2009A16 Outline the effects of acute exposure to air at altitude where barometric pressure is 347mmHg.
What compensatory mechanisms occur with gradual exposure to increasing altitude?

Summary

·   Rapid equilibration of atmosphere and alveolar air

·   Severe hypoxaemia

·   Loss of consciousness (LOC) and death unless brief

·   Insufficient time for compensation as outlined below

Mechanism of hypoxia

·   Alveolar gas equation: PAO₂ = FiO₂(P_atm – P_SVP-H2O) – PaCO₂/R

·   = 0.21 (347 – 47) -  40/0.8 = 63-50 = 13mmHg

·   PaO₂ <10mmHg due to diffusion limitation and venous admixture

Time to unconsciousness

·   ∝ 1/Cardiac index

o Circulation time from lung to brain: ~8 seconds

·   ∝ 1/CMRO₂

o Time from brain ischaemia to LOC: 5-20 seconds

·   Faster in children than adults (hence put your own mask on first)

Acute mountain sickness

·   Symptoms: headache, dizziness, nausea, fatigue, insomnia

·   Cause: ↓PaO₂, ↑PaCO₂

HAPE

·   Uneven HPV -> ↑↑blood flow through damaged capillaries -> ↑transudation

Right heart failure

·   Excessive HPV -> ↑mPAP -> ↑RV afterload -> failure

HACE

·   Cause: ↓PaO₂ -> cerebral vasodilation -> ↑transudate

·   Can result in coma, herniation and death

↑VA (most important)

·   Sensor:

o ↓PaO₂ sensed by peripheral chemoreceptors

o Carotid > aortic bodies

o Sensitive to PaO₂, especially if <60mmHg

·   Controller:

o ↑Stimulation of medullary resp centre

·   Effector:

o ↑Resp rate, ↑tidal volume -> ↑V_A -> ↓PACO₂ -> ↑PAO₂

o PACO₂ ∝ VCO₂ / V_A

·   Limitation:

o Note ↓PaCO₂ and ↑pH inhibit chemoreceptors

HPV

·   HPV ∝ 1/PAO₂^0.6 x PvO₂^0.4)

·   Phase 1: onset immediate, max at 5 mins

o ? K channel closure, ? ↓mitochondrial ROS, ? ↓ATP:ADP

·   Phase 2: onset 40 mins, max at 2 hours

o ?↑↓COX/LOX, ?↑↓gene expression

·   Effect:

o Local: matches ventilation to perfusion

o Global: causes more uniform distribution of pulmonary blood flow

Shift of OHDC

·   Moderate altitude: main effect ↑2,3-DPG -> right shift

o ↑Tissue uptake

·   High altitude: main effect ↓PaCO₂, ↑pH -> left shift

o ↓Tissue uptake (maladaptive)

o Minimal increase in pulmonary uptake due to flat upper part of curve

Central ischaemic response

·   Brainstem ischaemia -> ↑↑SNS output -> ↑cardiac output -↑DO₂ but also ↑VO₂

·   Occurs if PaO₂ <60mmHg

Plasma acidification

·   Of blood: ↓HCO₃^- reabsorption in kidney (~3 days)

o R shift OHDC -> ↑O₂ tissue uptake

o ↓inhibition of chemoreceptors -> further ↑VA

·   Of brain: ↑HCO₃^- efflux from CSF hence brain ECF (~1 day)

o ↓Inhibition of central chemoreceptors

·   This allows further increase in V_A

Increased ventilatory response

·   ↑Sensitivity of carotid bodies to ↓PaO₂ -> ↑V_A

·   ↑Sensitivity of respiratory centre to chemoreceptor input -> ↑V_A

RV hypertrophy

·   Global HPV -> ↑PA pressure -> ↑afterload, wall tension

Erythropoiesis

·   ↓pO₂ in renal interstitium -> ↑EPO -> erythropoiesis

·   ↑Hb (150-200g/L max)

·   ↑Hct (0.45 -> 0.6 max)

·   ↑CaO₂ (15 -> 20mL/100mL)

·   Note also ↑viscosity, ↑resistance to blood flow, ↑risk VTE

↑Tissue oxidative capacity

·   ↑VEGF expression -> angiogenesis -> ↓O₂ diffusion distance

·   ↑Mitochondria

·   ↑Myoglobin

·   ↑Oxidative enzymes e.g. Krebs cycle

·   All allow increased EO₂

From childhood

·   Alveolar hyperplasia -> ↑surface area

·   Hyperventilation -> Barrel chest -> ↑lung volume -> ↑alveolar surface area

·   ↓Ventilatory response to hypoxia

·   ↓Body size -> ↓VO₂

Across generations

·   ↑Expression of hypoxia-inducible transcription factors

·   Highest human habitation ~6000m

Problems not related to hypoxia

·   Cold exposure

·   UV light -> skin cancer

·   Cosmic radiation -> cancer