53.3 Life at High Altitude

Question 1

What are some of the challenges of being at high altitude?

Answer 1

• Temperature
• Humidity
• Solar radiation
• Remoteness
• Hypoxia

Question 2

At high altitudes, is there hypocapnia or hypercapnia?

Answer 2

Hypocapnia

Question 3

What is acute mountain sickness?

[IMPORTANT]

Answer 3

• Sickness that occurs during an ascent, typically before you acclimatise
• Risk factors include:
  
  • Speed of ascent
  • Final altitude
  • Individual predisposition
• Defined as headache and Lake Louise Score >3, in setting of recent ascent

Question 4

What is high altitude cerebral oedema (HACE)? What are the symptoms and treatment?

Answer 4

• Severe swelling of the brain due to fluid.
• Symptoms:
  
  • Headache, malaise, ataxia, confusion and coma
• Treatment:
  
  • Descent
  • Decompression
  • Oxygen
  • Dexamethasone [IMPORTANT]

Question 5

What are the causes of high altitude cerebral pulmonary oedema?

Answer 5

• Hypoxia leads to increased cerebral blood flow, increased cerebral blood volume and increased permeability of the BBB

Question 6

What is high altitude pulmonary oedema (HAPE)? What are the causes, symptoms and treatment?

Answer 6

• Severe swelling of the lungs due to fluid accumulation
• Causes:
  
  • Widespread pulmonary vasoconstriction upon ascent to high altitudes
  • Strong individual predisposition
  • Leading cause of death at high altitudes
• Symptoms:
  
  • Dry cough, then pink frothy sputum and progressive hypoxia
• Treatment:
  
  • Descent
  • Oxygen
  • Nifedipine [IMPORTANT] -> Calcium channel blocker that reduces vasoconstriction

Question 7

What is the treatment for altitude sickness?

Answer 7

• Altitude sickness -> Acetazolamide can be taken in advance to prepare:
  
  • This is a carbonic anhydrase inhibitor
  • It increases renal bicarbonate loss
  • Therefore, it gives a head start to acclimatisation to high altitudes since renal excretion of bicarbonate is required for central chemoreceptor adaptation and it is usually slow

Question 8

What is the treatment for high altitude cerebral oedema?

Answer 8

• High altitude cerebral oedema -> Dexamethasone:
  
  • This is a steroid
  • It acts to decrease inflammation and thus it prevents oedema, but the exact mechanism of action is not known

Question 9

What is the treatment for high altitude pulmonary oedema?

Answer 9

• High altitude pulmonary oedema -> Nifedipine
  
  • This is a calcium channel blocker, quite specific to the lungs
  • It acts to decrease vasoconstriction of the lungs, which prevents oedema

Question 10

What are the chronic haematological changes?

Answer 10

*↑regulation of erythropoietin
*Metabolic adaptations mediated by HIF (e.g. ↑ glycogen stores in Sk.muscle + changes to glucose metabolism)

Question 11

What happens to HIF in normal conditions?

Answer 11

Normoxia → ↓ [HIF]. Von Hippel-Lindau protein (w/ its ubiquitin ligase activity) tags HIF-α for degradation by proteosome complex

Question 12

What happens to HIF in hypoxic conditions and how does this allow it to regulate EPO?

Answer 12

Hypoxia → ROS production in Mit. inhibits prolyl hydroxylation of HIF-α by VDL-protein → HIF accumulation → TFs that bind to HRE in DNA → ↑-reg HRE expression (e.g. VEGF + EPO genes) → ↑ effector protein expression involved in O2 delivery + utilisation

Question 13

What is EPO? Where is it synthesised and what is its effect?

Answer 13

Erythropoietin
*Synthesised by interstitial cells of renal cortex (main) + perisinusoidal liver cells + pericytes of brain
*Jak2 cascade signalling → EPO induces erythroid progenitor cells to differentiate into mature RBCs → ↑ haematocrit → ↑ O2 blood content

Question 14

What can excessive polycythaemia lead to?

Answer 14

Excessive polycythaemia → ↑ blood viscosity → disrupts flow of blood through pulmonary capillaries → ↓ alveolar gaseous exchange → hypoxaemia.

Question 15

What is polycythemia?

Answer 15

A condition where there is an increased number of RBCs.

Question 16

What can cause polycythemia?

Answer 16

HIF upregulation (or other changes in the HIF pathway), which leads to increased EPO production and thus RBC production.

Question 17

How does polycythaemia affect oxygen delivery to tissues?

Answer 17

Polycythemia slows blood flow, which decreases oxygen delivery to tissues.

Question 18

What happens to pulmonary arterial pressure at high altitudes?

Answer 18

It increases due to vasoconstriction.

Question 19

Why does pulmonary vasoconstriction occur and is it always helpful?

Answer 19

• It occurs in hypoxic areas of the lungs
• This preserves flow to better oxygenated parts of the lungs, optimising ventilation/perfusion matching
• This is useful when it is local (e.g. in pneumonia) but it is harmful when it is widespread (e.g. at altitude)

Question 20

How does high altitude affect haemoglobin levels affected by altitude?

Answer 20

High altitude leads to high levels of haemoglobin.

Question 21

Give an example of a maladaptive change that happens at high altitude.

Answer 21

Maladaptive changes: HPV → HAPE + CMS
*Hypoxia → systemic vasculature dilates + pulmonary vessels constrict
- Beneficial when hypoxia acute + localised to lungs (e.g. pneumonia) - allows V/Q mismatch to be corrected
- Chronic (e.g. high altitude/ COPD) → pathological. Can cause pulmonary vascular remodelling + pulmonary HT → fluids drawn from from blood to lung tissue parenchyma due to ↑ starling forces → High-altitude pulmonary oedema (HAPE)

Question 22

What are the acute haematological changes?

Answer 22

*Dehydration at ↑ altitude → ↓ plasma vol → haemoconcentration ([Hb] ↑ relative to plasma vol → ↑ O2 carried in blood)
*Leftward (Bohr) shift in O2-dissociation curve
*Also rightward shift:

Question 23

How does a Leftward (Bohr) shift in O2-dissociation curve happen and how is this beneficial?

Answer 23

Respiratory alkalosis + ↓ PaCO2 from hyperventilation → ↓ [H+] binding to Hb → ↑ Hb binding affinity for O2 → ↑ SaO2 at given PaO2 → ↑ loading efficiency

Question 24

How does a Rightward (Bohr) shift in O2-dissociation curve happen and how is this beneficial?

Answer 24

E.g. 2,3-DPG production → ↑ RBC glycolysis (due to ↑regulation of erythropoietin) → ↓ Hb affinity for O2 → ↑ unloading efficiency.

Question 25

Where does a leftward/ rightward Bohr shift happen?

Answer 25

Cannot definitively say curve shifts systematically left/ right → perhaps curve shifts in different directions depending on function of certain tissue
E.g. lungs → ↑ loading efficiency (left), peripheral tissue → right - ↑ unloading efficiency (adequate perfusion)

Question 26

What are the acute CV adaptations?

Answer 26

*Peripheral ChemoRs stimulated → ↑ sympathetic drive → ↑ cardiac inotropy + chronotropy (↑ SAN firing) → ↑ CO → maximises O2 delivery to hypoxic tissues
*Dilation of systemic vasculature - vasodilator production (e.g. NO) → ↑ blood flow → ↑ O2 delivery

Question 27

What is the chronic effect of high altitude on the CV system?

Answer 27

Long term → acute changes abate w/ time → HR returns to baseline
*Suggested partly due to attenuated effects of catecholamines over prolonged exposure + ↓ sympathetic tone.

Question 28

How does high altitude increase ventilation initially?

Answer 28

*O2 atmospheric pressure ↓ as altitude ↑ → inspired + alveolar pO2 ↓ → ↓ arterial O2 saturation → hypoxaemia → hypobaric hypoxia
*↓ arterial pO2 1st detected by peripheral arterial chemoreceptors in carotid bodies → stimulate respiratory centre in medulla oblongata via glossopharyngeal/ vagus nerves → ↑ ventilation
*One of 1st physiological changes seen in acute high altitude exposure (w/in hours)

Question 29

What does increased ventilation cause at high altitude?

Answer 29

↑ ventilation → ↑ CO2 unloading → hypocapnia + respiratory alkalosis
*Detected by central chemoreceptors as ↓ [H+] in CSF → limit ventilation rate
*Competing balance → Cheynes-Hayes breathing (esp prevalent at night, impacting sleep quality. Tends to abate w/ time)
*Alternating phases of hyperpnoea + hypopnoea (induced by hypoxia/ hypocapnia resp.)

Question 30

What is the chronic respiratory adaptation to high altitude?

Answer 30

Respiratory acclimatisation → over days/ long-term minute ventilation shows progressive rise (reflecting balance reached between competing effects of hypoxia + hypocapnia)

Question 31

What is the mechanism driving the shift in balance to favour hyperventilation?

Answer 31

Exact mechanism driving shift in balance to favour hyperventilation unknown.
Suggested both central + peripheral adaptations
*↑ sensitivity of CCR to PaCO2 → ↓ effect of ↓ PaCO2 on ventilation
*Renal compensation for alkalosis/ hypocapnia → ↑ bicarbonate secretion → ↑ sensitivity of CCRs
*↓ plasma [HCO3-] → ↓ CSF HCO3– → ↓ inhibition of ventilatory centres by CCRs
*↑ sensitivity of PCRs to hypoxia → hyperventilation favoured over time.