Welcome, everyone, and thank you for joining us on today's session on high-altitude and high-altitude syndromes. I'm Dr. Bissonnette. I'm one of the EM-IM critical care faculty at Henry Ford Health in Detroit, Michigan. And this is the QR code for the lecture. I'll leave that up there just for a second. So today we hope to describe the pathophysiology of high-altitude syndromes, but also how to recognize, prevent, and treat those symptoms. To start, we'd like to use the case of a 45-year-old healthy male. He is planning to climb Mount Kilimanjaro in a five-day period, starting at 1,800 meters. He's physically fit, runs frequently, and recently completed a marathon. He wants your recommendation for the best way to prevent acute mountain sickness and high-altitude cerebral edema during his climb. Great. So what I hope to talk about today is our evidence-based recommendations from the Wilderness Society of America. We'll talk about how the athletic training is not generally thought to be protective, how there is evidence for hypoxic tents, though it is not as robust as the evidence for preventive medications, how remaining at intermediate altitudes is a very good idea, though typically we like to remain at slightly higher than 1,800 meters and usually for more time than one day. There is evidence for both acetazolamide as well as dexamethasone, but the side-effect profiles typically favor acetazolamide over dexamethasone, and we'll go through that through the presentation. So who develops high-altitude syndromes is typically those who are not acclimatized to high altitude, who rapidly ascend, and typically reach a final elevation of over 2,500 meters. Now that said, we shouldn't rule out high-altitude syndromes just because the altitude is less than that, as both acute mountain sickness and high-altitude pulmonary edema have been seen as low as 2,000 meters. Why do we develop this? Well, the reason I love high-altitude illness is it brings us back to the basics of pulmonary physiology and the alveolar gas equation. One of the main misnomers at altitude is that FiO2 decreases with elevation, when in fact it remains 21% throughout our entire atmosphere. What of course does decrease is our atmospheric pressure, and that will lead to less pressure pushing on the oxygen molecules at elevation. This pressure decreases, of course, because at elevation we have far fewer air molecules chemically standing on top of each other than at lower elevations. You can imagine that taking 21% of this relatively less dense air will lead to far fewer oxygen molecules for the alveoli as compared to 21% of the oxygen molecules closer to sea level, thus contributing to hypoxia at elevation. Some people like to quantify this elevation in what's called an equivalent FiO2. It's a theoretical construct where they will solve the alveolar gas equation for a given pressure that is known to exist at a certain elevation. They'll then use normal values for the remainder of the variables and calculate the PaO2. Having calculated that PaO2, they will then back solve the equation for an equivalent FiO2, this time returning atmospheric pressure to the 760 that remains at sea level, and otherwise using the same normal constants they did on the previous calculation. Doing this will give you an equivalent FiO2 that someone at sea level would have to breathe to approximate the hypoxic conditions that the alveolus experiences at altitude. It's more of a theoretical construct. It's often called normal-baric hypoxia, but it's a helpful reference point for what the body's experiencing in terms of something that we better understand than atmospheric pressure. Again, it is a misnomer, though. I just want to reiterate that we have 21% FiO2 throughout all elevations in our atmosphere, only pressure decreases. Of course, as our air pressure decreases with elevation via the alveolar gas equation, so too must our PaO2, and of course with less PaO2, we'll have less of a diffusion gradient for oxygen to go from the alveolus to the capillary, leading to hypoxia, compensatory hyperventilation, and reduction in our arterial carbon dioxide. However, the diffusion gradient between capillary and alveolus for carbon dioxide remains brisk because there's only 0.03% carbon dioxide in the atmosphere that we breathe, and so respiratory alkalosis still easily develops at altitude. Now, at sea level, we tend not to think very hard about Dalton's Law of Partial Pressures in most instances, and this is because we have very robust FiO2 and pressure atmospheric to take care of the oxygen that's displaced by saturated vapor pressure in the airways, and then by the carbon dioxide that exists in the alveolus as it diffuses from the capillary. At sea level, we typically have this simplified to about 150 for those on room air, and with normal values, the oxygen out will simplify to about 50, leaving a very robust PaO2 of about 100. When we have less atmospheric pressure, though, the oxygen that's displaced, both by water vapor as well as carbon dioxide, starts to play an increasingly important role and can lead to critical hypoxia. To illustrate this, you can see the barometric pressures decreasing with various elevations, but you'll see that water tension actually stays relatively constant, and that's because unlike boiling point, water vapor pressure does not change with elevation, and this is a slight oversimplification that ignores hyperventilation, but carbon dioxide stays relatively stable as well at altitude. So you can see as we have less total pressure with elevation, but we continue to subtract this constant 97 via Dalton's Law of Partial Pressures, we have progressively less remaining pressure that we can then multiply by 21% to get our PaO2, leading to low arterial oxygen saturations and contents. To further highlight just how important hyperventilation is at altitude, you can see this graph here where somebody who is able to mount a normal hyperventilatory response will not cross critical thresholds for hypoxia. Here I'll just take the example of 60 for PaO2 until past 10,000 meters, whereas somebody who cannot mount that hyperventilation and stays at a PCO2 of 40 will cross that threshold at 8,000, and someone who remains frankly hypercarbic at altitude because of a chronic lung disease or neuromuscular weakness, some other illness, they can cross that threshold at 5,500 feet. And of course, this isn't the full story, because PaO2 is not linearly related to our oxygen saturation, of course, because of the oxyhemoglobin dissociation curve. We know at altitude we will hyperventilate, and via the Bohr effect we will drop our PCO2, increase our pH, and we will left shift our oxyhemoglobin dissociation curve. So for any given PaO2, we will have a higher oxygen saturation. To illustrate just how important this is, you can see various saturations at various altitudes, and with a normal PCO2 of 40. You can see even if we decrease our PCO2 minimally to 35, there are significant changes in the arterial oxygen saturation, and you can see it as a nonlinear response. It has increased to delta as we ascend, and that is again because of the oxyhemoglobin dissociation curve. By the time you get to 8,000 feet, it can be the difference between a likely intolerable SAT and a potentially tolerable saturation. And of course, maintaining our oxygen saturation is really one of the only things we can do to maintain our arterial oxygen content at altitude, because it takes two to three weeks to increase our functional hemoglobin at altitude, and of course our dissolved oxygen is all but negligible. So the body must maintain the arterial SAT to maintain the oxygen content of the blood, and in addition, the only other thing we can do is increase our cardiac output. Going from top to bottom, there are multiple changes that happen at altitude. The first from the top would be the increase in cerebral blood flow. This occurs via a general increase in cardiac output to the whole body, but also locally due to regional cerebrovascular hypoxic vasodilation. The increased blood flow here is thought to play a role in both acute mountain sickness as well as high-altitude cerebral edema. I've talked already about the hyperventilation that occurs, and this is done to counteract alveolar hypoxia. I will talk to you as well about how pulmonary artery pressures increase at altitude. We've talked about cardiac output increasing, but I've not yet said that that happens primarily due to an increase in heart rate, as our stroke volume actually decreases at elevation. This happens, number one, because of less diastolic filling time with that elevated heart rate, and also via a diuresis, which will drop our plasma volume, as I'll discuss on the next slide. Over longer periods of time, we will increase our red blood cell count and our capillary density, which will help us increase our arterial oxygen content, and this will also increase our blood viscosity, which can put us at risk for clotting. The diuresis at altitude is probably no surprise to any intensivist. Of course, at the proximal convoluted tubule, we will absorb our sodium bicarbonate. In the face of a respiratory alkalosis, we will instead stop absorbing here. We will secrete that through the urine, and we will metabolically compensate for our respiratory alkalosis. Of course, acetazolamide works at the same pathway and in much the same way, and thus we'll see that used as both a preventive as well as a treatment medication for acute mountain sickness and high-altitude cerebral edema, in that it allows us to mount that all-important hyperventilation that we've already talked about without the significant deleterious effects of a markedly elevated pH. Moving from the pathophysiology now into the syndromes, I'd like to start with acute mountain sickness. Its epidemiology is difficult to quantify because it has a wide overlap with multiple syndromes, including things like simple hangovers, but it's thought to occur at approximately 10 to 25 percent of patients that exist at 2,500 meters, typically mild symptoms at that elevation. As we go higher, it is much more frequent, and it is much more severe. The pathophysiology is much less well understood as compared to high-altitude cerebral edema, but it's thought to be due to hypoxic cerebral vasodilation, which, very similar to migraine, can activate the trigeminal vascular system and lead to headache. There's also a thought that there can be an increased permeability of the blood-brain barrier, as many patients with severe acute mountain sickness have been seen to have cerebral edema on MRI, very similar to patients that have high-altitude cerebral edema. The cardinal symptom is headache, and you actually cannot make the diagnosis of acute mountain sickness without headache. That's often associated with anorexia, nausea, dizziness, malaise, and sleep disturbance. The time course is relatively rapid, usually developing within 6 to 12 hours, and symptoms go away relatively quickly as well, usually resolving within about one to two days with treatment. However, untreated, it can progress to high-altitude cerebral edema. High-altitude cerebral edema is much more rare, and it happens at higher elevations, usually over 4,000 meters. It's actually the disease that happens at the highest elevations of all those that we're going to talk about today. It has the same symptom complex as acute mountain syndrome, excuse me, acute mountain sickness, but its pathophysiology is better understood. It is known to progress from an intracellular cytotoxic edema, progressing to a vasogenic edema with protein extravasation and red blood cell extravasation. This in conjunction with the increased blood flow from cerebral vasodilation leads to cerebral edema, microhemorrhages, and given the increase in hyperviscosity that we talked about previously, you can also see thromboses in the brain. The final common pathway of all of this is brain herniation and death if untreated. The most common spot affected in high-altitude cerebral edema is the corpus callosum and specifically the splenium of the corpus callosum. Here you see T2 hyperintensities in a patient with HACE that have resolved at five-week follow-up. As we said, the symptom complex is the same as acute mountain sickness. What is different is the presence of neurologic signs. These are typically truncal ataxia, altered level of consciousness, and mild fever. Unlike acute mountain sickness, the absence of headache does not rule out high-altitude cerebral edema, and it's important to note how rapidly progressive it is, potentially developing coma within 24 hours. It is thought to exist along a continuum with high-altitude cerebral edema, with mild, moderate, and severe acute mountain sickness progressing then to high-altitude cerebral edema. And of course, at any point, these syndromes can be overlaid by high-altitude pulmonary edema, although typically this exists on the two-plus day timeframe, like high-altitude cerebral edema, rather than more rapidly starting like AMS. To delineate AMS from HACE, headache and vomiting that are poorly responsive to therapy can help suggest HACE, but it's really the lack of signs on acute mountain sickness as compared to their presence with HACE. Again, the timeframe is helpful, with HACE starting usually greater than or equal to two days at altitude. And there are important differential diagnoses for both of these conditions, but specifically for high-altitude cerebral edema, stroke, psychosis, intoxication, carbon monoxide, poisoning, hyponatremia, hypoglycemia, hypothermia, and hypoxic encephalopathy are important things to rule out, and someone at altitude is generally at higher risk for almost all of these as compared to someone at sea level. Risk assessment is really limited to history and physical. Multiple physiologic parameters and hypoxic ventilatory responses have been tested and are poorly discriminatory. It's really the final elevation, rate of ascent, and history of previous altitude illness that is going to inform your risk stratification. Though the literature is somewhat mixed, it's generally thought that good physical fitness is not protective, although it does help you estimate the likelihood that someone will successfully summit by estimating their ability to cope with the loss of exercise capacity with altitude. A full description of the grading classification or risk stratification as displayed by the Wilderness Society of Medicine is somewhat beyond the scope of this talk. However, I put this up here only to highlight again that it's really the history of previous altitude illness, the rate of elevation change per day, and the final elevation that informs your risk stratification of low, moderate, and high. Graduation can include acclimatization strategies, which I'll talk about on the next slide, but gradual ascent is recommended with a 1B level of evidence from the Wilderness Society of Medicine, who did follow the CHEST's recommendation on grading recommendations for these. We want to have our sleeping elevation change less than 500 meters per day, and it's very much the sleeping elevation that matters, as opposed to the awake change in elevation during the day. If terrain or logistics prevent this 500 meter per day change, we would like to use rest days, which are defined as days in which we do not change our sleeping elevation, to try to bring the average rate of ascent for our hike to less than 500 meters per day over the course of the hike. It's recommended that rest days, again defined as no change in sleeping elevation, occur every three to four days, and if we're going to exceed this, like the patient in our case example, prophylactic medication should be considered. Acclimatization strategies before ascending include pre-acclimatization, which can consist of normobaric or hypobaric hypoxia. These things show mixed results, but it's generally thought that longer exposures, closer to the time of the ascent, are more protective. Hypoxic tents, as we talked about, do have some evidence behind them. However, they're used for long periods of time, typically weeks, and hypoxic sleeping conditions are known to decrease sleep efficacy, specifically deep sleep, so chronic sleep deprivation or poor sleep quality over time has to be weighed against the possible benefits of pre-acclimatization. Stage ascent is typically recommended, though we like to go typically slightly higher than the patient in our case example, 2,000 to 3,000 meters, and longer, for greater than or equal to one week. While we're at that intermediate altitude, we can day climb or hike even higher, but return to that same elevation again for sleeping. We want to do this as close as possible to the time of planned ascent, and if we can, spending one night at intermediate altitude before getting to our staged ascent altitude is recommended. Preventative medications include ibuprofen, which is not disease-modifying, and acetazolamide for moderate to high-risk travelers, like our case example. There are multiple side effects of acetazolamide that should be tested for before someone ascends in order to make sure they do not confuse this for acute mountain sickness. The other thing is there is a small cross-reactivity with sulfa. This should obviously be tested for before the patient takes their first dose remote from medical care. However, someone who has had anaphylaxis or Stevens-Johnson syndrome to a sulfa should not test acetazolamide and should instead think about dexamethasone. This is also used in moderate to high-risk travelers as an alternative to acetazolamide. However, it is generally less recommended because of its cytoprec profile, particularly its neuropsychiatric side effects in an environment where the brain is already receiving multiple insults. It can be used, though, with those with unequivocal indications. We like to keep the courses shorter, typically shorter than one week, and we taper after a shorter duration than those who use steroids at sea level. Dosing is beyond the scope of this talk, but these are the wilderness guidelines, and I put this up here just to show that it can be dosed for both prevention and treatment of both acute mountain sickness and high-altitude cerebral edema. But the definitive treatment really is descent. We should be descending with grade 1A level of evidence. Descents as low as 300 to 1,000 meters have been shown to resolve symptoms in patients. And of course, someone with HACE should never descend alone because of the concern for altered mental status along the way. While descending or while awaiting descent, supplemental oxygen with a goal set of at least 90% is recommended. Hyperbaric chambers can be used. However, they can be limited by claustrophobia, altered mental status, and nausea, vomiting, because we're unable to have any other providers there. And they require a decent amount of management from a fellow hiker. Pharmacotherapy includes acetazolamide and dexamethasone for acute mountain sickness. But by the time we develop HACE, we should really be reaching for dexamethasone. But along the way, headache can be symptomatically treated with acetaminophen or ibuprofen. These are my references. And thank you for joining us for this part of the session. And I apologize. We had some airline issues. So our next presenter, unfortunately, was unable to make it. So I'm going to do her slides as well, if we can load them up. All right. So we're going to transition, then, into high-altitude pulmonary edema, or HAPE. These slides were prepared by Dr. Lubrin from Parkview Regional Medical Center and, unfortunately, is still in Indiana. This is the same slide. And today, we're going to talk about HAPE. We're going to delve into its pathophysiology. And we're going to discuss treatment as well. All right. We're going to start with a clinical case of a 33-year-old female physician. She has menorrhagia and recent anemia, who presented to your medical system with cough and worsening dyspnea. She had presented to Denver for a weekend ski trip from a city near sea level. Upon arrival to Denver at 1,600 meters, she immediately went to Breckenridge Ski Resort at 3,000 meters. She began skiing without acclimatization for two days without symptoms. And then on day three, she rapidly ascended to a higher elevation, about 4,000 meters near the peak, and went ski biking with increased exertion. She noticed that she developed a dry cough and dyspnea with exertion. What should she do? Should she A, descend? B, supplement with oxygen? C, take some albuterol treatments? Or D, keep exerting at altitude? All right. Give it just a second more. All right. I see a few last-minute votes coming in. Perfect. All right. Good. The answer here would be descend and supplement with oxygen. Good short-term retention. I like that from our previous lecture. As you will see, the treatment and prevention have many parallels between AMS, HACE, and HAPE. So moving on to HAPE, the definition is a non-cardiogenic pulmonary edema. It typically develops at 2,500 to 3,000 meters, though, again, has been seen as low as 2,000 meters. And it is actually the most common cause of death at altitude among the syndromes that we've talked about here today. It typically, like HACE, occurs on the two-plus-day time frame, but it tends not to occur after five days. So two to five days is kind of that window where patients are at highest risk. It was first reported, actually, in an autopsy in the late 1800s. It was not actually known at that point. The autopsy incorrectly attributed the case to cardiac failure. But it was of a Dr. Jack O'Tette, who was undergoing an autopsy from actually Dr. Wizard after ascending to a Mount Blank elevation of 4,350 meters. In the report, they described him as a robust, broad-shouldered man, and they thought that the most immediate cause of death was, therefore, probably a suffocative catarrh accompanied by acute edema of the lung. In the early 1900s out of Peru came a lot of case reports of something kind of similar, but nobody had really defined HAPE or really realized it as a clinical syndrome. And it wasn't until the 50s, with more Peruvian reports, as well as Dr. Houston in Aspen, Colorado, who really made the term high-altitude pulmonary edema come to light and put it on the map as a clinical syndrome at elevation. There are two types. One is lowlanders who ascend quickly. Type two is re-entry HAPE, so those who live at elevation go for a couple of weeks on a trip and then return to their home and realize that they've lost their acclimatization along the way. A clinical presentation is probably not a surprise to many of the lung doctors in the room, but it's nonproductive cough, exertional dyspnea, reduced exercise endurance, progression to dyspnea at rest, and wet cough. There's often pink, frothy sputum, and sometimes even frank homoptysis. The clinical findings, cyanosis, tachycardia, tachypnea, low oxygen saturation. Like high-altitude cerebral edema, fever can be seen from the inflammatory response, often rails on exam, bilateral infiltrates on chest X-ray, and EKG with RV strain patterns due to the increase in pulmonary pressures. The differential diagnosis is obviously wide, but of course, pneumonia, bronchospasm, mucus plug-in, PE, bronchitis, and cardiogenic pulmonary edema are top on that differential. And why does it occur? It occurs because of an accumulation of extravascular fluid in the alveolar spaces, preventing gas exchange. The reason is in large part due to hypoxic pulmonary vasoconstriction. However, there are modifiers of genetic predisposition and inflammation that also play a role. The pulmonary vasoconstriction is not homogenous. There are areas that are regionally over-perfused because of this heterogeneous pulmonary vasoconstriction. This leads to increased perfusion, leakage, and then filling of the alveoli with fluid. Overall, along the way, the combination of all these things are going to increase our pulmonary pressures. And unfortunately, much like heart failure, our body has many maladaptive responses to this syndrome. We'll have a poor ventilatory response, an increased sympathetic tone, decreased production of endothelial nitric oxide, and inadequate alveolar fluid clearance that we'll discuss on the next slide. So here you can see kind of the final physiologic pathway, where a blunted hypoxic ventilatory response will lead to alveolar hypoxia. This will also be modified by a brisk, unfortunately, hypoxic pulmonary vascular resistance response and modified by genetics. All of these things will lead to increased pulmonary hypertension or raised pulmonary pressures. And then the maladaptive responses that I mentioned here, sympathetic overactivity, endothelial dysfunction, the cold temperature and exercise will further increase that pulmonary pressure. We'll then have increased capillary pressure, endothelial stress, capillary leakage, and the syndrome of high-altitude pulmonary edema. Along the way, of course, we talked about that decreased alveolar clearance of sodium and water. We talked about how inflammation modifies this, and, of course, infection can play in as well, as those at altitude, of course, are at risk for infection as well. Treatment, there is no recommendation for, oh, I think we went too many slides, sorry. First is descent. We've talked about this. Typically, with HAPE, we need to go at least 1,000 meters, but again, symptoms can improve as low as 300 meters of descent. So getting down as far as you can and as quickly as you can is the name of the game. So oxygen, same as for AMS and for HACE. And then here, the most unique medicine we have is nifedipine, of course, trying to decrease our pulmonary pressures, which is at the root of this pathophysiology. That carries a grade 1C recommendation. In general, the recommendations for all of these high-altitude syndromes are difficult because they happen with a small number of patients, typically remote from medical care. So there are not a lot of high-quality, randomized, controlled studies to really inform this. So a lot of this, as you can see, is high-level recommendations with poor-quality evidence. Portable hyperbaric oxygen chambers can be used, just as for AMS and HACE. Beta agonists don't have any recommendation. Phosphodiesterase inhibitors have a 2C. CPAP and EPAP have a 2C. And importantly, both diuretics and specifically acetazolamide, which is used for AMS and HACE, should not be used for HAPE. So we do spare our patients from exposure to diuretics and acetazolamide when they have high-altitude pulmonary edema. And of course, resting from exertion is going to help the situation. If you do have concurrent AMS or HACE with HAPE, we should add dexamethasone. And that's one important treatment caveat for someone who has the overlap syndrome. If someone has recurrent HAPE, we would prevent, as we've already discussed, but an additional clinical workup can contain looking for intracardiac or intrapulmonary shunts, pre-existing pulmonary hypertension, or mitral valve stenosis. These are her sources. Thank you for joining this part of the session as well. Welcome, everyone. Thanks for coming. So I'll be talking about air transport, commercial and medical aspect of transport, and specifically probably a little more in-depth about the transport of patients with medical comorbidities and flying. My name is Suresh Kinney. I work at Mayo Clinic in the medical ICU as well as the health system for emergency medicine. So moving on. so today I'll be talking about some of the physiological changes that happen to altitude. I know Dr. Bessonette kind of mentioned altitude, but specifically things that may be more relevant to being on an airplane. The idea of the pre-flight preparation for those with pulmonary disease, because it becomes critically important for these patients, briefly touching on in-flight response on commercial flights, and briefly on medical transport. So first question is a 63-year-old male with a history of CPD with an FUP of 1 to 55% on chronic oxygen therapy of 2 liters, who wishes to take a two-hour flight, presents to your clinic asking for advice about his ability to safely fly with oxygen. His symptoms are well-controlled. He hasn't had any recent exacerbations. He's able to walk 100 yards without needing to take a break. What would you recommend? Increasing his O2 oxygen therapy? Recommending a hypoxia challenge test? Recommend six-minute walk test? Increase his oxygen to 4 liters? Or recommend that he not fly? Give it a few minutes, seconds. I think that's probably the most. So the answer is actually increase his oxygen to 4 liters, which I'll touch base on later on in this talk. So as Dr. Bessonette mentioned, when you're flying at altitude or flying on a commercial airplane, it really isn't a decrease in altitude, it's a decrease in the pressure. So commercial flights travel around 7,000 to 12,000 meters in the air. But in the U.S. and European standards, the cabin is pressurized around 8,000 feet. And because of the 8,000 feet, you have a difference of pressure and effectively have a different FiO2 equivalent. And this becomes a big deal because it's estimated around 2 to 4 billion annual flyers worldwide. So it's not an insignificant amount of people who do have medical comorbidities who are flying. And on that note, medical incidents have reported on 1 to 600 flights and on 1 in 30,000 patients. And specifically, the environmental and physiological changes can exacerbate chronic medical conditions. In the past 50 years, there's been a wide increase of medical transport, both fixed wing and rotary wing. And for all of the above, planning and preparation are key to help prevent any complications and manage any complications that occur. So I'll be talking about some physiological changes in flight. So as I kind of mentioned, the cabin is typically pressurized at 8,000 feet, which is equivalent to around 108 millimeters of mercury, again, at 21%. But effectively, your FiO2 becomes 15.4% at 8,000 feet. And other relevant factors that may not always be front of mind, but with Boyle's law, because of the decrease in pressure, there's an expansion of the gases. So if you're, for example, flying a medical transport with pressure at 8,000 feet, your ET tube that previously may have been filled with air is now expanding. Or if you have a pneumothorax, what happens to that pneumothorax now? Or any fluid in an IV bag can also expand. So those are some of the considerations that need to be thought of before you take someone to altitude. With Henry's law, which may be quite relevant for people in Hawaii who may be scuba diving, as there's decreasing partial pressures, nitrogen bubbles may come out of the solution, and you can get altitude decompression sickness. For example, that's why they recommend when you go scuba diving, you have to wait at least 24 hours before you hop on a flight because of this concern right here. In addition to those, there's a variety of other stresses that occur on the flight. The gravity, the temperature, the humidity, or the lack thereof, acceleration, the noise, the vibration, which all become a play and factor of patients with other comorbidities. We've seen this slide a couple times now, but for those who... So those are on the top right, where you're on your curve. However, as you go to altitude, you tend to move on different aspects of the curve, and the idea is you don't want to be in the steep part of the curve because small changes in your oxygen saturation will put you in the steeper part of the curve, which can cause more problems. And this is a slide that's going to focus on mainly, if you look over here, as Dr. Bissonnette had mentioned earlier, at baseline, any element of hypoxemia at altitude or on the plane, you have an increase in your ventilation as well as your increase in heart rate, but then you compound that with patients who may have other comorbidities, so you, in this scenario when you have hypobaric hypoxemia, you may have lung disease, you may have cardiac disease, or your level of exertion may increase, it creates a cycle where you may have end organ damage, and those are factors that we'll have to take into consideration when you manage these patients. And this is another slide kind of talking about as you increase your altitude and have you have a decrease in your effective FiO2, you can effectively get issues with cognition, impairment, headache, dizziness, which can impact your ability to stay safe on a flight. So with pre-flight preparation becomes really, really important. So those of us who are in the room who may have patients who are thinking about taking a flight, these are some of the considerations you may want to have with patients who may be taking a flight, who you may want to consider for further assessment or evaluation for oxygen on the airplane. So you want to look at the duration of the flight, timing, where they're flying to, are they flying to altitude, are they flying to sea level, what kind of equipment and medications are they able to carry. As far as respiratory conditions, if they have an FEV1 less than 50% or poorly controlled disease, that may be someone you may have to dig a little bit deeper on, if they have a history of pulmonary hypertension, restrictive lung disease, if they're on PACT therapy or chronic oxygen therapy, and if those are all true, you have to also look at what kind of portable oxygen concentrate are there. Your patient may need to reach out to the airline to discuss what's allowable, what's available. Some airlines are particular about what models they'll take, so you have to be very clear about what there needs to be before they can fly. Also battery life, it may provide a physician's certificate of need. So here's some kind of indications of flying. If you have obviously untreated respiratory disease that is active, you probably shouldn't fly. If you have untreated pneumothorax, as I mentioned earlier, it will get worse. You may have infections that are a risk to others, paroxygenic cysts, and severe hypoxemia. And that specifically can anyone above or on four liters of baseline may not be a great candidate to fly, given the lack of the ability to provide enough oxygen support for these patients on commercial flights. So this is from the British Thoracic Society, and this is their recommendation from 2022, with those with chronic obstructive airflow disease, and what their algorithm is to approach how to address these patients when they come to you. So does your patient require in-flight oxygen or hypoxia challenge test? So if their resting SABA is above 95%, and then you want to do basically a dyspnea score, and if it's greater than 2, you want to perform either a hypoxia challenge test, or you may not need to have a hypoxia challenge test or in-flight oxygen. However, if you have a dyspnea score greater than 2, and your SAT's less than 94%, you may consider a 6-minute walk test to see how they perform, because they may need to do a hypoxia challenge test, which I'll talk about in a few minutes what that actually is. But for those who are already on long-term oxygen therapy, and it's a type 1 respiratory failure, you can consider bumping their oxygen to 1 to 2 liters above their baseline to provide enough oxygen for them, going back to the initial question I had. For those with restrictive lung disease, it's a similar type process. You want to look at their baseline saturations, and then determine where they might fit on this algorithm to figure out if they would be a candidate for further testing, or just supplement oxygen as needed. In addition to the restrictive and obstructive lung disease, there is an entire consideration with those with neuromuscular disease, cystic lung disease, pulmonary hypertension specifically. Those with NIH class 3 or 4 should have in-flight oxygen. After neuromathurics, ideally 7 days after full resolution on chest x-ray, and after chest surgery, typically it's by the opinion of the surgeon, but ideally 4 weeks for non-essential, and 2 weeks for essential air travel. So the hypoxia challenge test, what it effectively does is it simulates that 15% that we were talking about. Most commonly, it's done at norobaric conditions, because it's quite difficult to get the hypobaric set up at many places. So what they effectively do is create a norobaric situation of providing 15% oxygen, and seeing how their body responds. And effectively, the consensus is if their saturation falls below 85%, they would benefit from having supplemental oxygen. And these are the different tests that can be considered. Again, C-level, looking at just saturations, the predictive equations that Dr. Bessonette was mentioning, the norobaric hypoxia oxygen test, and the hypobaric, which is probably the gold standard, but technically not always available at a lot of places. So shifting gears a little bit to, is there a doctor on board? I'm sure many of us flew here, and the considerations of in-flight emergencies are not uncommon. Their syncope is approximately the most common cause of calling for medical personnel on board, followed by GI and respiratory symptoms. In-flight cardiac arrests and diversions are pretty uncommon. If you look at the side of the screen here, these are the most common of the FAA-mandated emergency medicine kits, and there may be additional content. In addition, many flights may actually have a basic and advanced kit. They'll typically give you the basic kit, and you may have to ask for a more advanced kit if that's necessary. When you have an in-flight medical emergency, there's typically a ground-based medical support that's usually a third party that can help with recommendations regarding care. Then there's the medical volunteers who's ever on the flight, and your job is effectively to gather information, assist and assess an injured patient, aid in communication with the ground-based support, and administer any medications or perform any procedures. One thing to know is, in the U.S., Canada, and England, and Singapore, we have no legal duty to respond. However, in Australia and other European countries, there actually may be a mandate based on case law to actually respond to medical emergencies as a physician. This is a recommendation for response to in-flight medical emergencies. A lot of them are pretty standard, mainly being, don't fear litigation. There haven't been a lot of case reports for being sued for doing the right thing, but one thing I do want to highlight is, God forbid, a passenger were to pass away or were to have a death, never to declare them on the airplane. Let them ground first before the ground control manage that. Don't declare them on international waters or wherever you may be. Moving on to medical transport. Medical transport has been around since the 1700s, starting with the hot air balloon. I guess there was a trial using ducks, sheep, and roosters to determine how altitude affected living beings. Subsequently, we've evolved to the first air ambulance in 1917 with the French, and the modern era of medical transfer occurred in World War II, subsequent to the Vietnam. Then we started using helicopters in the Korean War, and more recently, in the civilian sector after the Vietnam War, as they transfer from critical access sites to hospitals to more advanced facilities. So with the fundamentals of medical transport, it's a collaboration between aviation and medicine, and there are two main ways of getting around, meaning a fixed ring or rotary ring, and what you choose is based on the distance, the speed, and how you can take off and landing. And there are four main types with regards to medical transports. There's the scene response, transfers, specialty care, and evacuation. And the medical personnel equipment can vary based on what you're in, and this is a list of some of the basic standard equipment that they may have on the flight. And more specifically, I think many of us have seen helicopter air transfer. Many times it's used to facilitate a higher level of care, to extract injured patients from a hostile terrain, or to expedite transfer to a trauma center. For example, when I work in our critical access facility, I highly rely on my air transport to get a very sick patient to, for a STEMI or a ICU level care in a timely fashion. What's interesting is there's very mixed literature on whether this truly affects mortality, because there's not very clear guidance or literature about what would require helicopter air transfer because it's so heterogeneous that it's difficult to make true guidelines on this topic. It has not shown to reduce total time to transfer required to transport because of the time to take off flight and to arrive, but it does reduce the time the patient is outside the hospital. But the most common causes of accidents related to helicopter air transport are related to instrument meteorological conditions, lost control, and controlled flight into terrain and night conditions. So with that, I'll hand off to Dr. Harrison to discuss. Good morning folks, or good afternoon, depending on what time zone you feel like you're currently living in. I'm getting a little hangry, so it must be time for lunch. So I'm going to talk to you about some of the pathophysiology and medical management concerns that we have in commercial space. So I'll introduce myself so you understand the context of what I'm talking about. I'm currently the chief medical officer and an operational flight surgeon at Axiom Space, and I've supported commercial space operations now for three different of the commercial companies. I still practice clinically at Mayo Clinic in Jacksonville, and my disclosure, I do own another suit jacket, if you're looking at that picture and looking at what I'm wearing today. I promise you. My disclosure is I am a shareholder at Axiom Space, so I do have potentially a conflict of interest, but I promise you I don't. So I'll let you scan this, if you haven't already, at any point in our talk so far today. And you're going to be disappointed with my question, because I'm going to leave you hanging, but hopefully you'll come up with the answer by the end of it. So the objectives of what we're doing for the next couple of minutes, I'm going to talk to you about some of the unique dangers and the physiologic changes that occur during commercial spaceflight, and how commercial spaceflight is different than what spaceflight has been under the control of a governmental agency for the last 60 or 70 years since its advent. I'm going to talk about some of the pressure on gas laws, because we have a big interest in hyperbaric rules as it relates to spaceflight, and I'll show you an example that you're probably familiar with, but you're unaware of the role that the gas laws played in that. And then an introduction of the practice of aerospace medicine as an operational flight surgeon in this environment. So here's the poll. After landing in the Gulf of Mexico following a 14-day mission to the International Space Station, the 57-year-old commercial astronaut complains of chest discomfort and subjective shortness of breath. So the most likely diagnosis is decompression illness, tension pneumo, toxic inhalation exposure, or all of the above. And like all good lies and stories, there's truth to each one of these cases, and we're going to talk about them. So this is a slide, if you ever see an aerospace medicine talk, you are going to see this slide There should probably be a reference at the bottom of it, but I have no idea who actually created this. In aerospace medicine, we deal with engineers a lot, so this gives them warm fuzzies, right? It's a two-by-two matrix, and it gives them something that they can relate to. But what we traditionally do in aerospace medicine is we're going to take normal physiology and we're going to put it in a very abnormal environment. And NASA has had that luxury. Their last astronaut selection, they had 18,000 applicants and they hired 10 people. So I want to do the opposite as a commercial space company, right? Ten people out of 18,000 potential customers doesn't keep the lights on. So what we want to do is come up with a way to get past that model and fly as many of those 18,000 people as we can, right? I would like to disqualify 10 potential customers. And so that's where we're coming in now with spaceflight, current and into the future. And this is probably the easier way to break it down, right? So healthy, acutely or chronically ill, this is your patient population that you're going to see at sea level. And then NASA's model has been how healthy do you have to be to be qualified to go to space or to be selected as an astronaut? What we're looking at is how sick can you be and I can still send you to space safely? And what happens? What do I have to do to make that paradigm work? And so we're going to talk about some of those things with some of the cases. You've seen some of the numbers and I apologize, leave it to the Canadian to put things up here and not in metric, but that's what you got on this particular panel. So I'm dealing in feet. And these are the numbers that you have to memorize for the aerospace boards and the hyperbaric boards, right? Starting at sea level, which is where we are right now, you've got your atmospheric pressure and where you are. The numbers that you want to remember as you go higher are 8,000, 18,000, 32,000, and then 46,000 or 62,000, sorry, is kind of interesting. So as you go from 8,000 or sea level to 8,000, you've got a 25% reduction in your atmospheric pressure. And so that's the airplane that you flew over here on from wherever in the continental U.S. to Hawaii. 18,000 is where you start to see significant risk of having altitude DCS and the U.S. Air Force actually has regulations regarding what they can expose their personnel to for training purposes because at 18,000 feet, there's about a 50% risk of having a DCS type event and a hit, which is a problem for your personnel. When you get to 32,000 feet, then you're going to start needing to use pressure breathing. So jet pilots are going to be flying basically using a CPAP type model, right? They are getting air pushed at them with a little bit of force behind it because the negative inspiratory pressure that you can generate at that altitude doesn't overcome the partial pressure that you've got at that altitude to get the oxygen that you need. Armstrong's line at 62,000 feet is interesting because it's at this point that body fluids boil at body temperature and the syndrome is called ebulism. And then the Kármán line at 300,000 feet is when you've actually left the atmosphere and you're into space. So this is where Virgin Galactic is going up with their suborbital flights, Blue Origin, and it's what we go beyond to get to the International Space Station, it's at 250 kilometers above Earth. So you can get bent both ways here in Hawaii, right? You can go scuba diving and get bent and if you survive that and get in your airplane too soon, you can get bent going the other way. So that's why we're interested. There is an atmospheric trade space in spaceflight, right? I would like to engineer my capsule to be as light as possible so the pressure that we're going to have inside that capsule may be lower than ambient. And so as Andrew has pointed out, right, you may see some syndromes like acute mountain sickness in some of your space flyers depending on how you design your vehicle. The alternate is, right, if I use a shirt sleeve environment and I try to put that in a space suit and I try to pressurize that space suit, I'm not going to be able to bend my elbows and bend my fingers and do the work that I require. So there's a lot of tradeoff in figuring out what you have to do to make the environment that you're working at in space work for the human. And we have messed it up historically. This is the aftermath of Apollo 1 where three astronauts lost their life in a fire. And so what happened here was it was 100% oxygen environment, which is very flammable. It was pressurized. There was a spark and a fire broke out. The door opened inwards, so when the pressure inside the capsule, because there's a relationship between pressure and temperature, when it increased, they couldn't open the door. And on their autopsy report, the partial pressure of carbon monoxide coming from the cardiac tissue was measured in the 600s. So they got a hyperbaric dose of carbon monoxide as a result of being in a fire in that environment. So we have messed it up and we take it very seriously in space flight. The other thing that happens is air flow doesn't occur the same as it does in microgravity. So you can get pockets of CO2 if you're working in an enclosed environment without good ventilation and good fans or too many people that can actually make astronauts, and it's happened, and it's symptomatic from CO2, hypercarbic exposure. So we pay attention to that. Another fatality that we've had as a result of changes in pressure, this is Soyuz 11 in 1971, and this capsule depressurized on re-entry and depressurized slowly and incapacitated the three cosmonauts that were in there. They had no communication with the ground. The Soyuz landed nominally, parachutes came out as they were supposed to, and the recovery crews were very surprised that they weren't getting any response from anybody inside. There's reports that there were some agonal signs of life from the crew members. There were attempts made just behind the capsule that you can't see here at resuscitating the three crew members, but they perished as a result of that. And so from that we've made some changes in terms of what we wear in terms of pressure suits when you come back into the Earth's atmosphere. There were also, so coming back to an American example, Columbia had evidence of rapid decompression on autopsy, and because the pathologist that was doing the autopsy wasn't familiar with what decompression looked like at the tissue level, were taking multiple samples of bone slices trying to get a good sample because they thought that the source that they were seeing was faulty and there was something wrong with their equipment because there were air bubbles inside the bone marrow. So the next thing, right, if I haven't scared you off commercial space flight yet, these are the fuels that we use, and they're called hypergolic fuels because we need them to burn in a vacuum, and these things are hazardous. And so as you can see here, there are no real OSHA levels for exposure. Things are being measured here in single digits in parts per million and parts per billion. Every animal model has ended either with acute toxic exposure that has led to death, or if it's been a smaller exposure that the animal's gotten, they've developed cancer 100% of the time afterwards. So these are our nasty substances. Monomethylhydrazine and nitrogen tetroxide are the two that we use. One's clear and one is yellow, so if you see a yellow or orange cloud around a space vehicle, run. But these are things, and we have had an example of this in the past. This is the Apollo Soyuz test project in 1974. There was a leak inside the capsule, and the astronauts, the three crew members that were inside the Apollo capsule got exposed, and that's just their pre-flight, one of them, their pre-flight chest x-ray and their post-flight chest x-ray. So it is an irritant, and so it'll irritate your eyes, it'll irritate your lungs, and they spent some time in the ICU, actually here in Hawaii, as a result of that. And you can find, the results from this are published, and you can find their blood gases, which weren't terribly deranged. It was more of a precautionary requirement for them to go to the ICU, and a security thing, right? We can lock down the ICU and keep the looky-loos from getting an interview with your crew member. But they were hospitalized as a result of exposure to hypergols. This is Gregory Olson, and so in the early 2000s, he flew on a Soyuz to the International Space Station as a commercial astronaut. A 57-year-old gentleman who has allowed his reports to be published, so that's why we're able to talk about this as openly as we are, and incredibly grateful for this. Dr. Richard Jennings, the author of the paper and one of the grandfathers of aerospace medicine, is the gentleman in the white hat in the back, and he was his flight surgeon. These are his medical conditions. So he had COPD, he had a history of bullae, he had a history of a spontaneous pneumothorax that was intervened upon. And then he had a bunch of other stuff that I don't know what that is, but it doesn't sound great. It would be disqualifying as a NASA astronaut, but he flew successfully. The reason this is even more interesting is his capsule depressurized on reentry. About 15 to 20% reduction in the pressure from the 760C level to what they were at. The reason it's even more important, he was the gentleman who was in the seat that had to intervene and fix the loss of cabin pressure. So if he'd been incapacitated as a result of recurrent pneumo or something, he was putting the other crew members at risk. So that's one of the things that we do when we start balancing off risk in aerospace medicine. What is your flight duty, and is it safety critical, and is it safety critical to everybody else that's on board? So the other thing I want you to look at, at this point, those of you that were paying attention and voted D are probably pretty happy with yourselves, because I've just demonstrated why every one of those conditions is going to be on your differential. He's 57 when he flew. If he lands and has those complaints, you've got to start devising your differential diagnosis and then acting upon it. So if you're thinking that it's a toxic exposure or DCS, you're going to look at his other two crew members and see what sort of shape they're in. Because if they have similar symptoms, then you're thinking that it's something inside the environment that's causing a problem. If not, and you know this history, and you know that he's potentially got a tension pneumo, you're going to want to examine this individual, and you're going to want to intervene upon it. You have to get him out of his spacesuit first. And there's not an easy way to do that. There is a procedure for cutting each individual spacesuit, and it's dependent on which spacesuit it is, because there are a number of safety critical elements in there, and some things that you're just not going to be able to get through with trauma shears. So there's actual training and certification for flight surgeons on the ground to understand how they have to get inside that spacesuit in the event of emergency, and if they have to cut it off. But if you're going to take it off nominally, it's going to take you five or ten minutes to get somebody fully out of their spacesuit and be able to intervene upon them. So if he had a tension pneumo and you had to do a needle decompression, you've got a few steps, and this is after he's out of the capsule, you've got a few steps that you have to do first. So this is what happens when a capsule lands, and this is the SpaceX model that we're using for NASA, for SpaceX, and for Axiom missions. The capsule lands and is dragged up onto a boat, and the crew is then egressed from the capsule, and then taken to this. This is the medical bay on board. So it looks like a very rudimentary trauma bay, because that's what it is, and you're hoping that you're not going to have to do anything too invasive. But there is capability here to do chest tubes, central lines, intubation, provide fluids, and then you're going to use the most important form of resuscitation that Dr. Kinney just talked about, and you're going to fly faster. If you have somebody that's sick and injured, you're going to load all four of the crew members into that helicopter, and you're going to take into account some of the considerations that you've got, that you may have some changes in pressure that the crew member or the devices that you've just installed may not respond well to. So you may be inflating your cuff with saline to make sure that you're not going to get some changes in pressure and loss of volume and leak. And you can see that this is how you would fit all four crew members into that helicopter. So you don't have a whole lot of room to work in either. So you're hoping to stabilize and identify any condition in that medical bay before you start loading people into the helicopter. So this is kind of ironic, because I labeled it the good flight surgeon as one you never see, and there are three flight surgeons in that particular picture. So we goofed. But aerospace medicine is a combined art, and so we start looking at things like extreme physiology and extreme environments, and hyperbaric and high-altitude medicine are important. The other reason, right, I just talked to you about all the things that Dr. Jennings had to do for Gregory Olson to fly, that prevention becomes very, very important. I would rather deal with a problem here on the ground well in advance of a mission than have my hair on fire inside that trauma bay and trying to fix something that I probably should have done some work on in advance. Wilderness medicine becomes important, because you're going to discover that you've got austere conditions and limited resources, and you probably have one ET tube. So if you goose it and break the cuff or something like that, you're going to have an interesting day. And so you want to make sure that you're prepared for that. And then there's a big role for emergency and critical care medicine in that. So with that, these are my points of contact, if you have any questions. This is one of my favorite pictures. This was taken for the Crew-1 launch, and it's my three kids before the mission. So that's the generation that commercial spaceflight is going to become routine for. And unfortunately it sort of has for these three. They don't care anymore about what daddy does. But it was really cool. So thank you very much. I don't know if we have much time left for questions, but I'll open it up.

high-altitude syndromes

acute mountain sickness

high-altitude cerebral edema

acetazolamide

dexamethasone

physiology

risk stratification

acclimatization strategies

descent