Introduction

Respiration is a vital process for 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 energy release. In mitochondria, digested nutrients undergo metabolic reactions, end up at the level of the electron transport chain, and release high-energy compounds (eg, adenosine triphosphate). 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 exhaled air. The respiratory rate (ie, the number of breaths per minute) is highly regulated to enable cells to produce the optimum energy at any given occasion. A complex nervous system of nerve tissues governs the rate of oxygen inflow and carbon dioxide outflow. It adjusts it accordingly in conditions that derange partial gas pressures in blood. Respiration involves the brain, brainstem, respiratory muscles, lungs, airways, and blood vessels. All these structures have structural, functional, and regulatory involvement in 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 the nucleus ambiguus, ventral to its semicompact division, and caudal to its compact division.[2] This group of neurons, named the pre-Botzinger complex, generates and modifies the basic respiratory rhythm and eventually relays it to respiratory motor neurons.[1] These neurons carry an altered breathing pattern to spinal motor neurons that innervate inspiratory and expiratory muscles, regulating the rate at which these muscles contract.

The hypothesis is that pre-Botzinger neurons generate respiratory oscillations from voltage-dependent sodium 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 proximal regions, some neurons depolarize without bursting oscillations and develop continuous action potentials.[1]

The cerebral respiratory center constantly accepts neural impulses from other central nervous system regions and centrifuges impulses from the periphery. Feedback impulses to the respiratory center are classified into chemical, mechanical, and higher cortical centers.[4]

Function

Information on partial pressure of oxygen (PaO₂) and partial pressure of carbon dioxide (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, carotid bodies, is at the bifurcation of a common carotid artery. Carotid bodies 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 about the elastic recoil of the lung and the thoracic wall modifies the respiratory rate so that the lung optimizes the respiratory work, maximizes the gas exchange, and minimizes 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 overinflation stimulates parenchymal stretch receptors via the vagus nerve, inhibits the respiratory center, and also prevents the apneustic center in the medulla from sending activating impulses to the respiratory center. The result of these processes is expiration.[6] Hyperinflation of the lung or the enlargement of lung capillaries starts nociceptors known as juxtacapillary receptors (J-receptors) that stimulate the respiratory center via the vagus nerve, increasing breathing rate.[7]

Higher cortical centers, as stated earlier, also account for changes in respiratory rate. Alterations in respiratory rate encountered in anxiety or even the differences in respiratory rate during sleep and nonsleep states are related to higher cortical centers. Psychological stress can result in respiratory patterns that differ from those 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 regular respiratory rate changes with age, with 12 to 20 respirations per minute for a resting adult. However, in the elderly population, an individual with more than 28 respirations per minute is deemed tachypneic.[9] Children have a higher respiratory rate than adults. The median respiratory rate in the first 2 years is reduced from 44 respirations per minute at birth to 26 respirations per minute 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 average 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 described earlier. Higher cortical centers can be affected by increased intracranial pressure, eg, in a patient with head trauma or pain in a patient with a rib fracture, resulting in an increased respiratory rate. The opposite effect on higher centers is observable in an individual who has taken central nervous system depressant substances.

Patients with several pathologic conditions leading to changes in respiratory rate may present with particular respiratory patterns identifying the causal condition. Cheyne-Stokes pattern includes a crescendo-decrescendo pattern of respirations between apneas or hypopneas. This respiratory pattern can occur 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]