Chapter 2 Normal Physiology: Hypoxia

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

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

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) * .2093 = 149 mmHg Mt Everest: (250-47) * .2093 = 42.5 mmHg 19,200 m: (47-47) * .2093 = 0

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: 20-40 mmHg Tissue: 5-20 Mitochondria: <1

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

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

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]

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 = 6.1 + log (24/{0.03 * 40}) pH = 6.1 + log (20) pH = 6.1 + 1.3 pH =7.4 HCO3- typically determined by the kidney PCO2 by the lung

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

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

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

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

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

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

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

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

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”

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-

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

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)

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

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

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

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

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

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