Regulation of Breathing

Published on 01/06/2015 by admin

Filed under Pulmolory and Respiratory

Last modified 22/04/2025

Print this page

This article have been viewed 4983 times

Chapter 14

Regulation of Breathing

Will Beachey

Chapter Objectives

After reading this chapter you will be able to:

Identify where the structures that regulate breathing are located.

Describe how the inspiratory and expiratory neurons in the medulla establish the basic pattern of breathing.

Describe the effect that impulses from the pneumotaxic and apneustic centers in the pons have on the medullary centers of breathing.

Identify the effect of various reflexes on breathing.

Describe how the central and peripheral chemoreceptors differ in the way they regulate breathing.

State how the central chemoreceptors respond differently to respiratory and nonrespiratory acid-base disorders.

Describe how the regulation of breathing in individuals with chronic hypercapnia differs from the regulation of breathing in healthy individuals.

Describe why administering oxygen to patients with chronic hypercapnia poses a special risk that is not present in healthy individuals.

Describe why ascending to a high altitude has different immediate and long-term effects on ventilation.

State why mechanically ventilated patients with head injuries may benefit from deliberate hyperventilation.

Describe the characteristics of abnormal breathing patterns.

Medullary Respiratory Center

Animal experiments show that transecting the brainstem just below the medulla (Figure 14-1, level IV) stops all ventilatory activity. However, breathing continues rhythmically after the brainstem is transected just above the pons (see Figure 14-1, level I). Until more recently, physiologists thought that separate inspiratory and expiratory neuron “centers” in the medulla were responsible for the cyclic pattern of breathing. Researchers believed that inspiratory and expiratory neurons fired by self-excitation and that they mutually inhibited one another. More recent evidence shows that inspiratory and expiratory neurons are anatomically intermingled and do not inhibit one another.¹ No clearly separate inspiratory and expiratory centers exist. Instead, the medulla contains several widely dispersed respiratory-related neurons, as shown in Figure 14-1. The dorsal respiratory groups (DRGs) contain mainly inspiratory neurons, whereas the ventral respiratory groups (VRGs) contain both inspiratory and expiratory neurons.

FIGURE 14-1 Dorsal view of the brainstem. Dashed lines I to IV refer to transections at different levels. (Modified from Beachey W: Respiratory care anatomy and physiology: foundations for clinical practice, ed 2, St Louis, 2007, Mosby.)

Dorsal Respiratory Groups

As shown in Figure 14-1, DRG neurons are mainly inspiratory neurons located bilaterally in the medulla. These neurons send impulses to the motor nerves of the diaphragm and external intercostal muscles, providing the main inspiratory stimulus.¹ Many DRG nerves extend into the VRGs, but few VRG fibers extend into the DRGs. Reciprocal inhibition is an unlikely explanation for rhythmic, spontaneous breathing.¹

The vagus and glossopharyngeal nerves transmit many sensory impulses to the DRGs from the lungs, airways, peripheral chemoreceptors, and joint proprioceptors. These impulses modify the basic breathing pattern generated in the medulla.

Ventral Respiratory Groups

VRG neurons are located bilaterally in the medulla in two different nuclei and contain inspiratory and expiratory neurons (see Figure 14-1). Some inspiratory VRG neurons send motor impulses through the vagus nerve to the laryngeal and pharyngeal muscles, abducting the vocal cords and increasing the diameter of the glottis. Other VRG inspiratory neurons transmit impulses to the diaphragm and external intercostal muscles. Still other VRG neurons have mostly expiratory discharge patterns and send impulses to the internal intercostal and abdominal expiratory muscles.

The exact origin of the basic rhythmic pattern of ventilation is unknown. No single group of pacemaker cells has been identified. Two predominant theories of rhythm generation are the pacemaker hypothesis and the network hypothesis.² The pacemaker hypothesis holds that certain medullary cells have intrinsic pacemaker properties (i.e., rhythmic self-exciting characteristics) and that these cells drive other medullary neurons. The network hypothesis suggests that rhythmic breathing is the result of a particular pattern of interconnections between neurons dispersed throughout the rostral VRG, the pre-Bötzinger complex, and the Bötzinger complex. This hypothesis assumes that certain populations of inspiratory and expiratory neurons inhibit one another and that one of the neuron types fires in a self-limiting way, such that it becomes less responsive the longer it fires. There is no definitive proof of either hypothesis; the precise origin of respiratory rhythm generation remains elusive.²

Inspiratory Ramp Signal

The inspiratory muscles do not receive an instantaneous burst of signals from the dorsal and ventral inspiratory neurons. Rather, the firing rate of DRG and VRG inspiratory neurons increases gradually at the end of the expiratory phase, creating a ramp signal (Figure 14-2). The inspiratory muscles contract steadily and smoothly, gradually expanding the lungs rather than filling them in an abrupt inspiratory gasp. During exercise, various reflexes and receptors influence the medullary neurons, steepening the ramp signal and filling the lungs more rapidly.

During quiet breathing, inspiratory neurons fire with increasing frequency for approximately 2 seconds and then abruptly switch off, allowing expiration to proceed for approximately 3 seconds.³ At the start of expiration, inspiratory neurons again fire briefly, retarding the early phase of expiration (see Figure 14-2). The inhibitory neurons that switch off the inspiratory ramp signal are controlled by the pneumotaxic center and pulmonary stretch receptors, which are discussed later in this chapter.

Pontine Respiratory Centers

If the brainstem is transected above the medulla (see Figure 14-1, level III), spontaneous respiration continues, although in a more irregular pattern. The pons does not promote rhythmic breathing; rather, it modifies the output of the medullary centers. Figure 14-1 shows two groups of neurons in the pons: (1) the apneustic center and (2) the pneumotaxic center.

Apneustic Center

The apneustic center is anatomically ill defined; its existence and function can be shown only if its connections to the higher pneumotaxic center and vagus nerves are severed. Under such circumstances, the DRG inspiratory neurons fail to switch off, causing prolonged inspiratory gasps interrupted by occasional expirations (apneustic breathing). Vagal and pneumotaxic center impulses hold the apneustic center’s stimulatory effect on DRG neurons in check.

Pneumotaxic Center

The pneumotaxic center is a bilateral group of neurons located in the upper pons (see Figure 14-1). The pneumotaxic center controls the “switch-off” point of the inspiratory ramp, controlling inspiratory time. Strong pneumotaxic signals increase the respiratory rate, and weak signals prolong inspiration and increase tidal volumes. The exact nature of the interaction between the pneumotaxic and apneustic centers is poorly understood. They apparently work together to control the depth of inspiration.³

Reflex Control Of Breathing

Muscle Spindles

Muscle spindles in the diaphragm and intercostal muscles are part of a reflex arc that helps the muscles adjust to an increased load. Muscle spindles are sensing elements located on intrafusal muscle fibers, arranged parallel to the main extrafusal muscle fibers (Figure 14-3). The extrafusal fibers that elevate the ribs are innervated by different motor fibers (alpha fibers) than the fibers that innervate the intrafusal spindle fibers (gamma fibers). When the main extrafusal muscle fiber and the intrafusal fibers contract simultaneously, the sensing element (spindle) of the intrafusal muscle fiber stretches and sends impulses over spindle afferent nerves directly to the spinal cord (see Figure 14-3). The spindle’s afferent (sensory) nerve synapses directly with the alpha motor neuron in the spinal cord, sending impulses back to the main extrafusal muscle. A single synapse reflex arc is created. Alpha motor neuron impulses cause the main extrafusal muscle fibers to contract with greater force, shortening the nearby intrafusal fibers. The stretch-sensitive spindle is unloaded, and its impulses cease. In this way, inspiratory muscle force adjusts to the load imposed by decreased lung compliance or increased airway resistance.

FIGURE 14-3 Stretch-sensitive muscle spindle located on the intrafusal fibers of intercostal muscles. Motor innervation for intrafusal fibers (gamma nerve fibers) is different than for extrafusal fibers (alpha nerve fibers). Spindle afferent nerve fibers synapse with alpha motor neurons in the spinal cord, creating a single synapse reflex arc.

Chemical Control Of Breathing

The body maintains the proper amounts of oxygen (O₂), carbon dioxide (CO₂), and hydrogen ions (H⁺) in the blood mainly by regulating ventilation. Physiologic mechanisms that monitor these substances in the blood allow ventilation to respond appropriately to maintain homeostasis. An increase in blood H⁺ concentration stimulates specialized nerve structures called chemoreceptors. Consequently, the chemoreceptors transmit impulses to the medulla, increasing ventilation. Centrally located chemoreceptors in the medulla respond to H⁺, which normally arises from dissolved CO₂ in the cerebrospinal fluid (CSF). Peripherally located chemoreceptors in the fork of the common carotid arteries and the aortic arch are also sensitive to H⁺ and indirectly to CO₂. These receptors are also indirectly sensitive to hypoxemia because hypoxemia increases the sensitivity of the peripheral chemoreceptors to H⁺.²

Central Chemoreceptors

Hydrogen ions, not CO₂ molecules, stimulate highly responsive chemosensitive nerve cells, located bilaterally in the medulla. Nevertheless, these central chemoreceptors are extremely sensitive to CO₂ in an indirect fashion. The chemoreceptors are not in direct contact with arterial blood (Figure 14-4). Instead, they are bathed in the CSF, separated from the blood by a semipermeable membrane called the blood-brain barrier. This membrane is almost impermeable to H⁺ and HCO₃⁻, but it is freely permeable to CO₂. When PaCO₂ increases, CO₂ diffuses rapidly through the blood-brain barrier into the CSF. In the CSF, CO₂ reacts with water (H₂O) to form H⁺ and HCO₃⁻ (see Figure 14-4). The H⁺ generated in this fashion stimulates the central chemoreceptors, which stimulate the medullary inspiratory neurons. PaCO₂ is indirectly the primary minute-to-minute controller of ventilation. CO₂ diffusing from the blood into the CSF increases [H⁺] almost instantly, exciting the chemoreceptors within seconds. Alveolar ventilation increases by approximately 2 to 3 L/min for each 1-mm Hg increase in PaCO₂.⁵

FIGURE 14-4 CO₂ stimulates the medullary chemoreceptors by forming H⁺ in the CSF. The blood-brain barrier is almost impermeable to H⁺ and HCO₃⁻ but is freely permeable to CO₂. (Modified from Beachey W: Respiratory care anatomy and physiology: foundations for clinical practice, ed 2, St Louis, 2007, Mosby.)

The stimulatory effect of chronically high CO₂ on the central chemoreceptors gradually declines over 1 or 2 days because the kidneys retain bicarbonate ions in response to respiratory acidosis, bringing the blood pH level back toward normal. The increased number of bicarbonate ions in the blood eventually diffuses across the blood-brain barrier into the CSF, where they buffer H⁺ and bring the CSF pH level back to normal. This activity removes the stimulus to the chemoreceptors, and ventilation decreases. An acute increase in PaCO₂ has a powerful effect on ventilation, which is greatly weakened after 1 or 2 days of adaptation.

Peripheral Chemoreceptors

The peripheral chemoreceptors are small, highly vascular structures known as the carotid and aortic bodies. The carotid bodies are located bilaterally in the bifurcations of the common carotid arteries. The aortic bodies are found in the arch of the aorta. These neural structures increase their firing rates in response to increased arterial [H⁺] regardless of its origin (i.e., whether from fixed acid accumulation or increased CO₂). The carotid bodies send their impulses to the respiratory centers in the medulla via the glossopharyngeal nerve, whereas the aortic bodies send their impulses over the vagus nerve. The carotid bodies exert much more influence over the respiratory centers than the aortic bodies do, especially with respect to arterial hypoxemia and acidemia.¹

Because the carotid bodies receive an extremely high rate of blood flow, they have little time to remove O₂ from the blood. Consequently, venous blood leaving the carotid bodies has almost the same O₂ content as the arterial blood entering them. The carotid bodies are exposed at all times to arterial blood, not venous blood, and they sense arterial (not venous) [H⁺].

Response to Decreased Arterial Oxygen

Traditionally, it was believed that the carotid bodies directly sense low PaO₂, implying that arterial hypoxemia represents an independent drive to breathe—the “hypoxic drive.” Although the peripheral chemoreceptors fire more frequently in the presence of arterial hypoxemia, they do so only because hypoxemia makes them more sensitive to H⁺.² That is, when PaO₂ is low, carotid body sensitivity to a given [H⁺] increases; in this way, hypoxia increases ventilation for any given pH. Conversely, elevated PaO₂ (hyperoxia) decreases carotid body sensitivity to [H⁺]. The carotid bodies respond to arterial hypoxemia only because hypoxia makes them more sensitive to [H⁺]. This means that if the arterial [H⁺] is extremely low (high pH), as in severe alkalemia, hypoxemia has little effect on the carotid bodies.² Simply stated, the ultimate effect of hypoxemia is to increase the sensitivity of the peripheral chemoreceptors to the given blood [H⁺], which increases their firing rate and brings about increased ventilation.

Because of their extremely high blood flow rates, the carotid bodies respond to decreased arterial partial pressure of O₂ (in the indirect way just described) rather than to an actual decrease in arterial O₂ content. That is, the extraction of O₂ by the carotid bodies from each unit of rapidly flowing blood is so small that their O₂ needs are met entirely by dissolved O₂ in the plasma. This is why conditions associated with low arterial O₂ content but normal PaO₂ (e.g., anemia and carbon monoxide poisoning) do not stimulate ventilation.⁵

When pH and PaCO₂ are normal (pH = 7.40 and PaCO₂ = 40 mm Hg), the nerve-impulse transmission rate of the carotid bodies does not increase significantly until the PaO₂ decreases to about 60 mm Hg.⁵ If PaO₂ decreases further from 60 mm Hg to 30 mm Hg, the rate of impulse transmission increases sharply and linearly because hypoxemia makes the carotid bodies much more sensitive to a pH of 7.40. A decrease in PaO₂ from 60 mm Hg to 30 mm Hg corresponds to the sharpest decrease in O₂ content on the O₂-hemoglobin equilibrium curve (i.e., the steepest part of the curve). Arterial hypoxemia does not stimulate ventilation greatly until the PaO₂ decreases to less than 60 mm Hg. O₂ plays no role in the drive to breathe in healthy individuals at sea level. High altitude causes a healthy person’s ventilation to increase because low barometric pressure decreases the inspired PO₂ and the arterial PO₂, which increases the sensitivity of peripheral chemoreceptors to their H⁺ environment. The resulting increase in ventilation is less than expected, however, because hyperventilation decreases PaCO₂ and increases arterial pH. The increased pH depresses the medullary respiratory center, counteracting the excitatory effect of a low PaO₂ on peripheral chemoreceptors. Hypoxemia-mediated hyperventilation may be impossible in certain conditions, such as severe chronic obstructive pulmonary disease (COPD), in which lung mechanics are so deranged that the stimulatory effect of hypoxemia on ventilation fails to decrease PaCO₂ regardless of the patient’s effort. In such instances, there is no alkalosis to counteract the stimulatory effects of hypoxemia on ventilation.

Rule of Thumb

Hypoxemia is not associated with an increased drive to breathe until PaO₂ is less than 60 mm Hg, after which the drive to breathe increases proportionally with the decrease in PaO₂.

Response to Increased PaCO₂ and Hydrogen Ions

For a given increase in PaCO₂ or [H⁺], the carotid bodies are less responsive than the central chemoreceptors. The peripheral chemoreceptors account for only 20% to 30% of the ventilatory response to hypercapnia.⁵ However, they respond to increased arterial [H⁺] more rapidly than do the central chemoreceptors. The explanation is that, in contrast to the central chemoreceptors, the carotid bodies are exposed directly to arterial blood. The body’s initial ventilatory response to metabolic acidosis is fairly quick, even though H⁺ crosses the blood-brain barrier with difficulty.

As stated earlier, hypoxemia increases the sensitivity of the peripheral chemoreceptors to H⁺ and to PaCO₂. Conversely, high PaO₂ (hyperoxia) decreases the peripheral chemoreceptors’ PCO₂ sensitivity to almost zero.² This means that when the PaO₂ is high, the ventilatory response to PaCO₂ is mainly due to the central chemoreceptors, which are unaffected by hypoxemia.

Because the only effect of hypoxia on the peripheral chemoreceptors is to increase their sensitivity to arterial [H⁺⁺]—and indirectly to PaCO₂—the following statements are true: (1) High PO₂ renders the peripheral chemoreceptors almost unresponsive to PCO₂, and (2) low PaCO₂ renders the peripheral chemoreceptors almost unresponsive to hypoxemia.² Coexisting arterial hypoxemia, acidemia, and high PaCO₂ (i.e., asphyxia) maximally stimulate the peripheral chemoreceptors.

Mini Clini

Delayed Hyperventilation at High Altitude

Problem

If a person ascends to an elevation of 10,000 feet above sea level, his or her inspired PO₂ decreases because of low barometric pressure. Consequently, the peripheral chemoreceptors become excited and stimulate an increase in ventilation. Why must a day or so pass at this altitude before ventilation increases to its maximal level?

Solution

Hypoxia-induced hyperventilation reduces PaCO₂ and creates alkalemia. This condition produces an alkalotic CSF because the blood-brain barrier is nearly impermeable to bicarbonate ions (HCO₃⁻); that is, as CO₂ diffuses out of the CSF in response to the low arterial blood PCO₂, HCO₃⁻ remains behind in the CSF. The central chemoreceptors are exposed to an alkalotic environment, diminishing the effect of the hypoxic ventilatory stimulus on peripheral chemoreceptors. In other words, the development of respiratory alkalosis limits the magnitude of hypoxia-induced hyperventilation. Over the first 24 hours or so of hyperventilation, HCO₃⁻ gradually diffuses out of the CSF across the blood-brain barrier, restoring the CSF pH level to normal. In addition, the kidneys excrete HCO₃⁻ to compensate for the respiratory alkalemia. Consequently, the blood pH level decreases toward normal, and the hypoxic ventilatory stimulus keeps the PaCO₂ low. As the CSF pH level returns to normal, the progressively unrestrained hypoxic stimulus increases ventilation further. It takes approximately 24 hours of high-altitude exposure before ventilation increases to its maximal level.

Individuals with chronic hypercapnia secondary to advanced COPD have depressed ventilatory responses to acute increases in arterial CO₂, partly because of their altered acid-base status and partly because their deranged lung mechanics prevents them from increasing their ventilation adequately.¹ The altered acid-base status arises from the preexisting high levels of blood buffer base, a compensatory response to chronic respiratory acidosis (see Chapter 13).

Rule of Thumb

The ventilatory response to hypoxemia is greatly enhanced by hypercapnia and acidemia.

Control of Breathing in Chronic Hypercapnia

A sudden increase in arterial PCO₂ causes an immediate increase in ventilation because CO₂ rapidly diffuses from the blood into the CSF, increasing the [H⁺] surrounding central chemoreceptors. If PaCO₂ increases gradually over many years, as might occur in the development of severe COPD and worsening lung mechanics, the kidneys compensate by increasing the plasma bicarbonate concentration, keeping the arterial pH within normal limits. As plasma bicarbonate levels increase, these ions slowly diffuse across the blood-brain barrier, keeping CSF pH within its normal range. The central chemoreceptors respond to [H⁺], not the CO₂ molecule; they sense a normal pH environment, even though the PaCO₂ is abnormally high.

This adaptation explains why the chronically high PaCO₂ of people with severe COPD does not overly stimulate their ventilation. Instead, the hypoxemia that accompanies chronic hypercapnia becomes the minute-to-minute breathing stimulus in the roundabout way discussed previously: Hypoxemia increases the sensitivity of the peripheral chemoreceptors to [H⁺], increasing the nerve impulses they transmit to the medulla and stimulating ventilation. Patients with severe COPD are invariably hypoxemic when breathing room air because their lungs have mismatches in ventilation and blood flow. It stands to reason that breathing supplemental O₂ would increase the PaO₂ and make the carotid bodies less sensitive to [H⁺], which would decrease ventilation further and increase the PaCO₂.

Oxygen-Associated Hypercapnia

PaCO₂ of chronically hypercapnic patients with COPD often increases acutely after these patients are given O₂. The reason for this phenomenon continues to be a subject of much debate and misunderstanding. The traditional explanation for this phenomenon is that O₂ breathing removes the hypoxic ventilatory stimulus and induces hypoventilation, but this explanation is probably overly simplified. (This explanation has been challenged only in the context of chronically hypercapnic and hypoxemic patients with COPD; no investigator has suggested a different kind of explanation for why severely hypoxemic, hyperventilating patients with no history of chronic hypercapnia decrease their ventilation and increase their PaCO₂ values after breathing supplemental O₂. That is, if one accepts that hypoxemia stimulates ventilation as earlier described, it logically follows that the removal of that stimulus via O₂ administration would cause ventilation to decrease and PaCO₂ to increase; however, when a chronically hypercapnic patient is involved, many investigators completely discount this mechanism as playing a causative role.) Nevertheless, the reduction in minute ventilation after O₂ breathing in patients with advanced COPD is not always severe enough to account for the increased PaCO₂.6,7 Some investigators suggest that O₂ breathing worsens the ventilation/perfusion ratio () relationships in the lungs and is responsible for the increase in PaCO₂.^6,7 Other investigators have suggested that O₂-induced hypercapnia is caused by the combined effects of hypoxic stimulus removal and redistribution of relationships in the lungs.^8,9

Breathing O₂ worsens the already poor relationships in patients with COPD because it abolishes hypoxic pulmonary vasoconstriction in poorly ventilated lung regions. As a result, vascular resistance of underventilated regions decreases, and they receive more blood flow, drawing blood away from well-ventilated regions (Figure 14-5). At the same time that poorly ventilated regions receive more blood flow, they become even less ventilated as O₂-rich inspired gas washes out resident nitrogen gas, making these alveoli more subject to absorption atelectasis (i.e., O₂ may be absorbed by the pulmonary circulation more rapidly than the slowed ventilation can replenish it—notice the further decreased in Figure 14-5, B). As a result, inspired gas tends to flow preferentially to the already well-ventilated alveoli (see Figure 14-5, B), increasing their . The increased in these alveoli is exaggerated further as a greater proportion of the cardiac output than before is redirected to poorly ventilated alveoli, whose vascular resistance is reduced by O₂ breathing.

FIGURE 14-5 Proposed mechanism whereby O₂ administration in chronically hypercapnic individuals induces further hypercapnia by creating mismatches. A, Low unit *(left)* is hypoxic and hypercapnic while breathing ambient air; this induces pulmonary vasoconstriction. B, Breathing 50% O₂ predisposes the poorly ventilated unit to absorption atelectasis, further decreasing its ventilation, and simultaneously relieves hypoxic vasoconstriction, increasing its blood flow. These events (1) lower the poorly ventilated unit’s ratio further and (2) divert blood flow away from and ventilation toward already well-ventilated units. The latter increases alveolar dead space (high ). (Modified from Beachey W: Respiratory care anatomy and physiology: foundations for clinical practice, ed 2, St Louis, 2007, Mosby.)

O₂ breathing causes more blood flow to be directed to poorly ventilated alveoli, which takes blood flow away from well-ventilated alveoli. The key point is that already underventilated alveoli receive additional blood flow, which causes blood PCO₂ to increase further. These events can occur without a decrease in overall minute ventilation.

Although some investigators believe the mechanisms just described explain why O₂ administration is associated with hypercapnia in COPD, other studies support an equally important role for O₂ suppression of the hypoxic ventilatory stimulus.8,9 These studies show that O₂ administration in acutely ill, chronically hypercapnic patients with COPD significantly reduces ventilation and increases the PaCO₂ level needed to stimulate ventilation.

The diagnosis of COPD on a patient’s medical record does not automatically mean the patient has a chronically high PaCO₂ or that O₂ administration may be associated with hypercapnia. These characteristics are present only in severe end-stage disease, which includes only a small percentage of patients with COPD. Concern about O₂-associated hypercapnia and acidemia is not warranted in most patients with a diagnosis of COPD. O₂ should never be withheld from acutely hypoxemic patients with COPD for fear of inducing hypoventilation and hypercapnia. Tissue oxygenation is an overriding priority; O₂ must never be withheld from exacerbated, hypoxemic patients with COPD for any reason. The clinician must be prepared to support ventilation mechanically if O₂ administration is accompanied by severe hypoventilation.

Central Chemoreceptor Response to Acute Carbon Dioxide Increase in Chronic Hypercapnia

As discussed earlier, the kidneys compensate for the acidic effects of chronic hypercapnia by increasing the plasma bicarbonate level, keeping the medullary chemoreceptor pH environment in the normal range. This does not mean that the medullary chemoreceptors cannot respond to further acute increases in PaCO₂. A sudden elevation in PaCO₂ immediately crosses the blood-brain barrier into the CSF, generating H⁺ that subsequently stimulates the medullary chemoreceptors. The resulting ventilatory response is depressed, however, for chemical and mechanical reasons: (1) The blood’s increased buffering capacity (high HCO₃⁻ level) in chronic hypercapnia prevents arterial pH from decreasing as sharply as it would in normal conditions, and (2) abnormal breathing mechanics impair the lung’s ability to increase ventilation appropriately. To illustrate the blood’s changed buffering capacity, compare a healthy person (pH = 7.40, PaCO₂ = 40 mm Hg, HCO₃⁻ = 24 mEq/L) with a chronically hypercapnic person (pH = 7.38, PaCO₂ = 60 mm Hg, HCO₃⁻ = 34 mEq/L). A sudden 30-mm Hg increase in PaCO₂ of both individuals causes the healthy person’s arterial pH to decrease to 7.21 and the hypercapnic person’s pH to decrease to only 7.24. (These values are calculated using the Henderson-Hasselbalch equation, assuming a 1-mEq/L increase in plasma HCO₃⁻ concentration for each acute 10-mm Hg increase in PaCO₂.) The central chemoreceptors of a chronically hypercapnic patient experience less stimulation than the central chemoreceptors of normal individuals for the same increase in PaCO₂. Several investigators have confirmed the reduced ventilatory response to CO₂ in chronic hypercapnia.10,11

Rule of Thumb

Tissue oxygenation is of overriding importance and must not be sacrificed because of undue concern about hypercapnia and acidemia in a patient with exacerbated COPD.

Ventilatory Response To Exercise

Strenuous exercise can increase CO₂ production and O₂ consumption by 20-fold.³ Ventilation normally keeps pace with CO₂ production, keeping PaCO₂, PaO₂, and arterial pH constant. Because arterial blood gases do not change during normal exercise, some other mechanism must be responsible for the increased ventilation in healthy individuals during exertion.

The exact mechanism responsible for this increase in ventilation is not well understood. Especially mysterious is the abrupt increase in ventilation at the onset of exercise, long before any chemical or humoral changes can occur in the body. Two predominating theories for this phenomenon are the following: (1) When the cerebral motor cortex sends impulses to exercising muscles, it apparently sends collateral excitatory impulses to the medullary respiratory centers; (2) exercising limbs moving around their joints stimulate proprioceptors, which transmit excitatory impulses to the medullary centers.1,3 Evidence also suggests that the sudden increase in ventilation at the onset of exercise is a learned response.^1,3 With repeated experience, the brain may learn to anticipate the proper amount of ventilation required to maintain normal blood gases during exercise.

Abnormal Breathing Patterns

Commonly described abnormal breathing patterns include Cheyne-Stokes respiration, Biot respiration, apneustic breathing, and central neurogenic hypoventilation and hyperventilation. In Cheyne-Stokes respiration, respiratory rate and tidal volume gradually increase and then gradually decrease to complete apnea (absence of ventilation), which may last several seconds. Tidal volume and breathing frequency gradually increase again, repeating the cycle. This pattern occurs when cardiac output is low, as in congestive heart failure, delaying the blood transit time between the lungs and the brain.⁴ In this instance, changes in respiratory center PCO₂ lag behind changes in PaCO₂.

For example, when an increased PaCO₂ from the lungs reaches the respiratory neurons, ventilation is stimulated; this lowers the PaCO₂ level. By the time the reduced PaCO₂ reaches the medulla to inhibit ventilation, hyperventilation has been in progress for an inappropriately long time. When blood from the lung finally does reach the medullary centers, the low PaCO₂ greatly depresses ventilation to the point of apnea. PaCO₂ increases, but an increase in respiratory center PCO₂ is delayed because of low blood flow rate. The brain eventually does receive the high PaCO₂ signal, and the cycle is repeated. Cheyne-Stokes respiration may also be caused by brain injuries in which the respiratory centers overrespond to changes in the PCO₂ level.

Biot respiration is similar to Cheyne-Stokes respiration except that tidal volumes are of identical depth. It occurs in patients with increased intracranial pressure (ICP), but the mechanism for this pattern is unclear.⁴

Apneustic breathing indicates damage to the pons. Central neurogenic hyperventilation is characterized by persistent hyperventilation driven by abnormal neural stimuli. It is related to midbrain and upper pons damage associated with head trauma, severe brain hypoxia, or lack of blood flow to the brain.¹² Conversely, central neurogenic hypoventilation means the respiratory centers do not respond appropriately to ventilatory stimuli, such as CO₂. It also is associated with head trauma and brain hypoxia as well as narcotic suppression of the respiratory center.¹²

Carbon Dioxide And Cerebral Blood Flow

CO₂ plays an important role in regulating cerebral blood flow. Its effect is mediated through the formation of H⁺ by CO₂.¹³ Increased PCO₂ dilates cerebral vessels, increasing cerebral blood flow, whereas decreased PCO₂ constricts cerebral vessels and reduces cerebral blood flow. In patients with traumatic brain injury (TBI), the brain swells acutely; this increases the ICP in the rigid skull to such high levels that blood supply to the brain might be cut off, causing cerebral hypoxia (ischemia). That is, high ICP may exceed cerebral arterial pressure and stop blood flow to the brain.

Mechanical hyperventilation has been used for many years in patients with TBI to decrease PaCO₂ and reduce the cerebral blood flow and ICP. In patients with TBI, a cerebral blood volume reduction of only 0.5 to 0.7 ml reduces the ICP by 1 mm Hg; for every 1-mm Hg acute reduction in PaCO₂ (between 20 mm Hg and 60 mm Hg), there is a 3% reduction in cerebral blood flow. Although an acute reduction in PaCO₂ reduces ICP, it also reduces cerebral blood flow and potentially causes cerebral ischemia. For this reason, the practice of inducing mechanical hyperventilation in patients with TBI is controversial; it seems counterintuitive to reduce blood flow and O₂ to an injured organ intentionally. In any event, hypoventilation in a head trauma patient with a preexisting high ICP is especially dangerous because the resulting hypercapnia dilates cerebral vessels and elevates the ICP even more.

Mini Clini

Mechanical Hyperventilation of a Patient With Traumatic Brain Injury

Problem

An automobile accident victim, previously healthy, sustained a closed head injury with accompanying high ICP. Mechanical ventilation in the intensive care unit is required. In ventilating this patient’s lungs, you can control the PaCO₂. What is your goal in establishing an appropriate PaCO₂?

Discussion

More than 40 years ago, clinical investigators showed that the volume of the swollen brain could be reduced by decreasing the PaCO₂. Since then, mechanical hyperventilation has been a cornerstone in managing increased ICP associated with TBI.¹³ Hyperventilation decreases ICP by causing cerebral vasoconstriction, ultimately reducing cerebral blood volume. This subject is not without controversy; hyperventilation-induced cerebral vasoconstriction has the potential to reduce cerebral blood flow to levels that cause cerebral hypoxia (ischemia). Over the last decade, this concern has dampened enthusiasm for hyperventilation in TBI. Both the proponents and the opponents of hyperventilation recognize that TBI poses an ischemic threat to the brain; proponents believe that the reduction of cerebral blood flow ultimately improves cerebral oxygenation by reducing the ICP, which helps sustain the cerebral perfusion pressure. Opponents point out that no other hypoxic organ in the body is treated by reducing its blood flow and O₂ supply. (Hyperventilation in this context is generally defined as PaCO₂ < 35 mm Hg.¹³)

The debate centers around the question of whether a hyperventilation-induced decrease in cerebral blood flow creates an additional hypoxic insult to the already ischemic brain and whether patients managed in this way have better clinical outcomes than patients in whom hyperventilation is not instituted. A comprehensive review of the subject published in 2005 concluded that hyperventilation produced no advantage in long-term clinical outcome of TBI compared with ventilation that maintained PaCO₂ in the normal range.¹³ The authors concluded that in TBI, hyperventilation therapy should be considered only for patients with high ICPs; no benefit can be expected if ICP is normal. They further concluded that hyperventilation is most appropriate in the second or third day after injury because cerebral blood flow is lowest in the first 24 hours after injury, and the risk of inducing ischemia through hyperventilation is greatest during this time. The authors advise against the hyperventilation of TBI patients to PaCO₂ less than 30 mm Hg because of the increased danger of cerebral ischemia. Finally, hyperventilation is effective for only about 24 to 48 hours because compensatory renal elimination of bicarbonate in the face of alkalemia restores the acid-base balance, negating the vasoconstrictive effect of hypocapnia. In any case, hypoventilation in patients with head trauma and increased ICPs is especially dangerous because hypercapnia dilates cerebral vessels and increases ICP further. Even opponents of hyperventilation generally maintain PaCO₂ of TBI patients in the low-normal range around 35 mm Hg.

Summary Checklist

• The DRGs and VRGs of neurons in the medulla generate the basic cyclic breathing pattern.

• Apneustic center impulses prevent medullary inspiratory neurons from switching off, creating a prolonged, gasping inspiration.

• Impulses from the pneumotaxic center inhibit the apneustic center, shortening inspiratory time and increasing respiratory rate.

• Various reflexes from peripheral sources affect the breathing pattern by altering the output of the medullary center.

• Central chemoreceptors in the medulla are bathed in the CSF, separated from arterial blood by a semipermeable membrane called the blood-brain barrier.

• The blood-brain barrier is almost impermeable to arterial H⁺ and bicarbonate ions, but it is freely permeable to arterial CO₂.

• Central chemoreceptors stimulate increased ventilation in response to the H⁺ formed in the CSF by the reaction between arterial CO₂ and H₂O.

• Peripheral chemoreceptors, located mainly in the carotid bodies, respond to arterial [H⁺]; hypoxemia increases the sensitivity of chemoreceptors to a given arterial pH.

• The peripheral chemoreceptors are indirectly stimulated by arterial CO₂ to the extent that CO₂ reacts with H₂O to form H⁺.

• The primary stimulus for breathing in healthy individuals is arterial CO₂, mediated through the central chemoreceptors via H⁺ formed by the reaction between H₂O and CO₂ molecules.

• The secondary stimulus for breathing in healthy individuals is arterial hypoxemia, which is not clinically significant until PaO₂ is less than 60 mm Hg.