Table 1- Hemodynamics and Gas Exchange in HLT (mean±SD)
Ventilation (VE, Umin) Arterial O 2 saturation (Sa0 2 %) Mixed venous O 2 saturation (Sv0 2 %) Arterial Pco, (PaC02 , kPa) Arterial pH Mixed venous pH Mixed venous Pco, (PVC0 2 , kPa)
Resting
On Exercise
9 (1.5) 98.0 (1.5)
29.5 (9.8) 98.0 (0.6)
69.7 (2.1)
42.0 (4.4)
5.2 7.4 7.4 5.4
(2.4) (0.02) (0.03) (0.5)
4.6 7.4 7.3 6.0
(0.7) (0.02) (0.03) (0.7)
For a comparable level of work VE in HLT patients was higher, 127.0 (8.3)% pred (based on V0 2 achieved), than in normals, 86.2 (3.8)% pred. The excessive ventilation in HLT was associated with a fall in PaC02 , but there were no changes in arterial pH and Pa02 • However, a marked fall in Sv0 2 and mixed venous pH, and a rise in PvC0 2 occurred. As the only innervated parts of the heart in these patients are the right atrium and the superior and inferior vena cava, the results suggest that in man chemoreceptors do exist in these areas (Armstrong et al. Science 1961;133:1897). This may explain the initial rise in ventilation in exercise in humans.
SESSION
Respiratory Muscle Fatigue and Ventilatory Failure . Charis Roussos,
u.o.. Ph.D., F.C.C.R*
T
he respiratory system consists of two parts: the lung (the gas-exchanging organ) and the ventilatory pump that ventilates the lung. Failure of the lung leads mainly to hypoxemia. Failure of the pump leads mainly to alveolar hypoventilation, which in turn leads to hypercapnia' (Fig 1). The failure of the pump theoretically may occur at any site from the central nervous system (CNS) to the contractile machinery. For practical purposes there are 3 major causes of pump failure: (1) The output of the CNS may primarily be inadequate-for example, after barbiturate intoxication; or the pattern of breathing is not optimal (for example, during an unsuccessful weaning period with the patient breathing with small tidal volume, resulting in an increase in VDNT). (2) There may be a mechanical defect such as flail chest, nerve damage, or kyphoscoliosis. (3) The muscles
may fail as force generator-that is, the muscles become
fatigued. This failure may occur when patients breathe against excessive inspiratory load and the energy demand exceeds the energy supply. However, under these conditions one may intuitively envisage 2 additional possibilities: either feedback loops that reduce and/or modify the output of the central nervous system are activated; or the CNS itself, due to sustained effort, reduces or alters its output. It follows that respiratory muscle fatigue is a complex phenomenon that involves changes in the muscle as well as the nervous system.':' Respiratory muscle fatigue may be compared to a car (the "muscles") and its driver (the CNS), which fail to achieve a required speed. If the demand for chemical energy (gasoline) exceeds the supply because of blocked fuel line or the car runs out of gas, this is analogous to fatigue within the respiratory muscles. If the driver slows down, it may be due to 2 mechanisms: because he perceives a fault in the engine (analogous to adaptation of the CNS as a result of the feedback loop) or because he has become tired and sleepy *Professor of Medicine, Chairman of Critical Care Department, University of Athens Medical School, Athens, Greece.
9
(analogous to fatigue of the CNS). An important concept of respiratory muscle fatigue is that it occurs after a period of work, in distinction to weakness, which does not follow some sort of exercise. Furthermore,
fatigue occurs when there is an imbalance between energy
demand and supply. Thus, fatigue may occur not only at very high work loads but even with the very modest work of breathing-ie, almost during quiet breathing if the blood supply to the muscle is severely reduced, as in shock. PATHOPI-JYSIOLOGY OF RESPIRATORY MUSCLE FATIGUE
Fatigue is the loss of force consequent to muscular exercise, particularly during submaximal intermittent contraction. However, much evidence suggests that the physiologic events underlying fatigue commence very early, well before the loss of force. The site and mechanism of fatigue have remained a subject of controversy over the last century, and naturally this controversy has not left the respiratory system unaffected. It is interesting, however, that the consensus to be deduced from the following pages was
I
Fatigue
I
FICURE 1. The respiratory system is depicted as consisting of two parts: (1) the lung, the gas-exchanging organ the failure of which is manifested by hypoxemia; and (2) the pump that ventilates the lung, consisting of the chest wall, the respiratory muscles, the respiratory centers that control them, and the nerves. Failure of the pump due to central depression, mechanical defect, or fatigue is manifested mainly by hypercapnia.
CHEST I 97 I 3 I MARCH, 1990 I Supplement
898
outlined elegantly in the first experiments regarding respiratory muscle fatigue conducted by Davis, Haldane, and Priestly" and by Davies, Brown, and Binger," These investigators concluded that both the CNS and the muscles may be responsible for fatigue. Site ofFatigue
Since the generation of a voluntary contraction involves the whole pathway from the brain to the contractile machinery, the various potential sites of failure can be divided into three broad categories: (1) those which lie within the eNS, (2) those concerned with neural transmission from CNS to muscle, and (3) those within the individual muscle fibers.
Muscle Contractile milure Skeletal muscle, including the diaphragm, is analogous to an engine. It converts chemical energy to heat and work. Thus, when the energy supply cannot meet the energy demand, fatigue ensues. Slow muscle, which has a high oxidative potential, is less susceptible to developing fatigue than fast muscle. 7-Q Extending these observations to the respiratory muscles, Farkas and Boussos"-" submitted hamsters to daily treadmill exercise and demonstrated that the hamster diaphragm becomes more resistant to fatigue after increasing its oxidative capability by developing lung emphysema (using elastase), The substances directly involved in the transformation of chemical energy into mechanical work in skeletal muscle are AD~ orthophosphate (Pi), hydrogen ions (H+), magnesium ions (Mg2+), and phosphocreatine (Pc). Using nuclear magnetic resonance (N~R), Dawson et alII showed that Pc breaks down progressively; and creatine, AD~ and H + levels 'rise while the direct source of energy, is reduced by only 25%. The latter finding is consistent with the results obtained in normal subjects performing dynamic exercise until exhaustion." Wh); then, does muscle fail? To answer this, we must consider changes in chemistry that take place in muscle fiber: ATP is hydrolyzed to AD~ Pi, and H + . Thus,
m
m
MgATP+ H20~MgADP+ Pi + H+ As the muscles fatigue, the concentration of all products increases considerably, and therefore this reaction is slowed. This observation leads to the hypothesis that the decline of muscle force is not due to depletion of ATP but to the reduced rate of ATP' breakdown resulting from product accumulation. Similar experiments with NMR in the diaphragm have not been done as yet. The increase in energy demands in excited muscles is provided mainly by the combustion of fat, blood glucose, and glycogen of the working muscles. The association of glycogen depletion with fatigue of the skeletal muscles" and the diaphragm":" is well-established. However, why glycogen depletion coincides with fatigue is not clear.' Perhaps there is a rate-limiting step in utilizing the blood-borne fuels for which glycogen is used. Thus, fatigue will occur when glycogen is depleted. Historically, lactic acid accumulation has received great attention as the culprit of fatigue in the skeletal muscles. Similarly, blood lactate elevation has 'also been found in subjects breathing through high inspiratory loads to exhaus80S
tion," but there is no direct evidence that the lactic acid produced by the respiratory muscles is the culprit in diaphragmatic fatigue. In addition, animals with low cardiac output (pericardiac tamponade) or Escherichia coli endotoxic shock develop substantially less lactic acidosis if they are ventilated rather than breathing spontaneously. In these experiments, diaphragmatic lactic acid is greater in the spontaneously breathing animals, which also develop diaphragmatic fatigue, than in the ventilated ones. 15,19.20 The effect of lactic acid on force generation is believed to be mediated by lowering pH. At low pH, Ca ' + is sequestered in the sarcoplasmic reticulum," and a larger amount of Ca ++ is needed to produce a given tension. In addition, hydrogen ions exert a direct negative effect on the contractile process itself. 22 To summarize, glycogen depletion, lactic acid accumulation, inability to utilize blood-borne substances, and decrease in the rate of ATP hydrolysis are merged to explain loss of force, but the exact interplay of all these factors is not yet identified either in other skeletal muscle or in the diaphragm. Neuromuscular Transmission Failure
When a nerve muscle preparation is stimulated continuously; failure of propagation between nerve and muscle can easily be demonstrated. This failure may occur presynaptically at nerve terminal branches, postsynaptically from a decrease of end-plate excitability, or from depletion of human muscles in ViVO. 23-25 However, experiments during maximum voluntary contraction, with one exception.v do not support neuromuscular transmission failure. 27,28 For the diaphragm, evidence that neuromuscular transmission andcell membrane excitation are adequate has been found in experiments in dogs in cardiogenic and septic shock. 15 •19 As the diaphragm became fatigued, the relationship of integrated phrenic nerve activity (Ephr) and diaphragmatic EMG activity remained unaltered; that is, when the diaphragm started failing as a force generator and greater stimulation was needed for an increment of transdiaphragmatic pressure, the relationship of Ephr and EMG was similar to that observed during the control period and to the earlier stage of the fatigue. However, these experiments may not be specific in testing this question; for example, changes in the action potential through the run may have compensated for discrepancies between Ephr and EMG. Teleologically, transmission block could be beneficial in some i~stances. As suggested by Nassar-Gentina et al29 and by Kugelberg and Lindergen," the muscle is protected against excessive depletion of its ATP store which would ultimately lead to rigor mortis. Support for this hypothesis may be deduced from experiments by Luttgaw," in which single muscle fibers were stimulated. He demonstrated that the reduction in action potential amplitude (action potential fatigue) was minimized when contraction was inhibited by hypertonic solution and was abolished completely in noncontracting fibers poisoned with cyanide or iodoacetate; that is, action potential was closely related to muscle 6ber contraction. These experiments therefore suggest a close relation between metabolism and fatigue of the neuromuscular junc~on. Neuromuscular transmission failure in man Aspen Lung Conference: Chronic Respiratory ~aiIu~
during diaphragmatic fatigue is not clearly understood. However, if high-frequency fatigue is due to failure of the neuromuscular junction, it may be inferred that such a failure can exist in the diaphragm of man. It has been clearly shown that normal subjects breathing against inspiratory loads develop high-frequency fatigue, 32 which may reflect neuromuscular junction failure.
Fatigue ofCNS
\
During short maximal contraction central fatigue does not, in some studies, appear to playa role, 33-35 since maximal nerve stimulation fails to increase the failing force. In contrast, during fatigue of intermittent submaximal contraction of the diaphragm, reduced CNS motor drive appears to be a factor. I Undoubtedly, the experimental protocol is complex, and the difference between the 2 muscle groups is intriguing. However, such findings are of particular importance in understanding the pathophysiology of ventilatory failure and need further testing. Central fatigue must not be confused with progressive decrease in the firing rate during maximum contraction, during which superimposed supramaximal electric tetanic stimulation does not increase muscle force. Several investigators have clearly shown that the central firing rate decreases during fatiguing muscle contraction." Experimentally, the gradual loss of force following prolonged maximum voluntary contraction can be accurately mimicked with electrical stimulation if the stimulation frequency can be accurately reduced, whereas, ifhigh stimulation frequencies are maintained too long, force loss is more rapid. Thus, it was proposed that the decrease in firing frequency is an adaptive mechanism to the alteration of muscle contractile characteristics. 34 It is well-established that fatigue is characterized not only by loss of force but also by slowing of the muscle contractile speed. In addition, it is known that for any muscle or motor unit the minimum excitation frequency required to generate force and tetanic fusion is proportional to its contractile speed. Thus, if during fatigue the degree of contractile slowing matches the decline in motoneuron firing rate, the latter does not result in any additional reduction in muscle force. Such an adaptation would be rather beneficial; it would avoid the failure of electrical propagation associated with high-frequency fatigue as well as the complete depletion of vital chemicals within the muscle cell, which might otherwise occur if high firing rates were maintained. An interesting question, of course, is how such an adaptation is brought about. In this context Hannerz and Crimby'" have presented evidence that motor neurons receive a tonic inhibitory drive from peripheral sources and that during a maximum voluntary contraction the motor neuron discharge rate increases if muscle afferents are partially blocked. In the diaphragm, during fatigue, muscle relaxation is prolonged;" but we have no information about alteration in firing rate. However, we have shown that afferent information via large (type I and II) and small (type III and IV) fibers affects the central respiratory controller's discharge in terms of firing rate, firing time and frequency of breathing;37 the latter is observed in states of diaphragmatic fatigue in both animals and humans. 15, 19,3I) It is tempting therefore to hypothesize that, as the contractile properties and the
diaphragmatic chemistry change during fatigue, afferents via the phrenic nerve may affect the output of respiratory centers in terms of firing rate or timing (frequency of breathing, duty cycle). Summary The diaphragm fails as a force generator whenever energy demand exceeds energy supply, during high resistive breathing, and/or during hypoxemia. 15 , 19,39 As fatigue ensues, contractile slowing increases" and central discharge firing decreases, either as fatigue of the CNS40 or adaptation to the altered chemistry and/or contractile characteristics of the muscles, which may prevent their self-destruction by excessive activation. Extending and enlarging this to the respiratory system, we hypothesize that, as the diaphragm contracts intermittently, the central controllers may modify the duration of contraction (Ti)and total duration of breathing cycle (Ttot). Such a strategy may optimize diaphragmatic function but at the cost, in some instances, of alveolar hypoventilation and CO 2 retention." This interaction, if it exists, is postulated to be mediated by the large and small phrenic afferents. DETERMINANTS OF CRITICAL TASK (PRESSURE, WORK)
The threshold of fatigue is that level of exercise which cannot be sustained indefinitely. This level, therefore, can be expressed as a percentage of the maximum performance. Bohmert" and Monod" Brst constructed such a relationship during isometric contraction to determine the critical force above which fatigue ensues. Similar approaches were also used by Monod and Sherrer" for intermittent contraction, an approach also adopted by Roussos and Macklem' and by Roussos et al43 in their original work on fatigue of the respiratory muscles. The model used in this approach was "the muscle as an engine"; that is, fatigue develops when the mean rate of energy demand (Ud) exceeds the mean rate of energy supply (Us). Ud>Us WIE>Us
(1) (2)
or W>UsE, or where W = mean muscle power and E = efficiency. Clearly, when UsE>W, the muscle can continue to work indefinitely, but when UsErts. Respir Physiol 1968; 5:187-201 21 Naess Y, Storm-Mathisen A. Fatigue of sustained tetanic contractions. Acta Physiol Scand 195.5;34:3.'51-66 22 Fabiato A, Fabiato f. Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiae and skeletal muscles. J Physiol (Lund) 1978; 276:233-55 23 Bigland-Ritchie B, Jones DA, \Voods JJ. Excitation [requency and muscle fatigue: electrical responses during human voluntary and stimulated contraction. Exp Neurol 1979; 64:414-27 24 Jardin J, Farkas G, Prefaut C, Thomas 0, Macklem PT, Roussos C. The failing inspiratory muscles under normoxic and hypoxic conditions. Am Rev Respir Dis 1981; 124:274-79 25 Monod H, Scherrer J. The work capacity of a synergic muscular group. Ergonomics 1965; 8:329-37 CHEST / 97 I 3 I MARCH, 1990 I Supplement
958
26 Sorli J, Crassino A, Lorange C, Milic-Emili J. Control of breathing in patients with chronic obstructive lung disease. Clin Sci Mol Med 1978; 54:295-304 27 Mead J. Control of respiratory frequency. J Appl Physiol 1960; 15:325-36 28 Merton PA. \hluntary strength and fatigue. J Physiol (Lond) 1954; 128:553-64 29 Nassar-Centina
v Passonneau ]V: Vergara JL, Rapoport SI. Metabolic correlates of fatigue and of recovery from fatigue in single frog muscle 6bers. J Cen Physiol 1975; 72:53~ 30 Kugelberg E, Lindegren B. Transmission and contraction fatigue of tar motor units in relation to succinate dehydrogenase activity of motor unit fibers, J Physiol (Lond) 1969; 288:285300
31 Luttgaw HC. The effect of metabolic inhibitors on the fatigue of the action potential in single muscle 6bers. J Physiol (Lond) 1965; 178:45-67 32 Aubier M, Farkas G, De Troyer A, Mozes R, Roussos C. Detection of diaphragmatic fatigue in man by phrenic stimulation. J Appl Physiol1981; 50:538-44 33 Bigland-Ritchie B, Jones DA, Hosking G~ Edwards RHT. Central and peripheral fatigue in sustained maximal voluntary contractions of human quadriceps muscles. Clin Sci Mol Med 1978; 54:609-14 34 Bigland-Ritchie B, Johansson R, Lippold OCJ, \\'ooos JJ. Contractile speed and EMC changes during fatigue of sustained maximal voluntary contractions. J Neurophysiol 1983; 50:31324 35 Grimby L, Hannerz J, Hedman B. Fatigue and voluntary discharge properties of single motor units in man. J Physiol (Lond) 1981; 316:543-54 36 Esau SA, Bellemare F, Grassino A, Permutt S, Roussos C, Pardy RL. Changes in relaxation rate with diaphragmatic fatigue in humans. J Appl Physiol 1983a; 54:1353-60 37 Jammes Y, Buchler B, Delpierre S, Rasidakis A, Grimand C, Roussos C. Phrenic afferents and their role in inspiratory control. J Appl Physiol 1986; 60:854-60 38 Cohen C, Zagelbaum C, Cross 0, Roussos C, Macklem PT. Clinical manifestations of inspiratory muscle fatigue. Am J Med 1982; 73:308-16 39 Roussos C, Moxham J. Respiratory muscle fatigue. In: Roussos C, Macklem PT (eds), The thorax. 1981; 829-70 40 Bellemare F, Bigland-Ritchie B. Central components of diaphragmatic fatigue assessed from bilateral phrenic nerve stimulation. J Appl Physioll987; 62:1307-16 41 Monod H. Contribution a I' etude du travail statique. These Med(Paris) 1956; 124 43 Roussos C, Fixley M, Gross 0, Macklem PT. Fatigue of inspiratory muscles and their synergistic behavior. J Appl Physiol 1979; 46:879-904 44 Roussos C, Aubier M. Neural drive and electromechanical alterations in the fatiguing diaphragm. In: Porter J," Whelan J (eds). Human muscle fatigue: physiological mechanisms. Ciba Foundation Symposium No. 82. London: Pitman Medical, 1981; 213-33 45 Bellemare F, Grassino A. Effect of pressure and timing of contraction on human diaphragm fatigue. J Appl Physioll982; 53:1190-95
46 Freedman S. Sustained maximum voluntary ventilation. Respir Physiol 1970; 8:230-40 47 Farkas G, Roussos C. Acute diaphragmatic shortening: in vitro mechanics and fatigue. Am Rev Respir Dis 1984b; 130:434-38 48 Otis AB. The work of breathing. Physiol Rev 1954; 34:449-58 49 Hussain S, Simkus G, Roussos C. Respiratory muscle fatigue, a cause of ventilatory failure in septic shock. J Appl Physiol 1985; 58:2033-40 50 Bigland-Ritchie B, Bellemare F, Woods JJ. Central and periph96S
eral fatigue in intermittent submaximal contractions. In: Porter R, Whelan J (eds), Human muscle fatigue: physiological mech-
anisms. Ciba Foundation Symposium No. 82. London: Pitman Medical, 1981
Effect of Chronic Malnutrition on Rat Diaphr,gm Contractility and Fatigue* D.] Prezant, M.D., F.C.C.R; B. Richner, M.D., L K. Aldrich, M.D., F.C.C.R; H. Naeashima, ~{.D.; and] Cahill, ~I.D. ~-Iib-fed male Wistar rats (C) were compared to a group
made malnourished (M) by reducing daily food intake to 25% of control for 10 weeks. Both groups (N = 10) had equal access to water and were of similar initial weight (185±2 g). Pneumonia was not a complication. Hemidiaphragm costal strips were bathed in modified Krebs solution (37°C) containing insulin and d-tubocurarine. At optimal length, isometric twitch (2 ms, sq wave) and tetanic tensions (400 ms trains at 10, 20, 60, 100 Hz) were measured at baseline (B), at 10 m of fatigue stimulation (5 impulses at 5
Hz; 30 trains/m) and after 10 m of recovery. Tension indices (BI) were normalized for muscle strip csa (g/cm"), and the fatigue resistance index (FRI) was defined as (FRI
= fatigue
indexlbaseline index).
Table I-Effects afChronic Malnutrition in Rats Malnourished Body weight (g) Diaphragm weight csa (ern") 10 Hz BI (g/cm") FRI(%)
100 Hz BI (g/cm") FRI(%)
(10wk)
Ad-Lib-Fed
340±7* 0.80 ± 0.05* 0.038 ± 0.002* 388.64±34.79* 43±3* 1536.14 ± 99.51 * 46±2*
477± 13 1.11±0.04 0.049 ± 0.002 294.78±24.20 29±2 1190.79±87.39 35±3
*p
Ventilation (VE, Umin) Arterial O 2 saturation (Sa0 2 %) Mixed venous O 2 saturation (Sv0 2 %) Arterial Pco, (PaC02 , kPa) Arterial pH Mixed venous pH Mixed venous Pco, (PVC0 2 , kPa)
Resting
On Exercise
9 (1.5) 98.0 (1.5)
29.5 (9.8) 98.0 (0.6)
69.7 (2.1)
42.0 (4.4)
5.2 7.4 7.4 5.4
(2.4) (0.02) (0.03) (0.5)
4.6 7.4 7.3 6.0
(0.7) (0.02) (0.03) (0.7)
For a comparable level of work VE in HLT patients was higher, 127.0 (8.3)% pred (based on V0 2 achieved), than in normals, 86.2 (3.8)% pred. The excessive ventilation in HLT was associated with a fall in PaC02 , but there were no changes in arterial pH and Pa02 • However, a marked fall in Sv0 2 and mixed venous pH, and a rise in PvC0 2 occurred. As the only innervated parts of the heart in these patients are the right atrium and the superior and inferior vena cava, the results suggest that in man chemoreceptors do exist in these areas (Armstrong et al. Science 1961;133:1897). This may explain the initial rise in ventilation in exercise in humans.
SESSION
Respiratory Muscle Fatigue and Ventilatory Failure . Charis Roussos,
u.o.. Ph.D., F.C.C.R*
T
he respiratory system consists of two parts: the lung (the gas-exchanging organ) and the ventilatory pump that ventilates the lung. Failure of the lung leads mainly to hypoxemia. Failure of the pump leads mainly to alveolar hypoventilation, which in turn leads to hypercapnia' (Fig 1). The failure of the pump theoretically may occur at any site from the central nervous system (CNS) to the contractile machinery. For practical purposes there are 3 major causes of pump failure: (1) The output of the CNS may primarily be inadequate-for example, after barbiturate intoxication; or the pattern of breathing is not optimal (for example, during an unsuccessful weaning period with the patient breathing with small tidal volume, resulting in an increase in VDNT). (2) There may be a mechanical defect such as flail chest, nerve damage, or kyphoscoliosis. (3) The muscles
may fail as force generator-that is, the muscles become
fatigued. This failure may occur when patients breathe against excessive inspiratory load and the energy demand exceeds the energy supply. However, under these conditions one may intuitively envisage 2 additional possibilities: either feedback loops that reduce and/or modify the output of the central nervous system are activated; or the CNS itself, due to sustained effort, reduces or alters its output. It follows that respiratory muscle fatigue is a complex phenomenon that involves changes in the muscle as well as the nervous system.':' Respiratory muscle fatigue may be compared to a car (the "muscles") and its driver (the CNS), which fail to achieve a required speed. If the demand for chemical energy (gasoline) exceeds the supply because of blocked fuel line or the car runs out of gas, this is analogous to fatigue within the respiratory muscles. If the driver slows down, it may be due to 2 mechanisms: because he perceives a fault in the engine (analogous to adaptation of the CNS as a result of the feedback loop) or because he has become tired and sleepy *Professor of Medicine, Chairman of Critical Care Department, University of Athens Medical School, Athens, Greece.
9
(analogous to fatigue of the CNS). An important concept of respiratory muscle fatigue is that it occurs after a period of work, in distinction to weakness, which does not follow some sort of exercise. Furthermore,
fatigue occurs when there is an imbalance between energy
demand and supply. Thus, fatigue may occur not only at very high work loads but even with the very modest work of breathing-ie, almost during quiet breathing if the blood supply to the muscle is severely reduced, as in shock. PATHOPI-JYSIOLOGY OF RESPIRATORY MUSCLE FATIGUE
Fatigue is the loss of force consequent to muscular exercise, particularly during submaximal intermittent contraction. However, much evidence suggests that the physiologic events underlying fatigue commence very early, well before the loss of force. The site and mechanism of fatigue have remained a subject of controversy over the last century, and naturally this controversy has not left the respiratory system unaffected. It is interesting, however, that the consensus to be deduced from the following pages was
I
Fatigue
I
FICURE 1. The respiratory system is depicted as consisting of two parts: (1) the lung, the gas-exchanging organ the failure of which is manifested by hypoxemia; and (2) the pump that ventilates the lung, consisting of the chest wall, the respiratory muscles, the respiratory centers that control them, and the nerves. Failure of the pump due to central depression, mechanical defect, or fatigue is manifested mainly by hypercapnia.
CHEST I 97 I 3 I MARCH, 1990 I Supplement
898
outlined elegantly in the first experiments regarding respiratory muscle fatigue conducted by Davis, Haldane, and Priestly" and by Davies, Brown, and Binger," These investigators concluded that both the CNS and the muscles may be responsible for fatigue. Site ofFatigue
Since the generation of a voluntary contraction involves the whole pathway from the brain to the contractile machinery, the various potential sites of failure can be divided into three broad categories: (1) those which lie within the eNS, (2) those concerned with neural transmission from CNS to muscle, and (3) those within the individual muscle fibers.
Muscle Contractile milure Skeletal muscle, including the diaphragm, is analogous to an engine. It converts chemical energy to heat and work. Thus, when the energy supply cannot meet the energy demand, fatigue ensues. Slow muscle, which has a high oxidative potential, is less susceptible to developing fatigue than fast muscle. 7-Q Extending these observations to the respiratory muscles, Farkas and Boussos"-" submitted hamsters to daily treadmill exercise and demonstrated that the hamster diaphragm becomes more resistant to fatigue after increasing its oxidative capability by developing lung emphysema (using elastase), The substances directly involved in the transformation of chemical energy into mechanical work in skeletal muscle are AD~ orthophosphate (Pi), hydrogen ions (H+), magnesium ions (Mg2+), and phosphocreatine (Pc). Using nuclear magnetic resonance (N~R), Dawson et alII showed that Pc breaks down progressively; and creatine, AD~ and H + levels 'rise while the direct source of energy, is reduced by only 25%. The latter finding is consistent with the results obtained in normal subjects performing dynamic exercise until exhaustion." Wh); then, does muscle fail? To answer this, we must consider changes in chemistry that take place in muscle fiber: ATP is hydrolyzed to AD~ Pi, and H + . Thus,
m
m
MgATP+ H20~MgADP+ Pi + H+ As the muscles fatigue, the concentration of all products increases considerably, and therefore this reaction is slowed. This observation leads to the hypothesis that the decline of muscle force is not due to depletion of ATP but to the reduced rate of ATP' breakdown resulting from product accumulation. Similar experiments with NMR in the diaphragm have not been done as yet. The increase in energy demands in excited muscles is provided mainly by the combustion of fat, blood glucose, and glycogen of the working muscles. The association of glycogen depletion with fatigue of the skeletal muscles" and the diaphragm":" is well-established. However, why glycogen depletion coincides with fatigue is not clear.' Perhaps there is a rate-limiting step in utilizing the blood-borne fuels for which glycogen is used. Thus, fatigue will occur when glycogen is depleted. Historically, lactic acid accumulation has received great attention as the culprit of fatigue in the skeletal muscles. Similarly, blood lactate elevation has 'also been found in subjects breathing through high inspiratory loads to exhaus80S
tion," but there is no direct evidence that the lactic acid produced by the respiratory muscles is the culprit in diaphragmatic fatigue. In addition, animals with low cardiac output (pericardiac tamponade) or Escherichia coli endotoxic shock develop substantially less lactic acidosis if they are ventilated rather than breathing spontaneously. In these experiments, diaphragmatic lactic acid is greater in the spontaneously breathing animals, which also develop diaphragmatic fatigue, than in the ventilated ones. 15,19.20 The effect of lactic acid on force generation is believed to be mediated by lowering pH. At low pH, Ca ' + is sequestered in the sarcoplasmic reticulum," and a larger amount of Ca ++ is needed to produce a given tension. In addition, hydrogen ions exert a direct negative effect on the contractile process itself. 22 To summarize, glycogen depletion, lactic acid accumulation, inability to utilize blood-borne substances, and decrease in the rate of ATP hydrolysis are merged to explain loss of force, but the exact interplay of all these factors is not yet identified either in other skeletal muscle or in the diaphragm. Neuromuscular Transmission Failure
When a nerve muscle preparation is stimulated continuously; failure of propagation between nerve and muscle can easily be demonstrated. This failure may occur presynaptically at nerve terminal branches, postsynaptically from a decrease of end-plate excitability, or from depletion of human muscles in ViVO. 23-25 However, experiments during maximum voluntary contraction, with one exception.v do not support neuromuscular transmission failure. 27,28 For the diaphragm, evidence that neuromuscular transmission andcell membrane excitation are adequate has been found in experiments in dogs in cardiogenic and septic shock. 15 •19 As the diaphragm became fatigued, the relationship of integrated phrenic nerve activity (Ephr) and diaphragmatic EMG activity remained unaltered; that is, when the diaphragm started failing as a force generator and greater stimulation was needed for an increment of transdiaphragmatic pressure, the relationship of Ephr and EMG was similar to that observed during the control period and to the earlier stage of the fatigue. However, these experiments may not be specific in testing this question; for example, changes in the action potential through the run may have compensated for discrepancies between Ephr and EMG. Teleologically, transmission block could be beneficial in some i~stances. As suggested by Nassar-Gentina et al29 and by Kugelberg and Lindergen," the muscle is protected against excessive depletion of its ATP store which would ultimately lead to rigor mortis. Support for this hypothesis may be deduced from experiments by Luttgaw," in which single muscle fibers were stimulated. He demonstrated that the reduction in action potential amplitude (action potential fatigue) was minimized when contraction was inhibited by hypertonic solution and was abolished completely in noncontracting fibers poisoned with cyanide or iodoacetate; that is, action potential was closely related to muscle 6ber contraction. These experiments therefore suggest a close relation between metabolism and fatigue of the neuromuscular junc~on. Neuromuscular transmission failure in man Aspen Lung Conference: Chronic Respiratory ~aiIu~
during diaphragmatic fatigue is not clearly understood. However, if high-frequency fatigue is due to failure of the neuromuscular junction, it may be inferred that such a failure can exist in the diaphragm of man. It has been clearly shown that normal subjects breathing against inspiratory loads develop high-frequency fatigue, 32 which may reflect neuromuscular junction failure.
Fatigue ofCNS
\
During short maximal contraction central fatigue does not, in some studies, appear to playa role, 33-35 since maximal nerve stimulation fails to increase the failing force. In contrast, during fatigue of intermittent submaximal contraction of the diaphragm, reduced CNS motor drive appears to be a factor. I Undoubtedly, the experimental protocol is complex, and the difference between the 2 muscle groups is intriguing. However, such findings are of particular importance in understanding the pathophysiology of ventilatory failure and need further testing. Central fatigue must not be confused with progressive decrease in the firing rate during maximum contraction, during which superimposed supramaximal electric tetanic stimulation does not increase muscle force. Several investigators have clearly shown that the central firing rate decreases during fatiguing muscle contraction." Experimentally, the gradual loss of force following prolonged maximum voluntary contraction can be accurately mimicked with electrical stimulation if the stimulation frequency can be accurately reduced, whereas, ifhigh stimulation frequencies are maintained too long, force loss is more rapid. Thus, it was proposed that the decrease in firing frequency is an adaptive mechanism to the alteration of muscle contractile characteristics. 34 It is well-established that fatigue is characterized not only by loss of force but also by slowing of the muscle contractile speed. In addition, it is known that for any muscle or motor unit the minimum excitation frequency required to generate force and tetanic fusion is proportional to its contractile speed. Thus, if during fatigue the degree of contractile slowing matches the decline in motoneuron firing rate, the latter does not result in any additional reduction in muscle force. Such an adaptation would be rather beneficial; it would avoid the failure of electrical propagation associated with high-frequency fatigue as well as the complete depletion of vital chemicals within the muscle cell, which might otherwise occur if high firing rates were maintained. An interesting question, of course, is how such an adaptation is brought about. In this context Hannerz and Crimby'" have presented evidence that motor neurons receive a tonic inhibitory drive from peripheral sources and that during a maximum voluntary contraction the motor neuron discharge rate increases if muscle afferents are partially blocked. In the diaphragm, during fatigue, muscle relaxation is prolonged;" but we have no information about alteration in firing rate. However, we have shown that afferent information via large (type I and II) and small (type III and IV) fibers affects the central respiratory controller's discharge in terms of firing rate, firing time and frequency of breathing;37 the latter is observed in states of diaphragmatic fatigue in both animals and humans. 15, 19,3I) It is tempting therefore to hypothesize that, as the contractile properties and the
diaphragmatic chemistry change during fatigue, afferents via the phrenic nerve may affect the output of respiratory centers in terms of firing rate or timing (frequency of breathing, duty cycle). Summary The diaphragm fails as a force generator whenever energy demand exceeds energy supply, during high resistive breathing, and/or during hypoxemia. 15 , 19,39 As fatigue ensues, contractile slowing increases" and central discharge firing decreases, either as fatigue of the CNS40 or adaptation to the altered chemistry and/or contractile characteristics of the muscles, which may prevent their self-destruction by excessive activation. Extending and enlarging this to the respiratory system, we hypothesize that, as the diaphragm contracts intermittently, the central controllers may modify the duration of contraction (Ti)and total duration of breathing cycle (Ttot). Such a strategy may optimize diaphragmatic function but at the cost, in some instances, of alveolar hypoventilation and CO 2 retention." This interaction, if it exists, is postulated to be mediated by the large and small phrenic afferents. DETERMINANTS OF CRITICAL TASK (PRESSURE, WORK)
The threshold of fatigue is that level of exercise which cannot be sustained indefinitely. This level, therefore, can be expressed as a percentage of the maximum performance. Bohmert" and Monod" Brst constructed such a relationship during isometric contraction to determine the critical force above which fatigue ensues. Similar approaches were also used by Monod and Sherrer" for intermittent contraction, an approach also adopted by Roussos and Macklem' and by Roussos et al43 in their original work on fatigue of the respiratory muscles. The model used in this approach was "the muscle as an engine"; that is, fatigue develops when the mean rate of energy demand (Ud) exceeds the mean rate of energy supply (Us). Ud>Us WIE>Us
(1) (2)
or W>UsE, or where W = mean muscle power and E = efficiency. Clearly, when UsE>W, the muscle can continue to work indefinitely, but when UsErts. Respir Physiol 1968; 5:187-201 21 Naess Y, Storm-Mathisen A. Fatigue of sustained tetanic contractions. Acta Physiol Scand 195.5;34:3.'51-66 22 Fabiato A, Fabiato f. Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiae and skeletal muscles. J Physiol (Lund) 1978; 276:233-55 23 Bigland-Ritchie B, Jones DA, \Voods JJ. Excitation [requency and muscle fatigue: electrical responses during human voluntary and stimulated contraction. Exp Neurol 1979; 64:414-27 24 Jardin J, Farkas G, Prefaut C, Thomas 0, Macklem PT, Roussos C. The failing inspiratory muscles under normoxic and hypoxic conditions. Am Rev Respir Dis 1981; 124:274-79 25 Monod H, Scherrer J. The work capacity of a synergic muscular group. Ergonomics 1965; 8:329-37 CHEST / 97 I 3 I MARCH, 1990 I Supplement
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26 Sorli J, Crassino A, Lorange C, Milic-Emili J. Control of breathing in patients with chronic obstructive lung disease. Clin Sci Mol Med 1978; 54:295-304 27 Mead J. Control of respiratory frequency. J Appl Physiol 1960; 15:325-36 28 Merton PA. \hluntary strength and fatigue. J Physiol (Lond) 1954; 128:553-64 29 Nassar-Centina
v Passonneau ]V: Vergara JL, Rapoport SI. Metabolic correlates of fatigue and of recovery from fatigue in single frog muscle 6bers. J Cen Physiol 1975; 72:53~ 30 Kugelberg E, Lindegren B. Transmission and contraction fatigue of tar motor units in relation to succinate dehydrogenase activity of motor unit fibers, J Physiol (Lond) 1969; 288:285300
31 Luttgaw HC. The effect of metabolic inhibitors on the fatigue of the action potential in single muscle 6bers. J Physiol (Lond) 1965; 178:45-67 32 Aubier M, Farkas G, De Troyer A, Mozes R, Roussos C. Detection of diaphragmatic fatigue in man by phrenic stimulation. J Appl Physiol1981; 50:538-44 33 Bigland-Ritchie B, Jones DA, Hosking G~ Edwards RHT. Central and peripheral fatigue in sustained maximal voluntary contractions of human quadriceps muscles. Clin Sci Mol Med 1978; 54:609-14 34 Bigland-Ritchie B, Johansson R, Lippold OCJ, \\'ooos JJ. Contractile speed and EMC changes during fatigue of sustained maximal voluntary contractions. J Neurophysiol 1983; 50:31324 35 Grimby L, Hannerz J, Hedman B. Fatigue and voluntary discharge properties of single motor units in man. J Physiol (Lond) 1981; 316:543-54 36 Esau SA, Bellemare F, Grassino A, Permutt S, Roussos C, Pardy RL. Changes in relaxation rate with diaphragmatic fatigue in humans. J Appl Physiol 1983a; 54:1353-60 37 Jammes Y, Buchler B, Delpierre S, Rasidakis A, Grimand C, Roussos C. Phrenic afferents and their role in inspiratory control. J Appl Physiol 1986; 60:854-60 38 Cohen C, Zagelbaum C, Cross 0, Roussos C, Macklem PT. Clinical manifestations of inspiratory muscle fatigue. Am J Med 1982; 73:308-16 39 Roussos C, Moxham J. Respiratory muscle fatigue. In: Roussos C, Macklem PT (eds), The thorax. 1981; 829-70 40 Bellemare F, Bigland-Ritchie B. Central components of diaphragmatic fatigue assessed from bilateral phrenic nerve stimulation. J Appl Physioll987; 62:1307-16 41 Monod H. Contribution a I' etude du travail statique. These Med(Paris) 1956; 124 43 Roussos C, Fixley M, Gross 0, Macklem PT. Fatigue of inspiratory muscles and their synergistic behavior. J Appl Physiol 1979; 46:879-904 44 Roussos C, Aubier M. Neural drive and electromechanical alterations in the fatiguing diaphragm. In: Porter J," Whelan J (eds). Human muscle fatigue: physiological mechanisms. Ciba Foundation Symposium No. 82. London: Pitman Medical, 1981; 213-33 45 Bellemare F, Grassino A. Effect of pressure and timing of contraction on human diaphragm fatigue. J Appl Physioll982; 53:1190-95
46 Freedman S. Sustained maximum voluntary ventilation. Respir Physiol 1970; 8:230-40 47 Farkas G, Roussos C. Acute diaphragmatic shortening: in vitro mechanics and fatigue. Am Rev Respir Dis 1984b; 130:434-38 48 Otis AB. The work of breathing. Physiol Rev 1954; 34:449-58 49 Hussain S, Simkus G, Roussos C. Respiratory muscle fatigue, a cause of ventilatory failure in septic shock. J Appl Physiol 1985; 58:2033-40 50 Bigland-Ritchie B, Bellemare F, Woods JJ. Central and periph96S
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Effect of Chronic Malnutrition on Rat Diaphr,gm Contractility and Fatigue* D.] Prezant, M.D., F.C.C.R; B. Richner, M.D., L K. Aldrich, M.D., F.C.C.R; H. Naeashima, ~{.D.; and] Cahill, ~I.D. ~-Iib-fed male Wistar rats (C) were compared to a group
made malnourished (M) by reducing daily food intake to 25% of control for 10 weeks. Both groups (N = 10) had equal access to water and were of similar initial weight (185±2 g). Pneumonia was not a complication. Hemidiaphragm costal strips were bathed in modified Krebs solution (37°C) containing insulin and d-tubocurarine. At optimal length, isometric twitch (2 ms, sq wave) and tetanic tensions (400 ms trains at 10, 20, 60, 100 Hz) were measured at baseline (B), at 10 m of fatigue stimulation (5 impulses at 5
Hz; 30 trains/m) and after 10 m of recovery. Tension indices (BI) were normalized for muscle strip csa (g/cm"), and the fatigue resistance index (FRI) was defined as (FRI
= fatigue
indexlbaseline index).
Table I-Effects afChronic Malnutrition in Rats Malnourished Body weight (g) Diaphragm weight csa (ern") 10 Hz BI (g/cm") FRI(%)
100 Hz BI (g/cm") FRI(%)
(10wk)
Ad-Lib-Fed
340±7* 0.80 ± 0.05* 0.038 ± 0.002* 388.64±34.79* 43±3* 1536.14 ± 99.51 * 46±2*
477± 13 1.11±0.04 0.049 ± 0.002 294.78±24.20 29±2 1190.79±87.39 35±3
*p
