Pulmonary changes at high altitude and altitude sickness

The air we breathe in has the same amount of oxygen (about 21 percent or just 0.21) at all altitudes. This is referred to as the Fraction of Inspired Oxygen or FiO2.

However, the atmospheric air pressure, or Patm, decreases with altitude from about 760 mmHg at sea level to about 500 mmHg at the top of a 3000 meter mountain.

So the problem is not that there’s proportionally less oxygen at high altitudes, but rather the problem is that the lower air pressure means that the same oxygen proportion will result in a lower partial pressure of oxygen in the alveoli, or PAO2 for short.

So when there’s an increase in altitude, the amount of oxygen getting to the alveoli reduces. But luckily, the body makes physiological changes to keep the tissues well oxygenated even at low atmospheric pressures.

Now if that fails, it can lead to altitude sickness. OK, so normally, the respiratory mucosa is a bit moist, and at 37 degree Celsius (a normal body temperature), some water molecules exist as water vapor.

These molecules create a pressure of their own known as the vapor pressure or pH2O, which is about 47 mm Hg. So the air we breathe in mixes up with these vapors and becomes humidified.

Now, at the end of inspiration, the air pressure within the alveoli becomes equal to the Patm, or the air pressure outside the body, but the composition is a bit different due to the humidification that takes place in the respiratory tract and alveoli.

So if we want to know how much of the dry air remains within the alveoli, we have to subtract this vapor pressure from the mixture and then, multiply the dry air pressure with FiO2, to get the amount of oxygen that gets into the alveoli.OK, now, across the alveolo-capillary membrane, gas exchange is happening all the time.

Some oxygen molecules are diffusing across the membrane and binding to the hemoglobin within red blood cells. At the same time, red blood cells are dropping off carbon dioxide which diffuses from the blood, through the membrane, and into the alveoli so that it can be released in exhalation.

OK, let's check the amount of each of the gas crossing the wall. If we assume that there is no carbon dioxide in the inspired air, then that means that all of the carbon dioxide that is in the alveoli must have come from deoxygenated blood in the capillaries.

The partial pressure of carbon dioxide in capillaries, or PaCO2, varies between 35 to 45 mm Hg, but let’s take the average, 40 mm Hg, and say that it’s the amount of CO2 that’s diffusing from the blood into the alveolar sacs.

Now while this is happening, oxygen is also diffusing in the other direction, from the alveoli to the blood. So we have to determine the amount of oxygen that’s leaving and subtract it from the amount that’s in the alveoli.

That gives us the steady state amount of oxygen partial pressure available in the alveoli, or PAO2. The amount of oxygen going into the blood, gets delivered to the body cells where it is used to oxidize substrates.

Now, it turns out that there’s a pretty reliable ratio of carbon dioxide entering the alveoli to oxygen entering the blood represented by PaO2, with a little a for arteriole.

This ratio is called the respiratory quotient or RQ. Rearranging a bit, that means that the amount of oxygen entering the blood is equal to the amount of carbon dioxide entering the alveoli divided by RQ.

RQ varies a bit, but for someone eating a mixed diet, RQ is about 0.8. So, if the amount of carbon dioxide entering the alveoli is 40 mm hg, the amount of oxygen that’s being exchanged would be PaCO2/RQ, or 40 mm hg/0.8 or 50 mm Hg.

To tie things up, the partial pressure of oxygen available in alveoli at the end of every inspiration is the partial pressure of oxygen in the inspired dry air, minus the partial pressure of oxygen that has already left the alveoli to the capillaries.

That’s the alveolar gas equation. So let’s see how the equation looks at sea level versus on top of a 3000 meter mountain.

At sea level, Patm is 760 mm Hg; which makes PaO2 equal 0.21 times [760 mm Hg - 47 mm Hg] – [40 mm Hg/0.8], and that works out to PaO2 of 100 mmHg.

This oxygen pressure is enough to maintain a sufficient arterial oxygen partial pressure above 75 mm Hg, which is enough to deliver oxygen to body tissues.On the other hand, at 3000 meters high, the Patm is 520 mm Hg.

So by applying the alveolar gas equation, alveolar PaO2 drops to around 45 mm Hg, which is alveolar hypoxia. Alveolar hypoxia means that not enough molecules are available to diffuse into the blood, leading to hypoxemia which is low oxygen in the blood, and finally tissue hypoxia, meaning tissues aren't getting enough oxygen either.

When this happens due to a low pressure in the inspired air, it’s called hypobaric hypoxia. Alveolar hypoxia causes pulmonary blood vessels to narrow in a process called hypoxic pulmonary vasoconstriction.

When that happens, the blood has to be under higher pressures to get through the narrow vessels, which increases pressure in the pulmonary circulation.

This is called pulmonary hypertension and when this happens across lots and lots of capillaries, less blood flows into the alveoli to get oxygenated, worsening the hypoxemia and tissue hypoxia even further.Now, to avoid this cycle early on, peripheral chemoreceptors in the walls of the carotid arteries and the aortic arch detect the hypoxemia and start firing more impulses.

The rapid firing rate notifies the respiratory centers in the brainstem that they need to increase the respiratory rate and the depth of breathing.

Together this is called hyperventilation. As the respiratory rate and depth of each breath increase, the minute ventilation - which is the volume of air that moves in and out of the lungs in a minute - increases.

As hyperventilation draws in more air, it then makes more oxygen available to diffuse to the blood and that corrects the hypoxemia and tissue hypoxia.

Also, when these peripheral chemoreceptors’ firing rate increases, it notifies the cardiac centers in the nucleus tractus solitarius located in the medulla oblongata.

The medulla oblongata responds by turning down the parasympathetic stimulation to the heart and increasing its sympathetic stimulation.

This results in a much-needed domino effect: faster heart muscle contractions (or heart rate), leading to a higher cardiac output (which is the amount of blood the heart pumps out in a minute), and all this improves tissue oxygenation.

Now, as you keep climbing higher, the atmospheric pressure drops even further, worsening the state of hypobaric hypoxia.

The body responds to this by increasing hyperventilation even more. Sustained hyperventilation doesn’t only take in more air, but it also causes excessive exhalation of CO2.Normally, CO2 binds to water in the blood and forms carbonic acid – H2CO3 Carbonic acid then dissociates into hydrogen H+ and bicarbonate ions HCO3- and helps buffer the blood pH.

So, in order to prevent blood pH fluctuations, the CO2 partial pressure in the blood (or PaCO2) needs to be kept within its range.

So, with sustained hyperventilation, PaCO2 levels fall, so there’s less hydrogen ion production, which means blood pH rises.

This is called respiratory alkalosis, and peripheral chemoreceptors respond by firing less to notify the respiratory centers in the brainstem to stop hyperventilation.

This causes the minute ventilation to decrease, making hypoxia worse. Now, the body has to deal with this respiratory alkalosis and get the respiratory drive restored.

It does so by having the kidneys excrete some of the bicarbonate ions, which causes the carbonic acid to dissociate into more bicarbonates, replacing the excreted ones, However, at the same time, this gives off more hydrogen ions.

Increased hydrogen ions lowers the blood pH, which restores the peripheral chemoreceptors firing rate and gets the respiratory centers in the brainstem to allow for hyperventilation again.

This helps meet the body’s oxygen demand. Alright, when people spend days to weeks at high altitudes, let’s say camping high along the slopes of Mount Everest, the body makes long-lasting physiological adjustments, called acclimatization.One of the changes that happen in acclimatization is that the transcription of genes encoding for Erythropoietin (or EPO) synthesis increases.

This results in the production of larger quantities of EPO - up to 1000 times higher than the usual amount. Large quantities of EPO signal the bone marrow to produce more red blood cells to carry more oxygen to the tissues.

Low oxygen in the body also signals some other cells (such as the smooth muscle cells of the aorta, and macrophages), causing them to produce larger amounts of vascular endothelial growth factor A or VEGF-A.

VEGF-A is a protein that promotes the formation of many other capillaries deep within tissues, through which more blood flow, thus improving oxygenation.

Also, as a result of hypoxemia, red blood cells start making more of a molecule called 2,3-Bisphosphoglycerate or just 2,3-BPG, raising its concentration in the blood, then in tissues.

2,3-BPG has a strong affinity for hemoglobin, so within tissues, it competes with oxygen, thus reducing oxygen-hemoglobin affinity and allowing more oxygen to be released from hemoglobin to the tissues.

Finally, sustained tissue hypoxia leads to increased endothelial nitric oxide synthase or just eNOS, which is the enzyme that splits the amino acid L-arginine into citrulline and nitric oxide.

Then, nitric oxide triggers a cascade of reactions that work on smooth muscles of blood vessels and cause them to relax and widen in diameter in a process called vasodilation.

This gives more space for blood to flow through, thus helping to deliver more oxygen to tissues.Sometimes adaptations to hypobaric hypoxia fail, resulting in some quite dangerous physiologic disturbances, which is commonly referred to as altitude sickness.

The most common form of altitude sickness is acute mountain sickness, and it’s known to start happening even at a moderate altitude: between 2000 to 3500 meters.

The precise mechanism is unclear, but it’s thought to result from increased cerebral vascularization due to larger amounts of VEGF-A and too much cerebral vasodilation caused by higher levels of nitric oxide.

This results in increased cerebral blood flow and increased intracranial pressure, meaning neurons start to malfunction as they get compressed.

With a further ascent to a higher altitude (like above 3500 meters), it can progress to a more severe form of altitude sickness called high altitude cerebral edema or HACE.

HACE is thought to happen when the intravascular pressure is high enough to cause plasma fluid to leak out in brain tissues and cause edema.Occasionally, altitude sickness can also appear as high altitude pulmonary edema or HAPE, which like HACE, usually occurs above 3500 meters.

It is thought to result from exaggerated pulmonary vasoconstriction and insufficient production of nitric oxide, which together, causes severe pulmonary hypertension.

This leads to a breaking down of pulmonary capillaries and allows plasma and blood cells to start leaking into the lung tissue.Symptoms of altitude sickness are those of increased intracranial pressure such as headache, nausea, vomiting, and dizziness.

It’s considered HACE when there’s progressive mental dysfunction and ataxia, which is a lack of coordination of voluntary muscles, causing gait abnormality and speech changes.

As HACE progresses, it results in coma and then death. On the other side, people with HAPE typically develop worsening shortness of breath and a non-productive cough.

As symptoms progress, the cough becomes productive with pink frothy sputum, and eventually, the individual starts coughing up frank blood.##SummaryAlright, as a quick recap, with an increase in altitude, the atmospheric air pressure falls, leading to hypobaric hypoxia.

Initially, the body responds to this by the process of accommodation, which consists of increasing respiratory rate and depth to improve minute ventilation and raising the heart rate for a greater cardiac output.

As time goes on, the body starts to acclimatize, which is the process by which it undergoes long-lasting adaptational changes that improve tissue oxygenation.

These include a higher concentration of EPO that lead to increased hematopoiesis, higher levels of VEGF-A that increase the number of blood vessels, nitric oxide synthesis that increases systemic vasodilation, and increased amount of 2,3 GPD to help hemoglobin easily release oxygen to tissues.

When the body fails to appropriately adapt to high altitude, it results in altitude sickness, which can present in different forms, such as acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema.

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