Respiratory Disease: Attention Turns to the Air Pump DLJDLEY F. ROCHESTER, M.D.

T he respiratory muscles constitute the body’s air pump, a part of the respiratory system as critical for

maintenance of life as is the heart. By and large physi- cians have taken the air pump for granted and have tended to ignore the possibility that it plays a role in clinical and physiologic manifestations of respiratory disease. Yet evidence accumulated in the last decade strongly suggests that air pump dysfunction in respira- tory disease is partly responsible for limitation of physical exercise capacity and that it contributes to the pathogenesis of dyspnea and respiratory failure [l].

The functions of the respiratory muscles and air pump are prescribed by two mechanisms, central nervous system control and intrinsic muscular responses to ex- ternal influences. This editorial focuses on the latter aspect. Space restrictions make it impossible to give credit to the many investigators whose work underlies this brief review. For detailed information on all facets of respiratory muscle physiology the reader is referred to the State-of-the-Art review by Derenne, Macklem and Roussos [2] and to the Proceedings of the Interna- tional Symposium on the Diaphragm, held at the Uni- versity of Virginia in 1978 [3].

The principal role of the respiratory muscles is to sustain breathing. The mechanics of the respiratory system are such that the energy required to breathe is derived almost entirely from contraction of the inspi- ratory muscles. The expiratory muscles often facilitate breathing by assisting with expiration or setting the position of the diaphragm prior to inspiration [4], but by far the greatest portion of ventilatory work is born by the inspiratory muscles, including the diaphragm, the in- spiratory intercostals and the accessory inspiratory muscles.

The inspiratory muscles, especially the diaphragm, are arranged around the thoracic cavity in such a way as to pull away from it. Goldman and his colleagues [4] have established that the diaphragm is primarily re- sponsible for the act of inspiration, the inspiratory in- tercostal and accessory muscles playing a supporting role. At rest the adult rib cage is stable enough to resist collapse when diaphragmatic contraction produces a

small negative intrathoracic pressure. At exercise or in obstructive disease of the airways, diaphragmatic con- traction produces a larger negative intrathoracic pres- sure and the chest wall would collapse unless it were further stabilized by simultaneous contraction of the inspiratory intercostal and accessory muscles. This ac- counts for the well known use of these muscles in asthma, chronic bronchitis and emphysema. At times, the roles of airmover and fixator are reversed [5]. This happens when the excursion of the diaphragm is limit- ed, as occurs normally in recumbent positions. It can also occur in diseases which limit or restrict diaphrag- matic excursion, such as severe emphysema or obesity. The fixating function of inspiratory muscles is critical in the infant whose thorax is extremely compliant.

Absence of the fixating function can have devastating consequences. In quadriplegics whose diaphragms are intact, air pump function is moderately impaired, but the inherent stability of the rib cage offsets loss of in- tercostal muscle function. In contrast, with bilateral diaphragmatic paralysis the function of the air pump is severely compromised because contraction of the other inspiratory muscles is largely dissipated in displacement of the flaccid diaphragm. The cardiac analogue is the ventricular aneurysm, in which the contractile energy of intact ventricular muscle is dissipated in distending the aneurysmal segment, with consequent reduction of stroke volume and cardiac output.

The respiratory muscles, like the heart, exhibit a characteristic length-tension relationship. For skeletal muscle there is an optimum resting length from which the muscle produces maximum contractile tension. A departure from this length in either direction reduces contractile force despite maximum neural stimulation. For muscles which surround cavities and by their con- traction generate pressures therein, it is more conve- nient to speak of the pressure-volume relationship which, for the heart, is known as the Frank-Starling law. In the heart, most alterations in the pressure-volume relation result from dilatation of the ventricle with elongation of the muscle fiber. The converse is true for the air pump. Inspiratory muscle force, expressed by

From the Pulmonary-Allergy Division, Department of Internal Medicine, University of Vir School of Medicine, Charlottesville, Virginia. This work was supported by Grants HL 21500 an d

inia HL

22022 from the U.S. Public Health Service-National Institutes of Health. Requests for reprints should be addressed to Dr. DudJey F. Rochester, BOX 225, University of Virginia Medical Center, Charlottesville, Virginia 22908.

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maximum static inspiratory pressure measured at the mouth, in the esophagus or across the diaphragm, is well preserved at low lung volumes at which the muscle fi- bers are stretched. However, at high lung volumes, when the diaphragm and the other inspiratory muscles are foreshortened prior to contraction, maximum in- spiratory contractile force is sharply curtailed. Thus, in obstructive lung diseases such as asthma, chronic bronchitis and emphysema, the inspiratory muscles sustain a severe mechanical disadvantage consequent to hyperinflation of the lung [l].

The Laplace relation, which relates tension in the wall of a cavity(T) to the pressure within (P), and to the radius of wall curvature (R], applies to the air pump as well as to the heart. For the diaphragm, the radius of curvature is negative with respect to the interior of the thoracic cavity, as is the pressure developed by diaphragmatic contraction. With extreme hyperinflation of the lungs, diaphragm muscle is shortened and flattened, thus re- ducing T and increasing R. Since P is proportional to T/R, as R increases, conversion of contractile tension to useful pressure is progressively compromised. Under these conditions contraction of the diaphragm is no longer effective in moving air or even in stabilizing the thoracic floor, and one observes inappropriate inward motion of the abdomen and lower rib cage during in- spiration [S].

Breathing is endurance work, and the respiratory muscles are well suited for it. The adult human dia- phragm contains a high proportion of muscle fibers which are rich in mitochondria and whose enzymes favor oxidative metabolism of lipids and carbohydrates [7]. In contrast, the respiratory muscles of infants are poor in endurance fibers and are unusually prone to fatigue [3]. Diaphragmatic endurance is enhanced by its rich blood flow, and in contrast to muscles in the limbs, diaphragmatic blood flow is not curtailed even at the highest levels of contractile effort. It has also been shown that the diaphragm, like the heart, is quite re- sistant to anaerobic metabolism (31.

Many disorders of the respiratory system increase the work of breathing or., to borrow from cardiologic ter- minology, increase the afterload on the air pump. In- creased afterload is particularly associated with upper airway obstruction, the obstructive pulmonary diseases, adult respiratory distress syndrome and thoracic re- strictive disorders such as obesity and kyphoscoliosis. A severe afterload may prevent the air pump from performing adequately, but this does not necessarily impair intrinsic inspiratory muscle contractility. It is important to assess inspiratory muscle function both in terms of the work that must be carried out to maintain adequate levels of ventilation and the capacity of the muscles to perform that work. For example, a severe tracheal stenosis can overwhelm air pump capacity, but with relief of the stenosis the air pump functions nor- mally because intrinsic muscular contractility is not impaired.

Does the air pump fail? Muscle fatigue is defined as

failure to sustain contractile tension. This can result from failure of central control and peripheral nervous mechanisms, or from failure of mechanisms intrinsic to the muscle cell [8]. The latter include excitation-con- traction coupling, energy metabolism and integrity of the contractile machinery. One form of acute fatigue occurs when muscles exert static or rhythmic efforts which exceed a critical fraction, for the diaphragm about 40 per cent of the maximum static contractile force. This can be induced in normal human respiratory muscles during maximal voluntary ventilation [7] or by breathing with maximal effort through a severe resistance to in- spiratory airflow [9].

There appear to be two forms of acute muscle fatigue [3,8]. High frequency fatigue, manifest by a loss of contractile tension within seconds, occurs when muscles are stimulated tetanically at frequencies of 69 to 100 Hz. This form of fatigue is thought to result from accumu- lation of potassium and depletion of sodium in the transverse tubular system: recovery is rapid. The second type of acute fatigue is called low frequency fatigue because it occurs when a muscle is stimulated tetani- tally at 20 Hz. It develops within minutes, and persists for up to 24 hours after the muscle has returned to the resting state. The cause is unknown, but it cannot be due to lactic acidosis or phosphagen depletion because levels of these metabolites rapidly return to normal after the muscle is at rest. Low frequency fatigue is clinically relevant. It develops at frequencies which are in the physiologic range for phrenic motoneurones, and it can occur in inspiratory muscles [3]. A third phenomenon associated with acute muscle fatigue is a shift from higher to lower frequencies in the power spectrum of the electromyogram [2,3]. The explanation for this phenomenon, which precedes the loss of contractile force, is also unknown. However, this and other changes in the surface electromyogram promise to be useful tools for detecting respiratory muscle fatigue in the clinical setting.

Metabolic events associated with intense muscular effort include intramuscular accumulation of lactic acid and phosphagen depletion. In an animal model of acute respiratory failure, diaphragm muscle lactate did not increase, but phosphagen, especially phosphocreatine, was depleted [lo]. Phosphocreatine depletion was not prevented by oxygen administration and may have been enhanced by respiratory acidosis. Severe respiratory acidosis also impairs muscle contractility, probably because of pH effects on the coupling of excitation and contraction rather than the inhibitory effects of acidosis on carbohydrate metabolism. Abnormalities of water and electrolyte metabolism, particularly potassium and phosphate depletion, also impair respiratory muscle function [I].

Chronic compromise of skeletal muscle function re- sults from undernutrition, disuse and myopathic pro- cesses. Each of these abnormalities reduces the number of contractile elements, the number and function of mitochondria, and impairs oxidative enzyme activity.

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Undernutrition has been shown to reduce diaphragm muscle mass, as well as respiratory strength and en- durance [l,ll]. Exhaustive exercise activates the lyso- somal system in skeletal muscle cells, with release of acid hydrolases and muscle fiber necrosis [12]. A growing body of evidence points to modification of both the acute and chronic fatigue mechanisms by endurance exercise training [1,3].

Recognition of air pump failure in respiratory diseases has important therapeutic implications, In some in- stances, such as acute respiratory failure, the primary goal is to reduce the afterload. This can be accomplished by mechanical ventilation or by removing the under- lying obstruction as in asthma or tracheal stenosis. It is critical to recognize and treat complications such as negative nitrogen balance, acidosis and electrolyte disturbances which further compromise muscle func- tion. During recovery from acute respiratory failure, it is important to avoid exhausting the respiratory muscles by premature or too rapid weaning from the mechanical ventilator. In chronic respiratory system disorders, such as chronic obstructive pulmonary diseases and thoracic restrictive disorders, it may be difficult to reduce af- terload or to correct the mechanical disadvantage to inspiratory muscles. Nonetheless, attention to nutritional status and appropriate schedules of respiratory muscle endurance training may well improve the patient’s ability to cope with the underlying respiratory disease.

REFERENCES

1. Rochester DF, Arora NS, Braun NMT, Goldberg SK: The respiratory muscles in chronic obstructive pulmonary disease (COPD). Bull Eur Physiopathol Respir 1979; 15: 951.

2. Derenne I-Ph. Macklem PT. Roussos CS: The resniratorv muscles: mechanics, control and pathophysiology. State- of-the-Art. Am Rev Respir Dis 1978; 118:119, 373, 581.

3. Rochester DF, Campbell EJM: Proceedings of the Interna- tional Svmoosium on the Diaphragm. Am Rev Resnir Dis 1979; 11ii1:

. _

4. Goldman MD, Grassino A, Mead J, Sears TA: Mechanics of the human diaphragm during voluntary contraction: dy- namics J Appl Physioll978; 44:840.

5. Macklem PT: A mathematical and graphical analysis of in- spiratory muscle action. Respir Physioll979; 38:153.

6. Sham IT. Goldberg NB, Druz WS, Fishman HC, Danon 1: Thoracoabdominal motion in chronic obstructive pulmd- nary disease. Am Rev Respir Dis 1977; 115:47.

7. Lieberman DA, Faulkner JA, Craig AB Jr, Maxwell LC: Performance and histochemical composition of guinea pig and human diaphragm. J Appl Physioll973; 34233.

8. Edwards RHT: Physiologic analysis of skeletal muscle weakness fatigue. Clin Sci Molec Med 1978; 54:463.

9. Roussos CS, Macklem PT: Diaphragmatic fatigue in man. J Appl Physiol 1977; 43:189.

10. Rochester DF, Arora NS, Goldberg SK: Effect of oxygen on diaphragm phosphagen depletion in a canine model of acute respiratory failure (abstract). Clin Res 1980; 28:431.

11. Arora NS, Rochester DF: Effect of nutrition on respiratory muscle strength and endurance [abstract]. Chest 1979; 76:344.

12. Vihko V, Salminen A. Rantamaki J: Exhaustive exercise, endurance training, and acid hydrolase activity in skeletal muscle. J Appl Physiol1979; 47:43.

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