High Altitude Physiology - Complete MD Exam Answer (10 Marks)

1. DEFINITION OF HIGH ALTITUDE

2. THE OXYGEN CASCADE AT HIGH ALTITUDE

• Sea level: PB = 760 mmHg, Inspired PO₂ = 159 mmHg, PaO₂ = 90-95 mmHg
• 4570 m (15,000 ft): PaO₂ = 48-53 mmHg, SaO₂ = 86%
• 8848 m (summit): PaO₂ = 26-33 mmHg, SaO₂ = 58%, PaCO₂ = 9.5-13.8 mmHg

3. ACCLIMATIZATION - ADAPTIVE RESPONSES

A. Pulmonary Acclimatization (Ventilatory Response)

• Hypoxemia is sensed by carotid body peripheral chemoreceptors
• Triggers hypoxic ventilatory response (HVR) - immediate rise in ventilation
• HVR raises alveolar PO₂ toward ambient PO₂
• Hyperventilation blows off CO₂ → respiratory alkalosis (↓PaCO₂, ↑pH)
• This alkalosis acts as a brake on the ventilatory drive (especially via medullary chemoreceptors)
• Net effect: ventilation at 4500 m is only ~2x sea level (not the maximal possible drive)
• Heart rate also increases due to sympathetic activation

• Over 4-7 days, ventilation progressively increases further
• Renal compensation - bicarbonate excretion normalizes pH → removes the brake
• Medullary chemoreceptors reset to lower PaCO₂ setpoint
• Final PaCO₂ at extreme altitude can fall to 9-14 mmHg
• Acetazolamide facilitates this by inducing bicarbonate diuresis (carbonic anhydrase inhibition)

B. Cardiovascular Acclimatization

• Sympathetic activation → tachycardia → increased cardiac output → compensates for decreased O₂ content
• Peripheral vasoconstriction → increased central blood volume

• Resting heart rate returns toward normal
• Pulmonary vasoconstriction (hypoxic pulmonary vasoconstriction - HPV) - redistributes blood flow to better-ventilated alveoli
• Right ventricular afterload increases (HPV is a double-edged sword)
• Blood volume initially contracts (from diuresis), then increases with polycythemia

C. Hematologic Acclimatization

• Within hours: serum erythropoietin (EPO) rises (HIF-1α mediated hypoxic response)
• Over days to weeks: red cell mass increases (polycythemia)
• Hematocrit rises (up to 55-60% at very high altitudes)
• 2,3-DPG (2,3-bisphosphoglycerate) increases → right shift of Hb-O₂ curve → facilitates O₂ unloading in tissues
• Respiratory alkalosis simultaneously produces a left shift → facilitates O₂ loading in lungs
• These opposing effects largely cancel out (Haldane effect)

D. Tissue/Cellular Acclimatization

• Increased capillary density in skeletal muscle (angiogenesis via VEGF)
• Increased mitochondrial density
• Shift to more efficient oxidative metabolism
• HIF-1α activates genes for glycolysis, erythropoiesis, angiogenesis, and vasomotor tone

E. Renal Acclimatization / Fluid Balance

• Peripheral venous constriction → increased central blood volume → triggers diuresis and natriuresis (via ANP, suppressed ADH)
• Plasma volume falls (hemoconcentration in early phases)
• Renal bicarbonate excretion compensates for respiratory alkalosis
• Aldosterone may increase in some individuals → sodium/water retention (a maladaptive response, promoting AMS)

F. CNS Acclimatization

• Cerebral blood flow increases acutely (hypoxic vasodilation) - helps maintain O₂ delivery
• Hyperventilation reduces PaCO₂ → cerebral vasoconstriction (counteracts the above)
• Net: modest cerebral vasoconstriction but maintained O₂ delivery
• Sleep is disturbed at altitude - periodic breathing (Cheyne-Stokes respiration) occurs due to oscillations in hypoxic/hypocapnic drives; more hypoxemia during sleep than waking

4. MALADAPTATION - ALTITUDE ILLNESSES

A. Acute Mountain Sickness (AMS)

• Incidence: 22-50% at 1850-4240 m
• Onset: 6-12 hours after arrival; peaks at 24-48 hours
• Lake Louise Criteria: headache + at least one of nausea/vomiting, fatigue/weakness, dizziness, poor sleep
• Pathophysiology: vasogenic cerebral edema from hypoxia-driven neuroinflammation, impaired cerebrovascular autoregulation, and raised ICP
• Treatment: acetazolamide 250 mg BD, dexamethasone 4-8 mg, supplemental O₂; descent if severe

B. High-Altitude Cerebral Edema (HACE)

• Severe end of AMS spectrum - life threatening
• Features: severe headache, ataxia (tandem gait failure), altered consciousness, papilledema
• Pathophysiology: vasogenic and cytotoxic edema, raised ICP, possible cerebral herniation
• Treatment: immediate descent is mandatory; dexamethasone 8 mg IV/IM/PO then 4 mg q6h; portable hyperbaric bag (Gamow bag); supplemental O₂

C. High-Altitude Pulmonary Edema (HAPE)

• Most lethal form of altitude illness; mortality >50% if untreated
• Incidence: 0.5-15% depending on altitude and rate of ascent
• Onset: 2-4 days after ascent above 2500 m
• Features: dry cough → frothy pink sputum, dyspnoea at rest, cyanosis, decreased exercise tolerance, crackles on auscultation
• Pathophysiology:
  • Exaggerated HPV → uneven pulmonary vasoconstriction → overperfusion of some capillary beds → non-cardiogenic pulmonary edema from elevated capillary pressure
  • HAPE-susceptible individuals have intense HPV and exaggerated pulmonary vascular responses
  • Inflammatory cells and mediators also contribute
• Treatment: descent 300-1000 m immediately; nifedipine 30 mg slow-release (↓pulmonary vascular resistance); supplemental O₂ is most effective; tadalafil/sildenafil (PDE5 inhibitors) as alternatives; dexamethasone; portable hyperbaric chamber

5. CHRONIC MOUNTAIN SICKNESS (Monge's Disease)

• Affects long-term high-altitude residents
• Features: excessive polycythemia (Hct >55%), headache, fatigue, cyanosis, right heart failure (cor pulmonale)
• Pathophysiology: Hb >21 g/dL → hyperviscosity → reduced O₂ delivery paradoxically
• Treatment: phlebotomy, descent, acetazolamide, medroxyprogesterone

6. HIGH-ALTITUDE RETINOPATHY

• Retinal hemorrhages at >5000 m; usually asymptomatic unless affecting the macula
• Due to increased retinal blood flow and vessel permeability under hypoxic conditions
• Flame-shaped and dot hemorrhages on fundoscopy

7. PHARMACOLOGY AT HIGH ALTITUDE

8. KEY PRINCIPLES FOR PREVENTION

• "Climb high, sleep low" principle
• Acclimatization above 3000 m: ascend no more than 300-500 m per day in sleeping altitude
• Rest day every 3rd day
• Acetazolamide prophylaxis: 125-250 mg BD starting 24 h before ascent
• Fitness does NOT protect against altitude illness

9. SUMMARY TABLE - PHYSIOLOGICAL CHANGES AT HIGH ALTITUDE