Control of Ventilation [2] สรช ย ศร ส มะ พบ., Ph.D. ภาคว ชาสร รว ทยา คณะแพทยศาสตร ศ ร ราชพยาบาล มหาว ทยาล ยมห ดล Describe the effects of alterations in chemical stimuli, their mechanisms and response to respiratory system Describe the relationships of ph, Pco 2, plasma HCO 3 Define alkalosis, acidosis and mechanisms that help to compensate for these disturbances
Organization of Respiratory Control System Higher Centers in CNS (Cerebral Cortex, etc.) Respiratory Rhythmic Generator (Medulla Oblongata) Receptor Reflexes (Pulmonary, Chest Wall, Airway) Inspiratory Muscles Expansion of Chest Wall & Inspiratory Airflow into Lungs Gas Exchange Chemoreceptors PO 2 PCO 2 H +
Chemoreceptor Reflex 3 chemical stimuli in the arterial blood Pco 2 (hypercapnia, > 43 mmhg) Hyperventilation Po 2 (hypoxemia, < 90 mmhg) ph or [H + ] (acidosis, ph < 7.36)
Respiratory Chemoreceptors Central chemoreceptors Medulla [and less well defined areas in brain] Respond to changes in ph, Pco 2 of cerebrospinal fluid (CSF) Peripheral chemoreceptors Carotid bodies and aortic arch Respond to changes in arterial ph, Pco 2, Po 2
Central Chemoreceptors They are separate from the medullary respiratory center (DRG, VRG) They are responsible for most of the respiratory response to CO 2 ( Pco 2 ) The response to CO 2 is mediated through a fall in the ph of cerebrospinal fluid They are not stimulated and are DEPRESSED by hypoxia
Central Chemoreceptors Paco 2 (hypercapnia) Pco 2 in CSF CO 2 + H 2 O H 2 CO 3 H + + HCO 3 CO 2 + H 2 O H 2 CO 3 H + + HCO 3 ph at central chemoreceptor stimulation of central chemoreceptor stimulation of medullary respiratory center increased ventilation Paco 2 to normal or near normal
BloodBrain Barrier Separates Blood from CSF and Brain Astrocytic endfoot lipid soluble carrier mediated
Central Chemoreceptors and Hypercapnia CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase Bloodbrain barriers H + Pco 2 ph H + Paco 2 CO 2 Brain vessels CO 2 activity of central chemoreceptors
BloodBrain Barrier (BBB) It separates the brain parenchyma and central chemoreceptors from arterial blood BBB has a high permeability to CO 2, but low permeability to ions (H +, HCO 3 ) [protein] in CSF and brain ECF is lower than that of blood plasma less buffering power of CSF only HCO 3 is buffer for CSF CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase
Compensatory Bicarbonate Shift in CSF carbonic CO 2 + H 2 O H 2 CO 3 H + + HCO anhydrase 3 Brain vessels Bloodbrain barriers H + Pco 2 ph H + Paco 2 CO 2 HCO 3 CO 2 HCO 3 Restoration of ph less activity of central chemoreceptors After many hours/days of arterial hypercapnia, brain restores ph in ECF, CSF by actively transport of HCO 3 from the blood into CSF
Peripheral Chemoreceptors (หน า 428) They respond to hypoxemia, hypercapnia and acidosis
Carotid Body It receives an extraordinarily high blood flow the largest per mass of any other tissue in the body
The Nobel Prize in Physiology or Medicine 1938 for the discovery of the role played by the sinus and aortic mechanisms in the regulation of respiration Corneille Jean François Heymans Ghent University Ghent, Belgium
Peripheral Chemoreceptors Discharge rate in the afferent nerves from the carotid body increases in response to decrease of arterial Po 2 (not by reduced oxygen content) decrease of arterial ph increase in arterial Pco 2 hypoperfusion of peipheral chemoreceptors The carotid bodies undergo hypertrophy and hyperplasia under chronic hypoxia They are usually lost in the operation of carotid endarterectomy
Ventilatory Response to Hypoxemia Ventilation starts to increase as Pao 2 decreases below 60 mmhg At the same degree of hypoxemia, ventilation is substantially elevated by a synergistic effect from hypercapnia
Ventilatory Response to Hypercapnia Ventilation increases linearly with acute increases in Paco 2 with the rate 25 L/min for each 1mmHg increase in Paco 2 Hypoxia increases the sensitivity of ventilatory response to hypercapnia
Ventilatory Response to Hypercapnia awake normal asleep narcotics anesthesia The response curve shift to the right and diminishing slope decreased sensitivity Drugs that depress the CNS depress the ventilatory response to hypercapnia 40 45 50 55
Ventilatory Control in Chronic Respiratory Failure Patients with chronic respiratory failure (e.g. chronic obstructive pulmonary disease) have hypoxemia and chronic hypercapnia PROBLEMS 1. Chronic hypercapnia CNS depression (carbon dioxide narcosis) อ านสร รว ทยา 2 หน า 5512 2. bicarbonate shift in CSF buffering of the brain activation of central chemoreceptor
Ventilatory Control in Chronic Respiratory Failure Q. What is the drive for breathing in these patients? A. The patients depend on their hypoxic drive to breathe via stimulation of peripheral chemoreceptor Q. What would happen if the physician gives such a patient supplement oxygen during acute condition such as pneumonia?
Ventilatory Control in Chronic Respiratory Failure Q. What would happen if the physician gives such a patient supplement oxygen during acute condition such as pneumonia? A. Removal of hypoxic drive after O 2 supplement Decrease in ventilation Increase in Paco 2 Conclusion: acute hypoxemia can be lifethreatening problem and must be treated with lowest amount of supplemental oxygen, which is necessary to raise Pao 2, to ~ 60 mmhg
Definitions: AcidBase Physiology An acid is a substance that can donate a hydrogen ion (proton) HX H + + X A base is a substance that can accept a hydrogen ion YOH Y + + OH HX + YOH H + + X + Y + + OH XY + H 2 O
Definitions: AcidBase Physiology A buffer is a molecule ably to accept/release H + so that changes in free [H + ] and the ph are minimized Acidosis is a process leading to excess production of H + Alkalosis is a process leading to excess production of base Acidemia: blood ph < 7.36 Alkaemia: blood ph > 7.44
CO 2 H 2 CO 3 HCO 3 Buffer System CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase CO 2 dissolved in blood combines with water to form carbonic acid, which is in equilibrium with hydrogen ions and bicarbonate Bicarbonate is the primary extracellular buffer and considered to be conjugate weak base
CO 2 H 2 CO 3 HCO 3 Buffer System CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase Henry s Law: The amount of CO 2 dissolved in blood is proportional to the Pco 2 in blood [CO 2 ]dissolved = 0.03 x Pco 2 Solubility coefficient = 0.03 mm/mmhg [CO 2 ] dissolved = 0.03 mm/mmhg x 40 mmhg [CO 2 ] dissolved = 1.2 mm
Henderson Hasselbalch Equation CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase K CO 2 + H 2 O H + + HCO 3 K = dissociation constant for the equilibrium K = [H+ ] [HCO 3 ] [CO 2 ] ph = log [H + ] ph = pk + log ph = pk + log [HCO 3 ] [CO 2 ] [HCO 3 ] 0.03 x Pco 2
Henderson Hasselbalch Equation CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase ph = pk + log [HCO 3 ] 0.03 x Pco 2 Paco 2 = 40 mmhg, [HCO 3 ] = 24 mm pk for CO 2 /HCO 3 equilibrium = 6.1 at 37ºC ph = 6.1 + log 24 mm (0.03 mm/mmhg) x 40 mmhg Ratio of [HCO 3 ] to dissolved CO 2 must be equal 20 for normal ph (log of 20 = 1.3) ph = 7.4
Acid Base Disorders FOUR primary disturbances: 1. Respiratory acidosis 2. Respiratory alkalosis 3. Metabolic acidosis 4. Metabolic alkalosis The body must maintain the ph of blood and cells The respiratory and renal systems provide compensatory mechanisms for the primary acidbase disturbances
Respiratory Acidosis It is characterized by Increased Paco 2 Decreased ph Pco 2 = K Vco 2 V A A mild increase in [HCO 3 ] serum carbonic CO 2 + H 2 O H 2 CO 3 H + + HCO anhydrase 3 ph = 6.1 + log [HCO 3 ] 0.03 x Pco 2
Compensatory Mechanisms for Respiratory Acidosis There will be metabolic compensation by increased in the production of bicarbonate that diffuses from intracellular back into the serum Increase in [HCO 3 ] serum The kidneys eliminates H + into urine and reabsorb HCO 3 back to the blood if the respiratory acidosis persists A metabolic change can compensate for respiratory disturbance
Respiratory Alkalosis It is characterized by Decreased Paco 2 Increased ph Pco 2 = K Vco 2 V A A mild decrease in [HCO 3 ] serum CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase ph = 6.1 + log [HCO 3 ] 0.03 x Pco 2
Compensatory Mechanisms for Respiratory Alkalosis The kidneys excretes more HCO 3 to urine A metabolic change can compensate for respiratory disturbance
Metabolic Acidosis It is characterized by A reduced [HCO 3 ] serum Low ph It is typically caused by the accumulation of nonvolatile acids in the body or loss of bicarbonate from the body CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase ph = 6.1 + log [HCO 3 ] 0.03 x Pco 2
Compensatory Mechanisms for Metabolic Acidosis The respiratory system compensates by increasing ventilation, and Paco 2 decreases A respiratory change can compensate for metabolic disturbance
Metabolic Alkalosis It is characterized by An increased [HCO 3 ] serum Elevated ph It is typically caused by the loss of nonvolatile acids from the body or excessive intake of bicarbonate into the body CO 2 + H 2 O H 2 CO 3 H + + HCO 3 carbonic anhydrase ph = 6.1 + log [HCO 3 ] 0.03 x Pco 2
Compensatory Mechanisms for Metabolic Alkalosis The respiratory system compensates by hypoventilation from reduced stimulation of chemoreceptors, and Paco 2 increases A respiratory change can compensate for metabolic disturbance
AcidBase Disorders and Compensatory Mechanisms Primary Disorder Primary Disturbance Compensatory Mechanism Compensatory Change Respiratory acidosis Paco 2 Metabolic alkalosis HCO 3 Respiratory alkalosis Paco 2 Metabolic acidosis HCO 3 Metabolic acidosis HCO 3 Respiratory alkalosis Paco 2 Metabolic alkalosis HCO 3 Respiratory acidosis Paco 2