Normal Acclimatization

Prepared by Inga Aksamit

Most people can acclimate to high altitude if given enough time. The body responds in a number of complex ways. Breathing is probably the most noticeable. The person who ascends to altitude often finds that even mild exertion makes them short of breath, causing more frequent and deeper breaths to bring additional oxygen to the lungs. An increase in heart rate may or may not be noticeable. Less obvious are other physiologic changes such as less plasma volume, more red blood cells, less blood flow to nonessential tissues (essential organs include the brain, heart and kidneys; nonessential organs include muscle and skin) and enzyme changes that trigger other processes. The major organs involved in acclimatization include the lungs, heart, kidney and endocrine system. When the body has adequate time to acclimate, the physiologic changes work together to increase oxygen delivery where it is needed. This is accomplished by increasing oxygen to the red blood cells, enhancing oxygen transfer between cells and optimizing metabolic efficiency.

Specific Changes

It’s convenient to separate the effects of hypoxia by system but each change is influenced by the other changes. Taken together, the ideal result is acclimatization.

Our focus here is on short term adaptation that occurs within hours of ascent as this is the typical scenario for many hikers. Long term adaptation over many weeks or months is outside the scope of this article.

Effect of hypoxia on organs

Lung
Hypoxia stimulates faster breathing and deeper breaths. This is a quick fix that brings in more oxygen but with a loss of carbon dioxide. This gets a little complicated, but carbon dioxide is a weak acid in solution. With the loss of carbon dioxide, the blood become more alkaline. The fastest way the body can normalize the pH is to try to decrease the loss of carbon dioxide by suppressing breathing. You can overcome this during the day when you’re thinking about it, but at night, respirations slow down. Another way the body can compensate is by the kidneys.

Kidney
The kidney plays a key role in acclimatization by regulating acid-base balance. When blood becomes alkaline, as it does with the loss of carbon dioxide, the kidneys excrete more bicarbonate (a base substance). The kidneys are the longer-term solution to maintaining pH in the face of blood that is too alkaline. The kidney also produces erythropoietin (see “Heart” below).

Heart, blood vessels and blood
Arteries constrict, raising blood pressure. The heart stroke volume (volume of blood pumped with each heart beat) decreases, but the amount of blood pumped (i.e. the cardiac output) actually increases. Plasma can escape from leaky capillaries into tissue, which concentrates the blood in the arteries. Though more oxygen is carried, the number of red blood cells does not increase (yet).

After additional time, hypoxia causes the kidney to release erythropoietin (EPO), which stimulates the bone marrow to make more red blood cells. After a few weeks, the additional red blood cells help with long-term acclimatization by increasing the oxygen-carrying capacity.

Increases in red cell volume and total hemoglobin mass increase within one to two weeks after ascent [1].

The blood becomes more acidic helping load oxygen onto the hemoglobin.

Muscles
When muscles are at rest, they use little oxygen. When we exercise, muscles release chemicals such as lactate, carbon dioxide and potassium. This creates a feedback loop to increase blood flow to deliver more oxygen to the muscles. This process can get disrupted at altitude. It can take 10-20 days for athletes to fully acclimate to elevations above 6500 feet for aerobic competitions. It can take weeks to months to fully acclimate above 18,000 feet [1].

Brain
When hypoxia occurs, blood flow to the brain increases and oxygen delivery is initially maintained at normal levels. This initial vasodilation and increased blood flow cause the headache that is so common. As described for the lung and kidney, increased respiration leads to alkalinization of the blood, which causes blood vessels to constrict, limiting blood flow to the brain. These opposing forces must be in a delicate balance to maintain brain function.

Edema

Abnormal swelling can occur when fluid leaks from the blood vessels and capillaries into the space between the cells, known as the interstitial space. This can be due to increased vascular permeability (how much a blood vessel wall allows molecules to travel through), increased blood pressure, hypoxia or physical damage to the capillaries. Peripheral edema, where swelling of the face, hands and/or feet occurs, is not dangerous in and of itself but may occur in persons susceptible to AMS [1].

Hormones, neurotransmitters and chemical messengers

• Hormones that can be affected include antidiuretic hormone (ADH), which can be decreased resulting in water in the urine.
• Neurotransmitters are impacted by hypoxia, distorting message from the nervous system. When the sympathetic nervous system is stimulated by hypoxia and/or cold temperatures, the neurotransmitters epinephrine and norepinephrine are released, resulting in the “fight or flight” response. This causes arteries to constrict and blood pressure to rise.
• Nitric oxide (NO) and endothelin are chemicals that play a role in managing blood flow and NO directs where oxygen is delivered. A NO deficiency is implicated in some cases of HAPE.
• The molecule 2,3-bisphosphoglycerate (2,3-BPG), also known as 2,3-disphosphoglycerate (2,3-DPG), binds to hemoglobin and affects the oxygen dissociation curve. 2,3-BPG increases at altitude and its effects are being studied.
• Aside from the oxygen saturation of hemoglobin, other factors that influence how readily hemoglobin binds oxygen include blood pH, blood bicarbonate levels, and the pressure of oxygen in the air (high altitudes in particular).
• Other substances that play a role in the response to hypoxia include acetylcholine, dopamine, VEGF, leptin, reactive oxygen species and more [1].

Effect on cells

A protein called “hypoxia inducible factor” is produced by all cell types, excluding red blood cells, related to acclimatization. This protein is inactive in the presence of oxygen. Under hypoxic conditions, this protein triggers a response that leads to the production of other proteins, including VEGF, erythropoietin, and others [1].

Time Requirement to Acclimate

How long does it take to acclimate fully? It depends on how high and how fast the ascent is. In general, a slow acclimatization or staged ascent will allow most people to acclimate to high or very high altitude. Susceptibility to altitude sickness varies quite a bit based on individual physiology and genetics. Some people feel fine and can start hiking at 8,000 feet while others benefit from a few days of taking it easy to allow the physiologic processes described above to take place. It can take four days to maximize the breathing changes and renal compensation for alkalosis. Most of this happens in the first two days but for the most sensitive, four days may make a difference. With Diamox, this can be shortened to one day.

Above 8,000-9,000 feet, a staged ascent is recommended as described in the “Wilderness Medical Society Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness” and “An Unofficial Acclimatization Guideline for JMT Hikers.” This involves restricting ascents to no more than 1,600 feet per day, with or without rest days, with additional considerations depending on previous history of AMS, the AMS risk category and how high the ascent is. These recommendations are designed to prevent altitude illness but it is likely that exercise performance is enhanced by taking even more time to acclimate [2].

De-acclimatization

When the acclimated person descends to low altitude, physiologic changes reverse. This is known as de-acclimatization. Plasma volume in blood increases at sea level, reversing the effects at altitude. It appears that some metabolic adaptation lasts for a week or two and that de-acclimatization is faster than acclimatization. It is possible that subsequent exposure to altitude may delay de-acclimatization [3] [2] [4]. Red blood cells that were produced in response to hypoxia have a life-span of more than 100 days. When descending, there will be more cells than needed, which will slow the production of red blood cells in the bone marrow, probably to below the normal replacement level, until it reaches the correct amount for the altitude for that person. During that interval, there will be excessive O2 carrying capacity until the equilibrium is re-established. This may last several weeks.

Acknowledgments

We would like to acknowledge Peter Hackett, MD and Ken Murray, MD who reviewed this document and made valuable suggestions.

References

1	Houston CS, Harris DE, Zeman E. Going higher: Oxygen, man, and mountains. The Mountaineers Books; 2005.
2	Muza SR, Fulco CS, Cymerman A. Altitude Acclimatization Guide. Technical Report. Natick MA: Army Research Inst Of Environmental Medicine, Thermal And Mountain Medicine Division; 2004.
3	Angelo, Nemkov T, Sun K, Liu H, Song A, Monte AA, Subudhi AW, Lovering AT, Dvorkin D, Julian CG, et al. AltitudeOmics: red blood cell metabolic adaptation to high altitude hypoxia. Journal of proteome research. 2016;15:3883-3895.
4	Army tech bulletin tb med 505, Altitude acclimatization and illness management. Tech. rep. Headquarters, Department of the Army. Washington DC; 2010.