Getting higher Man at High Altitude History, Physiology, Adaptation

It’s dangerous up there “The lakes of the snow mountains are inhabitet by poisonous dragons that breathe out poisonous clouds when enraged.” “Again, on passing the Great Headache Mountain, the Little Headache Mountain, the Red Land and the Fever Slope, men’s bodies become feverish, they lose colour and are attacked with headache and vomiting; the asses and cattle being all in like condition.” “The lakes of the snow mountains are inhabitet by poisonous dragons that breathe out poisonous clouds when enraged.” “Again, on passing the Great Headache Mountain, the Little Headache Mountain, the Red Land and the Fever Slope, men’s bodies become feverish, they lose colour and are attacked with headache and vomiting; the asses and cattle being all in like condition.”

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Historic Overview

To understand altitude sickness we must know about: composition of air change of composition of air over altitude physiology of respiration, the cardiovascular system and general metabolism Historic Overview

17th century: Gaspar Berti and Evangelista Torricelli (a student of Galileo’s) invent the Barometer. Florin Perier uses it to prove the change of pressure with altitude. 1670: Robert Hooke builds the first decompression chamber. What is Air?

Hookes’ Barrel

What is Air? 17th century: Gaspar Berti and Evangelista Torricelli (a student of Galileo’s) invent the Barometer. Florin Perier uses it to prove the change of pressure with altitude. 1670: Robert Hooke builds the first decompression chamber. 1674: John Mayow shows that “animals in breathing draw from air certain vital spirits that by means of respiration are transmitted into the mass of the blood”.

Oxygen: The Vital Spirit ~1680: Georg Stahl gives the name phlogiston to an alleged substance that is consumed in burning. Phlogiston has no weight, but levitiy, making things heavier when it leaves. ~1772: Carl Scheele generates vitriol air and proves that it supports life and combustion 1775: Joseph Priestley produces pure air, which may become a fashionable article in luxury. Antoine Laurent Lavoisier also produces pure air, stating that ordinary air contains two constituents: later to call the pure air oxygine.

Oxygen: The Vital Spirit ~1680: Georg Stahl gives the name phlogiston to an alleged substance that is consumed in burning. Phlogiston has no weight, but levitiy, making things heavier when it leaves. ~1772: Carl Scheele generates vitriol air and proves that it supports life and combustion 1775: Joseph Priestley produces pure air, which may become a fashionable article in luxury. Antoine Laurent Lavoisier also produces pure air, stating that ordinary air contains two constituents: later to call the pure air oxygine. Antoine Laurent Lavoisier

What’s wrong up there? 1793/1803: John Beddoes and Wilhelm von Humboldt attribute the problems to lack of oxygen at high altitude. 1875: Tissandier, Crocé-Spinelli and Sivel take a flight in the balloon Zénith. The latter two die from acute hypoxia. 1878: Paul Bert publishes La Pression Barométhrique, founding modern high-altitude physiology. In it he shows that the critical factor for mountain sicknesses is partial pressure of oxygen in the inspired air.

What’s wrong up there? 1793/1803: John Beddoes and Wilhelm von Humboldt attribute the problems to lack of oxygen at high altitude. 1875: Tissandier, Crocé-Spinelli and Sivel take a flight in the balloon Zénith. The latter two die from acute hypoxia. 1878: Paul Bert publishes La Pression Barométhrique, founding modern high-altitude physiology. In it he shows that the critical factor for mountain sicknesses is partial pressure of oxygen in the inspired air. Paul Bert

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Sleeping Problems “I was unable to sleep and passed so bad a night that I would not wish it on my worst enemy” Dr. Jacottet, Mont Blanc, Sep

Acute Mountain Sickness insomnia headaches faint nausea fatigue, weakness shortness of breath loss of appetite night blindness retinal haemmorhage

The Respiratory System Respiratory movement creates subatmospheric pressure in the lungs, leading to inspiration Carbon dioxide moves from the blood into the alveolar air, oxygen moves from the air into the blood Circulation carries oxygen blood to tissues and removes carbon dioxide from them

Secretion or Diffusion? How does the oxygen get into the bloodstream? 1891: Christian Bohr publishes his findings about active oxygen and carbon dioxide secretion in animal lungs 1896: John Haldane shows that arterial blood has a higher partial pressure of oxygen than alveolar air. He concludes that the lungs secrete oxygen into the blood. 1910: August and Marie Krogh show that diffusion adequately explains oxygen uptake

Secretion or Diffusion? How does the oxygen get into the bloodstream? 1891: Christian Bohr publishes his findings about active oxygen and carbon dioxide secretion in animal lungs 1896: John Haldane shows that arterial blood has a higher partial pressure of oxygen than alveolar air. He concludes that the lungs secrete oxygen into the blood. 1910: August and Marie Krogh show that diffusion adequately explains oxygen uptake Christian Bohr ( )

Secretion or Diffusion? How does the oxygen get into the bloodstream? 1891: Christian Bohr publishes his findings about active oxygen and carbon dioxide secretion in animal lungs 1896: John Haldane shows that arterial blood has a higher partial pressure of oxygen than alveolar air. He concludes that the lungs secrete oxygen into the blood. 1910: August and Marie Krogh show that diffusion adequately explains oxygen uptake John Haldane ( )

Secretion or Diffusion? How does the oxygen get into the bloodstream? 1891: Christian Bohr publishes his findings about active oxygen and carbon dioxide secretion in animal lungs 1896: John Haldane shows that arterial blood has a higher partial pressure of oxygen than alveolar air. He concludes that the lungs secrete oxygen into the blood. 1910: August and Marie Krogh show that diffusion adequately explains oxygen uptake Marie ( ) and August ( ) Krogh

The Oxygen Cascade

Oxygen dissociation curve

Hypoxic Ventilatory Response The first reaction of the system to lower than normal oxygen supply is mediated by a reaction in the peripheral chemoreceptors. Oxygen binds to K + channels in the membranes, opening them. When less oxygen is available, K + channels close, depolarizing the cell. This in turn opens Ca 2+ channels, triggering exocytosis of dopamine. Sensory neurons then transduct the signal to the respiratory center in the medulla. But the chemoreceptors are also sensitive to changes in plasma pH.

Hypoxic Ventilatory Response Hypoxia leads to hyperventilation Increased ventilation produces an increase in arterial oxygen pressure, but: The accompanying decrease in arterial pCO 2 produces alkalosis of the blood, partly masking the ventilatory reaction to hypoxia by supressing the chemoreceptor signal This becomes a problem during sleep, leading to periodic breathing

The Bohr effect The oxygen dissociation curve shifts to the left when blood pH increases, facilitating oxygen uptake in the lung. At the same time however, the release of oxygen to target tissues is decreased by that shift. The Hypoxic Ventilatory Response increases gas exchange in the lung, thus removing CO 2 from the blood. This leads to alkalosis of the blood, left shifting the dissociation curve.

The Bohr effect The oxygen dissociation curve shifts to the left when blood pH increases, facilitating oxygen uptake in the lung. At the same time however, the release of oxygen to target tissues is decreased by that shift. The Hypoxic Ventilatory Response increases gas exchange in the lung, thus removing CO 2 from the blood. This leads to alkalosis of the blood, left shifting the dissociation curve.

Mechanisms of AMS AMS is not directly caused by hypoxia. While oxygen levels throughout the body drop within minutes of exposure, AMS takes several hours to develop. High intercranial pressure due to increased leakage of fluid is thought to cause AMS. The mechanism leading to this is unclear. Possible mechanisms include a shift of fluids from the cells to extracellular space, general fluid retention (possibly via the renin/angiotensin/aldosterone system) or, less likely, antidiuretic hormone

High Altitude Cerebral Edema Symptoms include those of AMS, plus any kind of neurological disorder: ataxia, irrationality, hallucinations Can be accompanied by haemmorrhages or thrombosis HACE is life theatening. Untreated, the person will fall to a coma and die within hours to one or two days. Several theories have been proposed, including vasogenic (leakage through the BBB), cytogenic (cell swelling due to lack of oxygen), angiogenesis (severe tissue hypoxia releases factors causing leakage and capillary growth)

High Altitude Pulmonary Edema High pulmonary artery pressure (PAP) occurs regularly in persons with hypoxia. However, this is not sufficient for pulmonary edema, indicating, that either PAP is no direct indicator for capillary pressure, or that additional factors are required to develop HAPE such factors could be: inflammatory response, decreased clearance of extravascular fluid pulmonary edema worsens hypoxia, as it increases the alveolar-arterial fall in PO 2

Treatments AMS is usually not life-threatening, so treatment isn’t mandatory. However, additional oxygen leads to improvement of condition. Especially sleeping returns to normal. Application of acetazolamide (Diamox) improves condition. This is probably due to it blocking carbonic anhydrase, thus preventing respiratory alkalosis and not due to its mild diuretic properties. Descent is the best treatment. HAPE usually disappears quickly, HACE can take longer to wear off.

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Acclimatization During acclimatization an increase in the concentration of 2,3 diphosphoglycerate, an intermediary of glycolysis, appears, shifting the dissociation curve back to the right. On sensing hypoxia, the kidneys release erythropoietin, stimulating the bone marrow to produce more red blood cells. This increases the hematocrit, and improves oxygen transport at the cost of higher blood viscosity. Myoglobin, a substance in muscle tissue storing oxygen, increases. Myoglobin has a left-shifted dissociation curve, enabling it to rapidly supply oxygen, when supply ends

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Unsolved Problems Although the diagnosis and treatment of high altitude disorders are well established, none of them ist well understood. How does hypoxia lead to edema of the lung and the brain? What role does the hormonal fluid balance system have? Are AMS and HACE mediated by the same mechanisms?

Benefit of Research Gain of knowledge about the function of involved systems Better understanding of hypoxic conditions at sea level Development of treatments for those conditions Heart or ciculatory disorders, airway obstruction, alveolar defects, air pollution etc.

Final View