1. Chapter 2 Normal Physiology: Hypoxia

2. Topics Oxygen cascade from air-to-tissue
Effects of reduced barometric pressure
Alveolar ventilation equation
Hyperventilation
Acid-base changes
Control of ventilation

3. Case Study #2: Bill Mountain climber
Hyperventilates on exposure to hypoxia
What causes this? Is it good? Bad?
Alveolar gas equation
Relationship between PACO2 and PAO2
pH effects
Oxygen transport
Blood-myocyte O2 exchange

4. Case Study #2: Bill Barometric pressure and altitude
Dalton’s law of partial pressures
PiO2 varies with PB
PiO2 = PB * 20.93
SL: (760-47) * = 149 mmHg
Mt Everest: (250-47) * = 42.5 mmHg
19,200 m: (47-47) * = 0

5. Oxygen cascade: air to tissue
Po2 falls as it enters the body and ultimately reaches the tissues
Inspired air: 149 mmHg
Alveolar air: 100
Arterial blood: ~100
Capillary blood: mmHg
Tissue: 5-20
Mitochondria: <1

6. Hyperventilation: secret weapon
Tidal volume is a composite of dead space and alveolar gas
However, all Co2 comes from the alveolar gas
Vco2 = VA * Fco2
Pco2 = Fco2 * K
Pco2 = [Vco2/VA]*K
Alveolar ventilation eq.
PAO2 = PiO2 – [PACO2/R]
Normal: 149 – [40/0.8] =100 mmHg
Hypoxia: 100 – [40/0.8] = 50
Hypoxia + hyperventilation: 100 – [20/0.8] = 75

7. Alveolar and arterial gas
Reasons why arterial gas approaches but does not equal alveolar
Diffusion limitation (esp. at altitude)
Shunt
VA/Q mismatching

8. Acid-base status Has respiratory and metabolic components
In other words, the lung can affect acid-base
Henderson-Hasselbalch eq.
H2CO3 ↔ H+ + HCO3-
Dissociation constant of H2CO3; because H2CO3 and Co2 are proportional
KA = [H+] * [HCO3-]/[Co2]
Log KA = log [H+] + log [HCO3-]/[Co2]
-Log [H+] = - Log KA + log [HCO3-]/[Co2]
pH = pKA + log [HCO3-]/[Co2]

9. Acid-base status
Because CO2 obeys Henry’s law: At a constant temperature, the amount of a given gas dissolved in a given type and volume of liquid is directly proportional to the partial pressure of that gas in equilibrium with that liquid
pH = pKA + log [HCO3-]/{0.03 * Pco2}
pH = log (24/{0.03 * 40})
pH = log (20)
pH =
pH =7.4
HCO3- typically determined by the kidney
PCO2 by the lung

10. Acid-base status Davenport diagram HCO3- can be raised or lowered
Renal excretion or retention
Renal compensation
Pco2 can be raised or lowered
Hyper or hypo ventilation
Respiratory compensation
Respiratory acidosis, Respiratory alkalosis, metabolic acidosis, metabolic alkalosis

11. Respiratory alkalosis
Caused by hyperventilation
Altitude, anxiety
Decrease in Pco2
Elevates pH
Buffer line moves from A to C
Over time kidney compensates by excreting HCO3-
Buffer line moves from C to F
“compensated respiratory alkalosis”
Usu. Not complete
Degree to which it compensates can be derived by the distance betw. Buffer lines A-C and G-F or the base deficit

12. Respiratory acidosis Caused by hypoventilation
Drug overdose, chronic COPD
Increase in Pco2
Reduces pH
Buffer line moves from A to B
Over time kidney compensates by conserving HCO3-
Buffer line moves from B to D
“compensated respiratory acidosis”
Usu. Not complete
Degree to which it compensates can be derived by the distance betw. Buffer lines A-B and D-E or the base excess

13. Metabolic acidosis Hco3- falls Accumulation of lactic acid or diabetes
Move along line A-G
Respiratory compensation
Hyperventilation
Move from G to F
Base deficit will occur

14. Metabolic alkalosis Increase in HCO3- Vomiting Move along line A to E
Respiratory compenstaion
Hypoventilation
Move along line E to D
Base excess

15. Control of Ventilation
Basics
Ventilatory system can defend against
Changes in PiO2
Acid-base disturbances
Precisely controlled
Central controller
Sensors
Effectors

16. Control of Ventilation
Central Controller
Brainstem
Three main groups
Medullary respiratory center
Just below 4th ventricle
Dorsal (inspiration) and ventral (expiration) respiratory groups
Dorsal group responsible for the rhythmicity of the system
Inspiration can be “cut off” by pneumotaxic center: may help increase rate of breathing

17. Control of Ventilation
Expiratory center
Becomes active during exercise
Apneustic center
Inspiration
Prolongs insp
Increases depth of breathing
Coordinates switch betw insp and exp
Pneumotaxic center
Switches “off” inspiration
fine-tune respiratory rhythm

18. Control of Ventilation
Cortex
Breathing is under voluntary control
Can alter basic breathing pattern within limits
Can also help initiate changes in ventilation when exercise commences, “central command”

19. Control of Ventilation
Effectors
Muscles of respiration we discussed last week
Sensors
Central chemoreceptors
Respond to changes in the chemical composition of the blood or fluid surrounding it
Near the ventral surface of the medulla
Surrounded by ECF (extracellular fluid) and CSF
Respond to Co2 and assoc pH changes
Low buffering capacity of CSF
Responds readily to Co2
Co2 + H2O →H2CO3→H+ + HCO3-

20. Control of Ventilation
Peripheral chemoreceptors
Carotid bodies
Aortic bodies
Respond to
↑Pco2
↑H+
↓Po2
Carotid body almost wholly resp. for inc. ventilation in response to hypoxia
Respiratory compensation to metabolic acidosis

21. Control of Ventilation
Lung receptors
Pulm stretch receptors
Mechanoreceptors
Impulses travel along vagus nerve
Inhibit inspiration
Irritant receptors
In the airways
Respond to noxious gases
Bronchoconstriction and hyperventilation
Juxtracapillary or J receptors
Innervated by Vagus
Respond to engorgement of the capillaries
Pulmonary edema, pulm embolism, pneumonia and baraotrauma
Rapid, shallow breathing; may play a role in the dyspnea assoc with these diseases
Bronchial C fibers
In bronchial mucosa
Rapid, shallow breathing, bronchoconstriction, cough, increased vascular permeability and mucus secretion
Sensitive to chemical stimuli (ozone, cigarette smoke, capsaicin)

22. Integrated responses Response to Carbon Dioxide
Normally, the most important determinant in the control of ventilation
Very sensitive
Paco2 does not change by much, even with exercise (maybe 3 mmHg)
Normal rise in vent for an increase in Pco2 is 2-3 L/min/mmHg
For lower PAO2, higher vent for any Pco2 and steeper slope
Ventilatory sensitivity to CO2 varies
Lower in trained athletes and divers
Barbiturates severely depress respiratory centers

23. Integrated responses Response to O2
Doesn’t begin until subject is quite hypoxic
Increased PACO2 increases the sensitivity to hypoxia
Mostly a factor at altitude

24. Integrated responses Response to pH
Mostly caused by peripheral chemoreceptors
Acidemia causes increased ventilation
Alkalemia causes reduced ventilation
As the ventilatory changes cause corresponding changes in PaCO2 we call these ventilatory changes hyperventilation or hypoventilation

25. Integrated responses Response to Exercise
Ventilation increases up to 25 fold
PaCO2 does not rise (in humans), and usu. Falls
PaO2 may stay the same, rise or fall
pH falls

26. Acclimatization and High-altitude diseases
Hyperventilation
Hypoxemia stimulates peripheral chemoreceptors; blows off Co2, raises PAO2
PB 250 mmHg do calculation
Renal compensation reduces HCO3-
Polycythemia
Increased Hct and [Hb]
Increases O2 carrying capacity: draw eq.
EPO form kidney
Other features
Rightward shift in O2-Hb dissociation curve (Leftward at extreme altitude)
Improves off-loading of O2 at the tissues
Caused by ↑2,3 DPG at altitude
Increased capillary-to-fiber volume ratio
Muscle mass drops at altitude

27. Acclimatization and High-altitude diseases
Acute mountain sickness
Headache, dizziness, palpitations, insomnia, loss of appetite and nausea
Hypoxemia and resp. alkalosis
Chronic mountain sickness
Cyanosis, fatigue, severe hypoxemia, marked polycythemia
High altitude pulmonary edema
Severe dyspnea, orthopnea, cough, cyanosis, crackles and pink, frothy sputum
Life threatening
Associated with elevated Ppa (hypoxic pulm vasoconstriction)
High altitude cerebral edema
Confusion, ataxia, irrationality, hallucinations, loss of consciousness and death
Fluid leakage into brain