Introduction

Respiration is a vital process for the normal function at every level of organization from a cell to an organism; oxygen, supplied by local circulation at the tissue level, functions at the mitochondrial internal membrane as an essential mediator for the energy release. In mitochondria, digested nutrients undergo metabolic reactions, end up at the level of the electron transport chain, and release high-energy compounds (ATP). The main byproduct of this process, carbon dioxide, gets released in the venous blood returning to the lungs. Carbon dioxide diffuses through alveolar walls and dissolves in the exhaled amount of air. The respiratory rate, i.e., the number of breaths per minute, is highly regulated to enable cells to produce the optimum amount of energy at any given occasion. A complex nervous system of nerve tissues regulates the rate of oxygen inflow and carbon dioxide outflow. It adjusts it accordingly in conditions that tend to derange partial gas pressures in blood. Respiration is a process involving the brain, brainstem, respiratory muscles, lungs, airways, and blood vessels. All these structures have involvement structurally, functionally, and regulatory to respiration.

Organ Systems Involved

Breathing regulation occurs by a dense network of bilateral, symmetrical neurons located in the ventrolateral area of the medulla oblongata.[1] In humans, this area is proximal to nucleus ambiguus, ventral to its semi-compact division, and caudal to its compact division.[2] This group of neurons, named pre-Botzinger complex, generates and modifies the basic respiratory rhythm, and eventually relays it to respiratory motor neurons.[1] These neurons carry a modified pattern of breathing to spinal motor neurons that innervate inspiratory and expiratory muscles, regulating the rate these muscles contract.

The hypothesis is that pre-Botzinger neurons generate respiratory oscillations from voltage-dependent Na channels activated at a subthreshold level.[3] Endogenously secreted excitatory amino acids binding to non-NMDA receptors are also necessary for rhythmogenesis. Along with those rhythmically active neurons generating bursting oscillations, located either in the pre-Botzinger complex or in proximal regions, there are those neurons that depolarize without bursting oscillations and generate continuous action potentials.[1]

The cerebral respiratory center is constantly accepting neural impulses from other CNS regions and centrifuges impulses from the periphery. Feedback impulses to the respiratory center classify into three categories: chemical, mechanical, and from higher cortical centers.[4]

Function

Information on PaO2 and PaCO2 gets relayed to the respiratory center as feedback impulses from central and peripheral chemoreceptors. Cells in the pre-Botzinger complex are intrinsically chemosensitive to hypoxia.[5] CO2, as a lipid-soluble molecule, can easily permeate the blood-brain-barrier and change the concentration of hydrogen anions in the cerebrospinal fluid resulting in a different pattern of respiratory oscillations and minute ventilation; this is how the respiratory center initiates the respiratory compensation in response to metabolic acidosis or alkalosis. The primary peripheral chemoreceptor is at the bifurcation of a common carotid artery, and they are called carotid bodies. They are sensitive to changes in PaO2 or pH, and the respiratory center responds with a change in respiratory rate and volume.

Feedback from stretch receptors of muscles, tendons, and joints pertaining to the elastic recoil of the lung and the thoracic wall will modify the respiratory rate in a way that the lung will optimize the respiratory work; maximize the gas exchange and minimize the mechanical breathing work. Such feedback impulses also get relayed by parenchymal lung receptors. The Hering-Breuer reflex prevents excessive distension of lung parenchyma; lung over-inflation stimulates parenchymal stretch receptors and via the vagus nerve, inhibits the respiratory center and also prevents the apneustic center in medulla from sending activating impulses to the respiratory center. The result of these processes is expiration.[6] Hyperinflation of the lung or the distention of lung capillaries activates nociceptors known as J-receptors (juxtacapillary receptors) that, via the vagus nerve, stimulate the respiratory center resulting in an increase in breathing rate.[7]

Higher cortical centers, as stated earlier, also account for changes in respiratory rate. Alterations in respiratory rate encountered in anxiety state or even the differences in respiratory rate during sleep and non-sleep states are related to higher cortical centers. Psychological stress can result in respiratory patterns that are different from the ones produced by metabolic needs. Limbic, cortical, and forebrain regions receiving unpleasant feedback from the environment have a direct stimulatory effect on respiratory motor neurons of the spinal cord, thereby increasing ventilation.[8]

Clinical Significance

The normal respiratory rate changes with age are 12 to 20 respirations per minute for a resting adult. However, in the elderly population, an individual with more than 28 respirations/min is deemed tachypneic.[9] Children have a higher respiratory rate than adults. The median respiratory rate in the first two years is reduced from 44 respirations/min at birth to 26 respirations/ min during their second year of life.[10]

Along with blood pressure, temperature, and pulse rate, respiratory rate is one of the vital signs routinely monitored in a clinical setting.

An alteration from the normal respiratory rate is often a clinical manifestation of pathological conditions. These conditions induce changes in the previously mentioned feedback categories, and the resulting respiratory rate or volume change is an adjustment to the disease state. Metabolic acidosis states increase the tidal volume, while metabolic alkalosis has the opposite effect in ventilation, decreasing the respiratory rate. Interstitial diseases that change the mechanical input to the respiratory center lead to a rapid breathing rate. Congestive heart failure has the same effect by stimulating J-receptors with the mechanism as described earlier. Higher cortical centers can be affected by an increase in intracranial pressure, e.g., in a patient with head trauma or by pain in a patient with a rib fracture, resulting in an increased respiratory rate. The opposite effect on higher centers will be observable in an individual who has taken CNS depressant substances.

Patients with several pathologic conditions leading to changes in respiratory rate may present with very specific respiratory patterns identifying the causal condition. Cheyne-Stokes pattern includes a crescendo-decrescendo pattern of respirations between apneas or hypopneas. This respiratory pattern can present in patients with pontine lesions or heart failure.[11] Another pattern also found in patients with pontine lesions is Biot respiration, where groups of rapid inspirations occur between apneas. Biot respiration can also present in patients who use opioids.[12]