High Altitude Physiology — Complete 15-Mark Answer

1. INTRODUCTION & ALTITUDE CLASSIFICATION

• At 5500 m (Everest Base Camp): PB = 380 mmHg; ambient PO₂ = 80 mmHg (½ sea-level values)
• At summit of Everest (8848 m): PB ≈ 255 mmHg; inspired PO₂ = 21% × (255 − 47) = 44 mmHg (vs. 149 mmHg at sea level)

2. IMMEDIATE EFFECTS OF HYPOBARIC HYPOXIA (Unacclimatized)

• CNS: Drowsiness, lassitude, headache, decreased mental proficiency (falls to 50% of normal after 1 hour at 15,000 ft), impaired judgment and memory
• At >18,000 ft: Twitching, seizures
• At >23,000 ft: Coma → death
• Sympathetic surge → catecholamine release → ↑ HR, ↑ cardiac output, ↑ BP, ↑ venous tone

3. ACCLIMATIZATION — MECHANISMS (Core of 15-mark Answer)

A. Ventilatory Acclimatization (Most Important)

• Carotid body chemoreceptors sense ↓ arterial PO₂ → signal medullary respiratory centre → hypoxic ventilatory response (HVR)
• Ventilation rises to ~1.65× normal within seconds
• This hyperventilation ↓ PaCO₂ → respiratory alkalosis → ↑ pH
• The resulting alkalosis inhibits the central respiratory centre, dampening the HVR

• Over 2–5 days, bicarbonate concentration in CSF and brain tissue falls (via renal bicarbonate excretion)
• ↓ CSF HCO₃⁻ → ↓ CSF pH → removes the central inhibition → ventilation rises to ~5× normal
• Maximum ventilation is reached after 6–8 days at a given altitude
• Renal compensation (metabolic compensation for respiratory alkalosis): kidneys excrete dilute alkaline urine, restoring pH toward normal
• Acetazolamide (carbonic anhydrase inhibitor) accelerates renal bicarbonate excretion, hastening acclimatization

Alveolar gas equation: PAO₂ = PIO₂ − (PACO₂/R) As PACO₂ falls (hyperventilation), PAO₂ rises — this is the cornerstone of acclimatization.

B. Haematological Acclimatization (Polycythaemia)

• Hypoxia stimulates erythropoietin (EPO) release from peritubular cells of the kidney
• Over days to weeks: haematocrit rises from 40–45% → ~60%; haemoglobin from 15 g/dL → ~20 g/dL
• Blood volume increases by 20–30%
• Total body Hb increases by >50%
• This dramatically increases oxygen-carrying capacity

C. 2,3-Bisphosphoglycerate (2,3-BPG) — Haemoglobin Affinity Shift

• Respiratory alkalosis at altitude inhibits red cell glycolysis (via ↑ pH), initially shifting the O₂-Hb curve left (↑ affinity — beneficial for O₂ loading)
• Within hours, 2,3-BPG rises (pH normalizes → glycolysis resumes; also direct hypoxic induction)
• ↑ 2,3-BPG shifts the O₂-Hb curve right (↓ affinity), facilitating O₂ unloading to tissues at low PO₂
• At extreme altitude, the leftward shift from alkalosis may be more beneficial (improves O₂ loading) — a complex balance

D. Cardiovascular Acclimatization

• ↑ cardiac output by ~30% (↑ HR, ↑ stroke volume) — mediated by sympathetic activation
• Peripheral vasodilation in systemic tissues improves O₂ delivery

• Cardiac output returns toward normal as haematocrit rises (more O₂ per unit blood flow)
• Capillary angiogenesis in peripheral tissues (especially active muscle): ↑ capillary density → shorter diffusion distance for O₂
• Right ventricular hypertrophy due to pulmonary hypertension
• Pulmonary vasoconstriction (hypoxic pulmonary vasoconstriction, HPV): all alveoli have ↓ PO₂ → generalised pulmonary arteriolar constriction → ↑ pulmonary artery pressure → right heart strain

E. Pulmonary Acclimatization

• ↑ Pulmonary diffusing capacity: normal is ~21 mL O₂/mmHg/min; increases up to 3-fold at altitude
  • Mechanisms: ↑ pulmonary capillary blood volume (expanding alveolar surface); ↑ lung air volume; ↑ pulmonary arterial pressure recruiting upper zone capillaries
• Increased uniformity of ventilation-perfusion matching

F. Tissue/Cellular Acclimatization

• ↑ Mitochondrial density and oxidative enzymes in cells (especially in animals native to high altitude)
• ↑ Myoglobin content in muscle cells — acts as local O₂ store and facilitates intracellular O₂ diffusion
• ↑ Tissue capillary density in systemic tissues — angiogenesis mediated by HIF-1α and VEGF
• Improved efficiency of mitochondrial oxidative phosphorylation

4. MOLECULAR AND GENETIC BASIS — HIF PATHWAY

• In normoxia, HIF-1α is hydroxylated by prolyl hydroxylases (PHDs) → ubiquitinated by VHL → proteasomal degradation
• In hypoxia, PHDs are inactive → HIF-1α stabilises → dimerises with HIF-1β → binds hypoxia response elements (HREs)
• HIF-1α target genes: EPO, VEGF, glycolytic enzymes, transferrin, transferrin receptor
• HIF-2α (coded by EPAS1): key gene in Tibetan high-altitude adaptation → results in lower haemoglobin concentrations (paradoxically protective against hyperviscosity)
• Other adaptation genes in Tibetans: EGLN1, PPARA

5. PERIODIC BREATHING AT HIGH ALTITUDE

• Occurs commonly above 2700 m, especially during sleep
• Mechanism: hyperventilation → ↓ PaCO₂ → approaches/falls below apnoeic threshold → central apnoea → O₂ desaturation → hypoxic stimulus → ventilatory overshoot → cycle repeats (Cheyne-Stokes respiration)
• Worsens with depth of sleep and with greater respiratory alkalosis
• Treated by: acetazolamide (reduces alkalosis), supplemental O₂

6. HIGH-ALTITUDE ILLNESS SYNDROMES

A. Acute Mountain Sickness (AMS)

• Occurs at >2000–2500 m; ~50% of trekkers at >4000 m in Nepal
• Pathophysiology: hypoxia → cerebral vasodilation → ↑ cerebral blood flow/volume → vasogenic oedema (especially with rapid ascent)
• Symptoms (onset 1–6 hours post-ascent): bifrontal headache (worsens with Valsalva, bending), anorexia, nausea/vomiting, lassitude, insomnia
• Diagnosis: Lake Louise Score; SaO₂ correlates poorly
• Treatment: stop ascent/descend, acetazolamide 250 mg BD, dexamethasone 4–8 mg

B. High-Altitude Cerebral Oedema (HACE)

• Severe form of AMS; incidence ~0.1–4%
• Vasogenic oedema (↑ T2 signal on MRI): due to loss of cerebrovascular autoregulation → overperfusion, OR inflammatory mediator-mediated BBB permeability
• Features: ataxia, altered consciousness, coma within 12 hours if untreated
• Treatment: immediate descent (essential), dexamethasone 8 mg IM/IV, portable hyperbaric chamber (Gamow bag)

C. High-Altitude Pulmonary Oedema (HAPE)

• Most lethal altitude illness; incidence ~0.1–4%
• Pathophysiology: uneven HPV → overperfusion of non-constricted capillaries → mechanical stress → non-cardiogenic pulmonary oedema (high-pressure but not high-wedge-pressure); low HVR is a risk factor
• Features: dry cough progressing to pink frothy sputum, dyspnoea at rest, tachycardia, cyanosis, crackles
• Treatment: immediate descent, nifedipine 30 mg SR (reduces PAP), supplemental O₂, phosphodiesterase-5 inhibitors (sildenafil, tadalafil), dexamethasone, Gamow bag

7. CHRONIC MOUNTAIN SICKNESS (Monge's Disease)

• Long-term residents at altitude; excessive polycythaemia
• Mechanism: excessive erythropoiesis → ↑ blood viscosity → ↓ O₂ delivery → ↑ pulmonary hypertension → right heart hypertrophy → cor pulmonale
• Features: plethora, cyanosis, headache, confusion, cor pulmonale, heart failure
• Treatment: phlebotomy, descent, acetazolamide

8. SUMMARY TABLE: ACCLIMATIZATION RESPONSES

9. PREVENTION — PHARMACOLOGICAL

• Guyton & Hall Textbook of Medical Physiology, 14th ed., Ch. 44
• Boron & Boulpaep Medical Physiology, Ch. 61
• Harrison's Principles of Internal Medicine, 22nd ed., Ch. 399
• Tintinalli's Emergency Medicine, 9th ed., Ch. 216
• Rosen's Emergency Medicine, 9th ed., Ch. 132