Physiology, Respiratory Drive

Function

Each respiratory cycle begins with inspiration and ends with expiration. During inspiration, the diaphragm and the external intercostals contract, causing enlargement of the thoracic cavity. As a result, intra-pleural pressure decreases, and so does alveolar pressure, forcing the lungs to expand and air to move in. However, expiration occurs passively when the diaphragm relaxes, owing to the lungs' elastic properties. The respiratory control system drives respiratory cycles and consists of three components: the central neural respiratory generator, the sensory input system, and the muscular effector system.[5]

The rate and strength at which the diaphragm contracts, hence the frequency and volume of respiration, depend heavily on the firing pattern of pacemaker cells in the brainstem. On the other hand, the sensory input system sends signals to the brain to modulate respiratory patterns depending on metabolic demand. Together, these processes aim to optimize the lungs' function of taking in oxygen from the air and expelling carbon dioxide from the body.[6]

Mechanism

Intrinsic Respiratory drive

The respiratory center is composed of three distinct neuronal groups in the brain: the dorsal respiratory group in the nucleus tractus solitarius, the ventral respiratory group in the medulla, and the pontine respiratory group in the pons. The latter is further classified into the pneumotaxic center and the apneustic center.

The dorsal respiratory group is mainly inspiratory, while the ventral medullary group is primarily expiratory. The rostral half of the ventral medullary group additionally contains neurons responsible for rhythm generation. Of particular significance is the preBötzinger complex, whose neurons possess neurokinin 1 (NK1) receptors, a potential target for many pharmacological, physiological, and anatomical studies. The pontine groupings are responsible for modulating the intensity and frequency of the medullary signals with their pneumotaxic groups limiting inspiration and their apneustic centers prolonging and encouraging inhalation. Each of these groups communicates with one another in a concerted effort as the pace-making potential of respiration.[7][8][9]

Thoracic Neural Receptors

Mechanoreceptors found in the airways, trachea, lung, and pulmonary vessels provide sensory information to the respiratory center in the brain with regards to lung volume, airway stretch, and vascular congestion. There are two primary types of thoracic sensors: slow adapting stretch spindles and rapid adapting irritant receptors. The former conveys only volume information while the latter additionally responds to irritative chemical triggers such as harmful foreign agents and dust. Both types of mechanoreceptors transmit information to the respiratory center via cranial nerve X (the vagus nerve) to increase the breathing rate, the volume of breathing, or to stimulate cough. A notable example is the Pulmonary stretch reflex, also called the Herring-Breuer reflex, which prevents the lungs from over-inflating by sending inhibitory impulses to the inspiration center. Another type of receptor worth mentioning is the juxta-capillary receptors that respond to vascular congestion and interstitial edema in the lungs by sending signals to the brain to increase the breathing rate.

Peripheral Chemoreceptors

Peripheral chemoreceptors include the carotid and aortic bodies. The carotid bodies are located at the bifurcation of the common carotid arteries and send information to the respiratory center via cranial nerve IX, the glossopharyngeal nerve. The aortic bodies are situated within the aortic arch and send information to the brain via cranial nerve X, the vagus nerve. While capable of sensing carbon dioxide and hydrogen ions, the peripheral sensory system primarily detects low arterial oxygen levels (hypoxemia). Hypercapnia and acidosis increase the sensitivity of these sensors and, therefore, play a partial role in the receptor's function. The carotid bodies comprise approximately 15% of the total driving force of respiration. In healthy individuals, the respiratory center is more sensitive to rising carbon dioxide sensed by central chemoreceptors than decreasing oxygen levels. Oxygen runs the respiratory center only when there is severe hypoxemia.[10]

Central Chemoreceptors

Central chemoreceptors in the ventral surface of the medulla and the retrotrapezoid nucleus hold most of the remaining control over the respiratory drive. They primarily sense pH changes in the central nervous system caused by alterations in arterial carbon dioxide. Carbon dioxide is a lipid-soluble molecule that freely diffuses across the blood-brain barrier and forms hydron ions within the cerebrospinal fluid. Chemoreceptors, in turn, respond to pH changes as they become more acidic and send sensory input to the brain to stimulate hyperventilation. The result is a slow and deep breathing pattern that helps eliminate carbon dioxide from the body. Likewise, when arterial PCO2 drops, pH in the cerebrospinal fluid becomes alkalotic, and hypoventilation ensues. Therefore, arterial PCO2 is the chief determinant of the respiratory drive under normal conditions.[5][6][11][12][13][14][15]

Integration of Receptor Input

Respiratory centers located within the medulla and the pons are responsible for generating the baseline respiratory rhythm. However, an aggregated sensory input from the peripheral sensory system monitoring oxygen levels and the central sensory system monitoring pH modifies the rate and depth of respiration. These signals, along with several other sensory inputs coming from peripheral mechanoreceptors, modulate the respiratory rhythm to create a unified neural signal sent to the primary muscles of respiration. The total input culminates in a respiratory rate of approximately 12 breaths per minute for an average adult while at rest.[5][6][11][12][13][14][15]

Respiratory Drive During Sleep

A variety of changes in respiratory physiology occur while asleep, especially during the rapid eye movement stage, also referred to as REM sleep. During REM, breathing becomes very irregular with periods of hypopnea, apnea, and a continually changing tidal volume and respiratory rate. Paralysis of all accessory muscles of respiration ensues, and people become diaphragm dependent. Additionally, drive output from the respiratory controller in the brain declines, and the respiratory center becomes less responsive to changes in arterial PO2 and PCO2 as well. Finally, upper respiratory dilator muscles become hypotonic, leading to airway narrowing and increased airway resistance. Even though a healthy person can tolerate breathing changes during sleep, sleep becomes problematic in patients with pre-existing respiratory disease.[16]

Related Testing

Evaluation of Respiratory Drive

Assessment of a patient with hypercapnia, hypoxia, or abnormal ventilation should always begin with a thorough history and clinical examination to ascertain a root cause. A variety of tests, including pulmonary function testing, arterial blood gas values, and chest X-rays, may be indicated to determine the primary pathology.

Other tests of respiratory control are primarily used for research purposes or under exceptional circumstances when routine tests have failed to explain the abnormal levels of arterial oxygen and carbon dioxide levels. These tests include measuring hypoxic and hypercapnic ventilatory response, mouth occlusion pressure, elastic and resistive load testing, and analyzing the patient's breathing pattern. However, the harm or discomfort imposed by such tests limits their routine use unless proven to be significantly beneficial.[17][18]

Pathophysiology

As mentioned previously, the respiratory control center responds to altered levels of CO2 and O2 by changing the respiratory rate and pattern. Interestingly, the response to hypoxia differs from the response to hypercapnia. Hypoxia induces a breathing pattern of rapid and shallow breaths with a relatively higher increase in respiratory rate than tidal volume. The aim is to decrease the cost of breathing by avoiding the need to overcome the lungs' higher elastance at high volumes.

In simple terms, breathing with high tidal volumes requires more negative pressure generation in the intra-pleural space and, thus, more oxygen utilization by respiratory muscles, especially in an already hypoxic patient. In contrast, hypercapnia triggers a breathing pattern of deep and slow breaths with a relatively more significant increase in tidal volume than respiratory rate. This pattern aims to limit dead space ventilation and optimize carbon dioxide elimination.

Clinical Significance

Several conditions induce alterations in respiratory rate or pattern. These modifications occur due to changes in PaO2, PaCO2, or pH levels imposed by the disease process, which in turn augments the sensory drive sent from the central or peripheral control mechanisms to the brain. The adjustments manifest in the form of modified tidal volume or respiratory rate. [10]

Asthma

Asthma is a chronic obstructive airway disease characterized by reversible inflammation of the conducting airways in response to various allergenic and non-allergenic stimuli. During an acute asthma attack, severe inflammation occurs, leading to airway narrowing, excess mucus production, and bronchoconstriction. Subsequently, hypoxia develops due to impaired gas exchange. Hypoxia stimulates peripheral chemoreceptors, which, in turn, transmit the signal to the respiratory control center in the brain. The respiratory center increases its firing rate leading to enhanced respiratory rate and resultant hypocapnia. It is crucial to note that in asthmatics, paradoxical normalization of carbon dioxide levels is an indication that muscular fatigue is setting in and that total respiratory failure is imminent.[19]

Chronic Obstructive Pulmonary Disease

COPD is another chronic obstructive airway disease that shares many similarities with asthma. However, COPD is an irreversible process that gradually progresses over time, leading to chronic air-trapping and persistent hypercapnia. At first, central chemoreceptors sense hypercapnia as it would in a healthy individual and signal the respiratory center to increase breathing depth. As a result, a respiratory pattern of deep and slow breaths ensues. Studies have shown that supplemental oxygen during acute COPD exacerbation causes an increase in PaCO2 and a transient decrease in minute ventilation.

Previously, it was hypothesized that central chemoreceptors gradually become resistant to carbon dioxide levels in the blood such that the medullary sensors no longer respond to changes in pH as they would in a healthy counterpart. This led to the belief that hypercapnia no longer acts as the primary drive for respiration, and these patients become dependent on hypoxia for respiratory drive, causing generalized reluctance to administer supplemental oxygen during acute COPD exacerbation in the healthcare setting. This theory is no longer widely accepted as studies have shown that the transient decrease in minute ventilation in these patients is not sustained and does not consistently correlate proportionally with the degree of PaCO2 increase. Instead, administration of supplemental oxygen counteracts the reflex hypoxic pulmonary vasoconstriction that would otherwise shunt perfusion away from the damaged alveoli with poor ventilation to maximize perfusion to the "good" alveoli. The resulting dead space ventilation and ventilation-perfusion (V/Q) mismatch is likely a better explanation for the oxygen-induced increase in PaCO2. Another proposed mechanism is that supplemental oxygen causes a right shift in the hemoglobin-CO2 dissociation curve, increasing PaCO2, referred to as the Haldane effect.

COPD patients with an acute exacerbation have difficulty increasing their minute ventilation to blow off the excess CO2 and therefore struggle to normalize PaCO2 in this setting. Regardless of the specific physiologic mechanism for oxygen-induced hypercapnia, the relevant consensus is that patients with acute COPD exacerbation should be given titrated oxygen therapy with a target of 88-92% oxygen saturation to reduce both hypoxia and the risk of hypercapnia.[20]

Obesity Hypoventilation Syndrome

Obesity hypoventilation syndrome, also known as Pickwickian syndrome, is a condition that affects morbidly obese individuals. Obesity alters lung and chest wall mechanics leading to hypoventilation and resultant hypercapnia. The patient initially compensates by increasing respiratory drive and work of breathing. However, respiratory fatigue rapidly ensures that hypercapnia and hypoxia occur. As the condition progresses, chronic hypercapnia results in respiratory acidosis with compensatory HCO3 retention by the kidneys. Bicarbonate decreases the sensitivity of central chemoreceptors to changes in PCO2, leading to persistent hypercapnia.

Neuromuscular Disease

Neuromuscular disease is the terminology used to describe the various pathologies that affect muscular function. The problem could arise anywhere along the pathway of muscle control, beginning with the CNS and ending with the muscle itself. Examples include muscular dystrophies, such as Duchenne muscular dystrophy, and motor neuron diseases, such as poliomyelitis. Respiratory muscle weakness eventually occurs in neuromuscular diseases, causing hypoventilation and resultant hypoxia and hypercapnia. The core concept is that respiratory control centers are intact and attempt to respond appropriately to changing PO2 and PCO2 levels. However, the muscles lose the ability to respond to hypoxic and hypercapnic stimuli due to muscular weakness. Unaided, this leads to hypoxia and hypercapnia and, ultimately, death due to ventilatory failure.

Drugs

Inhalational anesthetics, narcotics, and minor tranquilizers are the most notorious pharmaceuticals for causing respiratory depression. Inhaled anesthetics decrease response to increased carbon dioxide and decreased oxygenation, thus blunting respiratory drive adjustments. Benzodiazepines, on the other hand, act on GABA receptors in the central nervous system. They effectively decrease all neural functions, including the respiratory pacemaking system in the brainstem. Similarly, opioid narcotics act on mu-opioid receptors in the central nervous system. They primarily target the preBötzinger complex within the pacemaking system of respiration, thus reducing the underlying drive for breathing. Finally, alcohol is nonpharmaceutical that depresses respiratory drive by blunting the body's response to increasing carbon dioxide levels.[21][22][11]

Congenital Central Hypoventilation Syndrome (CCHS)

Congenital central hypoventilation syndrome, sometimes known as Ondine's curse, is a rare genetic disease caused by a mutation that renders the respiratory center in the brain unresponsive to changes in PCO2. When breathing fails to happen unconsciously, the patient becomes dependent on conscious control (cortex). Patients generally have breathing problems during sleep that tend to get better while awake.[23]