Respiration in mammals requires the integration of two essential components to permit the flow and transfer of gases between the external environment and the blood. The lung, which is the gas exchange component of the system, is richly supplied with nerves but cannot function autonomously. The lung can only fulfill its function when aided by the conjoint action of the thoracic chamber enclosing it. The thorax is a complex assemblage of skeletal structures and muscles that performs diverse functions, one of which is breathing. Thus, the thorax acts as the pump component of the ventilatory system. The thorax includes the ventilatory muscles that are responsible for rhythmically displacing the chest wall to move air into and out of the lungs, and in so doing, maintains arterial blood gases within acceptable limits.
The function of the ventilatory muscles is an active area of research, as summarized in several excellent recent reviews on a variety of topics related to ventilatory muscle function (10,32,77). A key finding is that the ventilatory pump is a robust, multi-muscle pump. The actions of various ventilatory muscles, which are broadly classified as inspiratory or expiratory based on their mechanical actions, are highly redundant and provide several means by which air can be effectively displaced under a host of physiologic and pathophysiologic conditions(10,96). For example, even at rest, movement of air into and out of the lungs is the result of the recruitment of several muscles(12,17,87,97). In resting man, the tidal volume is the result of the coordinated recruitment of the diaphragm, the parasternal intercostal, and the scalene muscles(12,87,97). Even the expiratory phase of breathing at rest can be associated with active muscle muscle participation(11,17). Despite the fact that quiet breathing involves several muscles, under normal circumstances breathing demands only a small effort (32).
Morphologically and functionally, the ventilatory muscles are classified as striated skeletal muscles. The in situ function of the ventilatory muscles is governed by the same relationships that determine the contractile force of isolated, perfused muscles in vitro. These are the modulation of force output according to the precontractile or resting length of the muscle (force-length or length-tension relationship), the force response to the frequency of external stimulation or neural drive(force-frequency relationship), and the hyperbolic relationship between the force output of the muscle and its shortening rate (force-velocity relationship). In addition, respiratory muscle performance in situ is modified by other factors such as neural recruitment strategies, mechanical linkages between the muscles (10,33), linkages between the muscles and the thorax (55), and sometimes by the Laplace relationship. Besides sharing all common mechanical characteristics with the skeletal muscles of the limbs, the ventilatory muscles are prone to fatigue and are also endowed with the capacity to adapt to altered conditions, including physical exercise(4,6,41,51,70,101).
The ventilatory muscles are distinct from the skeletal muscles of the limbs in several aspects (25,83). First, whereas skeletal muscles of the limbs overcome inertial loads, the ventilatory muscles overcome primarily elastic and resistive loads. Second, the ventilatory muscles are under both voluntary and involuntary control. The third distinguishing feature is that the ventilatory muscles, which represent only 3% of body weight(77), are like the heart in that they have to contract rhythmically and generate the required forces for ventilation throughout the entire life of the individual. Thus, the ventilatory muscles have been referred to as the “other vital pump.” The ventilatory muscles, however, do not contain pacemaker cells, so that neural input from higher centers is required to initiate contraction. During breathing the activation of the various ventilatory muscles is highly coordinated, under the control of mechanical and chemical stimuli, and involves all levels of the central nervous system.
The last distinguishing feature of the respiratory muscles is related to their anatomic resting position. Fenn (25) points out that the resting length of the respiratory muscles is dictated by the balance between the inward recoil forces of the lung and the outward recoil forces of the chest wall. Changes between the balance of recoil forces will result in changes in the resting length of the respiratory muscles. Thus, simple and everyday life occurrences such as changes in posture will alter the operational length and the contractile strength of the ventilatory muscles. If uncompensated, these length changes would lead to decreases in the output of the muscles and hence a reduction in the ability to generate volume changes. The skeletal muscles of the limbs, on the other hand, are not constrained to operate at a particular resting length.
The uniqueness of the ventilatory pump muscles, therefore, originates primarily from their functional attributes. This article will review some of the more pertinent principles that govern ventilatory muscle function, especially in situ, and will highlight some of the design characteristics of the ventilatory pump that allows optimization of muscle function over a wide array of physiologic and pathophysiologic conditions.
EFFECT OF MUSCLE LENGTH ON FORCE OUTPUT
Effects of Lung Volume on Force-Generating Capacity
Maximal respiratory pressures vary with lung volume(2). Maximal static inspiratory pressure measured at the mouth (Pimax) is greatest at residual volume (RV), falls off slightly at functional residual capacity (FRC), and declines to zero at total lung capacity (TLC). In contrast, maximal static expiratory mouth pressure(Pemax) is greatest at TLC and declines progressively as lung volume is decreased through FRC to RV. However, the pressures recorded at the mouth reflect not only pressures generated from active muscle contraction but also the passive recoil components of the respiratory system.
To assess only the pressures generated by the respiratory muscles (Pmus), one must correct maximal static pressures measured at the mouth for respiratory system recoil (PRS). PRS is approximately -40 cm H2O at TLC, zero at FRC, and +40 cm H2O at RV. The shape of the curve relating expiratory Pmus to lung volume is similar to the curve for Pemax and lung volume except that Pmus is approximately 40 cm H2O at RV, whereas Pemax is near zero. In contrast, the curve relating inspiratory Pmus to lung volume shows that peak negative Pmus is observed at or just below FRC, with less negative pressures at higher and lower lung volumes. Moreover, at TLC, the inspiratory Pmus curve does not fall to zero, but rather is approximately -40 cm H2O, or about 35% of the FRC value.
The force produced selectively by the diaphragm includes both negative pleural and positive abdominal pressures. Thus, transdiaphragmatic pressure(Pdi) reflects the total force generated by the diaphragm. Pdi varies with lung volume in humans in much the same way that Pimax does. With maximal voluntary inspiratory effort against a closed airway (Muller maneuver), peak Pdi is attained near supine FRC (approximately 40% TLC), and Pdi is lower at lung volumes above and below supine FRC(61). In normal humans, Pdi generated by external phrenic stimulation falls by 60% between RV and TLC (85) and twitch Pdi responses to stimulation of the phrenic nerves progressively increase as lung volume is decreased from FRC to RV(36,60).
Force-Length Relationship In Vitro
The relationship between lung volume and maximal pressure generation reflects the force-length properties of the inspiratory and expiratory muscles(73). The force generated by excised, perfused diaphragm muscle in vitro in response to supramaximal stimulation of the muscle is more or less symmetrical around a peak force that is developed at the optimal resting length (Lo). Force falls to zero at lengths of approximately 50% and 160% of Lo (57). This property of muscle derives mainly from the sliding filament model and from impaired muscle activation and calcium release from the terminal cisternae of the sarcoplasmic reticulum (52,74).
McCully and Faulkner (57) showed that the in vitro length-tension relationship of mammalian diaphragm is fairly uniform across species. However, the shape of the length-tension relationship varies among the respiratory muscles. For example, the length-tension relationship of canine intercostal muscles is markedly compressed along the length axis(19,20). Therefore, at lengths shorter than Lo, the intercostal muscles generate considerably less maximal force than the diaphragm (18,20). Among respiratory muscles, the costal diaphragm has the broadest length-tension curve while the parasternal intercostal muscles have the narrowest. The costal diaphragm maintains force generation over a relatively wide range of operating lengths, whereas the parasternals are most vulnerable to losing force-generating capacity when they are shortened below Lo. Thus, the maximal generating capacity of any ventilatory muscle will be dictated largely by its in situ operating length.
In Situ Resting Length
The relationship between in situ resting length and optimal force-generating length (Lo) has been systematically evaluated for most of the inspiratory and expiratory muscles of the dog. In these experiments the operating length of a given respiratory muscle was assessed in situ using sonomicrometry (65,76), then the segment of the muscle bearing the sonomicrometry crystals muscle was excised with the crystals remaining in place for determination of in vitro contractile properties in a muscle bath. Thus, the precise relationship between the in situ length at FRC (Lfrc and Lo can be evaluated. When Lfrc/Lo is less than 1.0, the muscle is operating on the ascending limb of its length-tension curve, and its Lo lies, at least for inspiratory muscles, at a lung volume lower than FRC. Conversely, when Lfrc/Lo is greater than 1.0, the muscle is operating on the descending limb of its length-tension curve, and its Lo lies at a lung volume that is higher than FRC.
The values of Lfrc/Lo for primary canine inspiratory muscles are summarized in Figure 1A. Since Lfrc was measured in the supine, anesthetized dog, operating lengths in animals in normal canine postures are likely to be somewhat different (56). Studies of muscles of mastication reveal that the length of a muscle in situ is adjusted so that the Lo lies not at the resting length but at the length where the muscle is most likely to be recruited (34). If this is true of respiratory muscles, then Lfrc/Lo will be 1.0 at the lung volume where the particular muscle is most likely to be actively recruited. Consistent with this hypothesis, the Lfrc/Lo of costal diaphragm of the supine anesthetized dog is 0.95-0.97. Thus, the costal diaphragm is ideally situated for its role as the primary muscle of breathing.
Force-Length Relationship In Situ
Diaphragmatic force-length behavior must account for the effect of lung volume on Pimax and Pdimax, but to verify that this is the case, it is necessary to relate Pdi to diaphragm length. The length of the diaphragm and other respiratory muscle lengths can be measured directly in intact animals using a diaphragm slip preparation (43), sonomicrometry (20,65,66,76), and fluoroscopy (37,44). In humans, the lengths of the diaphragm silhouette and inter-rib distances reflecting the length of intercostal muscles have been measured on chest x-rays taken under static conditions at different lung volumes(8,53,84). In addition, three-dimensional information about the human diaphragm has been obtained using computerized tomography (95) or magnetic resonance imaging(29,68).
In humans and dogs, the in situ diaphragm muscle can shorten passively by approximately 40% over the entire vital capacity (VC)(8,76). In contrast, the lateral and parasternal intercostal muscles and the neck inspiratory muscles shorten by only 10% between RV and TLC (20,21,84). The relationship between Pdi and diaphragm length in situ resembles thein vitro force-length relationship(8,43,76), and the relationship between inspiratory Pmus and diaphragm length closely resembles that between Pdi and diaphragm length (8). Given the prominent shortening capacity of the diaphragm and the lesser shortening of the other inspiratory muscles, it is likely that the relationship between Pimax and lung volume results primarily from the force-length properties of the diaphragm.
In one study (8), the in situ force-length behavior of the human diaphragm had a flat top with no identifiable peak, putting into question the location of in situ optimal length. However, Pdi and diaphragm length were not measured at between 40% and 50% TLC where diaphragm muscle might be at its optimal resting length (Lo). Indeed, Lu et al. (54) report that Pdi amplitude is greatest at 40% TLC. However, the decrement of Pdi at RV can also be explained by submaximal activation of the diaphragm at RV (35). A better estimate of the lung volume corresponding to Lo of the in situ human diaphragm comes from twitch Pdi responses to bilateral stimulation of both phrenic nerves (85). The twitch Pdi response is greatest at RV, and it is only 5% less at approximately 40% TLC, which corresponds to supine FRC. At upright FRC, which is approximately 50% TLC, the twitch Pdi is 20% lower than at RV. Thus, Lo for in situ human diaphragm probably lies at a lung volume that is well below upright FRC, between RV and supine FRC. The Lo of the canine diaphragm also lies below FRC(22,43,56,76).
Acute Hyperinflation of the Lungs
The range of resting lengths (Lr) shown in Figure 1 has implications concerning interactions among the various ventilatory muscles. The muscles must be able to function effectively in situ over a wide range of conditions, in health and in acute and chronic pulmonary disease. In addition, these muscles must contract in a coordinated fashion to meet multiple demands. Thus, acute increases in lung volume, such as would accompany an asthma attack, produce unequal degrees of shortening in each of the inspiratory muscles (Fig. 2B). For example, passively increasing the lung volume of supine, anesthetized dogs from FRC to TLC shortens the diaphragm by 25% to 35%(20,22,65,76), whereas the parasternal intercostal muscles shorten by only 10% (13,20) and the neck inspiratory muscles shorten by only 5% (21). At TLC, the ratio Lr/Lo is approximately 0.7 for the diaphragm, 0.8 for scalene and sternomastoid muscles, and 1.0 for the parasternal intercostal muscles. Thus, the neck inspiratory and parasternal intercostal muscles maintain their force-generating ability much better than the diaphragm at high lung volumes(40). Because the parasternal muscles shorten to nearer their Lo while other respiratory muscles shorten away from their Lo(19,20), the integrated inspiratory muscle apparatus has a broader effective force-length range than any single inspiratory muscle.
EFFECT OF STIMULATION RATE ON FORCE OUTPUT
Maximal Activation of Respiratory Muscles
With supramaximal stimulation, the maximal specific force of mammalian diaphragm muscle strips in vitro is 20-25 N·cm2 of muscle cross-sectional area (57). In normal human volunteers, bilateral tetanic stimulation of the phrenic nerves yields a transdiaphragmatic pressure (Pdi) of approximately 200 cm H2O(5,58). This is approximately the same as the Pdi produced by maximal voluntary effort using a combined inspiratory and expulsive contraction pattern (5,48), and it corresponds to a specific force of approximately 20 N·cm2 (78).
To compare performance of in situ respiratory muscles with that of isolated, perfused muscle strips in vitro, it is necessary to know the extent to which the respiratory muscles are activated during spontaneous or voluntary efforts. The procedure used to test the level of activation during voluntary efforts is known as the twitch-occlusion technique. This technique consists of superimposing Pdi twitches onto voluntary Pdi of graded intensity; as the magnitude of voluntary Pdi increases, the twitch Pdi response decreases(5,26).
The activation of the respiratory muscles is dependent on the type of maneuver. Maximal voluntary efforts often fail to maximally activate the ventilatory muscles (27,35,58). For example, Hershenson et al. (35) showed that during inspiratory Muller maneuvers, Pdi is less than during abdominal expulsive maneuvers. Activation of the diaphragm is submaximal in Muller maneuvers, whereas it is maximal in abdominal expulsive maneuvers. In contrast, McKenzie et al.(58) found that during maximal inspiratory efforts the diaphragm is maximally activated but the inspiratory intercostal muscles are not. Hershenson et al. (35) concluded that when one respiratory muscle group contracts against another, the weaker group is maximally activated and the stronger group is submaximally activated to maintain balance. Gandevia et al. (27) similarly showed that the abdominal muscles are not fully activated during maximal expulsive efforts. Therefore, during respiratory maneuvers that require antagonistic contractions, the maximal pressure generated by the ventilatory musculature is likely limited by the strength of the weaker muscle group.
In Vitro Force-Frequency Relationship
The force output of isolated, perfused muscle strips increases as the frequency of external stimulation increases (72). Generally, maximal tetanic force at Lo is 3-4 times higher than twitch force, and the curve relating force to frequency rises in sigmoid fashion to plateau at a stimulation frequency that is dependent on the intrinsic contractile speed of the particular muscle being studied. In general, contraction velocities of diaphragm are faster in small animals than in large ones(16,82), and intrinsic phrenic nerve firing frequencies are higher in smaller animals than in large ones(39,45,50,81).
In Situ Force- or Pressure-Frequency Relationships
Transdiaphragmatic pressure (Pdi) responses to stimulation of the phrenic nerves mimic the responses of isolated, perfused diaphragm muscle strips to external stimulation(4,7,15,63,99,100). In humans, bilateral stimulation of human phrenic nerves begins to produce fusion of the Pdi contour at 8 impulses·s-1 (Hertz, Hz)(7). Similarly, tetanic stimulation of the sternomastoid muscle at frequencies ranging from 5 to 100 Hz generate a force-frequency response that is virtually identical to that of limb muscles(64).
Muscle Length and Contractile Speed
Shortening the resting length of a muscle shifts its pattern of contraction towards a faster twitch profile (72,93). The mechanism appears to be related to the effect of muscle length on the calcium activating system (52,74). Both slow and fast muscles exhibit similar alterations in twitch profile when resting length is varied (93). Acute shortening of respiratory muscles reduces their twitch force, time-to-peak-tension (TPT), and one-half relaxation time (1/2RT) as is demonstrated in mammalian diaphragm musclein vitro (24,86) as well as in situ (16,76,82). Acute shortening also increases the contractile speed, as determined by Pdi deflections, of thein situ human diaphragm (85) and sternocleidomastoid muscle (16,64).
The interrelationships among resting length, twitch profile, and force production are illustrated in Figure 2. This shows the force-frequency curve of the isolated canine costal diaphragm at Lo(86). At a stimulation frequency of 5 Hz, the force produced is approximately 40% of maximum (point A). At a stimulation frequency of 100 Hz, force output is maximal. The length-tension properties of the isolated, perfused canine diaphragm are such that reducing length to 70% Lo reduces maximal force at 100 Hz by 40%. If the twitch profile of the muscle were unchanged by shortening, tension at all other frequencies would also be reduced by 40%, as shown by the dashed predicted curve. For example, to generate 40% of the maximum force at Lo, one would predict that the shortened muscle would have to be stimulated at 20 Hz (point B). However, owing to the change in twitch profile, one actually has to stimulate the muscle at 40 Hz(point C) to generate 40% of the maximal force at Lo.
Maximal vs Submaximal Force Generation
The physiologic range of neural firing frequency ranges from 5 to 70 Hz, but most respiratory activity is governed by frequencies of 5 to 30 Hz. In this range of firing frequency, force output is submaximal. It is evident fromFigure 2 that submaximal force output is extremely sensitive to shifts in stimulation frequency. For example, by doubling firing frequency from 10 to 20 Hz, contractile force is also approximately doubled. In terms of breathing requirements, the frequency modulation effect is more important than the effect of changes in length in determining the force of contraction.
During normal breathing, the force required of the respiratory muscles is far below maximal. If the force required by the respiratory muscles is potentially limited by a constraint in resting length (see above), the deficit can be made up at least transiently by increasing firing frequency. For instance, the diaphragm shortened to 70% Lo can still produce 65% of maximum force but requires inordinately high drive to attain that force. By requiring very high firing frequencies in isolation, these muscles may be highly susceptible to fatigue because of impaired transmission at the level of the neuromuscular junction (47) or impaired excitation-contraction coupling (15).
There is another disadvantage to requiring a muscle to operate at a shortened length since the susceptibility of the human diaphragm to fatigue is even greater when the muscle is acutely shortened(28,30). In the acutely shortened muscle, Pdi/Pdimax is much higher than normal (6), and it is not surprising that the acutely shortened diaphragm fatigues relatively easily both in vitro (24) and in situ (80,89). Thus, it is clear that recruiting quiescent muscles to aid in situations of increased ventilatory demands becomes a more attractive option than increasing the drive to shortened, already active, units to accomplish the same task.
EFFECTS OF VELOCITY ON FORCE OUTPUT
Force-Velocity Relationship In Vitro
Isolated, perfused strips of diaphragm muscle contract without shortening when they have a large afterload but shorten during contraction against afterloads that are less than maximal specific force(75). The velocity of shortening varies inversely and hyperbolically with the magnitude of the afterload. In the rat, the maximal velocity of shortening is approximately 10 Lo·s-1, whereas in the human it is 2.5 Lo·s-1 (15).
Force-Velocity Relationship In Situ
Studies of respiratory muscle shortening velocity in situ use graded inspiratory or expiratory resistances to attain variable inspiratory and expiratory flow rates, reflecting variations in contraction velocities, during maximal voluntary efforts. Agostoni and Fenn (1) found that the negative or positive amplitude of peak alveolar pressure, reflecting force generation, is greater when inspiratory or expiratory flow is retarded by the resistance. These results are consistent with the hypothesis that peak inspiratory and expiratory pressures in man are limited by the velocity of inspiratory and expiratory muscle shortening rather than by the mechanics of the lungs or airways. Pengelly et al. (69) reported that Pdi elicited by stimulation of phrenic nerves is linearly and inversely related to mean inspiratory flow rate in cats and in humans. Moreover, the slope of the Pdi flow line in humans was the same during maximal voluntary efforts as with external stimulation of the phrenic nerves. Other investigators (38,62) show similar results.
During maximal voluntary dynamic efforts with no added external resistance, the velocity of shortening is high enough to exert significant effects on maximal available inspiratory pressures. This occurs during forced inspiratory and expiratory flow-volume curves, maximal voluntary ventilation, and high intensity exercise. Leblanc et al. (49) report that maximal dynamic inspiratory Pes falls by 5% for every liter per second of inspiratory flow, so the total reduction owing to the velocity of inspiratory shortening is 25% S at peak exercise ventilation.
Shape of the In Situ Force-Velocity Relationship
The in situ relationship between alveolar pressure (Pes) or Pdi and inspiratory flow rate is described as linear by some(1,69,88,90) whereas others found that respiratory muscle force is hyperbolically related to shortening velocity(31,42). For example, Goldman et al.(31) demonstrated that the relationship between Pdi and inspiratory flow rate is hyperbolic, provided that chest wall configuration is such that diaphragmatic shortening is represented by outward displacement of the abdomen.
Otis (67) showed on theoretical grounds how an inverse linear relationship between driving pressure and airflow could result from a hyperbolic inspiratory muscle force-velocity relationship, coupled with an exponential relationship for force or pressure dissipated in internal impedance of the respiratory system. In the absence of direct measurement ofin situ respiratory muscle shortening rates, the issue remainsin limbo. We agree with Otis that respiratory muscle force-velocity relationships are likely to be hyperbolic, as found for diaphragm musclein vitro (75).
CONTRIBUTION OF DIAPHRAGM TO INSPIRED VOLUME
Diaphragm Swept Volume
Diaphragm swept volume (DSV) is defined as volume displaced by the diaphragm as it descends from higher to lower in the thorax. DSV has been estimated in a number of ways, including external dimensions of rib cage and abdomen (3,91), ballistic displacement of abdominal contents (94), thoracic and diaphragmatic dimensions on chest X-ray or fluoroscope (8,79,91,92), and three dimensional computerized tomography(46,95). Overall, DSV is approximately 70% of VT and 60% of VC. In upright humans, DSV is a higher fraction of inspired volume between RV and FRC than between FRC and TLC (3,79). However, in the supine position, DSV is approximately the same fraction of inspired volume both below and above FRC (3,29).
The DSV is not necessarily produced by active contraction of the diaphragm. In normal adults, the end-expiratory position of the diaphragm is under mild passive stretch in the upright and supine positions(2,98). Contraction of the abdominal muscles during expiration increases transdiaphragmatic pressure(59,71) and lengthens the diaphragm(23). Relaxation of the abdominal muscles at the onset of inspiration permits substantial early inspiratory diaphragmatic descent with volume displacement and inspiratory airflow in the absence of active diaphragmatic contraction (9,14).
During spontaneous breathing, the dorsal excursion of the diaphragm is greater than the ventral excursion in both prone and supine postures(92), suggesting that the diaphragm may not be operating as a piston. The axial displacement between RV and TLC is greatest posteriorly and approximately 40% less anteriorly (91). Paiva et al. studied the diaphragm using magnetic resonance imaging and conclude from its shape that the diaphragm does not function like a piston in a cylinder(68). However, other investigators conclude that although the diaphragm does not behave like a piston topographically or anatomically, its functional behavior over the VC is essentially like a piston(29,91).
Among the respiratory muscles, the diaphragm has the greatest capacity for shortening and volume displacement. Active or passive displacement of the diaphragm accounts for approximately 60% of the tidal volume and 60% of the vital capacity. Although the diaphragm changes shape and configuration between full expiration and full inspiration, its volume displacing function can for the most part be represented by the piston in cylinder model.
Normal breathing does not require the respiratory muscles to approach the limits of their contractile performance. Only the diaphragmatic excursion approaches its limits over the entire vital capacity. Respiratory pressures are far from maximal during quiet breathing but may near the dynamic maximum at the extremes of physical exercise. Neural activation is also submaximal except at extremes of effort. Because the respiratory system operates well within its outer limits, there are multiple strategies to compensate for deficits. If the diaphragm is shortened substantially, it can still generate needed respiratory pressure if it receives more neural drive. Alternatively, other muscles can be recruited to take over for an impaired diaphragm. Thus, the whole system appears to be highly versatile.
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Keywords:©1996The American College of Sports Medicine
VENTILATORY MUSCLES; DIAPHRAGM; RESPIRATORY MECHANICS