Treatment of acute asthma
1997; Elsevier BV; Volume: 350; Linguagem: Inglês
10.1016/s0140-6736(97)90032-5
ISSN1474-547X
Autores Tópico(s)Respiratory and Cough-Related Research
ResumoThe drug treatment for acute severe asthma has changed little over the past two decades, comprising primarily of bronchodilators, corticosteroids, and oxygen. Most deaths from acute severe asthma are potentially preventable and this requires recognition of severity of the attack and delivery of optimum acute therapy, both in the community and in hospital. International and national guidelines have provided evidence-based consensus statements on the management of acute asthma in children and adults in general practice and hospital settings.1, 2 Audit studies in the UK have shown that many recommendations from previous national guidelines have not been adhered to in either the community or hospital, and this suggests that wider dissemination of the guidelines and improved education is required.3Neville RG Hoskins G Smith B Clark RA How general practitioners manage acute asthma attacks.Thorax. 1997; 52: 153-156Crossref PubMed Scopus (48) Google Scholar, 4Lipworth BJ Jackson CM Ziyaie D Winter JH Dhillon DP Clark RA An audit of acute asthma admissions to a respiratory unit.Health Bull. 1992; 50: 389-398Google Scholar As the international and national guidelines contain detailed algorithms for pathways of management in acute asthma exacerbations, it is not the intention to review the contents of these published reports here. A summary flow chart for the treatment of acute severe asthma is shown in figure 1, based upon the key points from the international1Global initiative for asthma: global strategy for asthma management and prevention. NIH, NHLBI, Bethesda1995Google Scholar and UK2Thorax. 1997; 52: S1-S21PubMed Google Scholar management guidelines. The agenda for this brief overview is to critically appraise some of the more contentious aspects of drug treatment in acute asthma, but not to deal with initial assessment, follow-up, and patient education. On a more general point, it is important to appreciate that interpretation of many studies in acute asthma is limited by their small sample size, making them vulnerable to statistical type IT error, although this may be overcome by meta-analysis where appropriate. The purpose of bronchodilator therapy in acute asthma is to reverse any bronchial smooth muscle spasm, in order to buy time until the anti-inflammatory effect of the corticosteroid begins to work after 6-12 hours. In view of the severity of airflow obstruction, it is imperative to achieve a maximum or near maximum response with minimum systemic adverse effects. High doses of inhaled β2-adrenoceptor agonists such as salbutamol are widely accepted as first-line bronchodilator therapy, although the role of the nebuliser for delivery has come under increasing scrutiny. The place of additional bronchodilator therapy with inhaled anticholinergics and the use of intravenous salbutamol or aminophylline are debated. The nebuliser, administered by mask or mouthpiece and driven by an air compressor or more preferably by high-flow oxygen, is the mainstay for delivering high doses of inhaled β2-agonists, and is easy for the patient to use during an acute attack. 5 mg nebulised salbutamol driven by 6 L/min oxygen has been shown to be a safe and effective treatment when administered by trained ambulance crew to patients with acute "severe asthma during transfer to hospital.5Ferguson RJ Stewart CM Wathen CG Moffat R Crompton GK Effectiveness of nebulised salbutamol administered in ambulances to patients with severe acute asthma.Thorax. 1995; 50: 81-82Crossref PubMed Scopus (22) Google Scholar The potential concern regarding inadvertent carbon dioxide retention with high-flow oxygen in patients with unsuspected chronic obstructive pulmonary disease is reduced by an age cut off of 50 years, along with diagnostic information from the patient or general practitioner. Conventional open-vent jet nebulisers are, however, relatively inefficient devices with much of the nominal dose being wasted during exhalation along with the residual volume at the end of nebulisation. Drug delivery to the lung depends on the performance of the nebuliser chamber and an adequate flow rate from the compressor source. When 17 commercially available jet nebulisers were evaluated under optimum operating conditions they showed an eight-fold variation in the respirable dose delivered.6Loffert DT Ikle D Nelson HS A comparison of commercial jet nebulisers.Chest. 1994; 106: 1788-1793Crossref PubMed Scopus (113) Google Scholar The performance of a nebuliser may be further compounded by variations in flow rate from a compressor which needs to be, although rarely is, regularly maintained. A large-volume spacer device with a metered dose inhaler is an alternative means of delivery, which allows tidal rebreathing with a mask or mouthpiece, and improves delivery of respirable particles. Two studies in acute severe asthma have shown an equivalent bronchodilator response from salbutamol when given via a holding chamber or a nebuliser, when the holding chamber used a six-fold lower nominal dose.7Idris AH McDermit MF Raucci JC Morrobel A McGorray S Hendels L Emergency department treatment of severe asthma: metered dose inhaler plus holding chamber is equivalent in effectiveness to nebuliser.Chest. 1993; 103: 665-672Crossref PubMed Scopus (173) Google Scholar, 8Colacone A Afilalo M Wokove N Kreisman H The comparison of albuterol administered by metered dose inhaler and holding chamber or wet nebuliser in acute asthma.Chest. 1993; 104: 835-841Crossref PubMed Scopus (111) Google Scholar Studies in acute asthma in children have shown a similar response to terbutaline given by a nebuliser or by large-volume spacer on a microgram equivalent or half microgram equivalent nominal basis.9Freelander M Van Asperen PP Nebuhaler versus nebuliser in children with acute asthma.BMJ. 1984; 288: 1873-1874Crossref PubMed Scopus (57) Google Scholar, 10Fuglasang G Pedersen S Comparison of nebuhaler and nebuliser treatment of acute severe asthma in children.Eur J Respir Dis. 1986; 69: 109-113PubMed Google Scholar The delivery of salbutamol from large-volume spacer holding chambers may be impaired by multiple actuations or inhalation delay,11Clark DJ Lipworth BJ Effects of multiple actuations, delayed inhalation and antistatic treatment on the lung bioavailability of salbutamol via a spacer device.Thorax. 1996; 51: 981-984Crossref PubMed Scopus (96) Google Scholar suggesting that repeated cycles of two puffs (200 μg) with a deep tidal breathing method should be employed in acute asthma. General practitioners should have a supply of large-volume plastic spacers which have been prewashed in detergent and drip-dried to reduce static charge. Use of a spacer in this way with up to ten sequential puff cycles of salbutamol (200 μg each time) will in most circumstances be equally or more effective than an inadequately serviced compressor in conjunction with a low-performance nebuliser. Improved lung delivery from a spacer might conceivably increase systemic absorption, although this is likely to be offset by reduced lung bioavailability due to reduced small airway calibre in acute asthma, as well as down-regulation and associated desensitisation of extrapulmonary β2-adrenoceptors. Further studies are required to look at spacer use in patients with acute severe asthma. The main disadvantages of a spacer are that it precludes concomitant use of an oxygen mask (but not nasal cannula) and requires patient cooperation and closer supervision by the doctor administering the treatment. Furthermore, there is a perception by many patients that a nebuliser represents high-technology therapy compared with the simpler plastic spacer, which many asthmatics will already be using for their inhaled corticosteroid therapy. In patients with more severe asthma and respiratory failure, continuous administration of β2-agonists may be easier via a nebuliser, particularly when anxiety impairs patient cooperation. It has been shown that routine substitution of metered-dose aerosol in conjunction with a spacer (Aerochamber) instead of nebulised β2-agonist therapy resulted in projected annual savings in one hospital amounting to US$83 000.12Bowton DL Goldsmith WM Haponick EF Substitution of metered dose inhalers for hand held nebulisers: success and cost savings in a large acute care hospital.Chest. 1992; 101: 305-308Crossref PubMed Scopus (148) Google Scholar How do portable dry-powder inhalers perform when given as repeated puffs by patients before the doctor's arrival? In a study of 62 patients with acute severe airflow obstruction, delivery of terbutaline given by dry-powder inhaler (Turbuhaler) or metered-dose inhaler plus large-volume spacer (Nebuhaler) was evaluated with two sequential 2·5 mg doses given 15 minutes apart.13Tonnesen F Laursen LC Evald T Stahl E Ibsen TB Bronchodilating effective terbutaline powder in acute severe bronchial obstruction.Chest. 1994; 105: 697-700Crossref PubMed Scopus (43) Google Scholar A 39% and 57% increase in forced expiratory volume at 1 second (FEV1) with the Turbuhaler compared with a 16% and 23% improvement with the Nebuhaler was seen for the two doses. 32 out of 33 patients with the Turbuhaler showed a greater than 10% increase in FEV1 after the second inhalation, compared with 13 out of 29 patients who showed less than a 10% change in FEV1 at the same time point with the Nebuhaler. This is in keeping with the observation that in acute asthma 98% of patients were able to generate sufficient inspiratory flow through a Turbuhaler, allowing a therapeutic dose of terbutaline to be delivered to the airways.14Brown PH Ning ACWS Greening AP McLean A Crompton GK Peak inspiratory flow through Turbuhaler in acute asthma.Eur Respir J. 1995; 8: 1940-1941Crossref PubMed Scopus (78) Google Scholar These findings are therefore reassuring for patients using dry-powder inhaler devices, although in the presence of tachypnoea the use of tidal breathing with a nebuliser or large-volume spacer would be preferable. There has been controversy about the possible harmful effects of inhaled fenoterol (a full agonist) compared with salbutamol (a weaker partial agonist). In particular, case-control studies from New Zealand suggested a putative association between fenoterol use and asthma deaths, which was attributed to its greater cardiac toxicity in conjunction with effects of hypoxaemia.15Crane J Burgess C Pearce NB Blasley Y The β-agonist controversy: a perspective.Eur Respir Rev. 1993; 3: 475-482Google Scholar However, a more detailed analysis of risk factors suggests that the association between fenoterol and severe life-threatening asthma is explained by preferential prescribing to patients with more severe disease.16Garrett J Lanes SF Kolbe J Rea HH Risk of severe life threatening asthma and β-agonist type: an example of confounding by severity.Thorax. 1996; 51: 1093-1099Crossref PubMed Scopus (62) Google Scholar Studies in stable asthmatics have shown that when fenoterol and salbutamol are administered on a microgram equivalent basis (from 100 μg to 4000 μg), there is no difference in bronchodilator potency, whereas systemic potency for β2-adrenoceptor responses is greater with fenoterol.17Lipworth BJ Newnham DM Clark RA Dhillon DP Winter JH McDevitt DG Comparison of the relative airways and systemic potencies of inhaled fenoterol and salbutamol in asthmatic patients.Thorax. 1995; 50: 54-61Crossref PubMed Scopus (41) Google Scholar In adequately oxygenated patients with acute severe asthma and dose titration of fenoterol (up to 3200 μg) or salbutamol (up to 1600 μg) given via a spacer (Aerochamber) with face mask, there was no evidence of clinically significant cardiac arrhythmias, despite the fact that the two-fold higher dose of fenoterol produced greater systemic β2-mediated effects.18Newhouse MT Chapman KR McCallum AL et al.Cardiovascular safety of high doses of inhaled fenoterol and albuterol in acute severe asthma.Chest. 1996; 110: 595-603Crossref PubMed Scopus (67) Google Scholar In particular, with respect to changes in QTc interval, less than 5% of patients had moderate prolongation (15-25%) and none showed severe prolongation (>25%). Another property of a partial agonist such as salbutamol is that it would be predicted from first principles to behave as a competitive antagonist at β2-adrenoceptors in the presence of raised adrenergic tone, as has been demonstrated under experimental conditions in healthy volunteers.19Grove A McFarlane LC Lipworth BJ Expression of the β2-adrenoceptor partial agonist/antagonist activity of salbutamol in states of low and high adrenergic tone.Thorax. 1995; 50: 134-138Crossref PubMed Scopus (20) Google Scholar However, this phenomenon is clinically unimportant in acute severe asthma and there is no role for routinely using a higher efficacy agonist such as fenoterol instead of salbutamol. Salmeterol, which is a weaker agonist than salbutamol, also shows the same β2-adrenoceptor antagonist effect in healthy volunteers.20Grove A Lipworth BJ Evaluation of the β2-adrenoceptor agonist/antagonist activity of formoterol and salmeterol.Thorax. 1996; 51: 54-58Crossref PubMed Scopus (23) Google Scholar However, prior treatment with single doses of salmeterol in stable asthmatic patients does not appear to impair the bronchodilator response to repeated puffs of either salbutamol or fenotero.21Smyth ET Pavord ID Wong CS Wisniewski AFZ Williams J Tattersfield AE Interaction and dose equivalence of salbutamol and salmeterol in patients with asthma.BMJ. 1993; 306: 543-545Crossref PubMed Scopus (52) Google Scholar, 22Grove A Lipworth BJ Effect of prior treatment with salmeterol and formoterol on airway and systemic β2-responses to fenoterol.Thorax. 1996; 51: 585-589Crossref PubMed Scopus (14) Google Scholar The rationale for the use of anticholinergic therapy is the presence of increased airway vagal tone which may not be overcome by treatment with high doses of inhaled β2-agonists alone. More recent studies have tended to reveal conflicting results on the benefit of adding nebulised ipratropium to nebulised salbutamol.23O'Driscoll RB Taylor RJ Horsley MG Chambers DK Bernstein A Nebulised salbutamol with and without ipratropium bromide in acute airflow obstruction.Lancet. 1989; i: 1418-1420Summary Scopus (157) Google Scholar, 24Schuh S Johnson DW Callahan S Cally G Levison H Effects of frequent nebulised ipratropium bromide added to frequent high dose albuterol therapy in severe childhood asthma.J Paediatr. 1995; 126: 639-645Summary Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 25Karpel JP Schacter NE Fanta C et al.A comparison of ipratropium and albuterol versus albuterol alone for the treatment of acute asthma.Chest. 1996; 110: 611-616Crossref PubMed Scopus (76) Google Scholar, 26Fitzgerald MK Grunfeld A Parae PD et al.The clinical efficacy of combination nebulised anticholinergic and adrenergic bronchodilators versus nebulised adrenergic bronchodilator alone in acute asthma.Chest. 1997; 111: 311-315Crossref PubMed Scopus (63) Google Scholar The variability in results probably relates to the criteria for patient selection, the small numbers of subjects in some studies, the dose and frequency of administered nebulised salbutamol, and the use of concomitant systemic corticosteroid therapy. Although mean improvements in FEV1 with ipratropium tend to be small, it is likely that larger increases may occur in certain individuals with an exaggerated degree of cholinergic tone who may also have impaired β2-adrenoceptor responsiveness. On the basis that high-dose nebulised ipratropium bromide has few systemic adverse effects, its use is advocated for patients with life-threatening features or for those who do not respond to initial high-dose inhaled β2-agonists, as suggested by the recommended guidelines. The available drugs for intravenous bronchodilator therapy are the β2-agonists and theophyllines. For salbutamol, the main disadvantage of the parenteral route of administration is systemic β2-mediated adverse effects, which are usually greater than those associated with the inhaled route. Nonetheless, it is conceivable in acute severe asthma that greatly reduced peripheral airway calibre would result in poor lung delivery when given by the inhaled route of administration. This effect can be partly offset by increasing the dose and frequency of the inhaled bronchodilator, as has been shown in studies of continuous nebulised salbutamol in patients with more severe airflow obstruction.27Rudnitsky GS Eberlein RS Schoffstall JM et al.Comparison of intermittent and continuously nebulised albuterol for treatment of asthma in an urban emergency department.Ann Emerg Med. 1993; 22: 1842-1846Summary Full Text PDF PubMed Scopus (86) Google Scholar, 28Shrestha M Bidadi K Gourlay S Heys J Continuous versus intermittent albuterol at high and low doses in the treatment of severe acute asthma in adults.Chest. 1996; 110: 42-47Crossref PubMed Scopus (69) Google Scholar The pharmacokinetic profile for high-dose nebulised salbutamol shows that rapid absorption occurs from the lung reaching a peak concentration within 10 minutes of inhalation.29Newnham DM Lipworth BJ Nebuliser performance, pharmacokinetics, airways and systemic effects of salbutamol given via a novel delivery system (Ventstream).Thorax. 1994; 49: 762-770Crossref PubMed Scopus (92) Google Scholar It is therefore conceivable that appreciable systemic concentrations may in part contribute to the bronchodilator effect. There is, however, considerable interindividual variability in lung bioavailability of salbutamol when given by the nebulised route in acute asthma, and a more predictable pharmacokinetic profile is achieved with the intravenous route.30Schuh S Parkin P Rajan A et al.High versus low dose frequently administered nebulised albuterol in children with severe acute asthma.Paediatrics. 1989; 83: 513-518PubMed Google Scholar, 31Janson C Plasma levels and effects of salbutamol after inhaled or iv administration for stable asthma.Eur Respir J. 1991; 4: 544-550PubMed Google Scholar Two large multicentre studies in acute severe asthma have compared treatment with either intravenous or nebulised salbutamol.32Swedish Society of Chest Medicine High dose inhaled versus intravenous salbutamol combined with theophylline in severe acute asthma.Eur Respir J. 1990; 3: 163-170PubMed Google Scholar, 33Salmeron S Brochard L Mal H et al.Nebulised versus intravenous albuterol in hypercapnic acute asthma.Am J Respir Crit Care Med. 1994; 149: 1466-1470Crossref PubMed Scopus (107) Google Scholar The intravenous salbutamol regimens were administered either as a 10 minute bolus of 5 μg/kg alone, 32Swedish Society of Chest Medicine High dose inhaled versus intravenous salbutamol combined with theophylline in severe acute asthma.Eur Respir J. 1990; 3: 163-170PubMed Google Scholar or as a 60 minute infusion of 500 μg in conjunction with hydrocortisone 200 mg.33Salmeron S Brochard L Mal H et al.Nebulised versus intravenous albuterol in hypercapnic acute asthma.Am J Respir Crit Care Med. 1994; 149: 1466-1470Crossref PubMed Scopus (107) Google Scholar Both studies showed a better bronchodilator response with the inhaled route. Higher plasma salbutamol concentrations were found with the inhaled route in one study32Swedish Society of Chest Medicine High dose inhaled versus intravenous salbutamol combined with theophylline in severe acute asthma.Eur Respir J. 1990; 3: 163-170PubMed Google Scholar and the intravenous route in the other, 33Salmeron S Brochard L Mal H et al.Nebulised versus intravenous albuterol in hypercapnic acute asthma.Am J Respir Crit Care Med. 1994; 149: 1466-1470Crossref PubMed Scopus (107) Google Scholar and in both cases higher levels were associated with greater systemic β2-mediated effects. The more relevant question—whether intravenous salbutamol improves the initial bronchodilator response when given in addition to nebulised salbutamol and intravenous corticosteroid–has been addressed in two studies.34, 35 In acute asthmatic adults, Cheong et al found that intravenous salbutamol 12 μg/min over 4 hours after an initial 5 mg dose of nebulised salbutamol and intravenous hydrocortisone, resulted in a greater improvement in peak flow than three successive nebulised 5 mg doses given over 2 hours, although tachycardia was more prominent in the intravenous group.34Cheong B Reynolds SR Rajan G Ward MJ Intravenous β-agonist in severe acute asthma.BMJ. 1988; 297: 448-450Crossref PubMed Google Scholar In a study of acute severe asthmatic children, a 10 minute single intravenous infusion of salbutamol (15 μg/kg) or saline was given in the first 2 hours in addition to optimum frequent nebulised salbutamol and intravenous hydrocortisone, with follow-up for 24 hours.35Browne GJ Penna AS Phung X Soo M Randomised trial of intravenous salbutamol in early management of acute severe asthma in children.Lancet. 1997; 349: 301-305Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar The recovery time to cessation of 30 minute administration of nebulised salbutamol was 4 hours for the intravenous group compared with 11·1 hours in controls, with intravenous salbutamol also being associated with a lower dependency on medical oxygen and with discharge from the emergency department 9·7 hours earlier than the control group. Systemic β2-mediated effects on plasma glucose and potassium did not differ between the two groups, although there was a higher proportion of tremor at 2 hours in those who received intravenous salbutamol. Studies with intravenous aminophylline have also revealed conflicting results as to whether there is improvement over and above the response to high-dose inhaled β2-agonist and systemic corticosteroid.36Murphy DG McDermott MF Rydman RJ Sloan EP Zalenski RJ Aminophylline in the treatment of acute asthma when β-adrenergics and steroids are provided.Arch Intern Med. 1993; 153: 1784-1788Crossref PubMed Scopus (45) Google Scholar, 37Huang D O'Brien RG Harman E et al.Does aminophylline benefit adults admitted to the hospital in acute exacerbation of asthma.Ann Intern Med. 1993; 119: 1155-1160Crossref PubMed Scopus (55) Google Scholar, 38DiGiulio G Kercsmar C Krug S Alpert S Marx C Hospital treatment of asthma: lack of benefit from theophylline given in addition to nebulised albuterol and intravenously administered corticosteroid.J Pediatr. 1993; 122: 464-469Summary Full Text PDF PubMed Scopus (68) Google Scholar, 39Strauss ARE Wertheim DL Bonagura VR Velacer DJ Aminophylline therapy does not improve outcome and increases adverse effects in children hospitalised with acute asthmatic exacerbations.Paediatrics. 1994; 93: 205-210PubMed Google Scholar As with other studies of second-line bronchodilator agents, the variability and results can be explained by methodological differences between studies. The acute therapeutic bronchodilator response to intravenous aminophylline is dependent on achieving adequate blood concentrations which requires monitoring, and its use is associated with drug interactions and more frequent adverse effects than other second-line agents such as nebulised ipratropium. There is, therefore, no rationale for deviating from the recommended guidelines in terms of reserving the use of intravenous bronchodilator therapy as second-line treatment except in life-threatening cases. The rationale for the administration of systemic corticosteroids in acute asthma is to reverse the inflammatory component which will not be ameliorated by bronchodilator therapy. The efficacy of systemic corticosteroids is borne out by clinical experience and data from meta-analysis.40Rowe BH Keller JL Oxman AD Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis.Am J Emerg Med. 1992; 10: 301-310Summary Full Text PDF PubMed Scopus (176) Google Scholar Conventionally, corticosteroids are administered systemically in acute asthma, although there appears to be no gain in most patients for intravenous over oral administration.41Harrison BDW Stokes TC Heart GJ Vaughan DA Ali MJ Robinson AA Need for intravenous hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure.Lancet. 1986; i: 181-184Summary Scopus (91) Google Scholar, 42Ratto D Alfaro C Sipsey J et al.Are intravenous corticosteroids required in status asthmaticus?.JAMA. 1988; 266: 527-529Crossref Scopus (127) Google Scholar Although there is evidence of a dose-response effect, there is little advantage with doses of prednisolone greater than 50 mg daily in adults.43Webb JR Dose of patients on oral corticosteroid treatment during exacerbations of asthma.BMJ. 1986; 292: 1045-1047Crossref PubMed Scopus (46) Google Scholar, 44Bowler SD Mitchel CA Armstrong JG Corticosteroids in acute severe asthma: effectiveness of low doses.Thorax. 1992; 47: 584-587Crossref PubMed Scopus (56) Google Scholar Dispersable prednisolone may be used as an alternative for patients who cannot swallow tablets whilst intravenous hydrocortisone or methylprednisolone should be used for patients who are vomiting or in cases with life-threatening features. In terms of disease control it has also been shown that tapering a short pulse of oral corticosteroids is unnecessary after acute asthma exacerbations provided that patients are also protected by concomitant inhaled corticosteroid therapy.45O'Driscoll BR Kalra S Wilson M Pickering CAC Carroll KB Woodcock AA Double-blind trial of steroid tapering in acute asthma.Lancet. 1993; 341: 324-327Summary PubMed Scopus (119) Google Scholar, 46Hatton MQF Vathenen AS Allen MJ Davies S Cooke NJ A comparison of abrupt stopping with tailing off oral corticosteroids in acute asthma.Respir Med. 1995; 89: 101-104Summary Full Text PDF PubMed Scopus (33) Google Scholar However, the dose of prednisolone should be individually titrated against the severity and recovery rate of the acute attack, as part of a personalised self-management plan. Can the anti-inflammatory effect of oral corticosteroids be achieved by high doses of inhaled corticosteroid in acute asthma? Although one might expect a much higher local airway concentration of corticosteroid with the inhaled route, this may be negated by poor peripheral aerosol delivery due to severe airway narrowing in an acute attack. There are concerns that high-dose inhaled corticosteroid might be inappropriately administered to patients with acute asthma in whom the severity of the attack has been underestimated. One possible compromise might be to use high-dose systemic corticosteroid in the first 24 to 48 hours, followed by high-dose inhaled corticosteroid, providing that the patient has responded adequately to initial therapy in terms of a peak expiratory flow (PEF) above 60% of predicted or best. However, the optimum duration of systemic corticosteroid therapy and when to institute inhaled corticosteroids remain unclear. Preliminary data have shown that following initial treatment with oral prednisolone and high-dose inhaled β2-agonist, recovery of lung function is similar after 7 days of follow-up treatment with budesonide 3200 μg per day to a tapering dose of prednisolone from 40 mg to 5 mg daily.47Youngchaiyud P Maranetra N Nana A et al.Can inhaled steroids replace oral therapy after an acute asthma attack?.Eur Respir J. 1996; 9: 53SGoogle Scholar In another study, inhaled fluticasone propionate 2000 μg per day was as effective as a 16-day reducing course of oral prednisolone in patients with a mild exacerbation of asthma (PEF greater than 60% predicted or best) who did not require hospital admission.48Levy ML Stevenson C Maslen T Comparison of short courses of oral prednisolone and fluticasone propionate in the treatment of adults with acute exacerbations of asthma in primary care.Thorax. 1996; 51: 1087-1092Crossref PubMed Scopus (93) Google Scholar These data should not be extrapolated to acute severe asthma (PEF less than 60% of predicted or best), where the benefits of systemic corticosteroid far outweigh any small potential risk of short-term systemic adverse effects. These types of studies looking at earlier sequential oral and inhaled corticosteroid therapy in less severe acute asthma exacerbations have primarily been driven by the pharmaceutical industry. It is, therefore, important to bear in mind the relative drug costs, as for example in the above study, 48Levy ML Stevenson C Maslen T Comparison of short courses of oral prednisolone and fluticasone propionate in the treatment of adults with acute exacerbations of asthma in primary care.Thorax. 1996; 51: 1087-1092Crossref PubMed Scopus (93) Google Scholar where there was a 34-fold difference in price for 2 weeks' treatment with inhaled daily fluticasone propionate 2000 μg (Flixotide, Allen and Hanbury's, UK) compared with daily oral prednisolone 25 mg (non-proprietary).49British National Formulary. British Medical Association and Royal Pharmaceutical Society of Great Britain, London1997Google Scholar It should also be pointed out that high doses of inhaled corticosteroids may be associated with systemic adverse effects, 50Lipworth BJ Clark DJ High-dose inhaled steroids in asthmatic children.Lancet. 1996; 348: 820Summary Full Text Full Text PDF PubMed Google Scholar although these are unlikely to be of clinical relevance in the short-term. Thus, the common sense and safe approach to acute asthma is to overtreat rather than undertreat, and as such all patients should receive systemic corticosteroid therapy as recommended by the guidelines. The acute bronchodilator response to repeated puffs of inhaled β2-agonist may be attenuated in patients receiving regular long-acting β2-agonists such as salmeterol and formoterol. This occurs as a consequence of down-regulation and associated desensitisation of β2-adrenoceptors, due to receptor occupancy for 24 hours.51Grove A Lipworth BJ Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients.Lancet. 1995; 346: 201-206Summary PubMed Scopus (144) Google Scholar Although studies in stable asthmatics have shown only a small reduction in mean bronchodilator response, there is considerable interindividual variability in susceptibility to desensitisation which appears to be associated with the Gly 16 polymorphism of the β2-adrenoceptor.52Tan KS, Hall IP, Dewar J, Dow E, Lipworth BJ. β2-adrenoceptor polymorphism is associated with susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet (in press).Google Scholar Doctors and patients alike should therefore be alert to the possibility that higher doses of salbutamol might be required in an acute attack for patients receiving regular long-acting β2-agonists. In-vitro studies show that corticosteroids prevent β2-agonist-induced down-regulation and gene expression of pulmonary β2-adrenoceptors.53Mak JCW Nishikawa S Shirasaki H Miyayasu K Barnes PJ Protective effects of a glucocorticoid on down-regulation on pulmonary β2-adrenergic receptors in vivo.J Clin Invest. 1995; 96: 99-106Crossref PubMed Scopus (243) Google Scholar Indeed it has been shown in stable asthmatics that intravenous hydrocortisone 200 mg rapidly reverses bronchodilator desensitisation induced by regular treatment with inhaled formoterol, and that this effect occurs within 1 hour of corticosteroid administration54Tan KS Grove A McLean A Gnosspelius Y Hall IP Lipworth BJ Systemic corticosteroid rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients.Am J Respir Crit Care Med. 1997; 156: 28-35Crossref PubMed Scopus (134) Google Scholar (figure 2). Although there are no comparable data in acute severe asthma, it is conceivable that β2-adrenoceptor down-regulation and desensitisation would, if anything, be compounded by effects of excessive β2-agonist consumption. Thus corticosteroids may have a dual effect in acute asthma with an early facilitatory effect on airway β2-adrenoceptor sensitivity and a later effect on airway inflammation, which further emphasises the need for corticosteroids to be administered as early as possible during an acute asthma attack. The current international and national guidelines for the treatment of acute asthma seem entirely appropriate in recommending high-dose inhaled β2-agonist in conjunction with systemic corticosteroid, and reserving second-line therapy with ipratropium bromide or intravenous bronchodilators for refractory or more severe cases. A greater awareness of the severity markers in acute asthma is also required, although when in doubt the safest axiom is always to overtreat rather than undertreat to prevent a potentially fatal attack. Further large-scale studies are required to resolve issues such as the use of large-volume spacers and the role of intravenous β2-agonists in acute severe asthma.
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