The Mechanics of Breathing

PETER T. MACKLEM

Professor of Medicine, McGill University, Montreal, Quebec, Canada

	INTRODUCTION

TOP INTRODUCTION CONCLUSION REFERENCES

In this essay, we provide a brief review of the state of knowledge of the mechanics of breathing at the time the Division of Lung Disease (DLD) of the National Heart, Lung, and Blood Institute (NHLBI) was created and how this provided a solid foundation for the explosion of new knowledge that has since developed. This new knowledge has had a profound impact on the practice of medicine and surgery. Two elements were required to establish the infrastructure: technologic innovations in the measurement of volumes, displacements, flows and pressures; and modeling so that the measurements could be interpreted.

	THE INFRASTRUCTURE

Rohrer (1) supplied the theoretical foundations and the models, but although his colleagues made some measurements of mechanical properties (2), progress was limited until after the Second World War. Rohrer's theoretical foundation was largely ignored, however, until it was rediscovered independently by Rahn and coworkers (5) in a landmark paper that opened up the entire field. Furthermore, although von Neergaard (6) had pointed out the importance of surface tension at the moist alveolar wall, gas interface, its role in health and disease remained unknown because physiologists ignored his ideas for 20 years.

Although the reasons for the meager advancement of knowledge of the mechanics of breathing between the two World Wars are unclear, an important contributing factor was certainly lack of adequate measuring devices. Christie (7) measured lung mechanics in patients in the 1930s, but to measure transpulmonary pressure as the pressure difference across the lung, it was necessary to create a small pneumothorax to insert a probe into the pleural space to measure the pressure there. Invasive procedures such as these certainly inhibited progress. However, in 1949, Buytendijk (8) introduced the measurement of esophageal pressure as an index of pleural pressurean advance utilized by other groups in the early 1950s.

In England, Christie turned once again to lung mechanics with his colleagues McIlroy and Marshall (9). At Harvard, Mead and Whittenberger (10) began their sustained investigations into the mechanics of breathing. Fry and colleagues (13) recognized that the mechanical properties of the lung could be expressed in terms of a three-dimensional plot of pressure, flow, and volume (13). Rohrer had already pointed out that measurement of these three variables was necessary to characterize the mechanical properties of the lungs. He and others had recognized the value of pressure-volume relationships in characterizing lung elastic properties and pressure- flow relationships in characterizing flow-resistive properties. What Fry and colleagues established was the importance of the third plane of the three-dimensional plot: the flow-volume relationships. Fry immediately recognized that this was quite different on expiration compared with inspiration. When he moved to the National Institutes of Health (NIH), he and Hyatt (14) focused on this difference in a brilliantly original way. To understand the particular nature of the flow-volume plane on expiration, they first decided to measure the relationship between transpulmonary pressure and flow holding volume constant so that it would not be a confounding variable. Thus, they discovered the fascinating properties of the iso-volume pressure-flow curve.

They showed that at constant expired volume, as pleural pressure increased, flow increased only to a point, so that with further increases in pleural pressure, flow reached a maximum and then decreased somewhat. When they presented their paper, Mead (15) pointed out that expired volume was not a complete measurement of lung volume because gas compression decreased volume more than that estimated by a spirometer at the mouth. It has since been shown (vide infra) that if gas compression is taken into account, the flow on an iso-volume pressure-flow curve plateaus and becomes constant.

When Hyatt and Fry constructed the first isovolume pressure-flow curves, they found that the plateau value of flow was uniquely determined by lung volume, and that it decreased monotonically with decreases in lung volume. Because plateau flow was effort-independent, this unique relationship between maximum flow and lung volume was easily determined by plotting flow against lung volume during a single forced expiratory vital capacity (14). Thus, the maximum expiratory flow-volume curve was born as the third plane of the three-dimensional plot of the mechanics of breathing.

Meanwhile, Mead and colleagues (10, 12) were using the esophageal balloon to measure the static and dynamic volume-pressure and pressure-flow relationships of lungs (10, 12). While the measuring devices for measuring pressure, flow, and volume now were available, Rohrer's model was required to make sense of the measurements. This model was stunning in its simplicity. It assumed that the lung with its millions of alveoli and thousands of airways both in series and in parallel could accurately be modeled as a single elastic element in series with a single tube as a flow-resistive element. Given its hidden assumptions, it is truly astonishing that this model is remarkably successful in characterizing the normal lung. As Otis and colleagues (16) realized, the model required all alveoli to inflate and deflate synchronously at all breathing frequencies. It required that the single measurement of transpulmonary pressure as mouth relative to pleural pressure be applicable to all airspaces, even those deep within the lung, which are not directly exposed to pleural pressure, and it required that the distribution of ventilation be independent of respiratory frequency. That the normal lung largely behaves within these constraints seems almost miraculous, even today. But it did not take long to determine that Rohrer's single compartment model could not be applied to diseased lungs. It was already known that in disease, dynamic lung compliance fell as respiratory rate increased (12).

Otis and colleagues (16) showed that when this occurred the lung became asynchronous and ventilation distribution became dependent on breathing frequency. However, Dixon and Brodie (17) had anticipated this discovery at the turn of the century. These remarkable investigators studied open-chested cats and thus were able to measure transpulmonary pressure easily. They investigated the effects of bronchoconstriction and separated out the flow-resistive and elastic components of transpulmonary pressure. Decades ahead of their time, they demonstrated that end-expiratory lung volume increased as bronchoconstriction and respiratory frequency increased. They also demonstrated that, with unilateral bronchoconstriction, the tidal volume of the constricted lung became less while that of the unconstricted lung increased, and that this redistribution of ventilation was frequency-dependent. They even anticipated the effects of surface tension and interdependence on promoting alveoli stability. They knew that two soap bubbles in parallel when connected in series were unstable, with the smaller one emptying into the larger. They were curious as to why the lung did not behave in the same way and stated that they would consider this problem later. Alas, they never did. Clements (18) has discussed in detail the mystery that it took 20 years for von Neergaard's work on surface tension in the lung to become recognized. Mead has similarly wondered why Rohrer's ideas took so long to bear fruit. It seems appropriate here to make the same point about Dixon and Brodie. They had a sufficient theoretical basis using implicit one- and two-compartment lung models to make sense of their measurements, but more importantly, even before Rohrer, they had developed the techniques to make the measurements in experimental animals. Thus, with Rohrer's theoretical development and Dixon and Brodie's experimental techniques, everything was in place for the study of respiratory mechanics to advance rapidly. It did not happen. It appears that, like many highly creative investigators in other areas in science, these scientists were just ahead of their time.

Another pair of investigators who were also ahead of their time were Duomarco and Rimini (19). Dixon and Brodie long have been recognized for their contributions to knowledge about the control of airway smooth muscle, but their contributions to other aspects of lung mechanics largely have been ignored. Similarly, Duomarco and Rimini long have been recognized for their modeling of the mechanical properties of the abdomen as a bag of saline with a hydrostatic gradient of 1 cm H₂O/cm descent. What they have not been recognized for is the framework they developed, which allows interpretation of respiratory pressure swings and chest wall displacements in terms of respiratory muscle use.

They recognized that inspiration could take place by three separate agencies: (1) contraction of the diaphragm; (2) contraction of nondiaphragmatic inspiratory muscles; and (3) relaxation of abdominal muscles. They considered what would happen when these muscles acted in isolation or in various combinations. In each case, pleural pressure would decrease, and the chest wall would expand, but with diaphragmatic contraction, this would be accompanied by an increase in abdominal pressure and an outward abdominal displacement. With both abdominal muscle relaxation and nondiaphragmatic inspiratory muscle contraction, abdominal pressure would decrease along with pleural pressure during inspiration, but in the former, the abdomen would expand; whereas, in the latter the abdomen would be displaced inward.

This framework was published in 1947 but was not applied until the late 1960s. Indeed, their work was ignored until Agostoni and Rahn (20) made the first measurements of transdiaphragmatic pressure in 1960. In fact, it was in part Duomarco and Rimini's work that stimulated Agostoni and Rahn to make systematic measurements of abdominal pressure (21).

The measurement of transdiaphragmatic pressure was a breakthrough that quantified the diaphragm's contribution to respiratory pressure swings and set the stage for assessing respiratory muscle action using Duomarco and Rimini's framework. However, to interpret the measurements, a technologic advance was necessary to measure the displacements of rib cage and abdomen separately. Although pneumographs were available to make crude measurements of rib cage and abdominal dimensions, the framework for estimating the separate contributions of the diaphragm, rib cage, and abdominal muscles did not come into widespread use until Konno and Mead (22) published their classic paper modeling the chest wall as a system of two compartments, each with a single degree of freedom, along with an appropriate methodology to measure chest wall displacements. In this paper, both framework and technologic advance came simultaneously. The combined development of transdiaphragmatic pressure measurement and accurate measurements of thoraco-abdominal displacements opened the door for rapid advances in the understanding of ventilatory pump function.

These examples from the history of the mechanics of breathing illustrate how a framework or model to interpret the data and the proper measurement techniques combine to advance a field of knowledge.

A classic example of a framework was the publication of the Campbell diagram in a monograph in 1958 (23). This was never published in a peer-reviewed journal because not a single experimental measurement was made. It was a graphic analysis based purely on models developed by others. This diagram was enormously influential in advancing our knowledge of the work of breathing. By plotting the relationship between the pressure difference across the chest wall during respiratory muscle relaxation (pleural relative to body surface pressure) and pleural minus mouth pressure against lung volume during breathing, Campbell showed that one could estimate the pressures necessary to generate inspiratory flow at any lung volume as the distance between the chest wall relaxation curve and the lung pressure volume curve. The dynamic hyperinflation that occurs with airway obstruction and rapid respiratory rates (as described by Dixon and Brodie [17]) increases this pressure difference. In today's parlance, this is known as intrinsic positive end-expiratory pressure (PEEPi). Intrinsic PEEP cannot be estimated by measuring transpulmonary pressure alone, which only measures the pressure difference across the lung. One must know the pressure across the chest wall or the total respiratory system during relaxation as well as lung volume to measure PEEPi. The attempts to do so in recent years without knowledge of the relaxation pressures (24, 25) are doomed to failure (26). These attempts, based on the reduction in transpulmonary pressure toward end-expiration, reveal ignorance of sinusoidal analyses of the dynamics of breathing, which show that there is always a decrease in transpulmonary pressure at end-expiration, the magnitude of which depends solely upon the magnitude of pulmonary resistance, and flow.

Two more important examples of advances in technology and modeling that occurred prior to the establishment of the DLD were the development of whole body plethysmography (27) and attempts to explain expiratory flow limitation by modeling it as a waterfall or a Starling resistor (28).

As Mead has described (15), it only took Arthur Dubois 1 week to figure out how to measure alveolar pressure, airway resistance, and absolute lung volume using a constant volume variable pressure whole body plethysmograph. When rebreathing from inside such a box, the pressure in the box only changes to the extent that humidification, temperature, or alveolar pressure change. Dubois minimized the first two relative to alveolar pressure by panting shallowly (29). This great technologic breakthrough has become the gold standard for measuring airway resistance and absolute lung volume ever since.

Mead realized that some of the problems encountered by the relationships between temperature, pressure, and volume of a gas, and which restricted the utility of body plethysmography using a constant volume box, could be overcome by a constant pressure, variable volume box (30). The volume displacement box developed by Mead allowed an answer to the question he put to Fry and Hyatt, because a volume displacement box measures both expired volume and the volume of gas compressed by alveolar pressure. Indeed, it was shown that if one measures total change in volume during forced expiration, one does obtain a plateau on the iso-volume pressure-flow curves (31). Volume displacement plethysmography allowed Jaeger and Otis to show that the work involved in compressing and expanding alveolar gas could be a substantial fraction of the work of breathing (32). It opened up the study of phonation, as the box could be used in the head out mode so that one could measure volumes, flows, and pressures while speaking or singing unimpeded by a mouthpiece (33).

The modeling of expiratory flow limitation by a waterfall or Starling resistor was one of Solbert Permutt's great contributions (28). He pointed out that the distance between a shower head and the bottom of the bathtub (the hydrostatic gradient) did not determine the flow rate out of the shower. The plateau on the iso-volume pressure-flow curve and the notion that maximum expiratory flow was like a Starling resistor or a waterfall stimulated Mead, Permutt, and their colleagues to further analyses and experimentation, which resulted in modeling the iso-volume pressure-flow curve as a variable flow resistance containing the flow-limiting segments, in series with a constant resistance upstream from equal pressure points (points in the airway where lateral intrabonchial pressure equaled pleural pressure), or upstream from the flow-limiting segments where the transmural pressure downstream from equal pressure points (Ptm¹) was just sufficient to limit flow (28, 34). Although considerable controversy developed, both points of view were not mutually exclusive, both were proven to be largely correct, and both emphasized the importance of lung elastic recoil pressure in determining the maximum expiratory flow-volume curve. At the same time, advances in pressure-measuring technology allowed equal pressure points and the flow-limiting segments to be located in the lung. They were shown to be in large airways (35). As important as these modeling and technologic advances were, the actual mechanics of expiratory flow limitation were not understood until Dawson and Elliott (36) published their wave speed analysis of expiratory flow limitation in 1977, another major modeling advance.

The framework of Duomarco and Rimini (19), the Campbell diagram (23), and the modeling of expiratory flow limitation (28, 34), allowed interpretation of measurements well beyond Rohrer's model, although a single compartment lung was implicitly or explicitly part of each. Yet, progress in understanding how the lungwith its millions of parallel and series of compartmentscould possibly act as a single compartment required further theoretical and technical advances. Technical advances included the development of new methods to measure pressure in small airways (37), the resistance of collateral ventilatory channels (38), and the compliance of nonhomogeneously ventilated airspaces (39, 40). Advances in modeling were required to understand how pleural pressure was transmitted to air spaces deep within the lung, and the distribution of stresses within the pulmonary parenchyma under both homogeneous and nonhonogeneous conditions.

Modeling already had resulted in the conclusion that synchrony and constancy of ventilation distribution independent of frequency required equality of time constants among the many parallel pathways in the lung (16). But given the inequality of pathway lengths between the trachea and the alveoli, this seemed unlikely. This situation was clarified when pressure measurement in 2-mm interior diameter airways demonstrated that, contrary to Rohrer's predictions, the peripheral airways only comprised a small component to the total flow resistance in the lung (37). This meant that the time constants of peripheral parallel airspaces were small relative to the period of the breathing cycle at normal breathing rates, which in turn allowed for considerable differences in time constants between parallel pathways distal to 2-mm airways without frequency dependent redistribution of ventilation or asynchrony at physiologic breathing frequencies. Thus, the distribution of ventilation in normal lungs was determined by the elastic properties of airspaces. The flow resistance of the airways did not play a role.

The understanding of synchrony and frequency independence of ventilation distribution was advanced further when Mead and associates (41) analyzed the distribution of stresses within the lung. They concluded that the pressure applied to airspaces deep within the lung was given by the sum of the forces transmitted to the outer surface of the airspace by the attached alveolar walls divided by the surface area (F/A) (41). If this was the same within the lung as at the pleural surface, the effective pressure inflating alveoli deep within the lung would be transpulmonary pressure. Furthermore, the pressure applied to such an airspace would be amplified if the attached alveolar walls were stretched or its surface area diminished. Any airspace that expanded less than its surrounding neighbors would have the pressure applied to it amplified for both reasons. The opposite would be the case if the airspace was overexpanded. They showed that the interconnected airspaces were also interdependent. Under nonhomogeneous conditions the behavior of one airspace influenced the behavior of its neighbors. This interdependence was shown to be important in minimizing asynchrony while promoting homogeneity of tidal volumes of parallel airspaces.

Finally, the technology to measure the mechanics of collateral ventilation completed the picture. The time constant for collateral ventilation (at least in excised dog lungs) was found to be short (42). The compliance of the collaterally ventilated space was less than that of the same space when it inflated and deflated in synchrony with the rest of the lung and the ratio of these two compliances was an index of the magnitude of interdependence. Collateral ventilation, interdependence, and small peripheral time constants satisfactorily accounted for synchrony and frequency independence of ventilation distribution.

While experiments proceeded to partition the pressure drop serially along the tracheobronchial tree (43) and these were in good agreement with predictions based upon newer anatomic measurements (44), other investigators began looking at regional differences in behavior among parallel elements due to the shape of the lung and chest wall and the effects of gravity (47, 48). These experiments depended upon technologic developments to measure regional lung ventilation using radioactive gases and local absolute pleural pressure over small regions of the lung. Both technologies were in agreement that, although the pleural liquid was a continuous sheet from top to bottom, the gradient in pleural pressure between superior and inferior lung regions was only a quarter to a fifth of what would be expected if the gradient were hydrostatic. This left investigators with the problem of modeling how this could be. Unraveling the reasons for this has been long, controversial, and incompletely resolved even today. The interested reader is referred to the review by Mead (15) for a history of this interesting controversy.

	HOW THE MECHANICS OF BREATHING HAS INFLUENCED MEDICINE

At the time when the DLD of the NHLBI was created, application of the mechanics of breathing to disease had already established that chronic obstructive pulmonary disease (COPD) was characterized by loss of lung elastic recoil, a fixed degree of airway obstruction (49), and a marked reduction in maximum expiratory flow rates (50). Asthma was clearly a condition in which airway obstruction was variable (51). Because of the serial partitioning of flow resistance within the airways, it was recognized that considerable obstruction could be present within the peripheral airways that might smolder for years before it produced symptoms or overt changes in lung function (37, 52). Furthermore, it was known that these airways were the site of obstruction in COPD (53).

In COPD, asthma, and airway obstruction in small airways, the normal synchrony and inhomogeneity was no longer seen (16, 54). These diseases were characterized by breakdown in the forces promoting synchrony and homogeneity, so that ventilation distribution changed systematically with breathing frequency, and dynamic ventilation distribution was no longer determined elastically but by the time constants of airspaces in parallel. Interstitial lung disease and pulmonary edema were known to stiffen the lung (55, 56). Acute and chronic hypercapnic respiratory failure was a mystery: it could not easily be explained by altered mechanical properties of the lung, so that most investigators and clinicians thought that it was due to an abnormality in ventilatory control. Indeed, many still think so, but today there are plausible alternatives to this hypothesis.

How has research into the mechanics of breathing since the DLD was established advanced clinical practice of respiratory medicine?

Acute Respiratory Distress Syndrome of Infancy

Fundamental research in the mechanics of breathing has unquestionably had its greatest successes in the field of pediatric medicine, where understanding of the role of surface tension in alveolar stability and how to stabilize the alveoli in the face of high surface tension and the absence of surfactant has led to dramatic reductions in mortality from the respiratory distress syndrome of infants. Increasing transpulmonary pressure alone maintains airspaces open. This advance came from knowledge of lung pressure-volume relationships in health and the respiratory distress syndrome. How the fundamental knowledge came to be applied to clinical practice has been well described by Comroe (57). Replacement of surfactant is now routine. Intelligent applications of the principles of respiratory mechanics has shown that the new mode of mechanical ventilation, high frequency oscillation, has much to offer in this condition. Unfortunately, a clinical trial of high frequency ventilation (58) was marred by failure to follow a basic principle of lung mechanics; i.e., if one wishes to provide adequate mechanical ventilation in the face of alveolar instability, one must recruit as many open alveoli as possible, and this requires an inflation to total lung capacity (TLC) immediately before starting the high frequency oscillations. The failure of some institutions to follow this protocol rigorously was probably a major cause of failure of this NHLBI-funded multicenter clinical trial (59).

Assisted Ventilation

Understanding the mechanics of breathing has also had a major impact on intensive care medicine and mechanical ventilation. One would not know what pressures to use in mechanical ventilation without knowledge of the pressure-volume characteristics of the respiratory system. When the DLD was established, knowledge of ventilatory pump function was at a stage where the situation was ripe for many advances. Understanding of the mechanics of breathing has resulted in the intelligent use of PEEP and continuous positive airway pressure (CPAP) in the ICU, of the mechanical problems of ventilation through endotracheal tubes, of the concept of barotrauma, of the benefits of permissive hypercapnia, and of new modes of mechanical ventilation (60, 61). In particular, the exciting development of proportional assist ventilation (62) would not have been possible without a detailed understanding of the mechanics of breathing in health and disease.

Hypercapnic Respiratory Failure

Research in the mechanics of breathing has shown that, if anything, the drive to the respiratory muscles from the brain stem respiratory centers is increased, not decreased, in hypercapnic respiratory failure (63). This has cast doubt on the idea that hypercapnia is due to an abnormality of ventilatory control and has set the stage for the concept that acute hypercapnic respiratory failure could be understood and treated by measuring and correcting the imbalance between energy supplies and demands of respiratory muscles. These ideas were stimulated by the demonstration that it was possible to fatigue the inspiratory muscles in humans by increasing work and/or diminishing energy supplies in ways that mimicked disease process (64, 65). Today, many believe that acute respiratory failure is caused by respiratory muscle fatigue and that respiratory muscle rest will cure fatigue and treat respiratory failure. However, due to lack of adequate technology to measure inspiratory muscle fatigue clinically at the bedside, this hypothesis has never been tested adequately. What is known is that in normal subjects fatigue does little to alter the control of breathing or exercise performance (66, 67), which casts doubt on its role in acute hypercapnia. A negative NHLBI clinical trial of ventilatory muscle rest clearly has demonstrated that fatigue does not play a significant role in chronic respiratory failure (68).

Recent studies have shown that expiratory flow limitation induced in normal subjects by expiring through a Starling resistor during exercise severely limits exercise performance and induces an acute respiratory acidosis (69). Indeed, this seems to be the only intervention short of breathing CO₂ that regularly increases arterial PCO₂ in normal subjects. This in turn suggests that it is not fatigue that is the primary event in acute respiratory failure but the dynamic hyperinflation and threshold load induced by airway obstruction. A phenomenon first described by Dixon and Brodie in 1902 (17) now seems nearly a century later to be a major factor in acute hypercapnic respiratory failure. When end-expiratory volume encroaches on TLC due to an increase in ventilatory drive in combination with expiratory flow limitation, the tidal volume becomes limited, and the only way to increase ventilation is to increase frequency, which starts a particularly hasty vicious circle that further increases end-expiratory lung volume, decreases tidal volume, increases respiratory frequency, and decreases alveolar ventilation, leading to CO₂ retention.

Obstructive Sleep Apnea

The huge advances in understanding sleep-disordered breathing in the last two decades also have been dependent on a detailed understanding of the mechanics of breathing (70). This has directly resulted in a cure for this condition by applying nasal CPAP (71).

COPD

While understanding the mechanics of breathing has failed to solve any of the major problems of COPD, it has certainly led to an understanding of its pathophysiology and improved diagnosis. It has focused research on the underlying mechanisms of loss of recoil and peripheral airway obstruction in an effort to identify means by which these processes might be prevented or arrested. This has resulted in a whole battery of new tests to detect peripheral airway obstruction in its early stages, and a much greater understanding of the lung in transition between health and disease (72).

Asthma

In the field of asthma, the most prevalent of all chronic respiratory diseases in developed countries, there is currently a major controversy between the molecular and cellular biologists, who focus on airway inflammation as the solution to this disease, and experts in lung mechanics, who feel that the disease will not be controlled until we understand the mechanics of excessive airway narrowing that characterizes asthma. From the point of view of a scientist trying to understand the reasons for abnormal airway narrowing in asthma, it is striking that airway smooth muscle is capable of shortening to the extent that all airways within the lung could be completely closed (73). However, in the normal lung this degree of airway narrowing cannot be provoked at normal upright functional residual capacity or greater lung volumes (74, 75). Normal lungs are protected against excessive airway narrowing. A plateau develops on the bronchial dose response curve so that even an increase in dose of smooth muscle agonists of several orders of magnitude fails to produce an increased response (74). This protective mechanism is lost in asthma, and understanding the protective mechanism and how it breaks down is, from the point of view of the physiologist, absolutely fundamental to solving the problem of asthma.

It would seem that normally the elastic load on airway smooth muscle is sufficiently large that it markedly limits the degree of airway smooth muscle shortening that is possible (76). Certainly diminishing the load by breathing at low lung volumes is the only intervention experimentally shown in normal subjects that abolishes the plateau and makes the normal lung behave like asthmatic lung (75). Failure to take deep breaths aggravates this asthmatic-like behavior (79, 80). Modeling the situation indicates that the normal plateau can, in principle, be abolished by increasing the thickness of the submucosa and mucosa by inflammation, by decreasing the load through unlinking of interdependence between airways and parenchyma or loss of local lung recoil, or by increasing the force developed by airway smooth muscle (76, 78). The current state of the art suggests that decreases in load and/or increases in smooth muscle force are likely to be the most important pathophysiologic abnormalities in asthma. Solving the problem of asthma will almost certainly require collaborative efforts between cell and molecular biologists and respiratory physiologists to determine how airway inflammation alters airway geometry, load, and airway smooth muscle structure and function, and leads to excessive airway narrowing.

Drug Testing and Assessment of Therapy

The mechanics of breathing is not like the molecular biology of neoplasia and inflammation, which frequently opens up possibilities for novel drug design. Thus, it is not as interesting as other areas of science to the pharmaceutical industry. Nevertheless, measurements of lung mechanics are indispensible in the assessment of drugs that influence airway function, and they are essential in determining the natural history of many respiratory diseases and whether therapy improves mechanical function.

Lung Volume Reduction Surgery

A totally unanticipated area where the mechanics of breathing is playing an important role is the evaluation of lung volume reduction surgery for emphysema (81, 82) and the development of tests of mechanical function that will predict which patients will benefit (83, 84).

	SUMMARY

TOP INTRODUCTION CONCLUSION REFERENCES

It is clearly evident that research into the mechanics of breathing fostered and funded by the DLD of the NHLBI has been directly responsible for major advances in understanding, diagnosis, prevention, treatment, and rehabilitation of many of the most important respiratory diseases that affect mankind.

	Footnotes

Correspondence and requests for reprints should be addressed to Peter T. Macklem, INSPIRAPLEX, Montreal Chest Institute, 3650 St. Urbain, Montreal, QC, H2X 2P4 Canada.

Acknowledgments: Dr. Jere Mead, my mentor, read this article in draft form and, as usual, made many helpful suggestions. I am grateful to him, not just for his assistance with this manuscript, but for the plentitude of help I have received from him throughout my career. I dedicate this paper to him.

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29. DuBois, A. B., S. Y. Bothelho, and J. H. Comroe Jr.. 1956. A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and patients with respiratory disease. J. Clin. Invest. 35: 327-335 .

30. Mead, J.. 1960. Volume displacement body plethysmograph for respiratory measurements in human subjects. J. Appl. Physiol. 15: 736-740 [Free Full Text].

31. Ingram, R. H. Jr., and D. P. Schilder. 1966. Effect of gas compression on pulmonary pressure, flow and volume relationship. J. Appl. Physiol. 21: 1821-1826 [Free Full Text].

32. Jaeger, M. J., and A. B. Otis. 1964. Effect of compressibility of alveolar gas on dynamics and work of breathing. J. Appl. Physiol. 18: 83-91 .

33. Bouhuys, A., D. F. Proctor, and J. Mead. 1966. Kinetic aspects of singing. J. Appl. Physiol. 21: 483-496 [Free Full Text].

34. Mead, J., J. M. Turner, P. T. Macklem, and J. B. Little. 1967. Significance of the relationship between lung recoil and maximum expiratory flow. J. Appl. Physiol. 22: 95-108 [Free Full Text].

35. Macklem, P. T., and N. J. Wilson. 1965. Measurement of intrabronchial pressure in man. J. Appl. Physiol. 20: 653-663 [Abstract/Free Full Text].

36. Dawson, S. V., and E. A. Elliott. 1977. Wave-speed limitation on expiratory flow: a unifying concept. J. Appl. Physiol. 43: 498-515 [Abstract/Free Full Text].

37. Macklem, P. T., and J. Mead. 1967. Resistance of central and peripheral airways measured with a retrograde catheter. J. Appl. Physiol. 22: 395-401 [Free Full Text].

38. Hilpert, P. 1970. Kollaterale Ventilation Habilitationsschrift, aus der Medizinishcen (thesis). Tübingen Universitatsklinik, Tübingen, West Germany.

39. Menkes, H., G. Gamsu, R. Schroter, and P. T. Macklem. 1972. Interdependence of lung units in isolated dog lungs. J. Appl. Physiol. 32: 675-680 [Free Full Text].

40. Takashima, T., and J. Mead. 1972. Tests of a model of pulmonary elasticity. J. Appl. Physiol. 33: 576-581 [Free Full Text].

41. Mead, J., T. Takashima, and D. Leith. 1970. Stress distribution in lungs: a model of pulmonary elasticity. J. Appl. Physiol. 28: 596-608 [Free Full Text].

42. Woolcock, A. J., and P. T. Macklem. 1971. Mechanical factors influencing collateral ventilation in human, dog, and pig lungs. J. Appl. Physiol. 30: 99-115 [Free Full Text].

43. Macklem, P. T., A. Woolcock, J. C. Hogg, J. A. Nadel, and N. J. Wilson. 1969. Partitioning of pulmonary resistance in the dog. J. Appl. Physiol. 26: 798-805 [Free Full Text].

44. Olsen, D. E., G. A. Dart, and F. G. Filley. 1970. Pressure drop and fluid flow regime of air inspired into the human lung. J. Appl. Physiol. 28: 482-494 [Free Full Text].

45. Pedley, T. J., R. C. Schroter, and M. F. Sudlow. 1970. The prediction of pressure drop and variation of resistance within the human bronchial airways. Respir. Physiol. 9: 387-405 [Medline].

46. Pedley, T. J., R. C. Schroter, and M. F. Sudlow. 1970. Energy losses and pressure drop in models of human airways. Respir. Physiol. 9: 371-386 [Medline].

47. Milic-Emili, J., J. A. M. Henderson, M. B. Dolovich, D. Trop, and K. Kaneko. 1966. Regional distribution of inspired gas within the lung. J. Appl. Physiol. 21: 749-759 [Free Full Text].

48. Agostoni, E.. 1972. Mechanics of the pleural space. Physiol. Rev. 52: 57-128 [Free Full Text].

49. Mead, J., I. Lindgren, and E. A. Gaensler. 1955. Mechanical properties of the lungs in emphysema. J. Clin. Invest. 34: 1005-1016 .

50. Fry, D. L., and R. E. Hyatt. 1960. Pulmonary mechanics: a unified analysis of the relationships between pressure, volume and gas flow in the lungs of normal and diseased human subjects. Am. J. Med. 19: 672 .

51. Butler, J., C. G. Caro, R. Alcala, and A. B. DuBois. 1960. Physiological factors affecting airway resistance in normal subjects and in patients with obstructive respiratory disease. J. Clin. Invest. 39: 584-591 .

52. Mead, J.. 1970. The lungs' `quiet zone' (editorial). N. Engl. J. Med. 282: 1318-1319 .

53. Hogg, J. C., P. T. Macklem, and W. M. Thurlbeck. 1968. Site and nature of airway obstruction in chronic obstructive lung disease. N. Engl. J. Med. 278: 1355-1360 .

54. Woolcock, A., N. J. Vincent, and P. T. Macklem. 1969. Frequency dependence of compliance as a test for obstruction in small airways. J. Clin. Invest. 48: 1097-1106 .

55. Macklem, P. T., and M. R. Becklake. 1963. The relationship between the mechanical and diffusing properties of the lungs in health and disease. Am. Rev. Respir. Dis. 87: 47-56 .

56. Cook, C. D., J. Mead, G. L. Schreiner, N. R. Frank, and J. M. Craig. 1959. Pulmonary mechanics during induced pulmonary edema in anesthetized dogs. J. Appl. Physiol. 14: 177-186 [Abstract/Free Full Text].

57. Comroe, J. 1977. Premature Science and Immature Lungs, Part 3: In Retrospectroscope. Van Gehr Press, Meulo Park, CA. 161-182.

58. HIFI Study Group. 1989. High-frequency oscillatory ventilation compound with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants. N. Engl. J. Med. 320: 88-93 [Abstract].

59. Bryan, A. C., and A. B. Froese. 1991. Reflections on the HIFI trial. Pediatrics 87: 565-567 [Abstract/Free Full Text].

60. Hall, J. B., G. A. Schmidt, and L. D. H. Wood, editors. 1992. Principles of Critical Care. McGraw Hill, New York.

61. Schmidt, G. A., J. B. Hall, and L. D. H. Wood. 1994. Management of the ventilated patient. In J. F. Murray and J. A. Nadel, editors. Textbooks of Respiratory Medicine. W. B. Saunders, Philadelphia.

62. Younes, M.. 1992. Proportional assist ventilation: new approach to ventilatory support. Am. Rev. Respir. Dis. 145: 114-120 [Medline].

63. Aubier, M., D. Murciano, M. Fournier, J. Milic-Emili, R. Pariente, and J. P. Derenne. 1980. Central respiratory drive in acute respiratory failure of patients with chronic obstructive pulmonary diseases. Am. Rev. Respir. Dis. 122: 191-199 [Medline].

64. Roussos, C. S., and P. T. Macklem. 1977. Diaphragmatic fatigue in man. J. Appl. Physiol. 43: 189-197 [Abstract/Free Full Text].

65. Roussos, C. S., M. Fixley, D. Gross, and P. T. Macklem. 1979. Fatigue of inspiratory muscles and their synergic behaviour. J. Appl. Physiol. 46: 897-904 [Abstract/Free Full Text].

66. Yan, S., P. Sliwinskï, A. P. Gauthier, I. Lichros, S. Zakynthinos, and P. T. Macklem. 1993. Effect of global inspiratory muscle fatigue on ventilatory and respiratory muscle responses to CO₂. J. Appl. Physiol. 75: 1371-1377 [Abstract/Free Full Text].

67. Slinwinskï, P., S. Yan, A. P. Gauthier, and P. T. Macklem. 1996. Influence of global inspiratory muscle fatigue on subsequent respiratory muscle activity during exercise. J. Appl. Physiol. 80: 1270-1278 [Abstract/Free Full Text].

68. Shapiro, S. H., P. Ernst, K. Gray-Donald, J. G. Martin, W. O. Spitzer, S. Wood-Dauphinée, A. Beaupré, and P. T. Macklem. 1992. The effect of negative pressure ventilation in severe chronic obstructive pulmonary disease: a double-blind randomized clinical trial. Lancet 340: 1425-1429 [Medline].

69. Kayser, B., P. Slinwinskï, S. Yan, M. Tobiasz, and P. T. Macklem. 1997. Respiratory effort sensation during exercise with induced expiratory flow-limitation in healthy humans. J. Appl. Physiol. 83: 936-947 [Abstract/Free Full Text].

70. Phillipson, E. A. 1994. Sleep disorders. In J. F. Murray and J. A. Nadel, editors. Textbook of Respiratory Medicine. W. B. Saunders, Philadelphia.

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72. Macklem, P. T., and S. Permutt, editors. 1979. The Lung in the Transition between Health and Disease: Lung Biology in Health and Disease, Vol. 12. Marcel Dekker Inc., New York.

73. Stephens, N. L., E. A. Kroeger, and J. P. Metha. 1962. Force velocity characteristics of respiratory airway smooth muscle. J. Appl. Physiol. 26: 685-692 [Free Full Text].

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75. Ding, D. J., J. G. Martin, and P. T. Macklem. 1987. Effects of lung volume on maximal methacholine-induces bronchoconstriction in normal humans. J. Appl. Physiol. 62: 1324-1330 [Abstract/Free Full Text].

76. Moreno, R. H., J. C. Hogg, and P. D. Paré. 1986. Mechanics of airway narrowing. Am. Rev. Respir. Dis. 133: 1171-1180 [Medline].

77. Okazawa, M., T. R. Bai, B. R. Wiggs, and P. D. Paré. 1993. Airway smooth muscle shortening in excise of canine lung lobes. J. Appl. Physiol. 74: 1613-1621 [Abstract/Free Full Text].

78. Macklem, P. T.. 1996. A theoretical analysis of the effect of airway smooth muscle load on airway narrowing. Am. J. Respir. Crit. Care Med. 153: 83-89 [Abstract].

79. Skloot, G., S. Permutt, and A. Togias. 1995. Airway hyper-responsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J. Clin. Invest. 96: 2393-2403 .

80. Pellegrino, R., B. Violante, and V. Brusasco. 1996. Maximal bronchoconstriction in humans: relationship to deep inhalation and airway sensitivity. Am. J. Respir. Crit. Care Med. 153: 115-121 [Abstract].

81. Brantigan, O. C., E. Mueller, and M. B. Kress. 1959. A surgical approach to pulmonary emphysema. Am. Rev. Respir. Dis. 80: 194-202 [Medline].

82. Cooper, J. D., E. P. Trulock, A. N. Tafillon, G. A. Patterson, M. S. Pohl, and P. A. Deloney. 1995. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J. Thorac. Cardiovasc. Surg. 109: 106-116 [Abstract/Free Full Text].

83. Sciurba, F. A., R. M. Rogers, R. J. Keenan, W. A. Slivka, J. Gorcsan III, and P. F. Ferson. 1996. Improvements in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysema. N. Engl. J. Med. 334: 1095-1099 [Abstract/Free Full Text].

84. Fessler, H. E., and S. Permutt. Lung volume reduction surgery and airflow limitation. Am. J. Respir. Crit. Care Med. (In press)