RESPIRATORY MUSCLE FATIGUE: MECHANISMS, EVALUATION AND THERAPY

Transcription

1 British Journal of Anaesthesia 1990; 65: RESPIRATORY MUSCLE FATIGUE: MECHANISMS, EVALUATION AND THERAPY J. MOXHAM Stimulated by the research of the Montreal Group in the mid and late 1970s, there has now been more than a decade of intensive study of respiratory muscle fatigue. Roussos and Macklem [61] demonstrated elegantly that the endurance of the diaphragm was similar to other skeletal muscles and that large inspiratory resistive loads could be sustained for only short periods, whereas loads of less than 40% of maximum could be sustained indefinitely. Other complementary studies followed, investigating endurance time and the fatigue of the respiratory muscles in a variety of physiological situations, including hypoxia and hyperinflation [28, 60]. What was the relevance of these findings to patients, particularly those with breathlessness and respiratory failure? The Montreal Group extrapolated from their research findings and postulated (and promulgated) that respiratory muscle fatigue was a key factor in hypercapnic respiratory failure [59]. The conclusion that fatigue is crucial to ventilatory failure has led to the suggestion that many hypercapnic patients have "chronic" respiratory muscle fatigue [58]. Before accepting the central role of respiratory muscle fatigue (acute or chronic) in ventilatory failure and determining its clinical significance, it is necessary to be able to define and then identify such "fatigue". A workable definition of muscle fatigue is the inability to sustain tension with repeated activity [16]. The question arises, of course, as to whether this failure to sustain force (or work) is the result of the subject not trying hard enough or perhaps a weak link in the chain of events from die central nervous system to the peripheral contractile apparatus (fig. 1). Studies on skeletal muscle using animal models KEY WORDS Muscle: respiratory, fatigue. "PtYChs" Peripheral Nerve Neuromutcular Junction Muicle Cell Membrane Trantverte Tubular System Calcium Relute Actin myotin Cro«- bridge Formation FORCE FIG. 1. Command chain for voluntary contraction of skeletal muscle. (Reproduced, with permission, from [16].) and also in man, both in vivo and in vitro, have focused on the key areas of the command chain depicted in figure 1 in an attempt to highlight the weak link and thus the primary site of fatigue. One possibility is that the central nervous system fails optimally to drive peripheral muscle (so called "central fatigue"). Central fatigue Central fatigue has long been documented for sustained, highload voluntary contractions of limb J. MOXHAM, M.D. ; Department of Respiratory Medicine, King's College Hospital, Denmark Hill, London SW.

2 44 BRITISH JOURNAL OF ANAESTHESIA a if H Time (s) FIG. 2. Central fatigue (quadricep muscle). Top: Before a prolonged maximum voluntary contraction (MVC) is begun, percutaneous electrical stimulation (shaded) produces 53% of maximum force. As the MVC continues there is excessive force loss, stimulated force becoming a higher percentage of voluntary force, confirming inadequate activation (central fatigue). Bottom: In a repeat study, central fatigue is overcome when the subject is asked to make extra efforts before each stimulation period (stimulated force remains a steady percentage of voluntary force). (Reproduced, with permission, from [11].) muscle [11,12] (fig. 2). While seemingly performing of their best, subjects exhorted to do better are able to improve force generation. Submaximal central activation can be demonstrated elegantly by the technique of twitch interpolation [41]: during a low force voluntary contraction, a superimposed electrical stimulus produces a twitch response; during maximum voluntary contractions, all motor units can be fully activated and an added stimulus, therefore, causes no twitch response; the decline in the superimposed twitch is proportional to the level of voluntary activation and the level of central activation can, therefore, be determined from the twitch response. The technique has been used to study central fatigue of the diaphragm during prolonged inspiratory loading in normal subjects [9]. Bellemare and Bigland-Ritchie demonstrated substantial central fatigue of the diaphragm at the point at which subjects failed to meet target respiratory pressures. They concluded that central fatigue was responsible for approximately 50% of performance failure. They and others have extrapolated from these observations in highly motivated physiologists to conclude that 60 central fatigue is likely to be important in clinical ventilatory failure. However, it is known that central fatigue is very dependent on the task involved, with prolonged, tedious and boring tasks producing more central fatigue than short term fatiguing loads [11, 41]. In the earlier studies in limb muscles, some subjects did not exhibit central fatigue and it therefore remains uncertain if such fatigue, varying from person to person and between tasks, is of any relevance to ventilatory failure. Studies in patients are clearly needed. If central fatigue is unlikely to be the "weak link " in the command chain the next question is: can the more peripheral neuromuscular components respond to central drive without fatigue? Peripheral fatigue During maximum voluntary contractions central motor neurone firing frequency is initially very high (the force generated matches that following 100 Hz supramaximal electrical stimulation [41]). Studies in patients with respiratory failure indicate that they have very high central drive [22, 54]. The central drive in patients with chronic obstructive pulmonary disease and hypercapnia may be as high as 50% of maximum drive [22]. Given the curvilinear relationship between firing frequency and tension generation (frequency-force curve), any additional tension requirement (e.g. exercise or increased airways resistance) demands a disproportionately high central firing frequency (fig. 3). What, then, is the response of peripheral muscle to high frequency stimulation? High frequency fatigue High frequency nerve stimulation generates maximum tension from muscle, but rapid force loss occurs as stimulation continues (fig. 4). Lower frequency stimulation produces less initial force, as expected, but tension is well maintained and soon exceeds that of high frequency stimulation. The rapid force loss with high frequency stimulation is the result of failure of excitation (failure of propagation at the neuromuscular junction and muscle cell membrane), and therefore is paralleled by a progressive reduction in the EMG signal. Were such fatigue to develop in the respiratory muscles, rapid, "catastrophic" [18] force loss and respiratory pump failure would follow. Although one study of the effect of exhaustive, inspiratory loading in rabbits has demonstrated excitation failure [1], high frequency fatigue has not been

3 RESPIRATORY MUSCLE FATIGUE demonstrated following physiological exercise in man and it is doubtful whether such excitation failure ever contributes to force failure [42]. When seeking to maximize muscle tension, what strategies can be adopted if high frequency fatigue is to be avoided? Stimulation frequency (Hz) FIG. 3. Frequency-force curve of skeletal muscle (including the respiratory muscles). Patients with severe pulmonary disease (e.g. COPD) are likely to be placed at the top of the steep section of the curve. Any increase in muscle tension requirement demands a disproportionately large increase in motor neurone firing frequency. (Reproduced, with permission, from [36].) _ 40 z S 30 ^ Time (s) Hz SO Hz FIG. 4. A: Electrical stimulation of the ulnar nerve at a high frequency (80 Hz) results in rapid force loss in the adductor pollicis muscle, whereas stimulation at a lower frequency (20 Hz), produces a smaller initial force which is well maintained. B: The muscle action potential decreases rapidly at 80 Hz, but is unchanged at 20 Hz. (Reproduced, with permission, from [11].) Central wisdom When trained subjects sustain a prolonged voluntary contraction of a limb muscle there is gradual force loss (fig. 5) [11] and, over the second half of the contraction, a parallel gradual decrease in EMG activity. The force profile of the muscle can be mimicked by nerve stimulation. Initially, high frequency stimulation is required to match the maximum voluntary contraction (MVC), but the frequency must then be progressively reduced to optimize force generation. If stimulation frequency is increased during the study, force is not increased (i.e. there is no central fatigue); rather it decreases as a consequence of high frequency fatigue. These studies suggest that during a prolonged, maximum, voluntary effort there is a gradual reduction in central firing frequency to optimize force generation (notwithstanding the gradual decrease in tension), and the CNS exerts a "central wisdom", thus avoiding the adverse effects on tension generation of both central fatigue and high frequency fatigue. Although it has not been demonstrated that the same central wisdom occurs in progressive hypercapnic ventilatory failure, there are no data to suggest otherwise. When considering techniques of detecting the weak links in the command chain, and if the analysis above is correct, it is almost certainly a fruitless task seeking to demonstrate central fatigue or high frequency fatigue in patients with ventilatory failure. Low frequency fatigue If the CNS modifies central drive to optimize muscle excitation, the question then arises as to whether distal, peripheral, contractile failure occurs. Is the weak link in the chain the peripheral contractile machinery? Electrical stimulation techniques may be used to investigate such possibilities and the contractile characteristics of many skeletal muscles, including the diaphragm and sternomastoid have been studied extensively [5, 16, 17, 20, 49, 50]. In man the diaphragm can be stimulated via the phenic nerve and contractile responses documented in terms of trans-

4 46 BRITISH JOURNAL OF ANAESTHESIA B 5 45 S 30 + Hz ^ MVC Time(s) Tima (a) 60 5 ms FIG. 5. Top: Maximum voluntary contractions (MVC) of the adductor pouicis muscle sustained for 60 s. A : During an electrically stimulated contraction, the force of the MVC is matched by initial stimulation at 60 Hz, followed by progressive reduction of the stimulation frequency to 20 Hz. B: The surface EMG for voluntary and stimulated contractions are closely matched. Bottom: The EMG M-waves during MVC and stimulated contractions are well maintained. (Reproduced, with permission, from [11].) diaphragmatic pressure (Pdi) (fig. 6). Severe prolonged exhaustive inspiratory loading reduces the contractility of the diaphragm, and the frequency-force curve shifts to the right; the force reduction is particularly pronounced in response to low frequency stimulation (low frequency fatigue). When experimentally induced, this type of fatigue is long lasting [19] (minutes or hours) and associated with much damage of muscle fibres, demonstrable by electron myography [55]. Low frequency fatigue of the respiratory muscles would be expected to impair force generation at physiological firing frequencies, and has been shown to reduce the ventilatory response to carbon dioxide [52]. For some time, low frequency fatigue was considered to be a potentially important aspect of ventilatory failure [51]. However, the development of this type of fatigue requires massive loading possible in the physiology laboratory, but of debatable relevance to clinical ventilatory failure. Furthermore, with the ex- Poe Pdi Stimulation frequency (Hz) Time (s) FIG. 6. Oesophageal (Poe), gastric (Pga) and transdiaphragmatic (Pdi) pressures with stimulation of the right phrenic nerve at 1, 10, 20, 50 and 100 Hz in a normal rested subject. (Reproduced, with permission, from [47].)

5 RESPIRATORY MUSCLE FATIGUE 47 ception of a few case reports [51], it has proved very difficult to document low frequency fatigue of the respiratory muscles in the clinical setting. The difficulty of demonstrating low frequency fatigue may reflect the problems of applying sophisticated techniques to sick patients, but it may also be because overt low frequency fatigue, with consequent muscle damage, does not readily occur in the clinical context because the CNS will not (or cannot) drive the peripheral contractile apparatus sufficiently hard. Thus it may be that, during progressive force failure, the respiratory muscle output is optimized by central nervous system control to avoid central fatigue, high frequency fatigue and low frequency fatigue. In the respiratory system, it may be that central drive is modified to avoid these types of overt fatigue and thereby optimize ventilation, albeit at the cost of hypercapnia. Support of the concept that central nervous system output is modified to avoid overt fatigue comes from studies of patients failing to wean from mechanical ventilation [65]. When the load on the respiratory muscles, necessary to achieve adequate ventilation, is so great as to be unsustainable (a very high tension time-index [10] see below), patients adopt rapid and shallow patterns of breathing (fig. 7). This reduces the work of breathing and can be sustained, but only at the cost of hypercapnia and acidosis, causing weaning failure. THE PROCESS OF FATIGUE Fatigue is best understood, not as a single event, but as a continuous "process" that starts when a muscle is subjected to a sufficiently heavy load that will eventually become unsustainable. As time passes, a multitude of physiological alterations occur within the loaded muscle and along the whole length of the command chain. Although the tension generated decreases progressively, dangerous energy depletion (leading to rigor), muscle damage and excitation failure probably do not occur, because of the adaptive modification of central drive. To determine that a load is potentially fatiguing, one approach would be to use techniques that can detect the early physiological responses to excessive loading. Early Changes in the Process of Fatigue The electromyogram (EMG) When skeletal muscle undertakes a high load contraction which sooner or later will not be 800n -» W Time (min) FIG. 7. Ventilatory frequency and tidal volume in a patient discontinued from ventilatory support (arrow) during a weaning trial. The patient developed hypercapnia and acidosis, and failed to wean. Note the rapid, shallow respiration immediately mechanical ventilation was withdrawn. (Reproduced, with permission, from [65].) sustainable, the EMG signal alters. There is a progressive reduction in the high frequency component of the signal, relative to lower frequencies. This reduction in the EMG "high:low" frequency ratio occurs early during fatiguing contractions and precedes force loss. These EMG changes are a signal that the muscle is heavily loaded and that the fatigue process is underway. As yet the cause of the EMG power spectrum shift is unknown [62]. Since EMG measurements are non-invasive, it had been hoped that this technique would be helpful in predicting respiratory muscle fatigue in patients. Some studies have indeed shown a decrease in the respiratory muscle high: low ratio during weaning failure [14]. However, because no absolute high:low ratio is associated with the fatiguing process, it is necessary to monitor the EMG for change, and this has proved difficult in the clinical situation. An additional problem is that alterations of lung volume and the pattern of breathing also influence the high:low ratio. The initial promise of this technique for detecting fatiguing loads has, therefore, not been fulfilled. Maximum relaxation rate The rate of decline of tension following contraction of skeletal muscle is an active, energy-

6 48 BRITISH JOURNAL OF ANAESTHESIA Before fatigue 3Os After fatigue lomin Pm Pm FIG. 8. Pressure measured in the oesophagus (Poe), nasopharynx (Pnp) and mouth (Pm) during a sniff manoeuvre in a normal subject, before, 30 s after and 10 min after inspiratory resistive loading to exhaustion. Note the reduced slope of the pressure wave with fatigue (reflecting the slowing of muscle contraction and relaxation) and the subsequent recovery. (Reproduced, with permission, from [33].) consuming process and not simply a passive event. The maximum relaxation rate (MRR) can be measured and expressed as the percentage force loss in 10 ms [66]. MRR is slowed by cold and hypothyroidism. It also slows early in the fatiguing process before force loss. MRR can be measured from voluntary or stimulated contractions and, for the respiratory muscles, from mouth, nasopharyngeal, oesophageal or transdiaphragmatic pressures. Several investigators have demonstrated slowing of MRR with exhaustive inspiratory loading in man [21, 37]. In normal subjects and patients with respiratory muscle weakness, pressures in the mouth and nasopharynx closely reflect those in the oesophagus during a natural sniff [32]. Inspiratory loading causes slowing of MRR in all sites, with mouth and nasal pressure measurements having the advantage of being less invasive [33] (fig. 8). The natural sniff is an excellent manoeuvre for generating wave forms suitable for MRR assessment and patients can be taught to sniff without difficulty. The sniff manoeuvre generates high pressures because the nose has a collapsible flow limiting segment (the nasal valve), which acts as a Starling resistor [32]. Thus during a sniff the nose narrows and large intrathoracic pressures are generated. Intubated patients are, of course, unable to sniff naturally, but they can perform sniff-like manoeuvres if a Starling resistor (acting as an artificial nose) is attached to the tracheal tube. Studies in normal subjects with such a device demonstrate that the pressure amplitude and MRR in the airway closely reflects oesophageal pressure and the slowing of MRR following inspiratory loading is detected easily [24]. Of the available early indicators of the fatiguing process, the measurements of MRR may be the most applicable to clinical situations. Recent studies of MRR in sustained, maximum, voluntary ventilation (MW) [53] have shown a progressive slowing of MRR during MW, but no slowing with levels of ventilation that are a small fraction below maximum. This suggests that truly maximum ventilation is associated with the onset of the process of muscle fatigue, and that during M W the respiratory muscles can be driven very hard (i.e. without significant central fatigue). Furthermore, slowing of MRR (for example, during weaning) indicates that the respiratory muscles are being subjected to an unsustainable load and ventilation will fail. Studies of MRR in weaning are currently being undertaken and in several patients failing to wean, relaxation has slowed, with prompt recovery when mechanical ventilation was reinstituted [J. Goldstone, personal communication]. Respiratory muscle load and capacity The onset of the fatiguing process occurs when the load imposed on the respiratory muscles is excessive when related to pump capacity (fig. 9). Many studies have investigated fatiguing loads in normal subjects and have concluded that, when the mean inspiratory pressure is a high fraction of maximum pressure (a high tension time index (TTI)), fatigue will develop. Thus a load is fatiguing if: Pm/Pimax x TI/TT = > where Pm = mean inspiratory pressure; Pimax = maximum inspiratory pressure; Ti = inspiratory

7 RESPIRATORY MUSCLE FATIGUE 49 Pump Capacity CNS Output Respiratory Drive Respiratory / \ PUMP Load on the pump ~W The Fatiguing Process... FIG. 9. Scheme to illustrate the central importance of the respiratory muscle pump and the crucial balance between load and capacity. When the ratio of load to capacity is high, fatigue could develop, but oven high frequency or low frequency fatigue are averted by adaptation of central drive. (Modified and reproduced, with permission, from [23].) time; Tr = duration of a complete respiratory cycle [10]. Mean inspiratory muscle pressure is a function of tidal volume (FT) and dynamic compliance (Cdyn) in addition to inspiratory time. Milic- Emili has reconsidered the equation and elaborated the "Inspiratory Effort Quotient" (IEQ) [46]. ThusatFRC: (JC.FT/Cdyn)x(7i/7\) Pimax = IEQ where K is a constant dependant on the shape of the inspiratory driving pressure wave, and is approximately These equations work quite well in the laboratory, but are more difficult to apply in clinical situations. A major problem is the measurement of Pimax in sick patients, and the value of Pimax is, of course, a major determinant of the IEQ or TTI. Pimax is conventionally measured by asking patients to make a maximum inspiratory effort from FRC or residual volume (RV) against an occluded airway; a manoeuvre that many patients with an intubated trachea find difficult. Greater patient effort can be achieved by occluding inspiration for periods of up to 20 s, during which patients make greater and greater inspiratory efforts, and Pimax is greater with this method [40]. A second problem is the theoretical one that static Pimax is probably not an appropriate measurement of the maximum capacity of the inspiratory muscles for dynamic manoeuvres. Since the respiratory muscles shorten during inspiration, the maximum available pressure for inspiration will be considerably less than the static Pimax. These considerations make an absolute "threshold" value for a fatiguing TTI or IEQ misleading. However, it is clear that success or failure in weaning is related to respiratory muscle load in relation to capacity and much research is currently being undertaken to assess the load on the respiratory muscles, and their capacity, in the Intensive Care Unit. The measurement of tidal volume, and pressure swings within the thorax, is teaching us much about the work of breathing in these patients, and the observation that unsustainable loads and, therefore, weaning failure is associated with rapid, shallow breathing is clinically important [64]. From the work of Tobin and colleagues, it has become clear that in the adult a rate of ventilation > 25 b.p.m. or a tidal volume of < 300 ml is commonly associated with weaning failure [65]. Measurement of P 01 has been used to assess respiratory muscle fatigue and predict weaning failure [38]. P 01 reflects the final pressure generation of the respiratory system and therefore reflects central drive, peripheral neuromuscular activation, generation of muscle tension and the translation of tension into inspiratory pressure. A high P o! indicates high neuromuscular activation in response to a large respiratory load. Thus a high P 0l suggests that ventilation may eventually fail. However, of more importance is the relationship between load and maximum sustainable capacity (as embodied in the TTI or the IEQ). Therefore the measurement of P 01 provides only limited information. THERAPEUTIC STRATEGIES From a therapeutic point of view all three key determinants of respiratory muscle pump function (fig. 9) require careful consideration: is central drive optimal; is the respiratory load as low as possible; and has pump capacity been maximized? Respiratory drive. Available data suggest that, in most circumstances, central drive is appropriate to drive the respiratory muscle pump optimally in order to meet its load most effectively. If inadequate drive were a problem, it would be expected that respiratory stimulants (e.g. doxapram, almitrine) would be helpful. Such drugs sometimes produce short term improvements in ventilation, but often at the cost of excessive

8 50 BRITISH JOURNAL OF ANAESTHESIA TABLE I. Factors reducing respiratory muscle force and TABLE II. Metabolic abnormalities that impair muscle pressure generation contractility Muscle shortening (length-tension relationship) Diaphragm flattening (law of Laplace) Increased inspiratory flow rate (force velocity relationship) Weakness (including neuromuscular block) Fatigue breathlessness. From a theoretical point of view, over-stimulation of the CNS with consequent over-riding of "central wisdom" is likely eventually to intensify fatigue and be counterproductive. In patients with CNS depression caused by drugs (e.g. diazepam, morphine), therapeutic stimulation of respiratory drive is, of course, one approach to the management of ventilatory failure. Ventilatory load. Excessive ventilatory load is the most common cause of imbalance in the drive-load-capacity relationship. Increased airways resistance (chronic obstructive pulmonary disease (COPD), asthma) and reduced compliance (pulmonary oedema, fibrosis) are common problems. Factors increasing ventilatory requirements (exercise, fever, sepsis, hypoxia, carbohydrate loading, etc.), all impose an increased load. This load is reflected by the mean inspiratory pressure Pm in the I'll, and influences tidal volume, respiratory timing and dynamic compliance in the IEQ. The causes of the increased load are usually easily apparent and therapy obvious. The importance of chest wall stiffness (e.g. pleural thickening) and decreased abdominal compliance (e.g. after abdominal surgery) are sometimes not appreciated. In a patient close to the onset of fatigue, a small reduction of load (e.g. minor bronchodilatation in COPD) can be critical. Pump capacity. A multitude of factors can impair respiratory muscle pump capacity (tables I, ID- Respiratory muscle weakness has many causes [36], but is most commonly the result of generalized wasting. Wasting and weakness of the respiratory muscles is known to occur in malnourished patients [2], and may also develop in patients mechanically ventilated for prolonged periods, as a consequence of disuse atrophy. The treatment by diaphragm pacing of paralysis secondary to high cervical cord lesions leads to Hypophosphataemia Hypomagnesaemia Hypokalaemia Hyper- and hypothyroidism Steroid therapy Other drugs (e.g. myasthenic syndromes) Hypoxia Hypercapnia great strengthening of the muscle, suggesting die prior development of profound disuse atrophy [56]. Weakness is also a part of many neuromuscular disorders (e.g. motor neurone disease, myositis, myasthenia gravis), acute [67] and chronic steroid therapy, and metabolic disturbances [6, 7, 15]. Hemidiaphragm paralysis greatly reduces maximum transdiaphragmatic pressures, but is symptomatic only where there is co-existing weakness of other respiratory muscles or pulmonary disease [34]. Respiratory muscle weakness can be a feature of thyroid diseases [43], Addison's disease [44] and the Eaton-Lambert myasthenic syndrome [35]. Hypoxia, if severe, can impair skeletal muscle contractility and potentiate fatigue [28]. Hypercapnic acidosis also impairs limb and respiratory muscle performance [29]. Sepsis, particularly when accompanied by shock, markedly impairs muscle contractility and enhances fatigue [25, 26]. In man, viral upper respiratory tract infections are associated with weakness of die respiratory muscles [45]. Adequate nutrition is crucial to the maintenance of muscle mass and, in die critically ill, parenteral nutrition can increase respiratory muscle strength [30]. It is not yet clear if supplementing the diet of wasted patients with stable chronic lung disease (e.g. COPD) can achieve weight gain, increased respiratory muscle strength and improved ventilatory function [38]. Similarly, die role of respiratory muscle training to increase strength or enhance endurance remains in doubt [57]. Drug therapy to enhance respiratory muscle contractility would appear desirable, and several compounds (particularly the mediyl xanthines) increase skeletal muscle performance when administered at high concentrations during in vitro

9 RESPIRATORY MUSCLE FATIGUE 51 studies [3]. Most studies in man have centred around the use of aminophylline and theophylline. Initial reports suggested an important positive inotropic effect of aminophylline on the respiratory muscles [4], but following a large number of studies the benefit of this drug remains a matter for debate [3, 48]. Indeed, there is evidence that aminophylline increases muscle energy consumption and potentiates fatigue [27]. Thus, for the patient poised at the onset of fatigue, a drug which enhances contractility at the expense of excessive energy utilization could hasten respiratory muscle pump failure. The ideas of acute and chronic respiratory muscle fatigue have provided the rationale for respiratory muscle "rest". In his Amberson lecture to the American Thoracic Society, Dr Peter Macklem proposed that the use of rest therapy could benefit thousands of patients [39] a sentiment amplified by others [58]. Assisted ventilation, particularly nasal positive pressure ventilation, can "capture" the breathing of patients and may "put the respiratory muscles to rest" [8, 13, 31]. Long term nocturnal domiciliary ventilation can be very successful in the control of ventilatory failure in patients with muscle weakness, kyphoscoliosis and thoracoplasty [63]. This therapy improves day-time arterial oxygen and carbon dioxide tensions and has been reported to improve respiratory muscle strength. The mechanism whereby nocturnal assisted ventilation improves long term day-time blood-gas tensions is not clear. Improved sleep quality, control of cor pulmonale, better matching of ventilation-perfusion, resetting of central respiratory controllers and an increase in lung/chest wall compliance are all possibilities. That such rest relieves fatigue and thereby improves respiratory muscle function is an attractive hypothesis but pure speculation. The data demonstrating "fatigue" and its reversal by rest are not available. Furthermore, the likelihood that fatigue is an integrated process, and the improbability of the respiratory muscles developing overt fatigue (as analysed above), suggests that rest therapy is unlikely to be beneficial through the mechanism of relief of fatigue. Since persisting reduction in contractility probably does not occur, rest per se cannot, therefore, improve contractility. CONCLUSIONS At the onset of the fatigue process, central drive is modified to avoid catastrophic force loss or peripheral muscle damage. As it is unlikely that overt high frequency or low frequency fatigue are allowed to develop, it is similarly unlikely that any therapy directed at the treatment of such muscle fatigue (rest or drugs) will be of any value. The correct therapeutic strategy is a careful evaluation of the three key components of the system: drive, load and capacity. In most circumstances, central respiratory drive will be appropriate and further increases in drive unnecessary and potentially damaging. The crucial balance, therefore, becomes the relationship between respiratory load and respiratory capacity; careful assessment of load and capacity greatly increases our understanding of the patient's problems. Most therapy is directed at reducing load; however, great care must be taken to optimize pump capacity. Unfortunately, the assessment of pump capacity remains rather crude. The impact of respiratory load, in relation to capacity, on respiratory timing and tidal volume provides very useful clinical information. Further study of respiratory drive, load and capacity will hopefully reveal other clinical parameters, in addition to the rate and depth of breathing, that will allow the identification of patients in danger of the fatiguing process and, therefore, deteriorating ventilatory failure. REFERENCES 1. Aldrich TK. Transmission failure of the rabbit diaphragm. Respiratory Physiology 1987; 69: Arora NS, Rochester DF. Respiratory muscle strength and maximal voluntary ventilation in undernourished patients. American Review of Respiratory Disease 1982; 126: Aubier M. Pharmacotherapy of respiratory muscles. Clinics in Chest Medicine 1988; 9: Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos C. Aminophylline improves diaphragmatic contractility. New England Journal of Medicine 1981; 305: Aubier M, Farkas G, De Troyer A, Mozes R, Roussos C. Detection of diaphragmatic fatigue in man by phrenic nerve stimulation. Journal of Applied Physiology 1981; SO: Aubier M, Murciano D, Lecocguic Y, Viires N, Jacquens Y, Squara P, Pariente R. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. New England Journal of Medicine 1985; 313: Aubier M, Viires N, Piquet J, Murciano D, Blanchet T, Mariry C, Gherardi P, Pariente R. Effects of hypocalcemia on diaphragmatic strength generation. Journal of Applied Physiology 1985; 58: Bach JR, Alba A, Mosher R, Delaubier A. Intermittent positive pressure ventilation via nasal access in the

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