Regulation of breathing

Breathing is regulated by central and peripheral mechanisms, as follows:

1. Medullary respiratory center: It is located in the reticular formation in the medulla. It has two groups of nuclei - inspiratory nuclei of the dorsal respiratory group and the expiratory nuclei of the ventral respiratory group. The inspiratory nuclei sets the frequency of inspiration. They receive inputs from chemoreceptors and lung mechanoreceptors via cranial nerves IX and X and send outputs to the diaphragm via the phrenic nerve. The phrenic nerve shows a characteristic pattern of action potentials with alternating periods of quiescence and bursts of action potentials with increasing frequency. Diaphragmatic contraction initiates inspiration. The expiratory nuclei are inactive during quiet breathing but are activated in exercise and increased expiratory effort.

2. Apneustic center: It is located in the lower pons. Stimulation causes apneusis which is characterised by deep, gasping inspiration with a pause followed by brief period of expiration. It is not seen in good health and indicates a poor prognosis. Damage to the pons and medulla by stroke, trauma, tumors or ketamine can cause apneusis.

3. Pneumotaxic center: It is located in the upper pons and inhibits the inspiratory center. It regulates the tidal volume and respiratory rate when needed.

4. Cerebral cortex: The cerebral cortex can temporarily override the respiratory center. Hyperventilation causes decreased PaCO2 while hypoventilation causes increased PaCO2.

5. Chemoreceptors: They are of two types - central and peripheral. The central chemoreceptors are located in the ventral medulla. The central chemoreceptors are sensitive to changes in pH of the CSF. Decrease in CSF pH leads to hyperventilation while increase in CSF pH leads to hypoventilation. The central chemoreceptors respond indirectly to changes in arterial PCO2. CO2 can easily diffuse across the BBB and blood- CSF barrier. In the CSF, it is converted to H+ and HCO3- ions. Increased H+ decreases the pH which activates the central chemoreceptors which direct the inspiratory center to increase the respiratory rate.

   The peripheral chemoreceptors are located in the carotid bodies at the bifurcation of the common carotid artery and in the aortic bodies near the arch of aorta. They are responsive to O2, CO2 and H+. Impulses from the peripheral chemoreceptors are relayed to the inspiratory center by cranial nerves IX and X. Drop in arterial PO2 below 60 mmhg, increase in arterial Pco2 or decrease in arterial pH activate the peripheral chemoreceptors producing an increase in the respiratory rate. Only the carotid bodies are sensitive to decreased pH or acidosis.

6. Other receptors like stretch receptors in the lung, joint and muscle mechanoreceptors etc also influence breathing.

Gas Exchange: Oxygen from the alveoli diffuses across the alveolar wall to enter the pulmonary capillary while CO2 from the capillary diffuses across to enter the alveoli. Under normal conditions, at sea level, the PalvO2 is 100 mmhg, the PvO2 is 40 mmHg, PvCO2 is 46 mmhg, PaO2 is 100 mmhg (after oxygenation in alveoli) and PaCO2 is 40 mmhg (after CO2 diffusion into the alveoli). P stands for respective partial pressures. The partial pressure of a gas is determined by the amount of dissolved gas e.g. PaO2 will be determined only by the amount of O2 that is dissolved in blood and not by the hemoglobin - bound O2. Diffusion of gases across the alveolar wall is directly proportional to the partial pressure gradient for that gas, available surface area and diffusion coefficient while it is indirectly proportional to the thickness of the membrane barrier.

DLco: It is the diffusing capacity for CO. It measures the combined effects of the diffusion coefficient , surface area, thickness of the membrane barrier and the time taken to combine with proteins in the capillary blood. Normal DLco should be more than 80% of predicted values.

DLco may be high or low in obese individuals. DLco may be falsely decreased if the patient has a severe restrictive or obstructive disease as they may not be able to inspire an adequate amount of CO. Therefore it is often adjusted by the alveolar volume (VA), and listed as the DLco/VA.

Diffusion and perfusion limited gas exchange: Gas exchange can be limited by perfusion or diffusion, depending on the prevailing conditions. Characteristics are shown in the table below:

At high altitude, atmospheric pressure is lower than sea level, which leads to decreased Palv and decreased Pa, partial pressure gradient will be lower and oxygen will equilibrate slowly along the length of the capillary. The body responds by increasing the respiratory rate and RBCs increase 2,3 BPG levels.

Oxygen transport in blood: Oxygen is transported in blood in two forms - free, dissolved form and bound to hemoglobin as oxyhemoglobin. Only 2% of oxygen is in the dissolved form. 98% of oxygen is transported as oxyhemoglobin. Oxygen binds to iron in the ferrous Fe2+ state , present in the heme moiety of hemoglobin.

Carbon Dioxide transport in blood: CO2 is transported in blood in three forms - as bicarbonate ion or HCO3-, as carbaminohemoglobin and as dissolved CO2. HCO3- accounts for 90% of the transport of CO2. Co2 binds with hemoglobin as well as albumin. It binds to a different Hb site than O2. When less O2 is bound to Hb, the affinity of Hb to CO2 increases called Haldane effect. It helps in transporting CO2 from the tissues back to the lungs.

Role of carbonic anhydrase and HCO3- : Carbonic anhydrase enzyme catalyzes the reversible reaction H2O + CO2 = H2CO3 = HCO3- + H+.

Carbonic anhydrase is present in high concentrations in the RBCs. H+ is buffered by deoxyhemoglobin while HCO3- enters the plasma in exchange for Cl-, also called chloride shift. HCO3- thus reaches the lungs. Oxygen in the lungs causes the release of H+ from deoxyHb. At the same time, HCO3- enters the RBC in exchange for Cl- and combines with H+ to form H2CO3. H2CO3 dissociates into CO2 and H2O which are exhaled out of the lungs.

Hypoxia, hypoxemia and A-a gradient: It’s important to know the difference between hypoxia and hypoxemia. In hypoxia tissues either cannot utilize oxygen or they do not get enough oxygen. Whereas, hypoxemia means PaO2 or partial pressure of oxygen of less than 80 mm Hg or arterial blood hemoglobin saturation of less than 95%.

Causes of hypoxemia: There are three causes of hypoxemia: low inspired oxygen concentration, hypoventilation, or venous admixture. Venous admixture can be due to V/Q defects, shunts, diffusion defects and circulatory shock. The causes can be separated by the A-a gradient.

A-a Gradient = PAO2 – PaO2

Where PAO2 represents alveolar oxygen pressure and PaO2 represents arterial oxygen pressure. The arterial oxygen pressure (PaO2) can be directly assessed with an arterial blood gas test (ABG) or venous blood gas test (VBG). The alveolar oxygen pressure (PAO2) is not easily measured directly, instead, it is estimated using the alveolar gas equation. PAO2 increases as the inspired oxygen concentration or FiO2 increases and decreases as the PaCO2 increases.

Ideally, A-a gradient should be zero, but due to physiological mismatch in V/Q normal range is 5-10 mmhg. It increases normally with age.

All causes of hypoxemia will lead to tissue hypoxia. Other causes of hypoxia are anemia, CO poisoning, methemoglobinemia, cyanide poisoning and shock.

Response of the respiratory system to exercise