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?

List:

· Acute exposure: 347mmHg

· Acute exposure: other adverse effects

· Immediate compensation

· Short-term compensation

· Medium term compensation

· Long term compensation

· Other

Acute exposure: P_atm = 347mmHg

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(Patm – PSVP-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 exposure: other adverse effects

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

Immediate compensation (<1 minute)

↑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 -> ↑VA -> ↓PACO2 -> ↑PAO2 o PACO2 ∝ VCO2 / VA · 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

Short term compensation (1-3 days)

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 VA
Increased ventilatory response	· ↑Sensitivity of carotid bodies to ↓PaO2 -> ↑VA · ↑Sensitivity of respiratory centre to chemoreceptor input -> ↑VA

Medium term compensation (~3 weeks):

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

Long term compensation:

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

Other: (from examiner’s report)

Problems not related to hypoxia

· Cold exposure · UV light -> skin cancer · Cosmic radiation -> cancer