Dorsal Respiratory Group of Neurons

The DRG is spatially associated with the tractus solitarius, which is the principal tract for the ninth and tenth cranial (glossopharyngeal and vagus) nerves. These nerves carry afferent fibers from the airways and lungs, heart, and peripheral arterial chemoreceptors. The DRG may constitute the initial intracranial site for processing some of these visceral sensory afferent inputs into a respiratory motor response (Berger, 2000).

On the basis of lung inflation, three types of neurons have been recognized in the DRG: type Iα (I stands for inspiratory), type Iβ, and pump (P) cells. Type Iα is inhibited by lung inflation (Cohen, 1981a). The axons of these neurons project to both the phrenic and the external (inspiratory) intercostal motoneurons of the spinal cord. Some type Iα neurons have medullary collaterals that terminate among the inspiratory and expiratory neurons of the ipsilateral VRG (Merrill, 1970).

The second type, Iβ, is excited by lung inflation and receives synaptic inputs from pulmonary stretch receptors. There is controversy as to whether Iβ axons project into the spinal cord respiratory neurons; the possible functional significance of such spinal projections is unknown. Both Iα and Iβ neurons receive excitatory inputs from the central pattern generator (or central inspiratory activity) for breathing, so that when lung inflation is terminated or the vagi in the neck are cut, the rhythmic firing activity of these neurons continues (Cohen, 198la, 1981b; Feldman and Speck, 1983).

The third type of neurons in the DRG receives no input from the central pattern generator. The impulse of these neurons, the P cells, closely follows lung inflation during either spontaneous or controlled ventilation (Berger, 1977). The P cells are assumed to be relay neurons for visceral afferent inputs (Berger, 2000).

The excitation of Iβ neurons by lung inflation is associated with the shortening of inspiratory duration. The Iβ neurons appear to promote inspiration-to-expiration phase-switching by inhibiting Iα neurons. This network seems to be responsible for the Hering-Breuer reflex inhibition of inspiration by lung inflation (Cohen, 198la, 1981b; von Euler, 1986, 1991).

The DRG thus functions as an important primary and possibly secondary relay site for visceral sensory inputs via glossopharyngeal and vagal afferent fibers. Because many of the inspiratory neurons in the DRG project to the contralateral spinal cord and make excitatory connections with phrenic motoneurons, the DRG serves as a source of inspiratory drive to phrenic and possibly to external intercostal motoneurons (Berger, 2000).

Ventral Respiratory Group of Neurons

The VRG extends from the rostral to the caudal end of the medulla and has three subdivisions (Fig. 3-5). The Bötzinger complex, located in the most rostral part of the medulla in the vicinity of the retrofacial nucleus, contains mostly expiratory neurons (Lipski and Merrill, 1980; Merrill et al., 1983). These neurons send inhibitory signals to DRG and VRG neurons and project into the phrenic motoneurons of the spinal cord, causing its inhibition (Bianchi and Barillot, 1982; Merrill et al., 1983). The physiologic significance of these connections may be to ensure inspiratory neuronal silence during expiration (reciprocal inhibition) and to contribute to the “inspiratory off-switch” mechanism.

The nucleus ambiguus (NA) and nucleus paraambigualis (NPA), lying side by side, occupy the middle portion of the VRG. Axons of the respiratory motoneurons originating from the NA project along with other vagal efferent fibers and innervate the laryngeal abductor (inspiratory) and adductor (expiratory) muscles via the recurrent laryngeal nerve (Barillot and Bianchi, 1971; Bastel and Lines, 1975). The NPA contains mainly inspiratory (Iγ) neurons, which respond to lung inflation in a manner similar to that of Iα neurons. The axons of these neurons project both to phrenic and external (inspiratory) intercostal motoneuron pools in the spinal cord. The nucleus retroambigualis (NRA) occupies the caudal part of the VRG and contains expiratory neurons whose axons project into the spinal motoneuron pools for the internal (expiratory) intercostal and abdominal muscles (Merrill, 1970; Miller et al., 1985).

The inspiratory neurons of the DRG send collateral fibers to the inspiratory neurons of the NPA in the VRG. These connections may provide the means for ipsilateral synchronization of the inspiratory activity between the neurons in the DRG and those in the VRG (Merrill, 1979, 1983). Furthermore, axon collaterals of the inspiratory neurons of the NPA on one side project to the inspiratory neurons of the contralateral NPA, and vice versa. These connections may be responsible for the bilateral synchronization of the medullary inspiratory motoneuron output, as evidenced by synchronous bilateral phrenic nerve activity (Merrill, 1979, 1983).

Pontine Respiratory Group of Neurons

In the dorsolateral portion of the rostral pons, both inspiratory and expiratory neurons have been found. Inspiratory neuronal activity is concentrated ventrolaterally in the region of the nucleus parabrachialis lateralis (NPBL). The expiratory activity is centered more medially in the vicinity of the nucleus parabrachialis medialis (NPBM) (Fig. 3-5) (Cohen, 1979; Mitchell and Berger, 1981). The respiratory neurons of these nuclei are referred to as the pontine respiratory group (PRG), which was, and sometimes still is, called the pneumotaxic center, although the term is generally considered obsolete (Feldman, 1986). There are reciprocal projections between the PRG neurons and the DRG and VRG neurons in the medulla. Electrical stimulation of the PRG produces rapid breathing with premature switching of respiratory phases, whereas transaction of the brainstem at a level caudal to the PRG prolongs inspiratory time (Cohen, 1971; Feldman and Gautier, 1976). Bilateral cervical vagotomies produce a similar pattern of slow breathing with prolonged inspiratory time; a combination of PRG lesions and bilateral vagotomy in the cat results in apneusis (apnea with sustained inspiration) or apneustic breathing (slow rhythmic respiration with marked increase end inspiratory hold) (Feldman and Gaultier, 1976; Feldman, 1986). The PRG probably plays a secondary role in modifying the inspiratory off-switch mechanism (Gautier and Bertrand, 1975; von Euler and Trippenbach, 1975).

Respiratory Rhythm Generation

Rhythmic breathing in mammals can occur in the absence of feedback from peripheral receptors. Because transection of the brain rostral to the pons or high spinal transection has little effect on the respiratory pattern, respiratory rhythmogenesis apparently takes place in the brainstem. The PRG, DRG, and VRG have all been considered as possible sites of the central pattern generator, although its exact location is still unknown (Cohen, 1981b; von Euler, 1983, 1986). A study with an in vitro brainstem preparation of neonatal rats has indicated that respiratory rhythm is generated in the small area in the ventrolateral medulla just rostral to the Bötzinger complex (pre-Bötzinger complex), which contains pacemaker neurons (Smith et al., 1991).

The pre-Bötzinger complex contains a group of neurons that is responsible for respiratory rhythmogenesis (Smith et al., 1991; Pierrefiche et al., 1998; Rekling and Feldman, 1998). Although the specific cellular mechanism responsible for rhythmogenesis is not known, two possible mechanisms have been proposed (Funk and Feldman, 1995; Ramirez and Richter, 1996). One hypothesis is that the pacemaker neurons possess intrinsic properties associated with various voltage- and time-dependent ion channels that are responsible for rhythm generation. Rhythmic activity in these neurons may depend on the presence of an input system that may be necessary to maintain the neuron’s membrane potential in a range in which the voltage-dependent properties of the cell’s ion channels result in rhythmic behavior. The network hypothesis is the alternative model in which the interaction between the neurons produces respiratory rhythmicity, such as reciprocal inhibition between inhibitory and excitatory neurons and recurrent excitation within any population of neurons (Berger, 2000). The output of this central pattern generator is influenced by various inputs from chemoreceptors (central and peripheral), mechanoreceptors (e.g., pulmonary receptors and muscle and joint receptors), thermoreceptors (central and peripheral), nociceptors, and higher central structures (such as the PRG). The function of these inputs is to modify the breathing pattern to meet and adjust to ever-changing metabolic and behavioral needs (Smith et al., 1991).

Airway and Pulmonary Receptors

The upper airways, trachea and bronchi, lungs, and chest wall have a number of sensory receptors sensitive to mechanical and chemical stimulation. These receptors affect ventilation as well as circulatory and other nonrespiratory functions.

Tracheobronchial and Pulmonary Receptors

Three major types of tracheobronchial and pulmonary receptors have been recognized: slowly adapting (pulmonary stretch) receptors and rapidly adapting (irritant or deflation) receptors, both of which lead to myelinated vagal afferent fibers and unmyelinated C-fiber endings (J-receptors). Excellent reviews on pulmonary receptors have been published (Pack, 1981; Widdicombe, 1981; Sant’Ambrogio, 1982; Coleridge and Coleridge, 1984).

Slowly adapting (pulmonary stretch) receptors

Slowly adapting (pulmonary stretch) receptors (SARs) are mechanoreceptors that lie within the submucosal smooth muscles in the membranous posterior wall of the trachea and central airways (Bartlett et al., 1976). A small proportion of the receptors are located in the extrathoracic upper trachea (Berger, 2000). SARs are activated by the distention of the airways during lung inflation and inhibit inspiratory activity (Hering-Breuer inflation reflex), whereas they show little response to steady levels of lung inflation. The Hering-Breuer reflex also produces dilation of the upper airways from the larynx to the bronchi. Although SARs are predominantly mechanoreceptors, hypocapnia stimulates their discharge, and hypercapnia inhibits it (Pack, 1981). In addition, SARs are thought to be responsible for the accelerated heart rate and systemic vasoconstriction observed with moderate lung inflation (Widdicombe, 1974). These effects are abolished by bilateral vagotomy.

Studies by Clark and von Euler (1972) have demonstrated the importance of the inflation reflex in adjusting the pattern of ventilation in the cat and the human. In cats anesthetized with pentobarbital, inspiratory time decreases as tidal volume increases with hypercapnia, indicating the presence of the inflation reflex in the normal tidal volume range. Clark and von Euler demonstrated an inverse hyperbolic relationship between the tidal volume and inspiratory time. In the adult human, inspiratory time is independent of tidal volume until the latter increases to about twice the normal tidal volume, when the inflation reflex appears (Fig. 3-6). In the newborn, particularly the premature newborn, the inflation reflex is present in the eupneic range for a few months (Olinsky et al., 1974).

FIGURE 3-6 Relationship between tidal volume (Vt) and inspiratory time (Ti) as ventilation is increased in response to respiratory stimuli. Note that in region I, Vt increases without changes in Ti. Also shown as dashed lines are the Vt trajectories for three different tidal volumes in region II.

(From Berger AJ: Control of breathing. In Murray JF, Nadel JA: Textbook of respiratory medicine, Philadelphia, 1994, WB Saunders.)

Apnea, commonly observed in adult patients at the end of surgery and anesthesia with the endotracheal tube cuff still inflated, may be related to the inflation reflex, because the trachea has a high concentration of stretch receptors (Bartlett et al., 1976; Sant’Ambrogio, 1982). Deflation of the cuff promptly restores rhythmic spontaneous ventilation.

Rapidly adapting (irritant) receptors

Rapidly adapting (irritant) receptors (RARs) are located superficially within the airway epithelial cells, mostly in the region of the carina and the large bronchi (Pack, 1981; Sant’Ambrogio, 1982). RARs respond to both mechanical and chemical stimuli. In contrast to SARs, RARs adapt rapidly to large lung inflation, distortion, or deflation, thus possessing marked dynamic sensitivity (Pack, 1981). RARs are stimulated by cigarette smoke, ammonia, and other irritant gases including inhaled anesthetics, with significant interindividual variability (Sampson and Vidruk, 1975). RARs are stimulated more consistently by histamine and prostaglandins, suggesting their role in response to pathologic states (Coleridge et al., 1976; Sampson and Vidruk, 1977; Vidruk et al., 1977; Berger, 2000). The activation of RARs in the large airways may be responsible for various reflexes, including coughing, bronchoconstriction, and mucus secretion. Stimulation of RARs in the periphery of the lungs may produce hyperpnea. Because RARs are stimulated by deflation of the lungs to produce hyperpnea in animals, they are considered to play an important role in the Hering-Breuer deflation reflex (Sellick and Widdicombe, 1970). This reflex, if it exists in humans, may partly account for increased respiratory drive when the lung volume is abnormally decreased, as in premature infants with IRDS and in pneumothorax.

When vagal conduction is partially blocked by cold, inflation of the lung produces prolonged contraction of the diaphragm and deep inspiration instead of inspiratory inhibition. This reflex, the paradoxical reflex of Head, is most likely mediated by RARs. It may be related to the complementary cycle of respiration, or the sigh mechanism, that functions to reinflate and reaerate parts of the lungs that have collapsed because of increased surface force during quiet, shallow breathing (Mead and Collier, 1959). In the newborn, inflation of the lungs initiates gasping. This mechanism, which was considered to be analogous to the paradoxical reflex of Head, may help to inflate unaerated portions of the newborn lung (Cross et al., 1960).

C-Fiber endings

Most afferent axons arising from the lungs, heart, and other abdominal viscera are slow conducting (slower than 2.5 m/sec), unmyelinated vagal fibers (C-fibers). Extensive studies by Paintal (1973) have suggested the presence of receptors supposedly located near the pulmonary or capillary wall (juxtapulmonary capillary or J-receptors) innervated by such C-fibers. C-fiber endings are stimulated by pulmonary congestion, pulmonary edema, pulmonary microemboli, and irritant gases such as anesthetics. Such stimulation causes apnea followed by rapid, shallow breathing, hypotension, and bradycardia. Stimulation of J-receptors also produces bronchoconstriction and increases mucus secretion. All these responses are abolished by bilateral vagotomy. In addition, stimulation of C-fiber endings can provoke severe reflex contraction of the laryngeal muscles, which may be partly responsible for the laryngospasm observed during induction of anesthesia with isoflurane or halothane.

In addition to receptors within the lung parenchyma (pulmonary C-fiber endings), there appear to be similar nonmyelinated nerve endings in the bronchial wall (bronchial C-fiber endings) (Coleridge and Coleridge, 1984). Both chemical and, to a lesser degree, mechanical stimuli excite these bronchial C-fiber endings. They are also stimulated by endogenous mediators of inflammation, including histamine, prostaglandins, serotonin, and bradykinin. Such stimulation may be a mechanism of C-fiber involvement in disease states such as pulmonary edema, pulmonary embolism, and asthma (Coleridge and Coleridge, 1984).

The inhalation of irritant gases or particles causes a sensation of tightness or distress in the chest, probably caused by its activation of pulmonary receptors. The pulmonary receptors may contribute to the sensation of dyspnea in lung congestion, atelectasis, and pulmonary edema. Bilateral vagal blockade in patients with lung disease abolished dyspneic sensation and increased breath-holding time (Noble et al., 1970).

Central Chemoreceptors

The medullary, or central, chemoreceptors, located near the surface of the ventrolateral medulla, are anatomically separated from the medullary respiratory center (Fig. 3-7). They respond to changes in hydrogen ion concentration in the adjacent cerebrospinal fluid rather than to changes in arterial Pco₂ or pH (Pappenheimer et al., 1965). Since CO₂ rapidly passes through the blood-brain barrier into the cerebrospinal fluid, which has poor buffering capacity, the medullary chemoreceptors are readily stimulated by respiratory acidemia. In contrast, ventilatory responses of the medullary chemoreceptors to acute metabolic acidemia and alkalemia are limited because changes in the hydrogen ion concentration in arterial blood are not rapidly transmitted to the cerebrospinal fluid. In chronic acid-base disturbances, the pH of cerebrospinal fluid (and presumably that of interstitial fluid) surrounding the medullary chemoreceptors is generally maintained close to the normal value of about 7.3 regardless of arterial pH (Mitchell et al., 1965). Under these circumstances, ventilation becomes more dependent on the hypoxic response of peripheral chemoreceptors.

FIGURE 3-7 View of the ventral surface of the medulla shows the chemosensitive zones. The rostral (R) and caudal (C) zones are chemosensitive. The intermediate (I) zone is not chemosensitive but may have a function in the overall central chemosensory response. The roman numerals indicate the cranial nerves.

(From Berger AJ, Hornbein TF: Control of respiration. In Patton HD et al., editors: Textbook of physiology, ed 21, Philadelphia, 1989, WB Saunders.)

Peripheral Chemoreceptors

The carotid bodies, located near the bifurcation of the common carotid artery, react rapidly to changes in Pao₂ and pH. Their contribution to the respiratory drive amounts to about 15% of resting ventilation (Severinghaus, 1972). The carotid body has three types of neural components: type I (glomus) cells, presumably the primary site of chemotransduction; type II (sheath) cells; and sensory nerve fibers (McDonald, 1981). Sensory nerve fibers originate from terminals in apposition to the glomus cells, travel via the carotid sinus nerve to join the glossopharyngeal nerve, and then enter the brainstem. The sheath cells envelop both the glomus cells and the sensory nerve terminals. A variety of neurochemicals have been found in the carotid body, including acetylcholine, dopamine, substance P, enkephalins, and vasoactive intestinal peptide. The exact functions of these cell types and the mechanisms of chemotransduction and the specific roles of these neurochemicals have not been well established (Berger, 2000).

The carotid bodies are perfused with extremely high levels of blood flow and respond rapidly to an oscillating Pao₂ rather than a constant Pao₂ at the same mean values (Dutton et al., 1964; Fenner et al., 1968). This mechanism may be partly responsible for hyperventilation during exercise.

The primary role of peripheral chemoreceptors is their response to changes in arterial Po₂. Moderate to severe hypoxemia (Pao₂ less than 60 mm Hg) results in a significant increase in ventilation in all age groups except for newborn, particularly premature, infants, whose ventilation is decreased by hypoxemia (Dripps and Comroe, 1947; Rigatto et al., 1975b). Peripheral chemoreceptors are also partly responsible for hyperventilation in hypotensive patients. Respiratory stimulation is absent in certain states of tissue hypoxia, such as moderate to severe anemia and carbon monoxide poisoning; despite a decrease in oxygen content, Pao₂ in the carotid bodies is maintained near normal levels, so that the chemoreceptors are not stimulated.

In acute hypoxemia, the ventilatory response via the peripheral chemoreceptors is partially opposed by hypocapnia, which depresses the medullary chemoreceptors. When a hypoxemic environment persists for a few days, for example, during an ascent to high altitude, ventilation increases further as cerebrospinal fluid bicarbonate decreases and pH returns toward normal (Severinghaus et al., 1963). However, later studies demonstrated that the return of cerebrospinal fluid pH toward normal is incomplete, and a secondary increase in ventilation precedes the decrease in pH, indicating that some other mechanisms are involved (Bureau and Bouverot, 1975; Foster et al., 1975). In chronic hypoxemia that lasts for a number of years, the carotid bodies initially exhibit some adaptation to hypoxemia and then gradually lose their hypoxic response. In people native to high altitudes, the blunted response of carotid chemoreceptors to hypoxemia takes 10 to 15 years to develop and is sustained thereafter (Sorensen and Severinghaus, 1968; Lahiri et al., 1978). In cyanotic heart diseases, the hypoxic response is lost much sooner but returns after surgical correction of the right-to-left shunts (Edelman et al., 1970).

In patients who have chronic respiratory insufficiency with hypercapnia, hypoxemic stimulation of the peripheral chemoreceptors provides the primary impulse to the respiratory center. If these patients are given excessive levels of oxygen, the stimulus of hypoxemia is removed, and ventilation decreases or ceases. Pco₂ further increases, patients become comatose (CO₂ narcosis), and death may follow unless ventilation is supported. Rather than oxygen therapy, such patients need their effective ventilation increased artificially with or without added inspired oxygen.

Response to Carbon Dioxide

The graphic demonstration of relations between the alveolar or arterial Pco₂ and the minute ventilation () is commonly known as the CO₂ response curve (Fig. 3-8). This curve normally reflects the response of the chemoreceptors and respiratory center to CO₂. The CO₂ response curve is a useful means for evaluation of the chemical control of breathing, provided that the mechanical properties of the respiratory system, including the neuromuscular transmission, respiratory muscles, thorax, and lungs, are intact. In normal persons, ventilation increases more or less linearly as the inspired concentration of carbon dioxide increases up to 9% to 10%, above which ventilation starts to decrease (Dripps and Comroe, 1947). Under hypoxemic conditions the CO₂ response is potentiated, primarily via carotid body stimulation, resulting in a shift to the left of the CO₂ response curve (Fig. 3-8) (Nielsen and Smith, 1951). On the other hand, anesthetics, opioids, and barbiturates in general depress the medullary chemoreceptors and, by decreasing the slope, shift the CO₂ response curve progressively to the right as the anesthetic concentration increases (Fig. 3-9) (Munson et al., 1966).

FIGURE 3-8 Effect of acute hypoxemia on the ventilatory response to steady-state Pao₂ in one subject. Inspired oxygen was adjusted in each experiment to keep Pao₂ constant at the level as indicated.

(From Nielsen M, Smith H: Studies on the regulation of respiration in acute hypoxia, Acta Physiol Scand 24:293, 1951.)

FIGURE 3-9 CO₂ response curve with halothane. Family of steady-state CO₂ response curves in one subject awake and at three levels of halothane anesthesia. Note progressive decrease in ventilatory response to Pao₂ with increasing anesthetic depth (MAC; ventilatory response in awake state was measured in response to end-tidal Pco₂).

(Courtesy Dr. Edwin S. Munson; data from Munson ES, et al.: The effects of halothane, fluroxene, and cyclopropane on ventilation: a comparative study in man, Anesthesiology 27:716, 1966.)

A shift to the right of the CO₂ response curve in an awake human may be caused by decreased chemoreceptor sensitivity to CO₂, as seen in patients whose carotid bodies had been destroyed (Wade et al., 1970). It may also be caused by lung disease and resultant mechanical failure to increase ventilation despite intact neuronal response to carbon dioxide. In patients with various central nervous system dysfunctions, the CO₂ response may be partially or completely lost (Ondine’s curse) (Severinghaus and Mitchell, 1962). In the awake state, these patients have chronic hypoventilation but can breathe on command. During sleep, they further hypoventilate or become apneic to the point of CO₂ narcosis and death unless mechanically ventilated or implanted with a phrenic pacemaker (Glenn et al., 1973).

It has been difficult to separate the neuronal component from the mechanical failure of the lungs and thorax, because the two factors often coexist in patients with chronic lung diseases (Guz et al., 1970). Whitelaw and others (1975) demonstrated that occlusion pressure at 0.1 second (P_0.1, or the negative mouth pressure generated by inspiratory effort against airway occlusion at FRC) correlates well with neuronal (phrenic) discharges but is uninfluenced by mechanical properties of the lungs and thorax. The occlusion pressure is a useful means for the clinical evaluation of the ventilatory drive.

As mentioned previously, hypoxemia potentiates the chemical drive and increases the slope of the CO₂ response curve (). Such a change has been interpreted as “a synergistic (or multiplicative) effect” of the stimulus, whereas a parallel shift of the curve has been considered as “an additive effect.” This analysis may be useful for descriptive purposes, but it is misleading. Because ventilation is the product of tidal volume and frequency (), an additive effect on its components could result in a change in the slope of the CO₂ response curve. Obviously, the responses of tidal volume and frequency to CO₂ should be examined separately to understand the effect of various respiratory stimulants and depressants.

Milic-Emili and Grunstein (1975) proposed that ventilatory response to CO₂ be analyzed in terms of the mean inspiratory flow (Vt/Ti, where Vt is tidal volume and Ti is the inspiratory time) and in terms of the ratio of inspiratory time to total ventilatory cycle duration or respiratory duty cycle (Ti/Ttot) (Fig. 3-10). Because the tidal volume is equal to Vt/Ti × Ti and respiratory frequency (f) is I/Ttot, ventilation can be expressed as follows:

FIGURE 3-10 Schematic drawing of tidal volume and timing components on time-volume axes. Vt, Tidal volume; Ti, inspiratory time; Te, expiratory time; Ttot, total time for respiratory cycle; f, respiratory frequency; Vt/Ti, mean inspiratory flow rate; Ti/Ttot, respiratory duty cycle.

The advantage of analyzing the ventilatory response in this fashion is that Vt/Ti is an index of inspiratory drive, which is independent of the timing element. The tidal volume, on the other hand, is time dependent, because it is (Vt/Ti) × T_I. The second parameter, Ti/Ttot, is a dimensionless index of effective respiratory timing (respiratory duty cycle) that is determined by the vagal afferent or central inspiratory off-switch mechanism or by both (Bradley et al., 1975). From this equation, it is apparent that in respiratory disease or under anesthesia, changes in pulmonary ventilation may result from a change in Vt/Ti, Ti/Ttot, or both. A reduction in Ti/Ttot indicates that the relative duration of inspiration decreased or that expiration increased. Such a reduction in the Ti/Ttot ratio may result from changes in central or peripheral mechanisms. In contrast, a reduction in Vt/Ti may indicate a decrease in the medullary inspiratory drive or neuromuscular transmission or an increase in inspiratory impedance (i.e., increased flow resistance, decreased compliance, or both). By relating the mouth occlusion pressure to Vt/Ti, it becomes clinically possible to determine whether changes in the mechanics of the respiratory system contribute to the reduction in Vt/Ti (Milic-Emili, 1977).

Analysis of inspiratory and expiratory durations provides useful information on the mechanism of anesthetic effects on ventilation. Figure 3-11 illustrates the effect of pentobarbital, which depresses minute ventilation, and diethyl ether, which “stimulates” ventilation in newborn rabbits. With both anesthetics the mean inspiratory flow (Vt/Ti) did not change, but Vt decreased because Ti was shortened. With pentobarbital, however, Te was prolonged disproportionately, and Ti/Ttot and frequency decreased; consequently, minute ventilation was decreased. With ether, on the other hand, ventilation increased as the result of disproportionate decrease in Te and consequent increases in Ti/Ttot and frequency (Milic-Emili, 1977).

FIGURE 3-11 Schematic summary of changes in the average respiratory cycle in a group of newborn rabbits before and after sodium pentobarbital anesthesia (left) and before and during ether anesthesia (right). Measurements obtained during spontaneous room air breathing. Zero on the time axis indicates onset of inspiration. Mean inspiratory flow is represented by the slope of the ascending limb of the spirograms.

(Modified from Milic-Emili J: Recent advances in the evaluation of respiratory drive, Int Anesthesiol Clin 15:75, 1977.)

Response to Hypoxemia in Infants

During the first 2 to 3 weeks of age, both full-term and premature infants in a warm environment respond to hypoxemia (15% oxygen) with a transient increase in ventilation followed by sustained ventilatory depression (Brady and Ceruti, 1966; Rigatto and Brady, 1972a, 1972b; Rigatto et al., 1975a) (Fig. 3-12). In infants born at 32 to 37 weeks’ gestation, the initial period of transient hyperpnea is abolished in a cool environment, indicating the importance of maintaining a neutral thermal environment (Cross and Oppe, 1952; Ceruti, 1966; Perlstein et al., 1970). When 100% oxygen is given, a transient decrease in ventilation is followed by sustained hyperventilation. This ventilatory response to oxygen is similar to that of the fetus and is different from that of the adult, in whom a sustained decrease in ventilation is followed by little or no increase in ventilation (Dripps and Comroe, 1947). By 3 weeks after birth, hypoxemia induces sustained hyperventilation, as it does in older children and adults.

FIGURE 3-12 Effect on ventilation of 14% oxygen (hypoxia) from room air and then to 100% oxygen (hyperoxia) in three newborn infants. Ventilation (mean ± SEM) is plotted against time. During acute hypoxia there was a transient increase in ventilation followed by depression. Hyperoxia increased ventilation.

(Modified from Lahiri S, et al.: Regulation of breathing in newborns, J Appl Physiol 44:673, 1978.)

The biphasic depression in ventilation has been attributed to central depression rather than to depression of peripheral chemoreceptors (Albersheim et al., 1976). In newborn monkeys, however, tracheal occlusion pressure, an index of central neural drive, and diaphragmatic electromyographic output were increased above the control level during both the hyperpneic and the hypopneic phases in response to hypoxic gas mixture (LaFramboise et al., 1981; LaFramboise and Woodrum, 1985). These findings imply that the biphasic ventilatory response to hypoxemia results from changes in the mechanics of the respiratory system (thoracic stiffness or airway obstruction), rather than from neuronal depression, as has been assumed (Jansen and Chernick, 1983). Premature infants continue to show a biphasic response to hypoxemia even at 25 days after birth (Rigatto, 1986). Thus, in terms of a proper response to hypoxemic challenge, maturation of the respiratory system may be related to postconceptional rather than postnatal age.

Response to Carbon Dioxide in Infants

Newborn infants respond to hypercapnia by increasing ventilation but less so than do older infants. The slope of the CO₂ response curve increases appreciably with gestational age as well as with postnatal age, independent of postconceptional age (Rigatto et al., 1975a, 1975b, 1982; Frantz et al., 1976). This increase in slope may represent an increase in chemosensitivity, but it may also result from more effective mechanics of the respiratory system. In adults the CO₂ response curve both increases in slope and shifts to the left with the severity of hypoxemia (Fig. 3-8). In contrast, in newborn infants breathing 15% oxygen, the CO₂ response curve decreases in slope and shifts to the right (Fig. 3-13). Inversely, hyperoxemia increases the slope and shifts the curve to the left (Rigatto et al., 1975a).

FIGURE 3-13 Mean steady-state CO₂ response curves at different inspired oxygen concentrations in eight preterm infants. The slope of the CO₂ response decreases with decreasing oxygen.

(From Rigatto H et al.: Effects of O₂ on the ventilatory response, J Appl Physiol 39:896, 1975.)

Upper Airway Receptor Responses in the Neonatal Period

Newborn animals are particularly sensitive to the stimulation of the superior laryngeal nerve either directly or through the receptors (such as water in the larynx), which results in ventilatory depression or apnea. In anesthetized newborn puppies and kittens, negative pressure or air flow through the larynx isolated from the lower airways produced apnea or significant prolongation of inspiratory and expiratory time and a decrease in tidal volume, whereas similar stimulation caused little or no effect in 4- to 5-week-old puppies or in adult dogs and cats (Al-Shway and Mortola, 1982; Fisher et al., 1985).

In a similar preparation using puppies anesthetized with pentobarbital, water in the laryngeal lumen produced apnea, whereas phosphate buffer with sodium chloride and neutral pH did not. The principal stimulus for the apneic reflex was the absence or reduced concentrations of chloride ion (Boggs and Bartlett, 1982). In awake newborn piglets, direct electric stimulation of the superior laryngeal nerve caused periodic breathing and apnea associated with marked decreases in respiratory frequency, hypoxemia, and hypercapnia with minimal cardiovascular effects. Breathing during superior laryngeal nerve stimulation was sustained by an arousal system (Donnelly and Haddad, 1986). The strong inhibitory responses elicited in newborn animals by various upper airway receptor stimulations have been attributed to the immaturity of the central nervous system (Lucier et al., 1979; Boggs and Bartlett, 1982).

Active Vs. Quiet Sleep

During the early postnatal period, full-term infants spend 50% of their sleep time in active or REM sleep compared with 20% REM sleep in adults (Stern et al., 1969; Rigatto et al., 1982). Wakefulness rarely occurs in neonates. Premature neonates stay in REM sleep most of the time, and quiet (non-REM) sleep is difficult to define before 32 weeks’ postconception (Rigatto, 1992). Neonates, particularly prematurely born neonates, therefore breathe irregularly.

Neurologic and chemical control of breathing in infants is related to the state of sleep (Scher et al., 1992). During quiet sleep, breathing is regulated primarily by the medullary respiratory centers and breathing is regular with respect to timing as well as amplitude and is tightly linked to chemoreceptor input (Bryan and Wohl, 1986). During REM sleep, however, breathing is controlled primarily by the behavioral system and is irregular with respect to timing and amplitude (Phillipson, 1994).

Periodic Breathing and Apnea

Pharyngeal Airway

The pharyngeal airway, unlike the laryngeal airway, is not supported by a rigid bony or cartilaginous structure. Its wall consists of soft tissues and is surrounded by muscles for breathing and for swallowing and is contained in a fixed bony structure (i.e., the maxilla, mandible, and spine) (Isono, 2006). Anatomic imbalance between the bony structure (the container—micrognathia, facial anomalies) and the amount of the soft tissues (the content—macroglossia, adenotonsillar hypertrophy, obesity) would result in the pharyngeal airway narrowing and obstruction (Fig. 3-14) (Isono, 2006).

FIGURE 3-14 A mechanical model of the pharyngeal airway (right) is produced based on structures surrounding the pharyngeal airway on a CT scan (left).

(From Isono S: Developmental changes of pharyngeal airway patency: implications for pediatric anesthesia, Pediatr Anesth 16:109, 2006.)

Even the normal pharyngeal airway is easily obstructed by the relaxation of the velopharynx (soft palate), posterior displacement of the mandible (and the base of the tongue) in the supine position during sleep, flexion of the neck, or external compression over the hyoid bone. The pharyngeal airway also is easily collapsed by negative pressure within the pharyngeal lumen created by inspiratory effort, especially when airway-maintaining muscles are depressed or paralyzed (Issa and Sullivan, 1984; Reed et al., 1985; Roberts et al., 1985). In neonates, with a relatively hypoplastic mandible, the oropharynx and the entrance to the larynx at the level of the aryepiglottic folds are the areas most easily collapsed (Reed et al., 1985).

Mechanical support to sustain the patency of the pharynx against the collapsing force of luminal negative pressure during inspiration is given by both the sustained muscle tension and cyclic contraction of the pharyngeal dilator muscles, acting synchronously with the contraction of the diaphragm. These include the genioglossus, geniohyoid, sternohyoid, sternothyroid, and thyrohyoid muscles (Fig. 3-15) (Bartlett et al., 1973; Pack et al., 1988; Thach, 1992). Similar phasic activities have been recorded in the scalene and sternomastoid muscles in humans (Onal et al., 1981; Drummond, 1987).

FIGURE 3-15 Lateral view of the musculature of the tongue and its relationship with a mandible and hyoid bone.

(From Kuna ST, Remmers JE: Pathophysiology and mechanisms of sleep apnea. In Fletcher EC, editor: Abnormalities of respiration during sleep, Orlando, FL, 1986, Grune & Stratton.)

A neural balance model of pharyngeal airway maintenance proposed by Remmers et al. (1978) and Brouillette and Thach (1979) and further modified by Isono (2006) is shown in Figure 3-16. In this model, the suction (collapsing) force created in the pharyngeal lumen by the inspiratory pump muscles (primarily the diaphragm) must be well balanced by the activities of pharyngeal airway dilator muscles to maintain upper airway patency. Increased nasal and pharyngeal airway resistance (partial obstruction) exaggerates the suction force. In addition, once pharyngeal closure occurs, the mucosal adhesion force of the collapsed pharyngeal wall becomes an added force acting against the opening of pharyngeal air passages (Reed et al., 1985).

FIGURE 3-16 A neural and anatomic balance model of the pharyngeal airway (PA) maintenance by Remmers et al. (1978) in adults and Brouillette and Thach (1979) in infants illustrating the balance of opposing forces that affect PA size. Airway collapsing forces (suction force created by inspiratory pump muscles) and dilating forces (pharyngeal dilator muscles) are shown on either side of the fulcrum, and neural mechanisms controlling this balance are in the box below the balance.

(Redrawn from Isono S: Developmental changes of pharyngeal airway patency: implications for pediatric anesthesia, Pediatr Anesth 16:109, 2006.)

Several reflex mechanisms are present to maintain the balance between the dilating and collapsing forces in the pharynx. Chemoreceptor stimuli such as hypercapnia and hypoxemia stimulate the airway dilators preferentially over the stimulation of the diaphragm so as to maintain airway patency (Brouillette and Thach, 1980; Onal et al., 1981, 1982). Negative pressure in the nose, pharynx, or larynx activates the pharyngeal dilator muscles and simultaneously decreases the diaphragmatic activity (Fig. 3-17) (Mathew et al., 1982a, 1982b; Hwang et al., 1984; Thach, 1992). Such an airway pressure reflex is especially prominent in infants younger than 1 year of age (Thach et al., 1989). Upper airway mechanoreceptors are located superficially in the airway mucosa and are easily blocked by topical anesthesia (Mathew et al., 1982a, 1982b). Sleep, sedatives, and anesthesia depress upper airway muscles more than they do the diaphragm (Sauerland and Harper, 1976; Ochiai et al., 1989, 1992). The arousal from sleep shifts the balance toward pharyngeal dilation (Thach, 1992).

FIGURE 3-17 Schematic illustration of sequence of events showing one of the ways in which the upper airway pressure reflex operates to preserve pharyngeal airway patency.

(From Thach BT: Neuromuscular control of the upper airway. In Beckerman RC et al., editors: Respiratory control disorders in infants and children, Baltimore, 1992, Williams & Wilkins.)

Laryngeal Airway

The larynx is composed of a group of cartilage, connecting ligaments, and muscles. It maintains the airway, and the glottis functions as a valve to occlude and protect the lower airways from the alimentary tract. It is also an organ for phonation (Proctor, 1977a, 1977b, 1986; Fink and Demarest, 1978). With the exception of the anterior nasal passages, the larynx at the subglottis is the narrowest portion of the entire airway system in all ages (Eckenhoff, 1951). The cricoid cartilage forms a complete ring, protecting the upper airway from compression.

For over half a century, the shape of pediatric larynx was thought to be “funnel shaped,” with the narrowest point at the laryngeal exit (cricoid ring), in contrast to the adult larynx, which is “cylindrical” in shape. This belief was based on the well-referenced classic paper by Eckenhoff in 1951; Eckenhoff quoted the work of Bayeux in 1897, more than half a century before his time, whose description was based on moulages (plaster casting) made from cadaveric larynx from 15 children between the ages of 4 months and 14 years. Indeed, Eckenhoff’s original paper cautioned that “the measurements so derived may not be completely applicable to the living” (Eckenhoff, 1951; Motoyama, 2009). More recently, however, both Litman and colleagues (2003) and Dalal and colleagues (2009) using two entirely different methodologies in living infants and children under general anesthesia, found that the dimensions of the larynx in infants and children are more cylindrical than funnel-shaped, as in adults, and the cylindrical shape does not change significantly with growth. In addition, both Litman and Dalal’s papers confirmed that the cricoid opening is the narrowest point of the larynx; however, in paralyzed children the opening at the vocal cords (lima glottidis) may be narrower than the opening of the cricoid cartilage, but it is expandable beyond the opening of the cricoid ring (Eckenhoff, 1951; Dalal et al., 2009). Perhaps more important clinically, both groups found with statistical significance that the cricoid opening is not circular but mildly elliptic with a smaller transverse diameter. This means that a tight-fitting, uncuffed endotracheal tube or even a “best-fitted” tube in young children with acceptable pressure leak (i.e., 20 cm H₂O) would exert more compression, if not ischemia, on the transverse mucosa of the cricoid ring (Motoyama, 2009). This finding provides theoretic evidence and further supports the recent trend of favoring cuffed endotracheal tubes over uncuffed endotracheal tubes in infants and children for their safety.

The glottis widens slightly during tidal inspiration and narrows during expiration, thus increasing laryngeal air flow resistance (Bartlett et al., 1973). Laryngeal resistance is finely regulated in neonates and young infants to dynamically maintain end expiratory lung volume (FRC) well above the small lung volume determined by the opposing elastic recoil forces of the thorax and the lungs, as is discussed in a later part of this chapter (Harding, 1984; England and Stogren, 1986). In infants with IRDS, expiration is often associated with “grunting” caused by narrowing of the glottic aperture. This grunting apparently maintains intrinsic positive end-expiratory pressure (PEEP), also known as PEEP_i or autoPEEP, during the expiratory phase and presumably prevent or reduce premature closure of airways and air spaces. In infants with IRDS, when grunting is eliminated by endotracheal intubation, respiratory gas exchange deteriorates rapidly and critically to the point of cardiorespiratory arrest unless continuous positive airway pressure (CPAP) is applied (Gregory et al., 1971).

Airway Protective Reflexes

Upper airway protective mechanisms involve both the pharynx and larynx and include sneezing, swallowing, coughing, and pharyngeal or laryngeal closure. Laryngospasm is a sustained tight closure of the vocal cords caused by the stimulation of the superior laryngeal nerve, a branch of the vagus, and contraction of the adductor muscles that persists beyond the removal of the stimulus. In puppies, it is elicited by repetitive stimulation of the superior laryngeal nerve with typical adductor after-discharge activity. This response is not evoked by the stimulation of the recurrent laryngeal nerve (Suzuki and Sasaki, 1977). Hyperventilation and hypocapnia, as well as light anesthesia, increase the activity of adductor neurons, reduce the mean threshold of the adductor reflex, or increase upper airway resistance (Suzuki and Sasaki, 1977; Nishino et al., 1981). Hyperthermia and decreased lung volume also facilitate laryngospasm produced by stimulation of the superior laryngeal nerve (Sasaki, 1979; Haraguchi et al., 1983). Contrarily, hypoventilation and hypercapnia, positive intrathoracic pressure, and deep anesthesia depress excitatory adductor after-discharge activity and increase the threshold of the reflex that precipitates laryngospasm (Suzuki and Sasaki, 1977; Ikari and Sasaki, 1980; Nishino et al., 1981). Hypoxia below an arterial Po₂ of 50 mm Hg also increases the threshold for laryngospasm (Ikari and Sasaki, 1980).

These findings are clinically relevant, suggesting a fail-safe mechanism by which asphyxia (hypoxia and hypercapnia) tends to prevent sustained laryngospasm. In healthy, awake adults, laryngospasm by itself is self-limited and not a threat to life. On the other hand, in the presence of cardiopulmonary compromise, such as may occur during anesthesia (particularly in infants), laryngospasm may indeed become life threatening (Ikari and Sasaki, 1980). Increased depth of anesthesia increases the reflex threshold and diminishes excitatory adductor after discharge in puppies (Suzuki and Sasaki, 1977). This finding is in accord with the clinical experience that laryngospasm occurs most readily under light anesthesia and that it can be broken by deepening anesthesia or awakening the patient. In puppies, positive intrathoracic pressure inhibits the glottic closure reflex and laryngospasm. This supports the clinical observation that during the emergence from anesthesia in infants and young children, maintenance of PEEP and inflation of the lungs at the time of extubation seem to reduce both the incidence and severity of laryngospasm (Motoyama, unpublished observation).

Infants are particularly vulnerable to laryngospasm. Animal studies suggest that during a discrete interval after birth and before complete neurologic maturation, there is a period of transient laryngeal hyperexcitability. This may relate to the transient reduction in central latency and a reduction in central inhibition of the vagal afferent nerve. If these observations in puppies are applicable to human infants, they may explain the susceptibility of infants and young children to laryngospasm and have some causal relation in unexpected infant death such as SIDS (Sasaki, 1979).

Infants, particularly premature neonates, exhibit clinically important airway protective responses to fluid at the entrance to the larynx (Davies et al., 1988; Pickens et al., 1989). This response seems to trigger prolonged apnea in neonates and breath-holding during inhalation induction of anesthesia in children. When a small quantity (less than 1 mL) of warm saline solution is dripped into the nasopharynx in a sleeping infant, it pools in the piriform fossa and then overflows into the interarytenoid space at the entrance to the larynx. This area is densely populated with various nerve endings, including a structure resembling a taste bud. The most common response to fluid accumulation is swallowing. The infant also develops central apnea with either the glottis open or closed; coughing is rare (Pickens et al., 1989). Apneic responses are more prominent with water than with saline solution (Davies et al., 1988).

These findings appear clinically important in pediatric anesthesia. During inhalation induction, pharyngeal reflexes (swallowing) are abolished, whereas laryngeal reflexes remain intact, as Guedel (1937) originally described for ether anesthesia. Secretions would accumulate in the hypopharynx without swallowing and cause breath-holding, resulting from central apnea, a closure of the glottis, or both. Positive pressure ventilation using a mask and bag instead of suctioning the pharynx would push secretions farther down into the larynx, stimulate the superior laryngeal nerve, and trigger real laryngospasm.

Effects of Anesthetic on Upper Airway Receptors

Inhalation induction of anesthesia is often associated with reflex responses such as coughing, breath-holding, and laryngospasm. Volatile anesthetics stimulate upper airway receptors directly and affect ventilation. In dogs spontaneously breathing through tracheostomy under urethane-chloralose anesthesia, an exposure of isolated upper airways to halothane caused depression of respiratory-modulated mechanoreceptors or pressure receptors, whereas irritant receptors and flow (cold) receptors were consistently stimulated in a dose-dependent manner (Nishino et al., 1993). Responses to isoflurane and enflurane were less consistent. Laryngeal respiratory-modulated mechanoreceptors may be a part of a feedback mechanism that maintains the patency of upper airways; the depression of this feedback mechanism may play an important role in the collapse of upper airways during the induction of anesthesia. Furthermore, activation of irritant receptors by halothane and other volatile anesthetics may be responsible for laryngeal reflexes such as coughing, apnea, laryngospasm, and bronchoconstriction seen during inhalation induction of anesthesia (Nishino et al., 1993).

The same group of investigators showed that in young puppies (younger than 2 weeks old), exposure of isolated upper airways to halothane (and to a lesser extent to isoflurane) resulted in a marked depression of ventilation (less than 40% of control) associated with decreases in both tidal volume and respiratory frequency (Sant’Ambrogio et al., 1993). Ventilatory effects caused by the exposure of isolated upper airways to volatile anesthetics were present but only mildly in 4-week-old puppies, whereas adult dogs were not affected. The superior laryngeal nerve section and topical anesthesia of the nasal cavity completely abolished the effects of halothane and isoflurane in the isolated upper airways of puppies (Sant’Ambrogio et al., 1993). Laryngeal receptor output in response to volatile anesthetics was not measured in this study. These findings in puppies appear to be clinically relevant because infants and young children often develop manifestations of upper airway reflexes during inhalation induction.

Effects of Anesthetics on Upper Airway Muscles

The genioglossus, geniohyoid, and other pharyngeal and laryngeal abductor muscles have phasic inspiratory activity synchronous with diaphragmatic contraction, in addition to their tonic activities that maintain upper airway patency in both animals and human neonates (Bartlett et al., 1973; Brouillette and Thach, 1979). The genioglossus and geniohyoid muscles increase the caliber of the pharynx by displacing the hyoid bone and the tongue anteriorly and are the most important muscles for the maintenance of oropharynx patency (Fig. 3-15). They have both phasic inspiratory activity and tonic activity throughout the respiratory cycle in awake humans (Onal et al., 1981). These activities of the genioglossus muscle and presumably other pharyngeal and laryngeal abductor muscles are easily depressed by alcohol ingestion, sleep, and general anesthesia; their depression would result in upper airway obstruction (Remmers et al., 1978; Brouillette and Thach, 1979; Nishino et al., 1984, 1985; Bartlett et al., 1990).

Sensitivity to anesthetics differs among various inspiratory muscles and their neurons. In studies in cats with the use of electromyography, Ochiai et al. (1989) demonstrated that the phasic inspiratory activity of the genioglossus muscle was most sensitive to the depressant effect of halothane at a given concentration, whereas the diaphragm was most resistant; the sensitivity of inspiratory intercostal muscles was intermediate (Fig. 3-18). In addition, phasic genioglossus activity was more readily depressed in kittens than in adult cats. Phasic genioglossus activity was completely abolished with 1.5% halothane or more in all kittens studied, whereas the activity was diminished but present in most adult cats even at 2.5% (Ochiai et al., 1992).

FIGURE 3-18 Decrease in phasic inspiratory muscle activity, expressed as peak height of moving time average (MTA), in percent change from control (1% halothane), during halothane anesthesia in adult cats. Values are mean ± SEM. *P < 0.05 compared with the diaphragm (DI); **P < 0.05 compared with the genioglossus muscle (GG).

(From Ochiai R et al.: Effects of varying concentrations of halothane on the activity of the genioglossus, intercostals, and diaphragm in cats: an electromyographic study, Anesthesiology 70:812, 1989.)

Early depression of the genioglossus muscle and other pharyngeal dilator muscles appears to be responsible for upper airway obstruction in infants and young children, especially during the induction of inhalation anesthesia. Because of the higher sensitivity to anesthetic depression, the upper airway muscles failed to increase the intensity of contraction to keep the pharynx patent while the diaphragm continues to contract vigorously and the negative feedback mechanism to attenuate its contraction may be diminished or lost (Brouillette and Thach, 1979; Ochiai et al., 1989; Isono et al., 2002). Partial upper airway obstruction may occur more often in infants and young children than is clinically apparent during anesthesia by mask without an oral airway. Keidan et al. (2000) found in infants and children breathing spontaneously under halothane anesthesia that the work of breathing (as an index of the degree of upper airway obstruction) significantly increased when breathing by mask without an oral airway than with an oral airway in place, even when partial upper airway obstruction was not clinically apparent. An addition of CPAP (5 to 6 cm H₂O) further improved airway patency as evidenced by significant decreases in the work of breathing (Keidan et al., 2000).

Effects of Anesthetic on Neural Control of Breathing

Most general anesthetics, opioids, and sedatives depress ventilation. They variably affect minute ventilation (), its components (Vt, f, Vt/Ti), and respiratory duty cycle (Ti/Ttot). All inhaled anesthetics significantly depress ventilation in a dose-dependent fashion (Fig. 3-9). This subject has been extensively reviewed; information in human infants and children, however, remains limited (Hickey and Severinghaus, 1981; Pavlin and Hornbein, 1986).

Studies in adult human volunteers using the occlusion technique and the timing component analysis have indicated that the reduction in tidal volume with anesthetics results primarily from a reduction in the neural drive of ventilation (Milic-Emili and Grunstein, 1975; Whitelaw et al., 1975; Derenne et al., 1976; Wahba, 1980). Inspiratory time tends to decrease, but the respiratory duty cycle is relatively unaffected. In several studies in children 2 to 5 years of age, breathing was relatively well maintained at a light level of halothane (0.5 minimum alveolar concentration [MAC]) (Murat et al., 1985; Lindahl et al., 1987; Benameur et al., 1993). In deeper, surgical levels of anesthesia (1.0 to 1.5 MAC), breathing was depressed in a dose-dependent manner and hypercapnia resulted. Decreased was associated with reduced Vt and increased respiratory frequency. The neural respiratory drive was depressed as evidenced by reduced Vt/Ti, whereas the duty cycle (Ti/Ttot) either tended to increase without changes in Ti or decreased slightly (Murat et al., 1985; Lindahl et al., 1987; Benameur et al., 1993). In infants younger than 12 months of age, ventilatory depression was more pronounced and the duty cycle did not increase, partly because of high chest-wall compliance and pronounced thoracic deformity (thoracoabdominal asynchrony) compared with older children (Benameur et al., 1993).

When an external load was imposed on the airway system of an awake individual, ventilation was maintained by increased inspiratory effort (Whitelaw et al., 1975). This response was greatly diminished or abolished by the effect of general anesthetics, opioids, and barbiturates (Nunn and Ezi-Ashi, 1966; Isaza et al., 1976; Kryger et al., 1976b; Savoy et al., 1982). In children under light halothane anesthesia (0.5 MAC), an addition of a resistive load initially decreased tidal volume. However, tidal volume returned to baseline within 5 minutes (Lindahl et al., 1987).

Effects of Anesthetic on Chemical Control of Breathing

In the dog, inhaled anesthetics diminish or abolish the ventilatory response to hypoxemia in a dose-dependent manner (Weiskopf et al., 1974; Hirshman et al., 1977). In human adult volunteers, the hypoxic ventilatory response was disproportionately depressed in light halothane anesthesia compared with the response to hypercapnia (Knill and Gelb, 1978). At 1.1 MAC of halothane, the hypoxic ventilatory response was completely abolished, whereas the hypercapnic response was about 40% of control in the awake state. Even at a subanesthetic or trace level (0.05 to 0.1 MAC), halothane, isoflurane, and enflurane attenuated the hypoxic ventilatory response to about 30% of the control group, whereas hypercapnic response was essentially intact (Knill and Gelb, 1978; Knill and Clement, 1984). The site of the anesthetics’ action appears to be at the peripheral (carotid) chemoreceptors, because of the rapid response in humans as well as the direct measurement of neuronal chemoreceptor output in the cat (Davies et al., 1982; Knill and Clement, 1984).

Subsequently, Temp and others (1992, 1994) challenged these findings by demonstrating that 0.1 MAC of isoflurane had no demonstrable ventilatory effect on hypoxia. On the other hand, Dahan and others (1994) confirmed the original findings by Knill and Gelb (1978). The reason for the conflicting results appeared to be related to the contribution of visual and auditory inputs (Robotham, 1994). The study by Temp and others (1994) was conducted while the volunteers were watching television (open-eyed), whereas the volunteers in the study by Dahan and others (1994) were listening to soothing music with their eyes closed (but not asleep).

Pandit (2004) conducted a meta-analysis of 37 studies in 21 publications and analyzed the conflicting response to hypoxia under trace levels of anesthetics. Pandit’s analysis supported the prediction by Robotham (1994) that the study condition has a major impact on the outcome of the study. Bandit concluded that the main factor for the difference in hypoxic response was the anesthetic agent used (p < 0.002). Additional factors included subject stimulation (p < 0.014) and agent-stimulation interaction (p < 0.04), whereas the rate of induction of hypoxia or the level of Pco₂ had no effect (Pandit, 2000).

The effect of subanesthetic concentrations of inhaled anesthetics on ventilation in infants and children has not been studied. However, high incidences of postoperative hypoxemia in otherwise healthy infants and children without an apparent hypoxic ventilatory response in the postanesthetic period suggest that the hypoxic ventilatory drive in infants and children may be blunted with the presence of residual, subanesthetic levels of inhaled anesthetics (Motoyama and Glazener, 1986).

Compliance of the Lungs and Thorax

When the lungs are expanded by the contraction of inspiratory muscles or by positive pressure applied to the airways, elastic recoil of the lungs and thoracic structures surrounding the lungs counterreacts to reduce lung volume. This elastic force is fairly constant over the range of normal tidal volumes, but it increases at the extremes of deflation or inflation (Fig. 3-22). The elastic properties of the lungs and respiratory system (lungs and thorax) are measured and expressed as lung compliance (Cl) or respiratory system compliance (Crs) in units of volume change per unit of pressure change. The following equation is derived:

FIGURE 3-22 Schematic representation of the pressure-volume (P-V) curve and compliance of the respiratory system (Crs). At the midpoint of the P-V curve (indicated as FRC awake), the slope and compliance (Crs = ΔP/ΔV) are the highest. When FRC is decreased to the lower, flatter portion of the P-V curve under general anesthesia or paralysis (indicated as FRC anesthetized), Crs decreases even without changes in the mechanics of the lungs or the respiratory system.

where ΔV is usually the tidal volume and ΔP is the change in transpulmonary pressure (the difference between the airway and pleural pressures [ΔP = Pao− Ppl]) for Cl, and for Crs, ΔP is transrespiratory pressure (the difference between the airway pressure at end-inspiratory occlusion and atmospheric pressure [ΔP = Pao − P_B]) necessary to produce the tidal volume. These measurements are made at points of no flow, that is, at the extremes of tidal volume when there is no flow-resistive component (static compliance). Lung compliance may vary with changes in the midposition of tidal ventilation with no inherent alteration in the elastic characteristics of the lungs (Fig. 3-22). The elastic properties of the lungs are described more accurately by measuring pressure-volume relationships over the entire range of TLC.

In normal persons, lung compliance measured during the respiratory cycle (i.e., the dynamic compliance during quiet breathing) is approximately the same as the static compliance. When there is airway obstruction, however, the ventilation of some lung units may be functionally decreased, resulting in decreased dynamic compliance, whereas the static compliance is relatively unaffected. This difference between static and dynamic compliance increases with increasing respiratory frequency (frequency dependence of compliance) and is a sign of airway obstruction (Woolcock et al., 1969).

Quiet, normal expiration occurs passively, resulting from the elastic recoil of the lungs and chest wall and involves little or no additional work. The situation in the infant or in the anesthetized and spontaneously breathing patient may be somewhat different, because expiration may have an active phase (Munson et al., 1966). To consider volume-pressure relationships from another point of view, a normal tidal volume may be obtained using transpulmonary pressures of approximately 4 to 6 cm H₂O in persons of all sizes, provided that the lungs are normal, they are normally expanded initially, and the airways are patent. The total transthoracopulmonary pressure needed to ventilate the lungs with positive pressure in a closed chest is, in the adult, approximately twice the required transpulmonary pressure during spontaneous breathing, because the thoracic structures must also be expanded. The chest wall in the newborn is extremely compliant and therefore requires almost no force for expansion (Fig. 3-21). The combined compliance of the chest wall and lungs, or the compliance of the total respiratory system (Crs), is expressed as follows:

where Cl is lung compliance and Cw is chest-wall compliance. The equation can be expressed in terms of elastance (E), an inverse of compliance (E = 1/C):

where Ers is the elastance of the total respiratory system, El is lung elastance, and Ew is chest wall elastance. Lung compliance in normal humans of different sizes is generally directly proportional to lung size (see Table 3-2). The compliance is expressed per unit of lung volume (e.g., per FRC, vital capacity [VC], or TLC) for comparison (termed specific compliance).

Developmental Changes in the Compliance of the Lungs and Thorax

After the initial period of neonatal adaptation, the compliance of the infant’s lungs is extremely high (elastic recoil is low), probably because of absent or poorly developed elastic fibers (Fig. 3-23) (Fagan, 1976, 1977; Motoyama, 1977). Oddly enough, their functional characteristics resemble those of geriatric, emphysematous lungs with pathologically high compliance caused by the loss of functioning elastic fibers (Fig. 3-24). Thus, at both extremes of human life, the lungs are prone to premature airway closure (Mansell et al., 1972). Elastic recoil pressure of the lungs at 60% TLC increases from about 1 cm H₂O in the newborn to 5 cm H₂O at 7 years of age and 9 cm H₂O at 16 years of age (Fagan, 1976, 1977; Zapletal et al., 1987).

FIGURE 3-23 Pressure-volume curves obtained from excised lungs at autopsy. Data are grouped by postnatal ages, as shown by symbols. It is evident that elastic recoil pressure (horizontal distance between nil distending pressure and the curve at a given distending volume) increases with postnatal development of the lungs.

(Data from Fagan DG: Post-mortem studies of the semistatic volume-pressure characteristics of infants’ lungs, Thorax 31:534, 1976; Fagan DG: Shape changes in static V-P loops for children’s lungs related to growth, Thorax 32:193, 1977.)

FIGURE 3-24 Static pressure-volume curves (deflation limbs) of the lungs in various conditions as indicated.

(From Bates DV, editor: Respiratory function in disease, ed 3, Philadelphia, 1989, WB Saunders.)

In infants the outward recoil of the chest wall is exceedingly small, because the rib cage is cartilaginous and horizontal, and the respiratory muscles are not well developed, whereas the inward recoil of the lungs is only moderately decreased compared with that in adults (Agostoni, 1959; Gerhardt and Bancalari, 1980). Consequently, the static balance of these opposing forces would decrease FRC to a very low level (Fig. 3-22). Such a reduction in FRC would make parenchymal airways unstable and subject them to collapse. In reality, however, dynamic FRC in spontaneously breathing infants is maintained at around 40% TLC, a value similar to that in adults in the supine position, because of a number of possible mechanisms or their combinations (Bryan and Wohl, 1986).

Maintenance of Functional Residual Capacity in Infants

Infants terminate the expiratory phase of the breathing cycle before lung volume reaches the relaxation volume, or true FRC, determined by the balance of opposing chest wall and lung elastic recoil (Kosch and Stark, 1979). This “premature” cessation of the expiratory phase, which PEEP_i with higher FRC, probably results partly from the relatively long time constant of the respiratory system in infants in relation to their high respiratory rate (Olinsky et al., 1974). Additional mechanisms may also help maintain dynamic FRC above the relaxation volume. Glottic closure, or laryngeal braking, during the expiratory phase of the breathing cycle is an important mechanism for the establishment of sufficient air space in the lungs during the early postnatal period (Fisher et al., 1982). Diaphragmatic braking, the diminishing diaphragmatic activity extending to the expiratory phase of breathing, is another important mechanism that extends expiratory time and maintains FRC (Box 3-2).

Among all mechanisms that maintain FRC, tonic contractions of both the diaphragm and the intercostal muscles throughout the respiratory cycle in awake infants appear to be most important. This mechanism effectively stiffens the chest wall and maintains a higher end expiratory lung volume (Muller et al., 1979). Henderson-Smart and Read (1979) have shown a 30% decrease in thoracic gas volume in sleeping infants changing from non-REM to REM sleep. This large reduction in dynamic FRC may result from loss of tonic activity of the respiratory muscles, loss of laryngeal braking, diaphragmatic braking, or all of these factors. All of these important mechanisms for maintaining FRC in infants (and to a lesser extent in older children) are lost with general anesthesia or muscle relaxants, causing marked reductions in FRC, airway closure and atelectasis (Serafini et al., 1999).

When is the FRC no longer determined dynamically but determined by the balance between the recoils of the thorax and the lungs to the opposing direction, as in adults? Colin and others (1989) have shown that, in infants and children during quiet, natural sleep, the transition from dynamically determined to relaxed end expiratory volume or FRC takes place between 6 and 12 months of age. By 1 year of age the breathing pattern is predominantly that of relaxed end-expiratory volume, just as in older children and adults. These findings coincide with the upright posture and development of thoracic tissue and muscle strength in infants.

The breathing pattern of infants younger than 6 months of age is predominantly abdominal (diaphragmatic) and the contribution of the rib cage (external intercostal muscles) to tidal volume is relatively small (20 to 40%), reflecting instability of the thorax or weakness of the intercostal muscles. After 9 months of age, the rib cage component of tidal volume increases to a level (50%) similar to that of older children and adolescents, reflecting the maturation of the thoracic structures (Hershenson et al., 1990). Furthermore, a study by Papastamelos and others (1995) has shown that the stiffening of the chest wall continues throughout infancy and early childhood. By 12 months of age, however, chest wall compliance (which is extremely high in neonates) decreases and nearly equals lung compliance. The chest wall becomes more stable and can resist the inward recoil of the lungs and maintain FRC passively. These relatively recent findings support the notion that the stability of the respiratory system is achieved by 1 year of age.

Effects of General Anesthesia on Functional Residual Capacity

General anesthesia with or without muscle relaxation results in a significant reduction of FRC in adult patients in the supine position soon after the induction of anesthesia, whereas FRC is unchanged during anesthesia in the sitting position (Rehder et al., 1971, 1972b, 1974; Westbrook et al., 1973). A decrease in FRC is associated with reductions in both lung and thoracic compliance, but the mechanism responsible for the reduction in FRC and the sequence of events that changes respiratory mechanics were not understood for many years.

In an excellent study, deTroyer and Bastenier-Geens (1979) showed that when a healthy volunteer was partially paralyzed with pancuronium, the outward recoil of the thorax decreased, whereas lung recoil (compliance) did not. This change altered the balance between the elastic recoil of the lung and thorax in opposite directions, and consequently FRC diminished. The compliance of the lungs decreased shortly thereafter, resulting from the reduced FRC and resultant airway closure. Based on their findings, deTroyer and Bastenier-Geens postulated that, in the awake state, inspiratory muscles have intrinsic tone that maintains the outward recoil and rigidity of the thorax. Anesthesia or paralysis would abolish this muscle tone, reducing thoracic compliance followed by a reduction in FRC, and eventually lung compliance in rapid succession (in a matter of a few minutes).

In healthy young adults, a reduction of FRC during general anesthesia is limited to between 9% and 25% from the awake control levels (Laws, 1968; Rehder et al., 1972; Westbrook et al., 1973; Hewlett et al., 1974; Juno et al., 1978). In older individuals, the average reduction in FRC is more (30%), probably because of lower elastic recoil pressure, increased closing capacity and further airway closure, and eventual atelectasis (Bergman, 1963).

With the more compliant thoraces of infants and young children, general anesthesia and muscle relaxation would be expected to produce more profound reductions in FRC than in adolescents and adults. Henderson-Smart and Read (1979) have shown a 30% reduction in thoracic gas volume (FRC) in infants, changing the sleep pattern from non-REM to REM sleep with increased muscle flaccidity. In children 6 to 18 years of age under general anesthesia and paralysis, Dobbinson and others (1973) found marked reductions in FRC (average reduction, 35%) from their own awake control values, as measured with a helium dilution technique. The average decrease in FRC among those younger than 12 years of age was 46%. Fletcher and others (1990) demonstrated that compliance of the respiratory system (Crs) in infants and children under general anesthesia decreased about 35%, a value comparable with the reduction reported in adults under similar conditions (Westbrook et al., 1973; Rehder and Marsh, 1986). This reduction in Crs occurred both during spontaneous breathing and during manual ventilation with low tidal volume after muscle relaxants were given. When tidal volume was doubled, however, Crs returned to preanesthetic control levels.

These findings are in accord with previous findings in adults and support the notion that anesthesia reduces FRC (deTroyer and Bastenier-Geens, 1979; Hedenstierna and McCarthy, 1980). The finding that a larger tidal volume increases Crs toward control values also indicates that FRC decreases to the lower, flatter portion of the pressure-volume curve, which would lead to airway closure (Fig. 3-22). Motoyama and others (1982a) reported moderate decreases in FRC (−46%) in children as measured with helium dilation and a marked decrease (−71%) in infants under halothane anesthesia and muscle paralysis, approaching the relaxation volume in the newborn infant reported by Agostoni (1959).

Until recently, the possible differential effect on FRC of general anesthesia without muscle paralysis vs. general anesthesia with muscle paralysis was not critically compared. Westbrook et al. (1973) reported a 25% reduction in FRC in healthy young adults in the supine position after anesthesia with intravenous sodium thiopental. They did not find a statistically significant difference in the extent of reductions in FRC with thiopental alone vs. those with an addition of muscle relaxant (d-tubocurarine), although the mean reduction in FRC was somewhat more with the relaxant. A more recent study in anesthetized infants and toddlers clearly demonstrated that addition of muscle paralysis in anesthetized children results in additional marked reductions in FRC (on top of the reduction by the effect of general anesthesia) (von Ungern-Sternberg et al., 2006). Furthermore, the reduction in FRC in infants less than 6 months of age was extreme (FRC, 21.3 to 12.2 mL/kg or −43%) as compared with reductions in toddlers (25.6 to 23.0 mL/kg or −10%) (von Ungern-Sternberg et al., 2006). This marked loss of FRC in infants represents the collapse of their extremely compliant thorax with inspiratory muscle paralysis and massive airway closure that would eventually result in atelectasis, uneven distribution of ventilation, V/Q imbalance, and hypoxemia unless the lungs are reexpanded and supported with PEEP.

Effect of Positive End-Expiratory Pressure Under General Anesthesia

Thorsteinsson and others (1994) reported that the lung volume at FRC (or relaxation volume, Vr) was at a lower, flatter portion of the pressure-volume (P-V) curve in all anesthetized infants and children studied. To restore FRC to the normal or steepest portion of the P-V curve of the respiratory system seen in the awake state (with the highest compliance), a PEEP of 5 to 6 cm H₂O had to be added to infants younger than 6 months of age and more than 12 cm H₂O in older children (Thorsteinsson et al., 1994). A more recent study in children (aged 2 to 6 years) also showed that PEEP as high as 17 cm H₂O is needed to raise the lung volume to the steepest portion (highest compliance) of the P-V curve (Kaditis et al., 2008).

Shortly after the induction of anesthesia and muscle relaxation in adult patients, increased density appearing on computed tomography (CT) scans in the dependent portion of the lung has been described in the literature. This increased density could be reduced or eliminated by adding PEEP (Brismar et al., 1985). Serafini and others (1999) were the first to report evidence of airway closure and atelectasis in young children (aged 1 to 3 years; mean age of 1.8 years) on a CT scan in the dependent portion of the lungs shortly after the inhalation induction of anesthesia and intubation. These patients were given three deep inflations of the lungs (sighs) with 40% oxygen in nitrous oxide and ventilated with 10 mL/kg of tidal volume. Atelectasis-increased density (airway closure or atelectasis) appeared on the CT scan almost immediately when patients were ventilated without PEEP (Fig. 3-25, A). When the patients were ventilated for 5 minutes with an addition of PEEP (5 cm H₂O) with the same ventilator settings and end tidal Pco₂, the density disappeared from the repeated CT scans in all 10 children studied, indicating the recruitment of atelectic lung segments (Fig. 3-25, B) (Serafini et al., 1999).

FIGURE 3-25 Computed tomography (CT) scan of the thorax during general endotracheal anesthesia. A, Transverse CT scan of the thorax 5 minutes after the induction of anesthesia without PEEP. Note the appearance of atelectasis (density) in the dependent regions of both lungs. B, Transverse CT scan of the thorax during anesthesia with a PEEP of 5 cm H₂O, showing the complete disappearance of atelectasis in the dependent regions of both lungs.

(From Serafini G et al.: Pulmonary atelectasis during paediatric anaesthesia: CT scan evaluation and effects of positive end-expiratory pressure (PEEP), Paediatr Anaesth 9:225, 1999.)

Because the stability of the thorax increases during the first year of life, it is likely that the thorax would resist the airway collapse and atelectasis with increasing age (Papastamelos et al., 1995). Motoyama (1996) examined this possibility by measuring respiratory system compliance in infants and young children under 6 years of age who were undergoing halothane-nitrous oxide endotracheal anesthesia. These patients were ventilated either with or without PEEP (6 cm H₂O) for 15 minutes preceded by deep sighs. After a period of ventilation with PEEP, respiratory system compliance was consistently higher after PEEP than without PEEP. There were significant age-related differences in the degree of increase in compliance after PEEP (6 cm H₂O) vs. no PEEP (Fig. 3-26). The average increase of respiratory system compliance with PEEP was greatest in infants younger than 8 months of age (75% higher with PEEP vs. without PEEP). In contrast, in older infants and toddlers (aged 9 months to 2.5 years), an average increase in compliance with PEEP was 22%; in children (aged 2.5 and 5.5 years), the increase was 9%, the level one would expect in adults. These results reflect greater reductions in FRC (or increases in airway closure and atelectasis) in the younger age groups (Motoyama, 1996).

FIGURE 3-26 Compliance of the respiratory system (Crs) under general anesthesia in infants and children and the effect of PEEP. An addition of PEEP (5 to 6 cm H₂O) improves (restores) Crs significantly in all age groups studied. The beneficial effect of PEEP was most dramatic in infants younger than 8 months (see text).

(From Motoyama EK: Effects of positive end-expiratory pressure (PEEP) on respiratory mechanics and oxygen saturation (SpO₂) in infants and children under general anesthesia, Anesthesiology 85:A1099, 1996.)

Persistent airway closure during general anesthesia would result in resorption atelectasis because alveolar gas (mostly oxygen and nitrous oxide) trapped below the occluded airways would be rapidly absorbed. Resultant pulmonary V/Q imbalance and right-to-left shunting of blood in the lung may reduce arterial Po₂ in the postanesthetic recovery room. Such an effect would be expected to be more profound in infants. Motoyama and Glazener (1986) studied arterial oxygen saturation (SpO₂) with a pulse oximeter in otherwise healthy infants and children before and after general anesthesia for simple, relatively short, surgical procedures (e.g., inguinal hernia repair or myringotomy tube insertions). On arrival at the postanesthetic care unit (PACU), the mean SpO₂ was 93% (estimated Pao₂, 66 mm Hg), significantly reduced from the preoperative value of 97%. In some children, SpO₂ decreased to the low 70s (estimated Pao₂ of less than 40 mm Hg). These patients showed no sign of hypoxic ventilatory stimulation with normal cutaneous Pco₂ (Motoyama and Glazener, 1986).

A large percentage (20% to 40%) of otherwise healthy infants and children develop oxygen desaturation (SpO₂ of less than or equal to 94%) during transport and on arrival at the PACU (Motoyama and Glazener, 1986; Pullertis et al., 1987; Patel et al., 1988). A later study of postoperative hypoxemia involving 1152 patients ranging from infants to adults has demonstrated that hemoglobin desaturation occurs sooner, is more pronounced, and lasts longer in infants than in children and longer in children than in adults (Xue et al., 1996). All children, therefore, should be given oxygen by mask during the transport from the operating room and on arrival at the PACU until they can maintain satisfactory oxygen saturation by pulse oximeter without supplemental oxygen (see Chapter 11, Monitoring).

Closing Volume and Closing Capacity

Beside the lungs and chest wall, the air passages themselves have a compliance that may be important. With deep inspiration, the airway caliber increases in size (interdependent of airways and lung volume), whereas the airway caliber decreases during passive expiration, with an even bigger increase during forced expiration with dynamic compression. Closing volume (CV) is the lung volume above RV at which air flow during expiration ceases from dependent lung zones (i.e., lower lung segments in the upright position), presumably because of the closure or collapse of small airways. Closing capacity (CC) is the sum of CV above RV plus RV.

Whether this closure is anatomic or merely the result of dynamic compression and reduction in flow (see Dynamic Properties) is controversial (Hughes et al., 1970; Hyatt et al., 1973). Because the patency of small airways depends in part on the elastic recoil of the lungs, CC as a percentage of TLC is relatively high in young children and would be even higher, at least theoretically, in infants (Mansell et al., 1972). CC increases with aging as well as with small airway disease, such as chronic bronchitis caused by smoking and emphysema in adults.

Lung compliance is reduced in most situations in which lung volume is decreased (e.g., the removal of lung tissue, atelectasis, and intrapulmonary tumors), although it is normal when corrected for lung volumes. Compliance is also decreased when surface forces are increased, as it is in IRDS with increased surface force (or decreased surfactant), or when elastic recoil is abnormally increased (e.g., in interstitial pulmonary fibrosis).

Emphysema is associated with a loss of elastic recoil and therefore an abnormal increase in compliance. Chest-wall compliance decreases with conditions such as scleroderma, kyphoscoliosis, and ankylosing spondylitis involving the thoracic structures.

Airway Resistance

The pressure required to overcome frictional resistance and produce flow between the alveoli (Palv) and the airway opening (Pao) is proportional to flow rate. Airway resistance (Raw) is expressed as pressure gradient across the airways (P = Pao− Palv) per unit flow ():

If the respiratory system is assumed to have a single compartment with a constant elastance or compliance (E = 1/C) and a constant resistance (R), the equation of forces acting on the respiratory system can be expressed as follows:

In tidal breathing, inertance (I) is very small and can be ignored. During normal tidal breathing, approximately 90% of the pressure gradient required is needed to overcome the elastic forces, and the remaining 10% of the pressure is expended to counter the flow resistance (Sly and Hayden, 1998).

Flow resistance is related to the length (l), radius of the tube (r), and the viscosity of the gas (η) as follows:

Assuming a laminar flow (as seen in small or peripheral airways), it is apparent from this equation (Poiseuille’s law) that the most important factor affecting flow resistance is the change in the radius of the tube (airways), because resistance is inversely proportional to the fourth power of the radius. (When the flow is turbulent, as occurs in large airways, the flow resistance increases approximately with r⁵.) Therefore, airway resistance in infants with smaller airway diameters is much higher, in absolute terms, than airway resistance in older children and adults. It might also be expected that inflammation or secretions in the airway system would result in exaggerated degrees of obstruction in infants compared with older children and adults (Fig. 3-27). One such example may be the severe and often life-threatening obstruction of upper airways seen only in infants and young children with acute supraglottitis (epiglottitis) and subglottic croup (laryngotracheobronchitis). However, in relation to body size, the caliber of airways in general is wider, and airway resistance is lower in infants and children compared with adults (Motoyama, 1977; Stocks and Godfrey, 1977).

FIGURE 3-27 Effect of inflammation on airway resistance in infants and adults. R, Flow resistance; r, radius of an air passage.

In absolute terms, airway resistance in the newborn is very high (19 to 28 cm H₂O/L per second). It decreases to less than 2 cm H₂O/L per second in the adolescent and the adult. In relative terms (as expressed per unit of lung volume, usually FRC or specific resistance), specific airway resistance is relatively low, or conductance (Gaw, the reciprocal of resistance; G = 1/R) is very high in the newborn. The specific conductance (sGaw = Gaw/FRC) decreases rapidly during the first year of life, indicating a rapid increase in lung volume (alveolar formation) in relation to airway size (Stocks and Godfrey, 1977, 1978). Between 6 and 18 years of age, Gaw increases linearly with increases in height; However, sGaw stays fairly constant throughout this period at about 0.2 L/sec per cm H₂O (Zapletal et al., 1969, 1976, 1987).

Distribution of Airway Resistance

Rohrer’s earlier work (1915) led to the belief that peripheral airways of small caliber were the major contributors to total airway resistance. However, the elegant morphometric studies of Weibel (1963) with airway castings in inflated lungs proved that the total cross-sectional area of each generation of airways increases dramatically toward the periphery, like a cross section of a trumpet, on the cross-sectional area vs. airway-generation plot (Fig. 3-28). Indeed, about two thirds of the total airway resistance exists between the airway opening and the trachea, and most of the remaining resistance is in the large central airways. The airways smaller than a few millimeters in diameter (peripheral airways) contribute only about 10% of total resistance (Macklem and Mead, 1967).

FIGURE 3-28 A, Diagrammatic representation of the sequence of elements in the conductive, transitory, and respiratory zones of the airways. B, Total airway cross-sectional area, AD, alveolar ducts; AS, alveolar sacs; z, order of generation of branching; A(z), in each generation, z. BR, Bronchi; BL, bronchioles; RBL, respiratory bronchioles; T, terminal generation; TBL, terminal bronchioles.

(From Weibel ER: Morphometry of the human lung, New York, 1963, Academic Press.)

These findings have important clinical implications. If the peripheral airways contribute little to the total airway resistance, disease processes involving small airways—such as emphysema in adults, cystic fibrosis (CF) in children, and bronchopulmonary dysplasia (BPD) in infants—will not be detectable by measurement of the total airway resistance. For instance, complete obstruction of half of the peripheral airways would increase the total airway resistance by only 5% to 6 %, an increase within the usual variation in measurements. For this reason, the peripheral airways used to be called the “quiet zone” of the lung (Mead, 1970). Apparently, the measurement of total airway resistance is not a sensitive clinical test for detecting small airway obstruction.

The airway system extends from the airway opening at the nares or the mouth to the alveolar duct at the periphery of the lung. Functionally, the airway system can be subdivided into the upper (extrathoracic) and lower (intrathoracic) airways. The upper airway begin at the airway opening (the mouth or the nose—normally the mouth in quiet breathing) and include the nasal or oral cavity, the pharynx, the larynx, and the upper most segment of the trachea before it enters into the thorax. The lower airway begins with the thoracic inlet of the trachea, the trachea, bronchi, bronchioli, and alveolar ducts entering the alveoli (Box 3-3).

Box 3-3 Airway System and Resistance

Upper airways: extrathoracic

Mouth/nose, pharynx, larynx (the narrowest segment)

Upper airway resistance: 65% of total Raw

Lower airways: intrathoracic

Lower airway resistance: 35% of total Raw

Central (large) airways: trachea, large bronchi

Peripheral (small) airways: small bronchi, bronchioli

Central airways: 90% of lower Raw (30%)

Peripheral airways: 10% of lower Raw (<5%)

Tissue Viscoelastic Resistance

It has been assumed that airway (frictional) resistance represents the majority of total respiratory system resistance during breathing, and the pressure needed to overcome tissue viscous resistance during inspiration was estimated to be about 35% in adults and 28% in children (Bryan and Wohl, 1986). However, studies since the 1980s in both anesthetized animals and humans on mechanical ventilation have indicated that viscoelastic resistance, or the energy required to counter the hysteresis or viscoelasticity of the lungs and thoracic tissues, contributes a significantly greater proportion of the total resistance than previously assumed (Milic-Emili et al., 1990). Furthermore, both airway resistance (Raw) and viscoelastic resistance (Rvis or ΔR) have been found to be flow and volume dependent (i.e., both Raw and Rvis change with volume and/or flow changes) and to the opposite directions. Airway resistance (Raw) increases with increasing flow as a result of higher turbulence, whereas Raw decreases with increasing lung volume, because airway caliber also increases with volume. The traditional view had been that the total resistance followed the same direction of flow resistance because it was thought to be the majority of total respiratory system resistance. Paradoxically, Rvis decreases with increasing flow, when the volume is kept constant, and when the flow rate is kept constant Rvis increases with increasing lung volume (Fig. 3-29) (D’Angelo et al., 1989). Furthermore, the direction of changes in total resistance followed that of Rvis rather than that of Raw. Studies in children who have been anesthetized and ventilated have shown a similar flow and volume dependence of RV exist in adults; that is, opposite of the direction of changes in Raw, although the total resistance did not necessarily follow the changes in Rvis that occurred in adults (Fig. 3-30) (Kaditis et al., 2008).

FIGURE 3-29 Flow and volume dependence of respiratory system resistance (Rrs) and its subdivisions, resistive component (Rint, mostly airway resistance, Raw) and viscoelastic component (ΔRrs or Rvisc) (Rrs = Rint + ΔRrs). A,I, Average relationship of Rrs and Rint with increasing inspiratory flow on X-axis at a constant inspiratory volume (0.47 L) in 16 anesthetized and paralyzed adult subjects. B,I, Similar relationship between ΔRrs with variable inspiratory flow. A,II, Average relationship of Rrs and Rint with variable inspiratory volume on X-axis at a constant inspiratory flow (0.56L/sec) in the same subjects as A,I, B,II, Similar relationship in terms of ΔRrs. Bars, 1SD.

(Modified from D’Angelo E et al.: Respiratory mechanics in anesthetized paralyzed humans, J Appl Physiol 67:2556, 1989.)

FIGURE 3-30 Flow and volume dependence of respiratory system resistance (Rrs) and its subdivisions, flow-resistive component (Rint or Raw) and viscoelastic component (ΔR or Rvis) (Rrs = Rint + ΔR), in eight healthy children aged 2.3 to 6.5 years under general endotracheal anesthesia. A, Average relationship of Rrs, Rint, and ΔR with increasing inspiratory flow on X-axis at a constant end-inspiratory volume (Vt, 12 mL/kg). ΔR and Rrs decreased significantly with increasing flow as in adults (see Fig. 3-29). B, Average relationship of Rrs, Rint, and ΔR with increasing volume on x-axis while flow was kept constant (15 mL/sec per kg) in the same subjects as in A. Rint decreases with increasing volume as expected, whereas ΔR increased with increasing volume. Unlike in adults, there was no volume dependence of Rrs; Bars, 1 SEM; V.₁ inspiratory flow; Vr, relaxation volume or end expiratory volume.

(From Kaditis AG et al.: Effect of lung expansion and PEEP on respiratory mechanics in anesthetized children, Pediatr Anesth 106:775, 2008.)

This evidence and new understanding on the behavior of viscoelastic resistance have important clinical implications. Traditionally, the patient with airway obstruction has been treated with large tidal volumes and a slow respiratory rate to allow complete exhalation to avoid intrinsic PEEP_i and air trapping. With the new understanding, it makes more sense to have patients breathe with a smaller tidal volume and higher respiratory rate in order to minimize total respiratory system resistance and decrease work of breathing (Kaditis et al., 1999b, 2008).

Time Constant of the Respiratory System

When the lung is allowed to empty passively from end inspiration to FRC, the speed of lung deflation is determined by the product of respiratory system resistance and compliance (R × C or R/E), which is a unit of time (time constant, τ). If the respiratory system is considered as a single compartment with a constant resistance and compliance within the tidal volume range of breathing (which is a reasonable assumption in healthy individuals), then τ = R × C.

Under these conditions, the volume-time profile can be represented by an exponential decay and at 1 time constant (1τ), tidal volume is reduced by 63%. It requires 3 × τ to nearly complete exhalation to FRC. In healthy children and adults, τ is 0.4 to 0.5 seconds; it is slightly shorter in neonates (0.2 to 0.3 seconds) (Bryan and Wohl, 1986). In patients with obstructive lung disease, such as bronchial asthma, τ is increased because of an increase in airway resistance; it is also increased markedly in patients breathing through an endotracheal tube under general anesthesia.

The Concept of Flow Limitation and Maximum Expiratory Flow-Volume Curves

During quiet breathing, pleural pressure remains subatmospheric, whereas during forced expiration, pleural pressure increases considerably above atmospheric pressure and in turn increases alveolar pressure. The resultant pressure gradient between the alveoli and the airway opening (atmospheric) produces the expiratory flow. In the periphery of the lungs this pressure within the airways is even higher than the increased pleural pressure by effort because of the additional elastic recoil pressure of the lung. In comparison, in major intrathoracic airways the pressure within the lumen is near atmospheric and lower than the surrounding pleural pressure. At some point along the airways the pressure within the airway lumen should equal the pleural pressure surrounding the airway (equal pressure point [EPP]) (Mead et al., 1967). During forced expiration, the airway between EPP and the trachea is dynamically compressed, and the flow rates consequently become independent of effort (i.e., additional expiratory effort or pressure does not increase flow) (Fig. 3-31). Under these circumstances (dynamic flow limitation), the maximum expiratory flow rate () is determined by the flow resistance of the upstream segment (Rus) between the alveoli and the EPP and the elastic recoil pressure of the lung (Pstl), as follows (Mead et al., 1967):

FIGURE 3-31 Flow-volume curves obtained when a subject performs a series of vital capacity expirations of graded effort, varying from a very slow breath out to one of maximal speed and effort.

(From Bates DV et al., editors: Respiratory function in disease: an introduction to the integrated study of the lung, Philadelphia, 1971, WB Saunders.)

According to the wave-speed theory of expiratory flow limitation, compliance or collapsibility of lower airways around the EPP (choke point) is an additional determinant of MEF rate (Dawson and Elliott, 1977; Hyatt, 1986).

The maximum expiratory flow volume (MEFV) curve obtained during forced expiration from TLC to residual volume relates instantaneous MEFs to corresponding lung volumes (Fig. 3-32). Clinically, the measurement of MEF rate is an extremely sensitive test for the detection of obstruction of the lower airways toward the periphery (quiet zone) of the lungs because it eliminates the component of upper airway resistance between the mouth and EPP and is independent of the degree of effort or cooperation by the patient (Zapletal et al., 1971) (see Measurements of Pulmonary Function).

FIGURE 3-32 MEFV curve on volume-flow axis on the right is contrasted with spirometric tracing (spirogram) on volume-time axis on the left during a single forced vital capacity (VC) maneuver. FEV_1.0, Forced expiratory volume in 1 second; PEFR, peak expiratory flow rate; MEF₅₀, MEF₂₅, MEF at 50% and 25%, respectively, of forced VC.

(From Motoyama EK: Airway function tests in infants and children, Int Anesthesiol Clin 26:6, 1988.)

Distribution of Flow Resistance

On the basis of physiologic measurements in lungs obtained at autopsy, Hogg and others (1970) reported that airway conductance of the peripheral airways in children younger than 6 years of age was disproportionately low (i.e., resistance was high). They postulated that the diameter of small airways of the same generation was disproportionately smaller in infants than in older children and adults. Although this theory is consistent with the high incidence of severe lower airway disease in infants, it conflicts with later physiologic data obtained from healthy infants. Studies of MEFV curves in anesthetized infants and children, and more recently in sedated infants, showed that at low lung volumes, the MEF normalizes for lung volume and that the conductance of the upstream segment is disproportionately high in infants and decreases with age, indicating that lower airway resistance toward the periphery of the lung parenchyma is relatively lower, rather than higher, in the early postnatal years (Fig. 3-33) (Motoyama, 1977; Lambert et al., 2004).

FIGURE 3-33 MEF at 25% FVC from forced deflation flow-volume curves vs. height in anesthetized boys and girls. MEF₂₅ is expressed in FVC units per second to normalize for lung size. FVC-adjusted MEF₂₅ is disproportionately higher in infants than in older children.

(From Motoyama EK: Pulmonary mechanics during early postnatal years, Pediatr Res 11:220, 1977.)

Low Ventilation/Perfusion Ratio and Lung Collapse While Breathing Oxygen

In a lung unit with a low regional V/Q ratio while breathing oxygen, collapse of the lung unit occurs, leading to atelectasis. As alveolar ventilation to the lung unit () decreases, regional expiratory volume (Ve) decreases progressively in comparison with regional inspiratory volume (Vi) as it approaches the amount of oxygen taken up by regional pulmonary blood flow. A point is reached at which the expired alveolar volume falls to zero (West, 1974). This situation occurs at the “critical” inspired V/Q. With inspired ratios less than the critical V/Q value, the lung unit becomes unstable; oxygen may enter rather than leave the lung unit during the expiratory phase or the unit may gradually collapse (Figure 3-41) (West, 1975). Figure 3-42 shows the calculated relationship between the critical inspired V/Q and the concentration of inspired oxygen (assuming mixed venous Po₂ of 40 mm Hg and Pco₂ of 45 mm Hg and no nitrogen exchange occurring across the whole lung). From Figure 3-42, it can be seen that lung units with V/Q of less than 0.01 become vulnerable when Fio₂ is increased above 0.5, whereas lung units with inspiratory of 0.1 are not at risk even with 100% oxygen (West, 1975). Although a V/Q of less than 0.1 is uncommon in normal awake children, lung units with a V/Q of less than 0.1 may occur in the diseased lung as well as in the normal lung under general anesthesia.

FIGURE 3-41 Schematic drawings to explain the development of shunts in lung units with low inspiratory caused by breathing high concentrations of oxygen. A, Stable; there is a small expired alveolar ventilation () and the unit is stable. B, Critical; inspired is decreased slightly from A and expired falls to zero. C, Unstable; inspired is further reduced and gas enters into the lung unit during the expiratory phase. D, Unstable; reverse inspiration during expiratory phase is prevented and the unit gradually collapses.

(From West JB: New advances in pulmonary gas exchange, Anesth Analg 54:409, 1975.)

FIGURE 3-42 Relationship between inspired oxygen concentration and critical inspiratory , the value at which the expired ventilation of a given lung unit falls to zero. Lung units whose is less than the critical value may be unstable and easily collapse.

(From West JB: New advances in pulmonary gas exchange, Anesth Analg 54:409, 1975.)