1383
Pathogenetic mechanisms have been identified that explain some of these changes. Reduced flow of nutrients to the limbs as a result of impaired cardiac output, peripheral vasoconstriction, and increased vascular stiffness may lead to underperfusion of muscle.4Maladaptive vasoconstrictor responses may prevent redirection of an already reduced blood flow from non-working muscle and liver to working muscle.5 Immobility is often a feature of patients with heart failure, since exercise tends to exacerbate breathlessness. Immobility per se may contribute to disuse atrophy and deconditioning of skeletal muscle, and is associated with a 25 % fall in protein synthesis in quadriceps muscle and atrophy of type I fibres (slow twitch, slow fatigue, oxidative fibres).6In patients
EDITORIALS
can
with severe systemic venous hypertension, increased back pressure on splanchnic vessels and lymphatics can result in malabsorption of nutrients;7 if malabsorption is severe, skeletal muscle may even be used as an energy source. Sympathetic nervous system activity is increased in heart failure,8 and neurohumoral compensatory mechanisms lead to raised catecholamine and corticosteroid secretion.99 In laboratory animals, administration of catecholamines or corticosteroids results in degradation of skeletal muscle protein and type IIb fibre
atrophy. 10,11 Magnetic
Skeletal muscle in heart failure Skeletal muscle abnormalities that limit exercise capacity in heart failure include weakness, muscle fatigue, and muscle wasting. Although such features are commonly present in patients with chronic left ventricular dysfunction, they are often overshadowed by concomitant breathlessness. Measurements of skeletal muscle function in patients with chronic heart failure have shown reduced maximum isometric force production of large locomotor muscles such as the quadriceps, and an increased tendency to fatigue (in the physiological sense).1 The symptomatic response of skeletal muscle to similar degrees of impairment of ventricular function is variable :2 some patients with left ventricular ejection fractions of 20% remain virtually symptom-free whereas others are severely limited with muscle wasting and cardiac cachexia. What do we know about skeletal muscle changes at the biochemical level? Morrison et aP studied patients with chronic left ventricular dysfunction (mainly due to coronary artery disease) who were not wasted or cachectic. Assessment of symptoms placed them in New York Heart Association categories lIb and III.
These researchers used gas chromatography
mass
muscle protein synthesis in the spectrometry quadriceps from 13C-leucine incorporation into muscle after a 7-hour infusion. They found that protein synthesis was reduced by 27% from normal to assess
values.
spectroscopy with 31P shows that, separate from blood flow changes in skeletal muscle, there is a primary metabolic abnormality. Under both aerobic and ischaemic conditions, repetitive finger flexion exercises at increasing workloads will increase phosphocreatine depletion and lower pH in patients with chronic left ventricular dysfunction relative to control subjects.12 Moreover, patients with severe symptoms show more rapid phosphocreatine depletion and a swifter fall in pH than less symptomatic patients; these observations indicate a more rapid reduction in oxidative metabolism and increase in anaerobic (glycolytic) metabolism on exercise. The metabolic abnormality does not correlate with left ventricular ejection fraction, and this fact may explain the heterogeneity of symptom response and exercise tolerance in patients with similar degrees of left ventricular dysfunction. What triggers the development of earlier anaerobic metabolism in some patients is unclear. Cell mediator responses in heart failure can likewise affect skeletal muscle. Preliminary studies have confirmed the presence of tumour necrosis factor in some patients with heart failure. However, although concentrations of tumour necrosis factor show an inverse correlation with bodyweight, this cytokine is not present in all patients with cardiac cachexia. 13,14 Studies of skeletal muscle fibre composition in patients with chronic left ventricular dysfunction have shown a reduced percentage of slow twitch type I oxidative fibres and a higher percentage of type IIb glycolytic fibres (fast twitch, fast fatigue); the type IIb fibres were smaller than those in normal resonance
1384
accompanied by a reduction in mitochondrial oxidative enzyme capacity and normal glycolytic and glycogenolytic enzyme capacity. There is increasing evidence for reversal or modulation of these pathological skeletal muscle changes with various interventions. Heart transplantation can lead to a return to normal both of exercise tolerance and of skeletal muscle protein synthesis. 16 The mechanism of this reversal is unknown but probably involves correction of cellular hypoxia and improvement in nutrient limb blood flow, mobility, and diet. Physical training can improve
16. Morrison WL, Gibson JNA, Johnston RN, Yacoub M, Rennie MJ. Improved whole body protein turnover following heart and lung transplantation. Lancet 1988; ii: 853-54. 17. Minotti JR, Johnson EC, Hudson TL, et al. Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest 1990; 86: 751-58. 18. Adamopoulos S. Effects of physical training on skeletal muscle metabolism in chronic heart failure: experimental and human study. Br Heart J 1992; 68: 127. 19. Consensus Trial Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987; 316: 1429-35. 20. Massey BM. Exercise tolerance in congestive heart failure: role of cardiac function, peripheral blood flow, and muscle metabolism. Am J Med 1988; 84 (suppl 3A): 75-82.
exercise tolerance and skeletal muscle metabolic response, as indicated by less depletion of phosphocreatine and higher pH at submaximum workloads.17,18 This effect can occur without associated changes in muscle mass, limb blood flow, or central cardiovascular response; so the explanation probably lies in improved oxidative capacity of skeletal muscle. Angiotensin converting enzyme inhibitors can improve prognosis and exercise intolerance19 and part of this effect may be due to redirection of blood flow from non-working to working muscle.5 From magnetic resonance spectroscopy, evidence is emerging that this’ effect stems from enhancement of skeletal muscle oxidative
All doctors should know how to treat acute severe asthma promptly and effectively; for those unfamiliar with prevailing therapeutic wisdom, authoritative guidelines have been published in the UK and the USA.l,2 Both sets of guidelines emphasise the importance of high-dose oral or intravenous
subjects.15 These changes
were
metabolism.2o 1. Buller NP, Jones D, Poole-Wilson PA. Direct measurement of skeletal muscle fatigue in patients with chronic heart failure. Br Heart J 1991; 65: 20-24. 2. Franciosa JA, Park M, Levine B. Lack of relation between exercise capacity and indices of resting left ventricular performance in heart failure. Am J Cardiol 1981; 47: 33-39. 3. Morrison WL, Harley AH, Gibson JNA, Smith K, Rennie MJ. Reduced skeletal muscle protein synthesis in chronic heart failure. Br Heart J 1991; 66: 90. 4. Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 1984; 69: 1079-87. 5. Levine TB, Levine AB. Regional blood flow supply and demand in heart failure. Am Heart J 1990; 120: 1547-51. 6. Gibson JNA, Morrison WL, Halliday D, et al. Decrease in human quadriceps muscle protein turnover consequent upon leg mobilisation. Clin Sci 1987; 72: 503-49. 7. Berkowitz D, Croll MN, Likoff W. Malabsorption as a complication of congestive heart failure. Am J Cardiol 1963; 11: 43-47. 8. Sterns DA, Ettinger SM, Gray KS, et al. Skeletal muscle metaboreceptor exercise responses are attenuated in heart failure. Circulation 1991; 84: 2034-39. 9. Francis GS. Neurohumoral mechanisms involved in congestive heart failure. Am J Cardiol 1985; 55A: 15-21. 10. Willmore DW, Long JM, Mason AD, Skreen RW, Pruit BA. Catecholamines: mediators of the hypermetabolic response to thermal injury. Ann Surg 1974; 180: 653-68. 11. Goldberg AL. Protein turnover in skeletal muscle: II. Effects of denervation and cortisone on protein catabolism. J Biol Chem 1969; 244: 3223-29. 12. Massie BM, Conway M, Yonge R, Frostick S, Ledingham J. Skeletal muscle metabolism during exercise under ischemic conditions in congestive cardiac failure. Circulation 1988; 78: 320-26. 13. Levine B, Kalman J, Mayer L, Fillit H, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323: 236-41. 14. McMurray J, Abdullah I, Dargie HJ, Shapiro D. Increased concentrations of tumour necrosis factor in "cachectic" patients with severe chronic heart failure. Br Heart J 1991; 66: 356-58. 15. Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990; 81: 518-27.
Steroids in acute severe asthma
glucocorticoid therapy. This advice has lately been questioned by two research groups .3 ’ Bowler and colleagues3 report that patients with acute severe asthma treated with a "low dose" steroid regimen-intravenous hydrocortisone 50 mg four times daily for 2 days followed by oral prednisolone 20 mg daily, in addition to beta-agonist and methylxanthine therapy-fared no differently from patients treated with a more conventional dose of 200 mg hydrocortisone, or a high dose of 500 mg followed, respectively, by 40 or 60 mg of oral prednisolone daily. Morell et al4 report that neither of two high-dose intravenous methylprednisolone regimens added significantly to the effects of placebo, again given in addition to usual bronchodilator and other supportive measures. So, should steroids be recommended for acute severe asthma, and if so, at what dose and for how long? Evidence of benefit of glucocorticoids from controlled trials dates from 1956, when the British Medical Research Council published a study of the effect of steroids in 32 patients with status asthmaticus who had not responded to 24 h of "standard" therapy with adrenaline, isoprenaline, aminophylline, oxygen, antibiotics, and sedatives.s Patients were then randomised to receive oral cortisone or placebo. Although lung function data were not presented, the patients who received cortisone recovered much more quickly than those who did not. However, as the researchers commented, the proportion of patients with status asthmaticus who reached the stage of randomisation was small. Most of their patients responded to standard therapy without steroids, and this has been the case in many subsequent reports of patients with acute severe asthma who have been treated with bronchodilators and other supportive therapy, but in whom steroids were withheld either for clinical reasons or in a placebo-controlled trial.4,6-16 If most patients with acute severe asthma will recover without systemic steroids, what does addition of steroids achieve?
Pathogenetic mechanisms have been identified that explain some of these changes. Reduced flow of nutrients to the limbs as a result of impaired cardiac output, peripheral vasoconstriction, and increased vascular stiffness may lead to underperfusion of muscle.4Maladaptive vasoconstrictor responses may prevent redirection of an already reduced blood flow from non-working muscle and liver to working muscle.5 Immobility is often a feature of patients with heart failure, since exercise tends to exacerbate breathlessness. Immobility per se may contribute to disuse atrophy and deconditioning of skeletal muscle, and is associated with a 25 % fall in protein synthesis in quadriceps muscle and atrophy of type I fibres (slow twitch, slow fatigue, oxidative fibres).6In patients
EDITORIALS
can
with severe systemic venous hypertension, increased back pressure on splanchnic vessels and lymphatics can result in malabsorption of nutrients;7 if malabsorption is severe, skeletal muscle may even be used as an energy source. Sympathetic nervous system activity is increased in heart failure,8 and neurohumoral compensatory mechanisms lead to raised catecholamine and corticosteroid secretion.99 In laboratory animals, administration of catecholamines or corticosteroids results in degradation of skeletal muscle protein and type IIb fibre
atrophy. 10,11 Magnetic
Skeletal muscle in heart failure Skeletal muscle abnormalities that limit exercise capacity in heart failure include weakness, muscle fatigue, and muscle wasting. Although such features are commonly present in patients with chronic left ventricular dysfunction, they are often overshadowed by concomitant breathlessness. Measurements of skeletal muscle function in patients with chronic heart failure have shown reduced maximum isometric force production of large locomotor muscles such as the quadriceps, and an increased tendency to fatigue (in the physiological sense).1 The symptomatic response of skeletal muscle to similar degrees of impairment of ventricular function is variable :2 some patients with left ventricular ejection fractions of 20% remain virtually symptom-free whereas others are severely limited with muscle wasting and cardiac cachexia. What do we know about skeletal muscle changes at the biochemical level? Morrison et aP studied patients with chronic left ventricular dysfunction (mainly due to coronary artery disease) who were not wasted or cachectic. Assessment of symptoms placed them in New York Heart Association categories lIb and III.
These researchers used gas chromatography
mass
muscle protein synthesis in the spectrometry quadriceps from 13C-leucine incorporation into muscle after a 7-hour infusion. They found that protein synthesis was reduced by 27% from normal to assess
values.
spectroscopy with 31P shows that, separate from blood flow changes in skeletal muscle, there is a primary metabolic abnormality. Under both aerobic and ischaemic conditions, repetitive finger flexion exercises at increasing workloads will increase phosphocreatine depletion and lower pH in patients with chronic left ventricular dysfunction relative to control subjects.12 Moreover, patients with severe symptoms show more rapid phosphocreatine depletion and a swifter fall in pH than less symptomatic patients; these observations indicate a more rapid reduction in oxidative metabolism and increase in anaerobic (glycolytic) metabolism on exercise. The metabolic abnormality does not correlate with left ventricular ejection fraction, and this fact may explain the heterogeneity of symptom response and exercise tolerance in patients with similar degrees of left ventricular dysfunction. What triggers the development of earlier anaerobic metabolism in some patients is unclear. Cell mediator responses in heart failure can likewise affect skeletal muscle. Preliminary studies have confirmed the presence of tumour necrosis factor in some patients with heart failure. However, although concentrations of tumour necrosis factor show an inverse correlation with bodyweight, this cytokine is not present in all patients with cardiac cachexia. 13,14 Studies of skeletal muscle fibre composition in patients with chronic left ventricular dysfunction have shown a reduced percentage of slow twitch type I oxidative fibres and a higher percentage of type IIb glycolytic fibres (fast twitch, fast fatigue); the type IIb fibres were smaller than those in normal resonance
1384
accompanied by a reduction in mitochondrial oxidative enzyme capacity and normal glycolytic and glycogenolytic enzyme capacity. There is increasing evidence for reversal or modulation of these pathological skeletal muscle changes with various interventions. Heart transplantation can lead to a return to normal both of exercise tolerance and of skeletal muscle protein synthesis. 16 The mechanism of this reversal is unknown but probably involves correction of cellular hypoxia and improvement in nutrient limb blood flow, mobility, and diet. Physical training can improve
16. Morrison WL, Gibson JNA, Johnston RN, Yacoub M, Rennie MJ. Improved whole body protein turnover following heart and lung transplantation. Lancet 1988; ii: 853-54. 17. Minotti JR, Johnson EC, Hudson TL, et al. Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest 1990; 86: 751-58. 18. Adamopoulos S. Effects of physical training on skeletal muscle metabolism in chronic heart failure: experimental and human study. Br Heart J 1992; 68: 127. 19. Consensus Trial Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987; 316: 1429-35. 20. Massey BM. Exercise tolerance in congestive heart failure: role of cardiac function, peripheral blood flow, and muscle metabolism. Am J Med 1988; 84 (suppl 3A): 75-82.
exercise tolerance and skeletal muscle metabolic response, as indicated by less depletion of phosphocreatine and higher pH at submaximum workloads.17,18 This effect can occur without associated changes in muscle mass, limb blood flow, or central cardiovascular response; so the explanation probably lies in improved oxidative capacity of skeletal muscle. Angiotensin converting enzyme inhibitors can improve prognosis and exercise intolerance19 and part of this effect may be due to redirection of blood flow from non-working to working muscle.5 From magnetic resonance spectroscopy, evidence is emerging that this’ effect stems from enhancement of skeletal muscle oxidative
All doctors should know how to treat acute severe asthma promptly and effectively; for those unfamiliar with prevailing therapeutic wisdom, authoritative guidelines have been published in the UK and the USA.l,2 Both sets of guidelines emphasise the importance of high-dose oral or intravenous
subjects.15 These changes
were
metabolism.2o 1. Buller NP, Jones D, Poole-Wilson PA. Direct measurement of skeletal muscle fatigue in patients with chronic heart failure. Br Heart J 1991; 65: 20-24. 2. Franciosa JA, Park M, Levine B. Lack of relation between exercise capacity and indices of resting left ventricular performance in heart failure. Am J Cardiol 1981; 47: 33-39. 3. Morrison WL, Harley AH, Gibson JNA, Smith K, Rennie MJ. Reduced skeletal muscle protein synthesis in chronic heart failure. Br Heart J 1991; 66: 90. 4. Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 1984; 69: 1079-87. 5. Levine TB, Levine AB. Regional blood flow supply and demand in heart failure. Am Heart J 1990; 120: 1547-51. 6. Gibson JNA, Morrison WL, Halliday D, et al. Decrease in human quadriceps muscle protein turnover consequent upon leg mobilisation. Clin Sci 1987; 72: 503-49. 7. Berkowitz D, Croll MN, Likoff W. Malabsorption as a complication of congestive heart failure. Am J Cardiol 1963; 11: 43-47. 8. Sterns DA, Ettinger SM, Gray KS, et al. Skeletal muscle metaboreceptor exercise responses are attenuated in heart failure. Circulation 1991; 84: 2034-39. 9. Francis GS. Neurohumoral mechanisms involved in congestive heart failure. Am J Cardiol 1985; 55A: 15-21. 10. Willmore DW, Long JM, Mason AD, Skreen RW, Pruit BA. Catecholamines: mediators of the hypermetabolic response to thermal injury. Ann Surg 1974; 180: 653-68. 11. Goldberg AL. Protein turnover in skeletal muscle: II. Effects of denervation and cortisone on protein catabolism. J Biol Chem 1969; 244: 3223-29. 12. Massie BM, Conway M, Yonge R, Frostick S, Ledingham J. Skeletal muscle metabolism during exercise under ischemic conditions in congestive cardiac failure. Circulation 1988; 78: 320-26. 13. Levine B, Kalman J, Mayer L, Fillit H, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323: 236-41. 14. McMurray J, Abdullah I, Dargie HJ, Shapiro D. Increased concentrations of tumour necrosis factor in "cachectic" patients with severe chronic heart failure. Br Heart J 1991; 66: 356-58. 15. Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990; 81: 518-27.
Steroids in acute severe asthma
glucocorticoid therapy. This advice has lately been questioned by two research groups .3 ’ Bowler and colleagues3 report that patients with acute severe asthma treated with a "low dose" steroid regimen-intravenous hydrocortisone 50 mg four times daily for 2 days followed by oral prednisolone 20 mg daily, in addition to beta-agonist and methylxanthine therapy-fared no differently from patients treated with a more conventional dose of 200 mg hydrocortisone, or a high dose of 500 mg followed, respectively, by 40 or 60 mg of oral prednisolone daily. Morell et al4 report that neither of two high-dose intravenous methylprednisolone regimens added significantly to the effects of placebo, again given in addition to usual bronchodilator and other supportive measures. So, should steroids be recommended for acute severe asthma, and if so, at what dose and for how long? Evidence of benefit of glucocorticoids from controlled trials dates from 1956, when the British Medical Research Council published a study of the effect of steroids in 32 patients with status asthmaticus who had not responded to 24 h of "standard" therapy with adrenaline, isoprenaline, aminophylline, oxygen, antibiotics, and sedatives.s Patients were then randomised to receive oral cortisone or placebo. Although lung function data were not presented, the patients who received cortisone recovered much more quickly than those who did not. However, as the researchers commented, the proportion of patients with status asthmaticus who reached the stage of randomisation was small. Most of their patients responded to standard therapy without steroids, and this has been the case in many subsequent reports of patients with acute severe asthma who have been treated with bronchodilators and other supportive therapy, but in whom steroids were withheld either for clinical reasons or in a placebo-controlled trial.4,6-16 If most patients with acute severe asthma will recover without systemic steroids, what does addition of steroids achieve?
