Respiratory Physiopathology III HIGH ALTITUDE PULMONARY EDEMA PY3002

2. LECTURE OUTLINE Physiological challenges faced by the respiratory system on ascent to high altitude Normal acclimatization process short term versus long term adaptations What happens when acclimatization failed ? Acute Mountain Sickness (AMS) High Altitude Cerebral Edema (HACE) High Altitude Pulmonary Edema (HAPE) At high altitude, respiration extracts utilizes a high proportion of the overall energy expenditure. In spite of a slight decrease in the work of breathing resulting from the lower density of the ambient air at high altitude, much greater volumes of air are necessary to supply enough oxygen to the body from atmospheric air, in which the level of oxygen is reduced. Delivery of oxygen is further impaired by a diffusion limitation of oxygen from the air to the blood, which increases with altitude. At extreme altitudes, a disabling sense of dyspnea is compounded by cerebral hypoxia, which may further limit exercise. Climbers to these heights have reported taking as many as 10 breaths per step as the rate of ascent progressively and tortuously slows. Reinhold Messner wrote of his first ascent of Mount Everest (8828m, barometric pressure 33.3kPa) without supplemental oxygen that �I am nothing more than a single narrow, gasping lung, floating over the mists and summits�. Thus, we come back to the lung as the primary and essential organ for human function and survival at high altitude without which the first step up could not be taken. At high altitude, respiration extracts utilizes a high proportion of the overall energy expenditure. In spite of a slight decrease in the work of breathing resulting from the lower density of the ambient air at high altitude, much greater volumes of air are necessary to supply enough oxygen to the body from atmospheric air, in which the level of oxygen is reduced. Delivery of oxygen is further impaired by a diffusion limitation of oxygen from the air to the blood, which increases with altitude. At extreme altitudes, a disabling sense of dyspnea is compounded by cerebral hypoxia, which may further limit exercise. Climbers to these heights have reported taking as many as 10 breaths per step as the rate of ascent progressively and tortuously slows. Reinhold Messner wrote of his first ascent of Mount Everest (8828m, barometric pressure 33.3kPa) without supplemental oxygen that �I am nothing more than a single narrow, gasping lung, floating over the mists and summits�. Thus, we come back to the lung as the primary and essential organ for human function and survival at high altitude without which the first step up could not be taken.

3. HOW HIGH IS HIGH-ALTITUDE? High altitude: 1,500-3,000m above sea level Very high altitude: 3,000-5,000m Extreme altitude: above 5,000m Highest peak of Ethiopia : Ras Dashau Highest peak of Central Andes of Chile/Argentina : Aconcagua, Highest peak of Ethiopia : Ras Dashau Highest peak of Central Andes of Chile/Argentina : Aconcagua,

6. On arrival at altitude, increased carotid body activity attempts to increase ventilation, and thereby to raise the arterial oxygen pressure back to the sea level value. However, this presents the body with a dilemma. An increase in breathing causes an increased excretion of carbon dioxide in the exhaled air. When CO2 is in body tissues, it creates an acid aqueous solution, and when it is lost in exhaled air, the body fluids, including blood, become more alkaline, thus altering the acid-base balance in the body. The dilemma is that ventilation is regulated not only to keep oxygen pressure constant, but also for acid-base balance. CO2 regulates breathing in the opposite direction from oxygen. Thus when the CO2 pressure (i.e., the degree of acidity somewhere within the respiratory centre) rises, ventilation rises, and when it falls, ventilation falls. On arrival at high altitude, any increase in ventilation caused by the low oxygen environment will lead to a fall in CO2 pressure, which causes alkalosis and acts to oppose the increased ventilation. Therefore, the dilemma on arrival is that the body cannot maintain constancy in both oxygen pressure and acid-base balance. Human beings require many hours and even days to regain proper balance. On arrival at altitude, increased carotid body activity attempts to increase ventilation, and thereby to raise the arterial oxygen pressure back to the sea level value. However, this presents the body with a dilemma. An increase in breathing causes an increased excretion of carbon dioxide in the exhaled air. When CO2 is in body tissues, it creates an acid aqueous solution, and when it is lost in exhaled air, the body fluids, including blood, become more alkaline, thus altering the acid-base balance in the body. The dilemma is that ventilation is regulated not only to keep oxygen pressure constant, but also for acid-base balance. CO2 regulates breathing in the opposite direction from oxygen. Thus when the CO2 pressure (i.e., the degree of acidity somewhere within the respiratory centre) rises, ventilation rises, and when it falls, ventilation falls. On arrival at high altitude, any increase in ventilation caused by the low oxygen environment will lead to a fall in CO2 pressure, which causes alkalosis and acts to oppose the increased ventilation. Therefore, the dilemma on arrival is that the body cannot maintain constancy in both oxygen pressure and acid-base balance. Human beings require many hours and even days to regain proper balance.

22. Twenty years ago, pioneering studies by Matthay et al. (3) revealed that alveolar fluid resorption in adult animals was not affected by manipulating Starling forces but via active transport of sodium (Na+) from the alveolar airspaces, across the alveolar epithelium, and into the pulmonary circulation. This creates an osmotic gradient that is responsible for the clearance of lung edema from the alveolar spaces (4�6). As depicted in Figure 1, Na+ uptake occurs on the apical surface of alveolar epithelial cells (AECs), predominantly through amiloride-sensitive Na+ channels (6, 7). (Amiloride is a specific Na+ channel inhibitor.) Subsequently, Na+ is actively extruded from the basolateral surface into the lung interstitium by the sodium potassium-adenosine triphosphatase (Na,K-ATPase); water follows because of the osmotic gradient (2, 8, 9). Experiments in human lungs, in situ animal models, and isolated rat lungs have demonstrated that lung liquid clearance is prevented by hypothermia�probably by inhibition of active metabolic processes for solute transport (10)�and inhibited by both amiloride and ouabain, a Na,K-ATPase inhibitor (8, 11, 12). The Na,K-ATPase is a plasma membrane enzyme that maintains electrochemical Na+ and K+ gradients across the plasma membrane by pumping Na+ out of the cell and K+ into the cell against their respective concentration gradients in an adenosine 5'-triphosphate-dependent process. Twenty years ago, pioneering studies by Matthay et al. (3) revealed that alveolar fluid resorption in adult animals was not affected by manipulating Starling forces but via active transport of sodium (Na+) from the alveolar airspaces, across the alveolar epithelium, and into the pulmonary circulation. This creates an osmotic gradient that is responsible for the clearance of lung edema from the alveolar spaces (4�6). As depicted in Figure 1, Na+ uptake occurs on the apical surface of alveolar epithelial cells (AECs), predominantly through amiloride-sensitive Na+ channels (6, 7). (Amiloride is a specific Na+ channel inhibitor.) Subsequently, Na+ is actively extruded from the basolateral surface into the lung interstitium by the sodium potassium-adenosine triphosphatase (Na,K-ATPase); water follows because of the osmotic gradient (2, 8, 9). Experiments in human lungs, in situ animal models, and isolated rat lungs have demonstrated that lung liquid clearance is prevented by hypothermia�probably by inhibition of active metabolic processes for solute transport (10)�and inhibited by both amiloride and ouabain, a Na,K-ATPase inhibitor (8, 11, 12). The Na,K-ATPase is a plasma membrane enzyme that maintains electrochemical Na+ and K+ gradients across the plasma membrane by pumping Na+ out of the cell and K+ into the cell against their respective concentration gradients in an adenosine 5'-triphosphate-dependent process.