Breathing at high altitudes Flashcards
What are the atmospheric changes as you ascent to high altitudes?
- As ascend barometric pressure drops and according to Dalton’s Law i.e. Ptot = P1 + P2 + Pn the
partial pressure of all the constituent gases also drops so PO2 drops - At altitude the reduction in PB has a knock on effect on the whole oxygen cascade and leads to
reduce O2 delivery to tissues i.e. acute hypobaric hypoxia so have physiological changes in
response
Describe the respiratory physiological changes at high altitude
At altitude physiological changes:
• Drop in PO2 at altitude detected by carotid bodies which signals to the medulla in response to cause hyperventilation i.e. hypoxic ventilatory response (HVR) and this is the most important physiological adaptation and feature of acclimatisation
- Hyperventilation reduces PACO2 and allows for greater PAO2 according to alveolar gas equation - also refer to oxygen cascade
- ALVEOLAR GAS EQUATION - PAO2 = PiO2 - PACO2/RQ (RQ = VCO2/VO2)
- Normally upon a PACO2 drop would cause ventilation rate to drop again but at altitude the central chemoreceptors stimulate hyperventilation at lower PCO2 levels and this is because of the reduced HCO3 - in CSF due to respiratory alkalosis
- Body attempts to compensate for respiratory alkalosis by increasing bicarbonate excretion in urine but it is not fast enough so carotid bodies sensitivity to CO2 also increases
- So hyperventilation at altitude is sustained due to HVR and this allows rise in PaO2 and SaO2
What are the cardiovascular changes which occur at high altitude?
DO2 = CO x CaO2
• CaO2 = ([Hb] x SaO2 x H) + (S x PaO2)
• H = Hufner’s constant i.e. 1.34ml per gram Hb and S = 0.0225ml per 100ml plasma per kPa O2
• Acute changes - drop in PO2 detected by carotid bodies which activates chemoreceptor reflex which increases sympathetic activity - HR increased, submaximal CO increased, myocardial contractility increased to increase DO2 as CaO2 will have dropped so aiming to increase CO to compensate
• Chronic changes - with acclimatisation max HR and max CO decreased but [Hb] increased to compensate
• Increase in [Hb] due to EPO upregulation by HIF-1 due to hypoxia and helps increase CaO2 and therefore DO2
What are the exercise limitations at high altitude?
VO2 = CO x (CaO2 - CvO2)
1. VO2 max (oxygen uptake/consumption) is highest rate O2 can be taken up and consumed during intense exercise and max is reached when increased work load does not result in increase in O2 consumption
- Measure of exercise/endurance performance and with increasing altitude VO2 max generally decreases along with exercise capacity
- Higher VO2 max at sea level is not a predictor for performance at altitude, if anything it is detrimental as will have greater reduction in VO2 max at altitude as they will have higher CO means blood passes through lungs quicker so will be more diffusion limited and CaO2 will be lower
- Initially after acute exposure to altitude VO2 max drops due to CaO2 drop
- After prolonged exposure to altitude [Hb] and ventilation increased so CaO2 is increased so theoretically VO2 max should increase
- But it does not as direct relationship between CaO2 and VO2 max has been lost due to CO max still being lower and becoming the limiting factor for VO2 max
- Also muscle blood flow during exercise is lower in chronic hypoxia as ventilatory muscles require more blood for hyperventilation and vital organs as well so working muscles get less and have lower work capacity
- Diffusion limitation at altitude - due to lower driving pressure for O2 from air to blood, lower affinity of Hb for O2 and decreased time for equilibration of alveolar O2 with pulmonary capillary due to hyperventilation
What is HAPE?
- Definition - severe non cardiogenic form of pulmonary oedema which affects susceptible people after rapid ascent to high altitude > 2500m
- Not cardiogenic as has normal wedge pressures and high protein oedema
- More likely if ascend too fast, exercise too much, have lower resp tract infection, have low HVR etc
- Can present 50% of the time without AMS
What are the signs and symptoms of HAPE?
- Symptoms - dysnpnoea, orthopnoea, reduced exercise capacity, chest pain, pyrexia headache,dry cough, haemoptysis etc.
- Signs - tachycardia, cyanosis, basal lung crackles, right ventricular heave (pulsation of chest
wall)
• Can progress to coma and death
What is the overperfusion mechansim of HAPE?
- High PAP - those susceptible to HAPE have increased PAP and exaggerated increase in response to hypoxia and exercise. May contribute to capillary stress failure and endothelial dysfunction. Lowering PAP with nifedipine or sildenafil has been shown to prevent HAPE and is commonly used in treatment.
- Uneven HPV and perfusion - due to hypoxic conditions at altitude where have vasoconstriction of pulmonary capillaries in poorly ventilated areas of the lung to equalise V/Q mismatches but may have higher blood flow through less constricted areas causing overperfusion leading to capillary stress failure
- Endothelial dysfunction - may worsen HPV via impaired release of vasodilators such as NO and increased release of vasoconstrictors such as ET-1
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Stress failure of pulmonary capillaries - damage to walls of capillaries due to high wall stress caused by uneven HPV and high PAP. Large proteins and RBCs can leak across alveolar capillary
barrier so have alveolar fluid leak causing the high protein oedema. Limited evidence for this as an EM slice from 2000 from John West is the only evidence for this
What is the inflammation mechanism of HAPE?
- Debate over role of inflammation in mediating alveolar capillary leak seen in HAPE
- Some HAPE patients show increased pro-inflammatory mediators and cytokines such as IL-1, IL-6, TNFα as well as increase leukocyte counts in bronchoalveolar lavage fluid (Kubo et al., 1998)
- May indicate that inflammation is responsible for the oedema and endothelial dysfunction
seen in HAPE - But another study showed no rise in leukocytes or inflammatory mediators in bronchoalveolarfluid of climbers in HAPE susceptible subjects, many of whom went on to develop HAPE (Swenson et al., 2002)
- The reason for the discrepancies between the two studies is that the Swenson study collected bronchoalveolar fluid far earlier just as HAPE began whilst the Kubo study collected fluid after HAPE was already well established and it is because of this that inflammation is thought to be a secondary event which occurs as a result of HAPE and the resulting oedema and it is not itself a cause of HAPE
What is the alveolar fluid clearance mechanism of HAPE?
- New mechanism proposed where ENaC Na channel and Na/K ATPase pump of alveolar epithelial cells removes fluid from alveoli and when it fails this predisposes to HAPE
- Sartori et al., 2002 - β agonist salmeterol which regulates alveolar fluid clearance shown to reduce incidence of HAPE by 50% in HAPE susceptible subjects and sodium dependent absorption of fluid from airways shown to lower in HAPE susceptible subjects
What is the treatment for HAPE?
- Nifedipine - L type Ca channel blocker - causes vasodilation, decrease in PAP and reduced TPR - but only adjunct to supplementary O2 or descent as has little effect on SaO2
- Sildenafil - PDE-5 inhibitor - promotes pulmonary vasodilation so decreases PAP by preventing cGMP breakdown by PDE allowing cGMP to mediate vasodilatory effects - similar to nifedipine but not as widely used
- Dexamethasone - glucocorticoid - promotes eNOS synthase by stabilising endothelium so may relieve stress failure of pulmonary capillaries and reduces oedema
- Acetazolamide - carbonic anhydrase inhibitor - bicarbonate diuresis causing metabolic acidosis so promote hyperventilation thus increasing PaO2 and reduces HPV
- Supplementary O2 - shown to decrease PAP and increases SaO2
- Hyperbaric chamber, descending etc.
Equation for partial pressure
Partial pressure = barometric pressure x concentration
Describe the effects of water vapour at high altitudes
- At high altitudes there is an increased proportion of water vapour in the respiratory tract.
- In normal physiological conditions, inspired air is warmed and saturated with water vapour in the upper airways.
- The saturated vapour pressure is temperature, not pressure dependent which means that even at high altitudes the pressure of water vapour will remain at 6.3Kpa whilst the barometric pressure decreases – thereby increasing the proportion of water vapour in the respiratory system – taking up the space which would have otherwise been taken up by oxygen.
What has Wolff et al (1999) shown?
- Wolff (1999) has shown that even mild hypoxia stimulates an increase in the activity of the carotid sinus nerve in the peripheral chemoreceptor.
- However, no change in ventilation was detected until altitudes of around 3000m where the PaO2 was 6.7kpa. It is postulated that up until 3000m hypoxia stimulates increased cerebral blood flow which decreases cerebral extracellular PCO2 as a result. This increases the pH around the central medullary chemoreceptors – which indicates that central and peripheral chemoreceptors exert an equal and opposite effect, opposing any increase in ventilation.
- However, above 3000m, peripheral CR stimulation exceed the central CR inhibition which leads to increase in ventilation which leads to a decrease in PACO2 and PaCO2.
- This then leads to a further increase in the pH of cerebral extracellular fluid meaning, the central CR can again act as a break to respiration were it not for changes which occur during the hypercapnic ventilatory response (HCVR).
Fan et al 2009
1. Fan et al (2009) observed a 1.3 l min−1 mmHg−1 increase in CO2 sensitivity following ascent to 5050 m.
Their study concluded that:
(1) ascent to high altitude enhances both ventilatory CO2 sensitivity and cerebrovascular CO2 reactivity
(2) hypercapnic cerebrovascular CO2 reactivity selectively correlates with pH at high altitude
(3) there is a close link between the central chemoreflex threshold and bicarbonate concentrations. These findings indicate that alterations in pH buffering may partly account for the observed changes in ventilatory and cerebrovascular responsiveness to hypercapnia following ascent to high altitude.
Kellog et al 1963
Kellogg et al 1963 demonstrated that with time spent at altitude, ventilation rate slowly rises. This then leads to low ECF PCO2 and reduced CSF HCO3- due to respiratory alkalosis. The body tries to compensate for the respiratory alkalosis by excreting bicarbonate however this is too slow and over time this may lead to resetting of the PCO2 chemostat to a lower level, making it more sensitive to drops in pH at higher altitudes so you start to hyperventilate at lower CO2 levels.
