individual to receive a HAST they would need a referral from a provider.  National Jewish Health is one of the few facilities in the nation that provides this service. Most patients that request this test in the state of Colorado are pilots that have had a recent ailment and need a work clearance prior to being exposed to the airplane cabin pressure, those that are interested in relocating to the mountains, planning on a high-altitude vacation and currently on supplemental oxygen, or those with a history of pulmonary embolism or lung resections.  Fleming states that they are anticipating an increase in High Altitude Simulation Testing being needed for patients that have recovered from COVID-19.  

However, there may be a vulnerable population that is not receiving the benefit of this test. Newborn babies that are delivered at 5000 feet but must return home to 8500 feet. Those that have experienced a chest trauma and must return home to altitude. Or maybe even those that have experienced an invasive surgery that involved the lungs, chest, spine, or abdomen.  These are all individuals that would benefit from knowing if they would need oxygen once they return back to elevation. Hopefully as people continue to heal from COVID the word will spread that this test is available to the public for those that are concerned about journeying to altitude.

Amanda Bergin is currently in her second year of her Family Nurse Practitioner Program for the Rural and Underserved at Regis University. She is a member of the class of 2021 and will be graduating in August. She started her medical career as a corpsman in the United States Navy and after the completion of her service, she returned to school to complete her bachelor’s degree of Science in Nursing at the Denver School of Nursing.  Amanda currently lives in a rural mountain community with very limited healthcare, and dreams to help her community start a family practice clinic. In her free time, she loves spending time with her family, fishing, camping and raising dairy goats.

Acclimation, Alcohol at Altitude, Altitude Science, Athletic Training, Health, High Altitude, High Altitude Training & Fitness

Effects and management of altitude on pre-existing cardiac conditions

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As someone with family history of cardiac illness and a personal history of both supraventricular tachycardia (SVT) and high blood pressure, I have always tried to manage my modifiable risk factors through a healthy diet and exercise. Over the past year or two, most of my exercise has been in the form of running, since it is more conducive to the schedule of a physician assistant student during COVID restrictions. However, in the past I have been a regular rock climber and soccer player. Through my own personal experience I have noticed that when I stick to a healthy diet, not giving in to my sweet tooth, and keeping up with regular exercise that my episodes of SVT are less frequent. However, recently I traveled up from Denver, Colorado for a rotation at the Ebert Family Clinic in the mountain town of Frisco, and in the first two days at high elevation experienced an episode of SVT for the first time in nearly 6 months.

In my first day at over 9000 feet, I experienced a slight headache after a full day seeing patients, but did not think much of it or even consider it to be a side effect of the altitude. I spent my first day at altitude without exercising but I decided that on day two I had acclimated enough to go for a short run. Midway into my run, and shorter of breath than I expected, I experienced an episode of SVT that lasted for about 2-3 minutes and forced me to sit for several more minutes to catch my breath. Catching my breath afterward took slightly longer compared to my normal episodes, which made sense to me given the reduced availability of oxygen, but it did lead me to wonder if the altitude was a contributing factor to precipitating an episode of SVT after several months without one.

About one year ago, High Altitude Health interviewed Dr. Peter Lemis, a cardiologist in Summit County, Colorado about his thoughts and findings practicing cardiology at elevation. The discussion included questions about arrhythmias at altitude and Dr. Lemis stated that “studies have shown that cardiac arrhythmias are increased initially, but people become acclimated after about 3-5 days and the risk returns to baseline”. However, Dr. Lemis also states that the studies may not have been conducted for a sufficient length of time due to his personal experience of seeing a great deal of both atrial fibrillation and atrial flutter in his own practice. He states that the hypoxia leads to an increase in arrhythmias, but that for atrial arrhythmias, patients may experience relief from them when placed on nocturnal oxygen. Dr. Lemis also notes that “many people have central apnea during sleep at altitude due to the brain’s blunted response to high CO2 and low O2”, which can be a risk factor for the development of heart problems. The use of Diamox can be helpful in acclimating to altitude due to making “your blood a little acidotic which increases your respiratory drive” and the use of nocturnal oxygen can also help with acclimatization to altitude.

In March of 2021, the journal of Frontiers in Medicine published an article titled Nocturnal Heart Rate and Cardiac Repolarization in Lowlanders with Chronic Obstructive Pulmonary Disease at High Altitude: Data from a Randomized, Placebo-Controlled Trial of Nocturnal Oxygen Therapy by Maya Bisang, Tsogyal Latshang, Sayaka Aeschbacher, et al. This study compared COPD patients at altitude with and without oxygen therapy at night and COPD patients not at altitude without oxygen looking at QT interval, heart rate, and SpO2. The results of the study found that without oxygen use at altitude patients experienced an increase in heart rate, a lengthened QT interval, and naturally, a lower SpO2 at night compared to those at altitude who utilized oxygen and those that were not at elevation. This study was observing patients that had COPD. The results could potentially be relevant to younger patients without COPD, like myself, but would need further research.

I also looked into information regarding high blood pressure at altitude and found some helpful information from the Institute for Altitude Medicine. They state that for patients visiting altitude with a history of hypertension (HTN), even if it is well controlled on pharmacotherapy, may still experience a temporary increase in blood pressure at altitude. “One explanation for this is due to the higher levels of adrenaline or stress hormones in your body due to lower oxygen levels,” as they describe. Their research has also found that increases in blood pressure at altitude generally return to base line after 1-2 weeks. In order to help manage HTN at altitude they recommend ensuring that blood pressure is well controlled at sea level, reducing salt from the diet, remaining on any medications for HTN, checking blood pressure at altitude, and observing for symptoms of HTN that would need medical care such as headache, dizziness, chest pain, or shortness of breath.

Through my research regarding effects of altitude and the possible role of them in my recent episode of SVT, I have found that altitude can have several different impacts on cardiac function that definitely could have played a role in triggering an episode. Coming to altitude, I likely had an increase in blood pressure to compensate for the reduced availability of oxygen that increased strain on my cardiac muscle. I may have had EKG changes overnight related to decreased responsiveness of my central nervous system to CO2 levels. I also had an increased risk of arrhythmia based on coming to elevation. It is possible that any or all of these effects could have contributed or triggered my episode of SVT. Thankfully, after almost a month of staying at altitude I have adjusted more and have not experienced another episode. I have continued to exercise after a short break to allow more time to acclimate, but I have not pushed myself as hard.

I have learned that no matter how healthy you are or what your risk factors are, there are important steps to stay healthy when coming to altitude. If possible, at least one day at an intermediate altitude can help your body begin to adjust to the change. Drinking plenty of water to stay hydrated and avoiding alcohol can lead to a more comfortable stay and more rapid acclimatization. Meeting with a healthcare provider could also allow you to start a prophylactic course of Diamox or supplemental oxygen use. Utilizing a personal pulse oximeter allows you to monitor your SpO2 level and determine if nocturnal supplemental oxygen could be useful as well. If you have risks for cardiac conditions or already have a diagnosis of heart disease, these recommendations are even more important to prevent poor outcomes including myocardial infarctions due to reduced oxygen availability. Finally, it is important to remember that traveling to altitude is not a benign choice and a discussion with your healthcare provider is important to be sure that your personal risks are appropriately managed so that you can enjoy your trip to high elevation.

Justin Frazier is currently in his second year of PA school at Red Rocks Community College in Arvada, CO, a member of the class of 2021 graduating in November. He attended Appalachian State University in Boone, NC for his undergraduate degree majoring in Cell and Molecular Biology with a double minor in Chemistry and Medical Humanities. During his undergraduate he worked for two and a half years as a CNA at a local nursing and rehabilitation facility. After completing his undergraduate degree he started working as an EMT for almost a year before transitioning to work in a family medicine office where he worked as a Medical Assistant until starting PA school. He enjoys working in a primary care setting where he can help to keep people healthy throughout their lives and wants to pursue a career in pediatrics after graduating this year. He enjoys hiking, camping, rock climbing, and spending time with his wife and young son.

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. 

Acclimation, Altitude Science, Athletic Training, Doc Talk, Health, High Altitude, High Altitude Training & Fitness

Doc Talk: a Californian Interviews South America’s Altitude Experts Dr. Gustavo Zubieta-Calleja & Dr. Natalia Zubieta-Urioste

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As a California native, I was unfamiliar with the impact high altitude had on the human body. I had only briefly learned about it in my exercise physiology course during my undergraduate studies. At best, I understood the difference between acclimation and acclimatization, and the advantages of living at high altitude for exercise performance. What I never really understood was how much all that information would mean to me when the next chapter in my life took me to Colorado.

In hindsight, I did everything against the book after moving to Colorado because I wanted to stay active and enjoy as much as I could before school started. I continued my daily workout routines, went whitewater rafting, and had a few drinks. More importantly, I was not hydrating adequately because I didn’t know you could drink straight from the tap. So… what happened? The end of my workout routines was met with dizziness and lightheadedness. On some occasions, I would notice my fingertips turn purple. My sleep would be interrupted by episodes of apnea. Though these symptoms did resolve eventually, they could have been prevented if I had followed a few simple rules.

As a student at Ebert Family Clinic in Frisco, CO at 9000′ alongside high altitude expert Dr. Christine Ebert-Santos, I had the opportunity to learn more about high altitude illness, interviewing Dr. Gustavo Zubieta-Calleja and his daughter Dr. Natalia Zubieta-Urioste from the High Altitude Pulmonary and Pathology Institute (IPPA) in La Paz, Bolivia. Dr. Zubieta has been practicing internal medicine and pulmonology at his father’s high altitude clinic since 1981. During our interview, we discussed their most recent publication Acute Mountain Sickness, High Altitude Pulmonary Edema, and High-Altitude Cerebral Edema: A view from the High Andes. When asked about what inspired him to follow his father’s footsteps, he replied, “My father created the first high altitude clinic in the world and that was a great inspiration to me. He did it with a visionary idea because at the time in 1970, nobody thought about putting a clinic like that out. I was born at home because my father was a physician and he preferred to deliver us. We [me and my siblings] were all delivered at home and then that home became the clinic in 1970. The clinic turned 50 this past year and our father also became our mentor at this clinic.”

The article addresses the two types of adaptation: genetic and physiologic. In his publication, he primarily addresses the physiologic mechanisms that must occur for one to adapt to the hypobaric environment that is high altitude. During my research, however, I found that Tibetans experienced the fastest phenotypically observable evolution in human history partially because their community has spent centuries living at that altitude. When I discussed my findings with Dr. Zubieta, he stated that much still needs to be done to determine if the Andean population has made similar genetic adaptations. He was optimistic about the studies to come as he strongly believes that all organisms must adapt if they want to survive and reproduce at high altitude. According to Dr. Zubieta, change is inevitable. He believes that the energy expenditure from the body’s initial response to the hypobaric environment is too costly forcing  the human body to adapt in a manner that will render it more effective in managing this energy expenditure via metabolism at the mitochondrial level.

We also discussed the different attitudes towards the use of acetazolamide, or Diamox. In the United States, acetazolamide is a diuretic commonly used to prevent the onset of acute mountain sickness. Dr. Ebert Santos highly recommends the use of acetazolamide to prevent acute mountain sickness while Dr. Zubieta and other providers reluctantly use it due to the risk of dehydration. A 125-milligram dose is adequate and unlikely to cause side effects, which Dr. Zubieta said can include fatigue, nausea, vomiting, abdominal pain, and diarrhea. (Most visitors to Colorado taking acetazolamide only experience tingling of the hands and feet and a flat taste to carbonated beverages.) Dr. Zubieta justifies his avoidance of acetazolamide as an “opportunity” to treat the patient’s underlying issues, stating that ascension to high altitude is a testament of one’s cardiovascular fitness and the use of acetazolamide compromises adaptation to high altitude. At the IPPA they have uncovered underlying conditions that explain their patients’ symptoms at altitude and resulted in better health upon returning to sea level.

 The Wilderness Medical Society has established a risk stratification for acute mountain sickness which further supports Dr. Zubieta’s infrequent use of acetazolamide. The society’s 2019 guidelines suggest that individuals with no history of altitude illness and ascending to an elevation no greater than 2,800 meters, and individuals who take more than two days to arrive at an altitude between 2,500 and 3,000 meters are considered low risk and the use of acetazolamide is not recommended. Instead, Dr. Zubieta recommends Ibuprofen and Acetaminophen for headache relief and oxygen in those with persistent symptoms of acute mountain sickness. He also emphasizes that oral hydration can be important in preventing high altitude illnesses.

Overall, Dr. Zubieta’s perspective on high altitude is fascinating. During my master’s program, I learned a systematic way to treat patients using guidelines or criteria backed by years of evidence that helps you, the provider, make an informed decision on a patient’s particular case. Dr. Zubieta reinforced the importance of treating each patient’s case individually to determine the underlying cause, rather than suggesting acetazolamide to everyone who doesn’t want to deal with acute mountain sickness. As for myself, seeing how physicians in other countries approach certain illnesses has definitely made me think twice about how to approach high altitude illness.

To learn more about Dr. Gustavo Zubieta and his clinic, you can visit his website at: https://altitudeclinic.com/

Born and raised in Northern Orange County of California, Michael Le is a second-year physician assistant student at the Red Rocks Community College Physician Assistant Program in Arvada, CO. Michael attended California State Polytechnic University Pomona otherwise known locally as Cal Poly Pomona where he earned his bachelor’s degree in Kinesiology. Shortly after, he worked as an EMT for Lifeline Ambulance, and physical therapy aide and post-anesthesia care unit technician at Fountain Valley Regional Hospital in Fountain Valley, CA. In his free time, Michael likes to cook and breed show rabbits.