High Altitude Sickness: Experiment to Determine low PO2 not low Baro, Treatment and Acclimitisation

How does pulmonary diffusing capacity change in acclimatisation?

- Acclimatization to high altitude causes two-three fold increase in pulmonary diffusion capacity: - Much of increase due to increase in blood volume of pulmonary capillaries, and to associated increase in capillary surface area available for diffusion. - Surface area expands further due to hypoxia stimulated increase in depth of inspiration. - Right ventricular hypertrophy increases pulmonary arterial pressure, increasing perfusion of the upper, well-ventilated regions of the lungs.

What causes AMS and HACE?

- Acute mountain sickness (AMS) and high-altitude cerebral oedema strike people who travel too fast to high altitudes that lie beyond their current level of acclimatization. - As altitude increases, barometric pressure falls. This fall in barometric pressure causes a corresponding drop in the partial pressure of oxygen (21% of barometric pressure) resulting in hypobaric hypoxia. - Hypoxia is the major challenge humans face at high altitude, and the primary cause of AMS and HACE

What is the most important factor against pulmonary hypertension?

- Although being physically fit provides some protection, most important factor is an undefined constitutive difference. - Least likely to develop ventilate more in response to hypoxia, tend to have higher PO2 and lower PCO2. - Higher PO2 and lower PCO2 typically lead to less cerebral vasodilation, higher PO2 minimizes pulmonary vasoconstriction

How is altitude adapted for?

- Although increases in ventilation and heart rate help maintain O2 delivery in acute hypoxia, costly from energy perspective, cannot be sustained for extended periods: - During prolonged residence at high altitude, reduced arterial PO2 triggers significant adaptations. - Changes enhance O2 delivery to tissues at cost lower than that exacted by short-term compensatory strategies. - Many adaptations as a result of increase in hypoxia inducible factor 1 (HIF- 1), which is a transcription factor that activates genes involved in erythropoiesis, angiogenesis and other processes.

What is the action of acetazolamide?

- Carbonic anhydrase inhibitor. - Carbonic anhydrase (CA) catalyzes the forward motion of molecules in the following equation: - CO2+H2O»H2CO3»H+ +HCO3. - In the kidneys, blocking CA leads to bicarbonate wasting in the tubules (alkalizes urine), loss of bicarbonate subsequently leads to a metabolic acidosis. In the meantime, H+ backs up due to acetazolamide CA inhibition in the tubule and enters the cell with Cl, then passes into the bloodstream, creating a hyperchloremic metabolic acidosis. - The drug forces the kidneys to excrete bicarbonate, the conjugate base of carbonic acid. By increasing the amount of bicarbonate excreted in the urine, the blood becomes more acidic. Acidifying the blood stimulates ventilation, which increases the amount of oxygen in the blood. - Sometimes taken prophylactically for acute mountain sickness not immediate fix, speeds up part of acclimatization process, taking up to day or two before.

What protects against altitude sickness?

- During first few days of exposure to high altitude, compensatory adjustments in both respiratory and CV system occur: tachycardia and hyperventilation, to improve oxygen supply to blood, and delivery of this oxygen to peripheral tissues

What is the action of EPO?

- EPO binds to cell surface erythropoietin receptors expressed on BFU-E cells. Triggers formation of pro-erythroblast progenitor cells. - Synthesised and secreted from kidney and liver cells, in periods of hypoxia or low RBC levels due to haemolytic anaemia. - Hypoxia promotes the availability of heterodimeric (α/β) hypoxia- inducible transcription factors (predominantly HIF-2) which stimulate the Epo enhancer.

What is the effect on cerebral blood flow of hypoxia?

- Effect of acute hypobaric hypoxia is to increase cerebral blood flow, but increase is limited by concomitant reduction in PaCO2, occurring as a result of hyperventilation. - Cerebral vasculature: PCO2 and hypoxia both potent stimulators of vasodilation for increased blood flow: maintenance of cerebral oxygen delivery critical factor for survival at high altitude, overall CBF determined by balance between hypoxic vasodilation and hypocapnia induced vasoconstriction. - Increased CO2 blow off due to increased ventilatory drive vasoconstriction, reduced blood flow to brain. - Cerebral autoregulation: process maintaining cerebral perfusion as BP varies is impaired in hypoxia, occurring in both acute exposure and native individuals.

How does the erythropoietin response occur?

- Erythropoietin response rapid, increased concentrations detectable 2 hours after arrival at altitude - EPO response peaks at 2 days, and provided remains at same altitude, EPO release returned to sea level values after three weeks. - Despite return to sea level concentrations, erythropoiesis continues at above base line levels. - If subject ascends to higher altitude, increased hypoxia will continue to trigger EPO production. - After 6 weeks, despite continuing increase in erythropoiesis and RBC mass, Hb concentration starts to plateau off, due to increase in plasma volume

What changes occur to the pulmonary circulation due to hypobaric hypoxia?

- Exposure to hypobaric hypoxia produces pulmonary vasoconstriction, resulting in pulmonary hypertension proportional to degree of hypoxia. - Hypoxic pulmonary vasoconstriction non-linear, highly variable between individuals. - In normal, lowland responders, commences at PAO2 of 75mmHg, corresponding to altitude of 2000m. - Pulmonary pressor response enhanced with exercise, with pulmonary artery pressure rising as high as 55-60mmHg during exercise at extreme altitude. - Normal is around 14mmHg at rest at sea level.

Symptoms of pulmonary hypertension

- Fatigue, dizziness, dyspnea. May progress to swelling in abdomen, ankles or legs, and syncope may occur. - Pulmonary oedema (HAPE), occurs as hypoxia leads to hypoxic pulmonary vasoconstriction, leading to increase in total pulmonary vascular resistance, pulmonary capillary pressure and transudation. - Worsens uptake of oxygen further, exacerbates low PAO2 and low gradient. o Certain individuals have exaggerated pulmonary vascular response, especially susceptible to AMS. - Cerebral and pulmonary oedema can be fatal if exposure to hypoxia not reversed, first by supplemental oxygen to breathe, then removal of individual from altitude.

What is the effect of hypobaric hypoxia on cognitive function?

- Generally accepted exposure to hypobaric hypoxia impairs cognitive function. - Expect degree of dysfunction proportional to altitude, but in fact changes are first seen at low altitude. - Impairment of task learning demonstrated at heights of 2440m, although this only influences performance if task is unfamiliar. - Acclimatization appears to give some degree of protection, yet clear evidence of residual impairment to CNS function after high altitude, which persists for up to 1 year after exposure.

How is high altitude defined?

- Height greater than 3000m above sea level, height at which medical problems and acute changes to physiology first observed. - Exposed to significantly reduced barometric pressure and consequently PO2 in air at altitude, significant physiological adaptations required to maintain respiration in active tissues to compensate for reduced oxygen supply.

What changes occur to capillary density from hypoxia?

- Hypoxia induces dramatic increase in tissue vascularity. - Tissue angiogenesis occurs within days of exposure to high altitude, triggered by growth factors that hypoxic tissues release. - Include vascular endothelial growth factor, fibroblast growth factor and angiogenin.

What changes occur to oxidative enzymes from hypoxia?

- Hypoxia promotes expression of oxidative enzymes in mitochondria, thereby enhancing tissue's ability to extract oxygen from blood. - Acclimatisation to high altitude therefore not only increases oxygen delivery, but also increases oxygen uptake by tissues.

What happens to the pulmonary circulation after acclimatisation?

- In acute exposure to hypoxia, breathing oxygen restores pulmonary pressure to sea level values, but once acclimatisation has occurred, this no longer happens. - Effect can be seen from 3 weeks after exposure, indicating even after relatively short period, structural changes occurring in pulmonary arteries. - First described 1946, only in recent years evident that dynamic control of pulmonary vascular pressure dependent on mediators released from vascular endothelium: - In particular on endothelial derived relaxing factor (NO), prostacyclin, thromboxane, endothelin and ANP. - Interplay of these factors in control of circulation at altitude remains unclear.

What is the effect of increasing Hb concentration?

- Increase in Hb concentration has effect of increasing arterial oxygen content of the blood for any given oxygen saturation. - Well acclimatized individual will have similar CaO2 and oxygen delivery as at sea level, since CO unchanged, at altitudes of up to 5500m.

What is increased ventilatory drive accompanied by?

- Increased ventilatory drive in acute altitude exposure accompanied by increase in heart rate, probably due to increased sympathetic drive accompanying acute hypoxaemia. - Increase in CO enhances oxygen delivery to tissues.

How is red blood cell mass stimulated?

- Normally red blood cell mass regulated within fairly narrow range, but renal hypoxia and NA release stimulates production and release of erythropoietin from interstitial cells of the peritubular capillary bed. - EPO growth factor acting on precursor cells of the bone marrow to produce proerythroblasts, and promotes accelerated development of RBCs from their progenitor cells.

Experimental Evidence: Hypoxic hypobaric altitude sickness

- Paul Bert - published summary of work on physiological effects of altering barometric pressure in 1878. - Before work, theory of low barometric pressure on surface of skin cause of dilating surface blood vessels, leading to bleeding from internal vessels and rupture. - Initial experiment: sparrow placed in bell jar, air pumped out until sparrow fell over apparently dead: admitted oxygen from adjoining bag, raising oxygen percentage and reviving sparrow. - Resumption of pumping resulted in collapse of sparrow at lower barometric pressure than before. - Rescue and further decompression could be repeated. - Results pointed to conclusion that mountain sickness due to lack of oxygen not barometric pressure: continued to ascertain whether less oxygen in arterial blood as result of circumstance. - Used double chamber operated by steam pump: dog tied down on circular frame, 33-46ml sample of arterial blood drawn as control when dog breathed atmospheric air. - Carotid artery cannulated, connected with tubing through wall of decompression chamber: blood aspirated despite decompression. - Chamber closed, decompressed to appropriate altitude: found significant decline in arterial oxygen concentration at inspired oxygen pressures corresponding to altitudes producing mountain sickness. - Final confirmation: Bert decompressed until experienced nausea, tachycardia at effective altitude of Mont Blanc (4807m): inhaled oxygen found that each breath of oxygen relieved both tachycardia and symptoms, returned after inhaling of oxygen stopped. - Breathing oxygen constantly kept pulse rate down despite further decompression to 1/3 atmospheric pressure (peak of Mount Everest).

What is physiologic polycythemia?

- Physiologic polycythemia involves an increased in proportion of the blood volume occupied by red blood cells, as a result of erythropoietin production. - Red blood cell mass slowly increases with prolonged hypoxaemia. - Haemoglobin concentration of blood increases from sea level value of 14-15g/dL, to values exceeding 18g/dL, and haematocrit rises from 40-45% to above 55%.

What is the physiological cause of chronic mountain sickness?

- Prolonged residence at high altitude. - Overproduction of RBCs, an exaggerated response to hypoxia. - Haematocrit can exceed 60%, thereby dramatically increasing blood viscosity, vascular resistance and increasing risk of thrombosis. - Combination of pulmonary hypoxic vasoconstriction and increased blood viscosity: increased afterload on heart, especially right side. - Conditions eventually lead to congestive heart failure of the right ventricle.

What are the symptoms of ascent to high altitude?

- Rapid ascent to high altitude may precipitate a constellation of mild symptoms, including drowsiness, fatigue, headache, nausea and decline in cognition. - Uncomfortable effects of acute hypoxia progressive with increasing altitude. - Some show symptoms at as low as 2100m, yet most only begin at 3500m. - Initially symptoms reflect inadequate compensatory response to hypoxaemia (vasodilation in brain), resulting in reduced oxygen delivery to the brain. - In longer term, symptoms may stem from mild cerebral oedema, resulting from dilation of cerebral arterioles, leading to increased capillary filtration pressure and enhanced transudation.

What does a reduction in arterial PO2

- Reduction in arterial PO2 stimulates peripheral chemoreceptors, causing immediate increase in ventilation: - Exposure to even mild hypoxia stimulates the peripheral chemoreceptors as witnessed by the increase in activity in the carotid sinus nerve. - Increased ventilation brings alveolar PO2 and therefore PaO2 closer to ambient PO2. - Also blows off CO2, producing a respiratory alkalosis, which inhibits peripheral, and especially the central chemoreceptors, decreasing ventilatory drive. - Increases the pH around the central medullary chemoreceptors causing them to exert an equal and opposite inhibitory effect opposing any increase in ventilation. - With increasing acute hypoxia peripheral chemoreceptor stimulation exceeds the central inhibition and ventilation increases.

Experimental Evidence: Effect of altitude on cerebral blood flow

- Severinghaus showed a 24% increase in cerebral blood flow after 6-12 hours of exposure to altitude of 3810m, in comparison to sea level, which had fallen to 13% above normal after 3-5 days. - Similar increases seen in both carotid and vertebral artery flow

Clinical Relevance: Acute Mountain Sickness

- Some who ascend rapidly to altitudes of 3000-3500m develop acute mountain sickness. - Symptoms: headache, fatigue, dizziness, nausea, dyspnea, sleep disturbance, peripheral oedema and vomiting, usually develop within first day, and last 3-5 days. - Primary problem is hypoxia, symptoms have two causes: - Progressive, more severe case of cerebral oedema (HACE). - Vasogenic oedema, could be caused by chemical mediators, mechanical disruption of BBB or both. - Mechanical disruption - cerebral capillary hypertension: evidence for impaired cerebral autoregulation, failure to reduce flow in response to raised BP. - The list of potential chemical mediators of BBB leak in cerebral oedema includes bradykinin, histamine, arachidonic acid, oxygen and hydroxyl free radicals, and perhaps iNOS- generated nitric oxide. - May also be stimulation of BBB by central NA output (Raichle et al 1978), could play role in BBB leak.

What is high altitude sickness?

- When effects of hypoxia outstrips ability to acclimatize, number of symptoms occur collectively known as high altitude sickness. - Occurs at variable heights in different individuals, typically above 3000m when acute exposure without time for acclimatization, but can begin as low as 2100m.

What is the action of nifedipine?

- useful in treating high altitude pulmonary oedema. - Calcium channel blocker, primarily on vascular smooth muscle cells by stabilizing voltage-gated L-type calcium channels in their inactive conformation. By inhibiting the influx of calcium in smooth muscle cells, nifedipine prevents calcium-dependent myocyte contraction and vasoconstriction. - Counteracts pulmonary hypoxic vasoconstriction.

What is the action of dexamethasone?

Dexamethasone is effective for preventing and treating AMS and HACE, and perhaps HAPO as well. Unlike acetazolamide, if the drug is discontinued at altitude before acclimatization, rebound can occur. Acetazolamide is preferable to prevent AMS while ascending, with dexamethasone reserved for treatment, as an adjunct to descent. Steroid with anti-inflammatory and immunosuppressant effects, used to treat high altitude cerebral oedema.

What will this essay discuss?

Discuss causes and symptoms of high altitude sickness, seminal experiments identifying cause is hypoxia, and how slow ascents and drugs can be used to combat sickness.

Why is a slow ascent important for AMS?

Slow ascent permits acclimatization and longer term adaptations to occur for improved resistance against low PO2.