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?
1385
Most randomised
placebo-controlled trials of
steroids in the first few hours or days after presentation with acute severe asthma, in both adults and children, have shown that airflow obstruction, symptoms, and arterial oxygen concentrations recover
quickly, with fewer treatment failures or relapses, in patients receiving steroids.5,8--10,13-16 The effect of steroids peaks at about 5 h after more
administration and lasts about 20 h.15 The effect is small, which is perhaps why some studies have not detected any difference over placebo.4,11,12 The balance of evidence therefore suggests that steroids are beneficial in acute severe asthma, but that the extent of benefit over and above that provided by bronchodilators and other supportive therapy is limited and in many cases immaterial. A small beneficial effect may nevertheless be critical to some patients. Although single high doses of systemic steroid are not entirely free from potentially important unwanted or toxic acute effects,17 inclusion of steroids in routine management of acute asthma is justified. So, which steroid, which route, and what dose? The evidence relating to these questions is complicated by the difficulties of comparing drugs and formulations of different potency and bioavailability. The fmding of no clear dose-response relation with intravenous hydrocortisone by Bowler et al3 accords with previous data for hydrocortisone12,18,19 and methylprednisolone,’,’021 although some researchers have suggested that higher doses or more potent steroids can elicit a greater effect.22,23 The explanation for these findings may be that all these studies have compared doses which are high in physiological terms19 and which therefore elicit similar, nearmaximum responses. However, there may be little justification for routine use of intravenous rather than oral steroids, since absorption of oral prednisolone is rapid24 in relation to the likely time-course of the therapeutic effect. 15 In a group of 52 adults with acute severe asthma, a placebo-controlled trial of intravenous hydrocortisone given in addition to oral prednisolone 45 mg followed by 15 mg 8-hourly for 24 h did not show any benefit from the addition of intravenous steroid.25 Patients with very severe asthma-PaC02 greater than 6-4 kPa-were excluded from this trial. It is also not clear whether the total of 75 mg prednisolone given in divided doses over the first 24 h, which is similar to the single oral dose recommended in the American guidelines,is more effective than the single 30-60 mg dose recommended in the UK.l The small but significant dose-response relation in the rate of recovery from acute severe asthma treated with single daily doses of prednisolone in the range 0-2-0-6 mg/kg26 suggests that doses at the upper end of this range are justified. How long oral therapy should be continued in adult patients is uncertain. In children a single dose of oral rednisolone should be adequate in most cases. 15 Overall, the evidence suggests that inclusion of steroids in the routine therapy of acute severe asthma
increases the likelihood of a rapid recovery, and that the drug of choice will usually be oral prednisolone. The dose should be 40 mg (about 0-6 mg/kg) for most adults, and should be given immediately and daily thereafter until recovery is complete. If the clinical response is not satisfactory, 8-hourly increments of 15 mg (0-2 mg/kg) can be added. Unless the patient is unable to swallow, retain, or absorb an oral dose, intravenous steroids should be reserved for extreme cases, and in those rare circumstances an initial dose of (or equivalent to) 200 mg of hydrocortisone 6-hourly is indicated to ensure a maximum effect. As soon as recovery is evident, Bowler and colleagues’ results suggests that 50 mg 6-hourly will suffice until oral therapy can be introduced. Higher dose steroid
regimens are unneccessary. 1. British Thoracic Society, Research Unit of the Royal College of Physicians of London, Kings Fund Centre, National Asthma Campaign. Guidelines for the management of asthma in adults: II—acute severe asthma. BMJ 1990; 301: 797-800. 2. National Asthma Education Program. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Maryland: US Department of Health and Human Services, Public Health Service, National Institutes of Health, 1991. 3. Bowler SD, Mitchell CA, Armstrong JG. Corticosteroids in acute severe asthma: effect of low doses. Thorax 1992; 47: 584-87. 4. Morell R, Orriols R, de Gracia J, Currull V, Pujol A. Controlled trial of intravenous corticosteroids in severe acute asthma. Thorax 1992; 47: 588-91. 5. Medical Research Council. Controlled trial of effects of cortisone acetate in status asthmaticus. Lancet 1956; ii: 803-06. 6. Luksza AR. A new look at asthma. Br J Dis Chest 1982; 76: 11-14. 7. Luksza AR. Acute severe asthma treated without steroids. Br J Dis Chest 1982; 76: 15-19. 8. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med 1986; 314: 150-52. 9. Fanta CH, Rossing TH, McFadden ER. Glucocorticoids in acute asthma. Am J Med 1983; 74: 845-51. 10. Younger RE, Gerber PS, Herrod HG, Cohen RM, Crawford LV. Intravenous methylprednisolone efficacy in status asthmaticus of childhood. Pediatrics 1987; 80: 225-30. 11. Stein LM, Cole RP. Early administration of corticosteroids in emergency room treatment of acute asthma. Ann Intern Med 1990; 112: 822-27. 12. McFadden ER, Kiser R, deGroot WJ, Holmes B, Kiker R, Viser G. A controlled study of the effects of single doses of hydrocortisone on the resolution of acute attacks of asthma. Am J Med 1976; 60: 52-59. 13. Loren ML, Chai H, Leung P, Rohr C, Brenner AM. Corticosteroids in the treatment of acute exacerbations of asthma. Ann Allergy 1980; 45: 67-71. 14. Pierson WE, Bierman CW, Kelley VC. A double-blind trial of corticosteroid therapy in status asthmaticus. Pediatrics 1974; 54: 282-88. 15. Storr J, Barrell E, Barry W, Lenney W, Hatcher G. Effect of a single oral dose of prednisolone in acute childhood asthma. Lancet 1987; i: 879-82. 16. Fiel SB, Swartz MA, Glanz K, Francis ME. Efficacy of short-term corticosteroid therapy in outpatient treatment of acute bronchial asthma. Am J Med 1983; 75: 259-82. 17. Lehr D. Isoproterenol and sudden death of asthmatic patients in ventricular fibrillation. N Engl J Med 1972; 287: 987-88. 18. Raimondi AC, Figueroa-Casas JC, Roncoroni AJ. Comparison between high and moderate doses of hydrocortisone in the treatment of status asthmaticus. Chest 1986; 89: 832-35. 19. Collins JV, Clark TJH, Brown D, Townsend J. The use of corticosteroids in the treatment of acute asthma. Q J Med 1975; 44: 259-73. 20. Tanaka RM, Santiago SM, Kuhn GJ, Williams RE, Klaustermeyer WB. Intravenous methylprednisolone in adults in status asthmaticus. Chest 1982; 82: 438-40. 21. Harfi H, Hanissian AS, Crawford LV. Treatment of status asthmaticus in children with high doses and conventional doses of methylprednisolone. Pediatrics 1978; 61: 829-31. 22. Haskell RJ, Wong BM, Hansen JE. A double-blind, randomised clinical trial of methylprednisolone in status asthmaticus. Arch Intern Med 1983; 143: 1324-27.
1386
MG, Collins JV, Brown D, Fairhurst NPA, Lambert RG. High-dose corticosteroids in severe acute asthma. BMJ 1976; ii:
23. Britton
73-74. 24. Morrison
PJ, Bradbrook ID, Rogergs HJ. Plasma prednisolone levels from enteric and non-enteric coated tablets estimated by an original technique. Br J Clin Pharmacol 1977; 4: 597-603. 25. Harrison BDW, Stokes TC, Hart GJ, Vaughan DA, Ali NJ, Robinson AA. Need for additional hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet 1986; i: 181-84. 26. Webb JR. Dose response of patients to oral corticosteroid treatment during exacerbations of asthma. BMJ 1986; 292: 1045-47.
Home cholesterol
testing
In most countries the proportion of the health budget spent on preventing disease is much smaller than the cost of the condition itself. Coronary heart disease (CHD) is a good example. In Britain, the health service spends 10 million ($15 million) on preventing CHD each year and ,500 million on treatment.1 Both the general public and the medical profession may be confused about the contribution of cholesterol to the CHD risk factor equation, but it is cholesterol that continues to make headline news and remains high on the list of factors perceived to cause heart disease by the public.Although some family practices and occupational health services offer screening to detect individuals at high CHD risk3and run coronary prevention programmes, for many individuals the first brush with CHD comes on admission to the coronary care unit with an acute cardiac event. Even after that it is doubtful whether more than a small proportion of those with raised cholesterol concentrations will be diagnosed and treated properly. In the UK, the Department of Health has been criticised for the variable extent of local commitment to heart disease prevention, especially in Scotland, which has the highest rate of heart disease in the world. In England it has likewise been slow to introduce comprehensive monitoring of risk factors despite advice from its own Standing Medical Advisory Committee and from independent bodies such as the King’s Fund Forum4 and the British Cardiac Society. By contrast, the chain store Boots the Chemist have not procrastinated: their market research must have shown that there is profit to be made from a cholesterol self-testing kit selling at 7.99. For this sum the purchasers receive a plastic test cassette with instructions, leaflets about CHD prevention and how to interpret the test, and advice about when to consult their general practitioner or, if they prefer, a freephone line by which they can receive counselling from staff trained independently of Boots. Clearly the ideal location for CHD screening is the family practitioner’s health centre where the total coronary risk can be assessed without undue emphasis on cholesterol. This remains true whether cholesterol is measured only when the presence of other risk factors demands it or in everybody screened. Experienced counselling can then be given in a setting where it will not engender too much anxiety.6
The test itself is also open to criticism. The only evaluation seems to have been carried out by laboratory workers who used not finger-prick blood but edetic-acid-treated venous blood or reference serum.The difficulty encountered by untrained members of the public in transferring blood from the finger tip into the test well of the cassette means that a high proportion of tests could fail to give a result or read falsely low. With respect to failures there is a warning on the test and Boots will replace the kit under these circumstances. The colour peak is hard to read, which is a serious disadvantage, since only 9 mm on the scale separates people with a "desirable" cholesterol from those who should consult their doctor for advice (described as "high" or "very high risk" in the instructions). The wealthy but anxious will purchase the test; and husbands whose wives are concerned about their health may well find one in their Christmas stocking. Nevertheless, CHD is increasingly a disease of the less well-off who will not buy such a kit and who are likely to benefit only from coronary prevention initiatives and from a coordinated nutritional and agricultural
policy. Twenty-sixth Report of the House of Commons Committee of Public Accounts: session 1988-89. Coronary Heart Disease. London: HM Stationery Office, 1989. 2. Health Education Authority. Health and lifestyle. Survey carried out by British Market Research Bureau on behalf of HEA, 1989. 3. Shaper AG, Pocock SJ, Phillips AN, et al. Identifying men at high risk of heart attacks: a strategy for use in general practice. BMJ 1986; 293: 1.
474-79. 4. Sixth King’s Fund Forum. Consensus statement: blood cholesterol measurement in the prevention of coronary heart disease. London: King Edward’s Hospital Fund for London, 1989. 5. Report of British Cardiac Society Working Group on Coronary Disease Prevention. London: British Cardiac Society, 1987. 6. Bhatnagar D, Durrington PN. Coronary risk factors: value of screening and preventive strategies. Fam Pract 1990; 7: 295-99. 7. Allen MP, DeLizza A, Ramel U, Jeong H, Singh P. A noninstrumented quantitative test system and its application for determining cholesterol concentration in whole blood. Clin Chem 1990; 36: 1591-97.
Desferrioxamine and cerebral malaria Unrousable coma in severe falciparum malaria is associated with mortality of about 15% in children and 20% in adults.12 In fatal cases the cerebral capillaries and venules are packed with erythrocytes containing mature forms of the malaria parasites. Microvascular obstruction results from the adhesive properties of these parasitised erythrocytes, which stick to vascular endothelium (cytoadherence), to unparasitised red cells (rosetting), and also to each other. The brain becomes ischaemic, but the excellent neurological recovery in most survivors, even after a lengthy coma, argues against a purely
hypoxic encephalopathy. There have been many explanations put forward for the pathophysiology of coma in severe malaria,3 but none is entirely satisfactory. Inflammatory immune damage and intravascular coagulation and thrombosis are not supported by pathological evidence. Cerebral oedema, if it occurs, is usually an
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?
1385
Most randomised
placebo-controlled trials of
steroids in the first few hours or days after presentation with acute severe asthma, in both adults and children, have shown that airflow obstruction, symptoms, and arterial oxygen concentrations recover
quickly, with fewer treatment failures or relapses, in patients receiving steroids.5,8--10,13-16 The effect of steroids peaks at about 5 h after more
administration and lasts about 20 h.15 The effect is small, which is perhaps why some studies have not detected any difference over placebo.4,11,12 The balance of evidence therefore suggests that steroids are beneficial in acute severe asthma, but that the extent of benefit over and above that provided by bronchodilators and other supportive therapy is limited and in many cases immaterial. A small beneficial effect may nevertheless be critical to some patients. Although single high doses of systemic steroid are not entirely free from potentially important unwanted or toxic acute effects,17 inclusion of steroids in routine management of acute asthma is justified. So, which steroid, which route, and what dose? The evidence relating to these questions is complicated by the difficulties of comparing drugs and formulations of different potency and bioavailability. The fmding of no clear dose-response relation with intravenous hydrocortisone by Bowler et al3 accords with previous data for hydrocortisone12,18,19 and methylprednisolone,’,’021 although some researchers have suggested that higher doses or more potent steroids can elicit a greater effect.22,23 The explanation for these findings may be that all these studies have compared doses which are high in physiological terms19 and which therefore elicit similar, nearmaximum responses. However, there may be little justification for routine use of intravenous rather than oral steroids, since absorption of oral prednisolone is rapid24 in relation to the likely time-course of the therapeutic effect. 15 In a group of 52 adults with acute severe asthma, a placebo-controlled trial of intravenous hydrocortisone given in addition to oral prednisolone 45 mg followed by 15 mg 8-hourly for 24 h did not show any benefit from the addition of intravenous steroid.25 Patients with very severe asthma-PaC02 greater than 6-4 kPa-were excluded from this trial. It is also not clear whether the total of 75 mg prednisolone given in divided doses over the first 24 h, which is similar to the single oral dose recommended in the American guidelines,is more effective than the single 30-60 mg dose recommended in the UK.l The small but significant dose-response relation in the rate of recovery from acute severe asthma treated with single daily doses of prednisolone in the range 0-2-0-6 mg/kg26 suggests that doses at the upper end of this range are justified. How long oral therapy should be continued in adult patients is uncertain. In children a single dose of oral rednisolone should be adequate in most cases. 15 Overall, the evidence suggests that inclusion of steroids in the routine therapy of acute severe asthma
increases the likelihood of a rapid recovery, and that the drug of choice will usually be oral prednisolone. The dose should be 40 mg (about 0-6 mg/kg) for most adults, and should be given immediately and daily thereafter until recovery is complete. If the clinical response is not satisfactory, 8-hourly increments of 15 mg (0-2 mg/kg) can be added. Unless the patient is unable to swallow, retain, or absorb an oral dose, intravenous steroids should be reserved for extreme cases, and in those rare circumstances an initial dose of (or equivalent to) 200 mg of hydrocortisone 6-hourly is indicated to ensure a maximum effect. As soon as recovery is evident, Bowler and colleagues’ results suggests that 50 mg 6-hourly will suffice until oral therapy can be introduced. Higher dose steroid
regimens are unneccessary. 1. British Thoracic Society, Research Unit of the Royal College of Physicians of London, Kings Fund Centre, National Asthma Campaign. Guidelines for the management of asthma in adults: II—acute severe asthma. BMJ 1990; 301: 797-800. 2. National Asthma Education Program. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Maryland: US Department of Health and Human Services, Public Health Service, National Institutes of Health, 1991. 3. Bowler SD, Mitchell CA, Armstrong JG. Corticosteroids in acute severe asthma: effect of low doses. Thorax 1992; 47: 584-87. 4. Morell R, Orriols R, de Gracia J, Currull V, Pujol A. Controlled trial of intravenous corticosteroids in severe acute asthma. Thorax 1992; 47: 588-91. 5. Medical Research Council. Controlled trial of effects of cortisone acetate in status asthmaticus. Lancet 1956; ii: 803-06. 6. Luksza AR. A new look at asthma. Br J Dis Chest 1982; 76: 11-14. 7. Luksza AR. Acute severe asthma treated without steroids. Br J Dis Chest 1982; 76: 15-19. 8. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med 1986; 314: 150-52. 9. Fanta CH, Rossing TH, McFadden ER. Glucocorticoids in acute asthma. Am J Med 1983; 74: 845-51. 10. Younger RE, Gerber PS, Herrod HG, Cohen RM, Crawford LV. Intravenous methylprednisolone efficacy in status asthmaticus of childhood. Pediatrics 1987; 80: 225-30. 11. Stein LM, Cole RP. Early administration of corticosteroids in emergency room treatment of acute asthma. Ann Intern Med 1990; 112: 822-27. 12. McFadden ER, Kiser R, deGroot WJ, Holmes B, Kiker R, Viser G. A controlled study of the effects of single doses of hydrocortisone on the resolution of acute attacks of asthma. Am J Med 1976; 60: 52-59. 13. Loren ML, Chai H, Leung P, Rohr C, Brenner AM. Corticosteroids in the treatment of acute exacerbations of asthma. Ann Allergy 1980; 45: 67-71. 14. Pierson WE, Bierman CW, Kelley VC. A double-blind trial of corticosteroid therapy in status asthmaticus. Pediatrics 1974; 54: 282-88. 15. Storr J, Barrell E, Barry W, Lenney W, Hatcher G. Effect of a single oral dose of prednisolone in acute childhood asthma. Lancet 1987; i: 879-82. 16. Fiel SB, Swartz MA, Glanz K, Francis ME. Efficacy of short-term corticosteroid therapy in outpatient treatment of acute bronchial asthma. Am J Med 1983; 75: 259-82. 17. Lehr D. Isoproterenol and sudden death of asthmatic patients in ventricular fibrillation. N Engl J Med 1972; 287: 987-88. 18. Raimondi AC, Figueroa-Casas JC, Roncoroni AJ. Comparison between high and moderate doses of hydrocortisone in the treatment of status asthmaticus. Chest 1986; 89: 832-35. 19. Collins JV, Clark TJH, Brown D, Townsend J. The use of corticosteroids in the treatment of acute asthma. Q J Med 1975; 44: 259-73. 20. Tanaka RM, Santiago SM, Kuhn GJ, Williams RE, Klaustermeyer WB. Intravenous methylprednisolone in adults in status asthmaticus. Chest 1982; 82: 438-40. 21. Harfi H, Hanissian AS, Crawford LV. Treatment of status asthmaticus in children with high doses and conventional doses of methylprednisolone. Pediatrics 1978; 61: 829-31. 22. Haskell RJ, Wong BM, Hansen JE. A double-blind, randomised clinical trial of methylprednisolone in status asthmaticus. Arch Intern Med 1983; 143: 1324-27.
1386
MG, Collins JV, Brown D, Fairhurst NPA, Lambert RG. High-dose corticosteroids in severe acute asthma. BMJ 1976; ii:
23. Britton
73-74. 24. Morrison
PJ, Bradbrook ID, Rogergs HJ. Plasma prednisolone levels from enteric and non-enteric coated tablets estimated by an original technique. Br J Clin Pharmacol 1977; 4: 597-603. 25. Harrison BDW, Stokes TC, Hart GJ, Vaughan DA, Ali NJ, Robinson AA. Need for additional hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet 1986; i: 181-84. 26. Webb JR. Dose response of patients to oral corticosteroid treatment during exacerbations of asthma. BMJ 1986; 292: 1045-47.
Home cholesterol
testing
In most countries the proportion of the health budget spent on preventing disease is much smaller than the cost of the condition itself. Coronary heart disease (CHD) is a good example. In Britain, the health service spends 10 million ($15 million) on preventing CHD each year and ,500 million on treatment.1 Both the general public and the medical profession may be confused about the contribution of cholesterol to the CHD risk factor equation, but it is cholesterol that continues to make headline news and remains high on the list of factors perceived to cause heart disease by the public.Although some family practices and occupational health services offer screening to detect individuals at high CHD risk3and run coronary prevention programmes, for many individuals the first brush with CHD comes on admission to the coronary care unit with an acute cardiac event. Even after that it is doubtful whether more than a small proportion of those with raised cholesterol concentrations will be diagnosed and treated properly. In the UK, the Department of Health has been criticised for the variable extent of local commitment to heart disease prevention, especially in Scotland, which has the highest rate of heart disease in the world. In England it has likewise been slow to introduce comprehensive monitoring of risk factors despite advice from its own Standing Medical Advisory Committee and from independent bodies such as the King’s Fund Forum4 and the British Cardiac Society. By contrast, the chain store Boots the Chemist have not procrastinated: their market research must have shown that there is profit to be made from a cholesterol self-testing kit selling at 7.99. For this sum the purchasers receive a plastic test cassette with instructions, leaflets about CHD prevention and how to interpret the test, and advice about when to consult their general practitioner or, if they prefer, a freephone line by which they can receive counselling from staff trained independently of Boots. Clearly the ideal location for CHD screening is the family practitioner’s health centre where the total coronary risk can be assessed without undue emphasis on cholesterol. This remains true whether cholesterol is measured only when the presence of other risk factors demands it or in everybody screened. Experienced counselling can then be given in a setting where it will not engender too much anxiety.6
The test itself is also open to criticism. The only evaluation seems to have been carried out by laboratory workers who used not finger-prick blood but edetic-acid-treated venous blood or reference serum.The difficulty encountered by untrained members of the public in transferring blood from the finger tip into the test well of the cassette means that a high proportion of tests could fail to give a result or read falsely low. With respect to failures there is a warning on the test and Boots will replace the kit under these circumstances. The colour peak is hard to read, which is a serious disadvantage, since only 9 mm on the scale separates people with a "desirable" cholesterol from those who should consult their doctor for advice (described as "high" or "very high risk" in the instructions). The wealthy but anxious will purchase the test; and husbands whose wives are concerned about their health may well find one in their Christmas stocking. Nevertheless, CHD is increasingly a disease of the less well-off who will not buy such a kit and who are likely to benefit only from coronary prevention initiatives and from a coordinated nutritional and agricultural
policy. Twenty-sixth Report of the House of Commons Committee of Public Accounts: session 1988-89. Coronary Heart Disease. London: HM Stationery Office, 1989. 2. Health Education Authority. Health and lifestyle. Survey carried out by British Market Research Bureau on behalf of HEA, 1989. 3. Shaper AG, Pocock SJ, Phillips AN, et al. Identifying men at high risk of heart attacks: a strategy for use in general practice. BMJ 1986; 293: 1.
474-79. 4. Sixth King’s Fund Forum. Consensus statement: blood cholesterol measurement in the prevention of coronary heart disease. London: King Edward’s Hospital Fund for London, 1989. 5. Report of British Cardiac Society Working Group on Coronary Disease Prevention. London: British Cardiac Society, 1987. 6. Bhatnagar D, Durrington PN. Coronary risk factors: value of screening and preventive strategies. Fam Pract 1990; 7: 295-99. 7. Allen MP, DeLizza A, Ramel U, Jeong H, Singh P. A noninstrumented quantitative test system and its application for determining cholesterol concentration in whole blood. Clin Chem 1990; 36: 1591-97.
Desferrioxamine and cerebral malaria Unrousable coma in severe falciparum malaria is associated with mortality of about 15% in children and 20% in adults.12 In fatal cases the cerebral capillaries and venules are packed with erythrocytes containing mature forms of the malaria parasites. Microvascular obstruction results from the adhesive properties of these parasitised erythrocytes, which stick to vascular endothelium (cytoadherence), to unparasitised red cells (rosetting), and also to each other. The brain becomes ischaemic, but the excellent neurological recovery in most survivors, even after a lengthy coma, argues against a purely
hypoxic encephalopathy. There have been many explanations put forward for the pathophysiology of coma in severe malaria,3 but none is entirely satisfactory. Inflammatory immune damage and intravascular coagulation and thrombosis are not supported by pathological evidence. Cerebral oedema, if it occurs, is usually an
