ACUTE SEVERE ASTHMA

313 be dissipated; the Medical Research Council is to have back that proportion of the money it lost under Rothschild and promises, in return, to become more interested in health service matters. To what possible end? If the internal (and recently much trimmed) mechanisms of the Department have found it difficult to relate commissioned research to a clear statement of policy, how can the M.R.C. do any better? And where, within it, are those able to judge the scientific value of the "disciplined enquiry"4 suited to health services research rather than the more well-tried and exacting methods of fundamental science? Nobody outside the Chief Scientist’s office has any clear idea why this apparently backward step is to be taken; the least that the Chief Scientist, and the Department, can do is to make the reasons explicit. Only then can the Health Services Research Units, who have at present to be content with little more than rumour, judge whether it is their own performance or the Department’s failure to translate their research findings into policy that is at fault.

ACUTE SEVERE ASTHMA ACUTE

severe

asthma remains

a

common

and lethal

disease5 with recommended therapies including sub-

adrenaline, inhaled (3-stimulants, intravenous aminophylline, and intravenous hydrocortisone up to 2 g daily. Theoretically, oral or parenteral compounds might be expected to work better than inhaled ones in a severe acute atcutaneous

tack of asthma but in four studies6-9 ir.travenous salbutamol was no more effective than inhaled salbutamol. Intravenous aminophylline has been reported more effective and faster acting than a lowish dose of intravenous salbutamol l° Mitenko and Ogilvie 11recommended a loading dose of 5’66 mg/kg aminophylline followed by infusion of 0’ 9 mg/kg, but such regimens dangerous. Hendeles and convulsions and cardiac arrhymsuch as side-effects, Serious other occur before can thias, symptom of toxicity such as any

Weinberger 12 reckon

nausea or

headache.13

single "safe" dosage regimen for intravenous aminophylline can be proposed because theophylline clearance varies greatly between patients; 14 saturable pathways may be affected by dietary methy[xanthines,l 5,16 and further reduction in theophylline clearance may result from liver disease 17 No

4. Cronbach LJ, Suppes P, eds. Research for tomorrow’s schools: disciplined enquiry for education. New York: MacMillan, 1969. 5. Editorial. Management of acute severe asthma. Br Med J 1978; i: 873. 6. Spiro SG, Johnson AJ, May CS, Paterson JW. Effect of intravenous injection of salabutamol and asthma. Br J Clin Pharmacol 1975; 2: 495-501. 7. Hetzel MR, Clark TJH. Comparison of intravenous and aerosol salbutamol. Br Med J 1976; ii: 919. 8. Lawford P, Jones BJM, Milledge JS. Comparison of intravenous and nebulized salbutamol initial treatment of severe asthma. Br Med J 1978; i: 84. 9. Nogrady SO, Hartley JPR, Seaton A. Metabolic effects of intravenous salbutamol in the course of acute severe asthma. Thorax 1977; 32: 559-62. 10. Evans WV, Monie RDH, Crimmins J, Seaton A. Aminophylline, salbutamol and combined intravenous infusions in acute severe asthma. Br J Dis Chest 1980; 74: 385-89. 11. Mitenko PA, Ogilvie RI. Rational intravenous dose of theophylline. N Engl J Med 1973; 289: 600-03. 12. Hendeles L, Weinberger MM, Poisoning patients with intravenous theophylline. Am J Hosp Pharm 1980; 37: 49-50. 13. Zwillich CW, Sutton FD, Neff TA, Cohn WM, Mathay RA, Weinberger MM. Theophylline-Induced seizures in adults. Correlation with serum concentration. Ann Intern Med 1975; 82: 784-87. 14. Hendeles L, Weinberger MM, Bighley L. Disposition of theophylline following a single intravenous aminophylline infusion. Am Rev Resp Dis 1978; 118: 97-103. 15. Lesko LJ. Dose-dependent elimination kinetics oftheophylline. Clin Pharmacokinetics 1979; 4: 449-59. 16. Monks TJ, Caldwell J, Smith RL. Influence of methylxanthine containing foods on theophylline metabolism and kinetics. Clin Pharmacol Ther 1979; 26: 513-24. 17. Piafsky KM, Sitar DS, Rangno RE, Ogilvie RI. Theophylline disposition in patients with hepatic cirrhosis. N Engl J Med 1977; 296: 1495-97. 18. Vicuna N, McNay JL, Ludden TH, Schwertner H. Impaired theophylline clearance in patients with cor pulmonale. Br J Clin Pharmacol 1979; 7: 33-37.

and heart failure Therapy also has to aim at the narrow windOW19 between bronchodilation and toxicity (8-20 mg/1). Nevertheless, intravenous aminophylline continues to be used very widely. McFadden and his group20 have reported a comparison of intravenous aminophylline, subcutaneous adrenaline, and inhaled isoprenaline in 48 patients with acute severe asthma. Aminophylline was given according to the Mitenko and Ogilvie regimen, but with greatly reduced doses (less than half) in patients who had previously received oral theophyllines; adrenaline 0’ 3 mg was given subcutaneously three times in the first hour; and isoprenaline 2 -5mg was given three times in one hour via a hand-held nebuliser. Before treatment there was no significant difference between the groups in forced expiratory volume in one second (FEV 1). After one hour bronchodilation was significantly greater in the adrenaline and isoprenaline groups than in the aminophylline group (AFEV0-761, 0-791, and 0-231, respectively). Serum theophylline concentrations were in the therapeutic range (mean 16.22 mg/1) and previous oral theophylline did,not seem to influence the rate of response in the isoprenaline and adrenaline groups. McFadden and coworkers report also that the maximum bronchodilator effect was attained more rapidly with adrenaline and isoprenaline than with aminophylline. Deaths from acute severe asthma can occur before medical advice is sought, after the primary care treatment, or in hospital. Ideally, patients should record their peak expiratory flow rate (PEFR) regularly in the same way that a diabetic patient monitors urinary glucose,21 adjusting therapy accordingly.22 In fact, such routine measurement of PEFR has not been much encouraged by doctors. One useful sign that asthma is getting out of control is a doubling of the number of aerosol puffs required over 48-72 hours:23 this indicates a need for medical advice either at primary care level or at a specialist centre.24 What about therapy during transfer of an acutely ill patient? In view of the possible hazards of intravenous aminophylline, perhaps after a slow intravenous injection of 200 mg hydrocortisone the patient should be given a subcutaneous or intramuscular injection ofa selective (32 stimulant (e.g., terbutaline 0-5mg or salbutamol 0’ 5 mg). If this cannot be done then the patient should be advised to take two puffs of pressurised aerosol P2 stimulant (or its equivalent as dry powder capsule) every 5 minutes during transfer to hospital or until symptoms are relieved. In moderately severe asthma managed in hospital, high-dose aerosol therapy has proved safe and effective.26 On the patient’s arrival in hospital treatment should be by inhaled 2 stimulant in the recommended nebuliser dose, plus hydrocortisone 200 mg intravenously every 6 hours. In those who are severely ill or in whom the PEFR has not increased after an hour’s treatment, intravenous aminophylline may be given in a dose of 5-66 mg/kg over 20-30 minutes followed by 19.

Jenne JW, Wyze E, Rood FS, MacDonald FM. Pharmacokinetics oftheophylline. Application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Ther 1972 13: 349-60.

20.

Rossing TH, Fanta CH, Goldstein DH, Snapper JR, McFadden ER, Jr. Emergency therapy of asthma: Comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Am Rev Resp Dis 1980; 122: 365-71. 21. Seaton A. Asthma-contrasts in care. Thorax 1978; 33: 1-2. 22. Prior JG, Cochrane GM. Home monitoring of peak expiratory flow rate using miniWright peak flow meter in diagnosis of asthma. J RoySoc Med 1980; 73: 731-33.

23. Cochrane GM. Bronchodilators. Practitioner 1979; 223: 489-98. 24. Crompton GK, Grant IWB, Bloomfield P. Edinburgh emergency asthma admission service: Report on 10 years’ experience. Br Med J 1979; ii; 1199-1201. 25. Pang LM, Rodriguez-Martinez F, Davis WJ, Mellins RB. Terbutaline in the treatment of status asthmatics. Chest 1977; 72: 469-73. 26. Cayton RM, WebberB, PatersonJW, ClarkTJH. A comparisonof salbutamol givenby pressure-packed aerosol or nebulization in acute asthma. BrJ Dis Chest 1978; 72: 222-24.

314 0’ 5 mg/kg per -hour23-unless there is liver disease, heart failure, or a story of recent oral theophylline intake, when the doses should be lower and serum theophylline levels monitored. Whenever intravenous aminophylline is given for longer than - 24 hours serum theophylline should be measured. Until nebulised P2 stimulants have been compared directly with aminophylline, in a trial similar to that of McFadden, nothing definite can be said about their relative safety and efficacy. Even in hospital, severe acute asthma is quite a dangerous condition. 24

POSTURAL RESPONSE OF INTRAOCULAR PRESSURE IN VASCULAR DISEASE ON recumbency, the intraocular pressure of patients with vascular hypertension, or diabetes, or central retinal vein obstruction (CRVO), or tributary retinal vein obstruction (TRVO) rises to a greater extent than that of normal controls. Patients with these diseases in only one eye show the same abnormal recumbency-induced rise in the apparently normal fellow eye. Williams et al. 1-3 postulate that there is some common systemic cause which is independent of open-angle

glaucoma. 1-3 CRVO is quite a likely diagnosis in a patient who presents with severe reduction in visual acuity, of rapid onset, in one or both eyes. Haemorrhages and exudates are scattered all over the fundus, and the dark, distended veins appear broken up into ballooned segments lying in oedematous retina. In TRVO, a wedge of fundus is affected, ’with its apex at an arteriovenous crossing. This "haemorrhagic retinopathy" in CRVO has been attributed to a combination of arterial ischaemia with venous obstruction, in contrast to the different condition "venous stasis retinopathy" attributed to venous stasis alone.5-8 The site of the obstruction is usually in or just behind the lamina cribrosa.9 The pathogenesis of the lesion is controversial, but one widely held view is that atherosclerosis has been acquired by a vein from a contiguous affected artery. Every ophthalmic house-surgeon is taught to look for glaucoma (open-angle or closed-angle) in the fellow eye. The eye with CRVO has a lower intraocular pressure than its fellow. 3,4 Many other systemic abnormalities, often in combination, are found in CRVO: McGrath et al. 10 have reported obseryations in 79 patients. Blood hyperviscosity, cryofibrinogenaemia, and hyperlipidaemia are prominent in any age group. In the over-50s, abnormal glucose tolerance, chronic lung disease, and raised IgA as well as hypertension were 23. Van Dellen RG. Theophylline. Practical application of new knowledge. Mayo Clin Proc 1979; 54: 733-45. 24. Cochrane GM, Clark TJH. A survey of asthma mortality in patients between the ages of 35 and 64 in the Greater London Hospitals in 1971. Thorax 1975; 30: 300-05. 1. Williams BI, Peart WS, Letley E. Abnormal intraocular pressure control in systemic hypertension and diabetes mellitus. Br J Ophthal 1980; 64: 845-51. 2. Williams BI, Peart WS. Retinal vein obstruction and intraocular pressure: abnormal postural response independent of facility of outflow. Br J Ophthal 1979; 63: 805-07. 3. Williams BI, Peart WS. Effect of posture on the intraocular pressure of patients with retinal vein obstruction. Br J Ophthal 1978; 62: 688-93. 4. Moore J. Retinal venous thrombosis. Br J Ophthal 1924; monogr. suppl. 2. 5. Hayreh SS. So-called central retinal vein occlusion: I Pathogenesis, terminology, clinical features. Ophthatmologica 1976; 172: 1-13. 6. Hayreh SS. So-called central retinal vein occlusion: II Venous stasis retinopathy.

Ophchalmologica 1976; 172: 14-37. Hayreh SS. Central retinal vein occlusion: differential diagnosis and management. Trans Am Acad Ophthalmol Otolaryngol 1977; 83: 379-91. 8. Hayreh SS, van Heuven WAJ, Hayreh MS. Experimental retinal vascular occlusion: I, Pathogenesis of central retinal vein occlusion. Arch Ophthal 1978; 96: 311-23. 9. Hayreh SS. Central retinal vein occlusion. In: Mausolf FA, ed. The eye and systemic disease. St. Louis: C. V. Mosby Co 1980: 225, 229. 10. McGrath MA, Wechsler F, Hunyor ABL, Penny R. Systemic factors contributing to 7.

retinal vein occlusion. Arch Intern Med 1978; 138: 216-20.

recorded. In the under-50s, important factors were head injury and the use of oestrogen-containing preparations, Blood hypercoagulability and abnormalities in platelet

aggregation have also been found. 9, 1I The abnormal recumbency-induced

rise of intraocular in CRVO and TRVO was discovered serendipipressure tously during a study of diurnal variations in intraocular pressure.3 Pressures were higher in the mornings, when the patients were still in bed, and lower in the evenings when pressures were measured in the sitting position. Investigations of the possible effect of posture were then started.3 In controls (46 eyes, 23 patients) the recumbency-induced rise was 0 - 6-+-SDI - 2 mmHg; in CRVO (22 eyes) it was 1 - 8±2 - 4, in the fellows of eyes with CRVO (22) it was 2 - 6±2’3; in TRVO (14 eyes) it was 3’ 1±2’3; and in the fellows of eyes with TRVO it was 2 - 1-4-2 - 2. These pressure rises were independent of facility of outflow of aqueous humour, which implies that underlying glaucoma, though present in a proportion of the abnormal eyes, cannot be the whole explan-

ation. (Other workers,12 using pneumatonography, have recorded a greater recumbency-induced pressure rise in glaucomatous eyes than in normal eyes but previous evidence was conflicting. The higher baseline pressure in glaucoma is

presumably relevant.) Since vascular hypertension as well as glaucoma has been generally accepted as predisposing to CRVO, one might expect hypertensives to show this loss of control of intraocular pressure; and a group of 95 hypertensives (BP> 150/90) did indeed show a higher recumbency-induced rise of pressure than normal, though a smaller one than in the patients with eye diseases.’ The difference was significant even when the older hypertensives were excluded so that the groups were matched more strictly for age. These rises were measured 15 minutes after recumbency. Drugs being taken by the hypertensives were judged non-contributory, and these subjects had the same baseline intraocular pressures as controls. The figures given cannot be reinterpreted as indicating orthostatic ocular hypotension rather than recumbency-induced ocular hypertension. Diabetic retinopathy has some similarities to the other retinopathies which have been studied. In a group of 14 diabetics, the mean rise of intraocular pressure was 4 -9±188 mm Hg which indicates a loss of postural control of the same order as in CRVO and TVO.Again, this rise occurred in patients in all the age-groups and also in a normotensive subgroup of diabetics. The first speculation on this apparent loss of postural control of intraocular pressure is that the higher pressure on recumbency may compress the retinal veins and mechanically increase the risk of CRVO, especially if other factors coexist. CRVO and TRVO in glaucoma are presumed to have a similar explanation. The mechanism of the rise, however, is conjectural: perhaps in predisposed patients there is a general rise in venous pressure on recumbency, at least above heart level, shared by the episcleral veins which will cause backpressure on the outflow of aqueous humour. A change in the properties of the walls of the veins might be responsible. But if episcleral venous pressure rises, so also should retinal-and choroidal-venous pressure and volume (aggravating the rise in intraocular pressure), which contradicts the retinal venous compression theory. This stimulating piece of research raises many matters for investigation. DA, Watson PG. Platelet aggregation in retinal vascular disease. In: Cant JS, ed. Vision and circulation. London: Henry Kimpton, 1976: 303-14. 12. Kriegelstein GK, Langham ME. Influence of body position on the intraocular pressure of normal and glaucomatous eyes. Ophthalmologica 1975; 171: 132-45. 11. Kok