ARTICLE IN PRESS Respiratory Medicine (2003) 97, 1067–1074 Formoterol (OXISs) Turbuhalers as a rescue therapy compared with salbutamol pMDI plus spacer in patients with acute severe asthma W. Boonsawat*, S. Charoenratanakul, C. Pothirat, K. Sawanyawisuth, T. Seearamroongruang, T. Bengtsson, R. Brander, O. Selroos Srinagarind Hospital, Khon Kaen, Thailand Siriraj Hospital, Bangkok, Thailand Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand Khon Kaen Hospital, Khon Kaen, Thailand AstraZeneca R&D Lund, Lund, Sweden KEYWORDS Formoterol Turbuhaler; Acute severe asthma; Salbutamol pMDI plus spacer; Reliever medication Summary Formoterol has a similar onset of effect to salbutamol but a prolonged duration of action. However, the relative efficacy of the two drugs in acute severe asthma is not known. This double-blind, double-dummy study compared the safety and efficacy of the maximum recommended daily dose of formoterol and a predicted equivalent dose of salbutamol in 88 patients presenting to the emergency department with acute severe asthma. Patients were randomized to formoterol 54 mg via Turbuhalers or salbutamol 2400 mg via pressurized metered dose inhaler (pMDI) plus spacer in three equal doses over 1 h. Following the full dose, mean FEV1 at 75 min increased by 37% for formoterol and 28% for salbutamol (P ¼ 0:18). The maximum increase in FEV1 over 4 h was significantly greater with formoterol compared with salbutamol (51% vs. 36%, respectively Po0:05) and formoterol was as effective as salbutamol at improving symptoms and wellbeing. Both treatments were well tolerated. Formoterol caused a greater decrease in serum potassium (difference – 0.2 mmol/l). In severe acute asthma, bronchodilator therapy with high-dose (54 mg) formoterol Turbuhaler provided equally rapid improvements in lung function of greater magnitude over 4 h than high-dose (2400 mg) salbutamol pMDI plus spacer. r 2003 Elsevier Ltd. All rights reserved. Introduction In hospital emergency departments, the primary therapy for patients presenting with acute severe asthma is administration of a rapid-acting b2 agonist within the first hour.1 In these emergencies, normal doses of short-acting b2 -agonists may be inadequate2 and repeated administration with higher doses are normally required. Poor or incomplete responses in the first 1–2 h may result *Corresponding author. Fax: þ 66-043-241-735. E-mail address: watcha b@kku.ac.th (W. Boonsawat). in hospital admission. In the USA, up to 20% of patients with a forced expiratory volume in 1 s (FEV1)o50% predicted normal are admitted following emergency room treatment for further observation and supervision of administration of additional doses of short-acting b2 -agonists.3 In this situation, a rapid-acting b2 -agonist with a long duration of action could reduce the need for more frequent administration of bronchodilator therapy. Formoterol is a selective b2 -agonist with a rapid onset of effect (p3 min) and a long duration of action (X12 h).4 Formoterol (Oxiss) Turbuhalers is at least as rapid acting as the short-acting 0954-6111/03/$ - see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0954-6111(03)00139-2 ARTICLE IN PRESS 1068 b2 -agonist, salbutamol, both in stable asthma5 and following methacholine-induced bronchoconstriction, a model of acute severe asthma.6 Importantly, the systemic effects of formoterol are similar in duration to those of salbutamol.7,8 A comparative dose–response study, in which patients with stable asthma received three doses of formoterol via Turbuhaler or two doses of salbutamol via pressurized metered dose inhaler (pMDI), suggested that the therapeutic index (the ratio between improvements in FEV1 over decrease in serum potassium levels) was more favourable for formoterol than for salbutamol.9 The unique pharmacodynamic properties of formoterol coupled with a good safety profile should allow it to be used to good effect as both maintenance and reliever therapy. However, few studies have examined formoterol Turbuhaler as reliever therapy during an acute exacerbation. To establish the safety and efficacy of formoterol for relief of acute exacerbations, it is appropriate to compare the efficacy and safety of the drug with a traditional reliever therapy in patients with acute asthma in an emergency room setting. The favourable balance between efficacy and safety of highdose formoterol Turbuhaler relative to high-dose terbutaline Turbuhaler in the treatment of acute severe bronchoconstriction has been confirmed,10 although similar comparisons with high-dose salbutamol have not been made. Previous studies suggest that formoterol 4.5 mg Turbuhaler is an equivalent bronchodilator dose to salbutamol 200 mg pMDI.4,8 The maximum daily dose of formoterol approved for use via Turbuhaler without physician consultation is 54 mg (12 inhalations), which is predicted to be equivalent to 2400 mg of salbutamol via pMDI. Short-acting b2 -agonists have often been administered by nebulizer in the emergency room. However, administration via pMDI plus spacer can produce equivalent bronchodilation with a more rapid onset and fewer side effects than with a wet nebulizer.11,12 Turbuhaler has also been shown to be an equally effective delivery device in an emergency setting.13,14 In a previous emergency department study, salbutamol Turbuhaler was shown to be as safe and effective as a double dose of salbutamol pMDI plus spacer.13 Similarly, terbutaline Turbuhaler increased FEV1 significantly more than the same dose administered via pMDI plus spacer in patients with acute severe bronchoconstriction.14 The aim of this 4-h study was to compare the efficacy and safety of cumulative administered high-dose formoterol 54 mg (3  18 mg) via Turbuhaler with salbutamol 2400 mg (3  800 mg) via pMDI plus spacer (multiple doses of salbutamol up to W. Boonsawat et al. 2400 mg in 1 h are recommended by the global initiative for asthma [GINA] guidelines for treatment of acute severe asthma1) in a defined group of patients presenting to an emergency room with acute severe bronchoconstriction. Methods Study design and patients This was a randomized, double-blind, doubledummy study with parallel groups, conducted at five centres in Thailand. A local independent ethics committee approved the protocol before the study commenced at each centre. Patients (18–67 years) diagnosed with asthma and presenting to the emergency department with acute severe bronchoconstriction were included in the study if their FEV1 was 30–60% of predicted normal values for the healthy non-smoking Thai population15 and, if aged X50 years, they had a pulse rate X100 beats/min on presentation as additional evidence of acute bronchoconstriction (no pulse criterion was set if o50 years). This criterion was added to ensure patients with chronic obstructive airways disease and fixed airway obstructions were not enrolled. Patients were excluded from the study if they required transfer to the intensive care unit, or nebulized or intravenous b2 -agonists at the initial assessment. Patients with oxygen saturation p91% in room air or a severe cardiovascular disorder were also excluded from the study. The patients therefore did not represent the most severe end of the spectrum of acute severe asthma. Within 30 min of arrival at the emergency department, written consent and demographic data were obtained and patients were randomized to receive formoterol Turbuhaler (Oxis, AstraZeneca, Sweden) or salbutamol pMDI (Baker Norton, UK) plus spacer (VolumaticTM, GlaxoSmithKline, UK). Formoterol (4  4.5 mg inhalations [18 mg]) was administered to patients at 0, 30 and 60 min, to give a total delivered dose of 54 mg, while salbutamol pMDI plus spacer (4  2 actuations of 100 mg) was given at 0, 30 and 60 min for a total dose of 2400 mg. As a result of the double-dummy design, subjects were given placebo from a Turbuhaler or pMDI plus spacer as appropriate and inhalations were started with Turbuhaler or pMDI in random order. To make a comparison between the investigational treatments possible, a single dose of oral prednisolone (60 mg) was not administered until 80 min after the first dose of study drug. ARTICLE IN PRESS Formoterol (OXISs) Turbuhalers as a rescue therapy 1069 Assessments Statistics FEV1 was measured by spirometry at baseline (0), 15, 45, 75, 120, 180 and 240 min after first administration of the study drug. At each assessment the highest FEV1 value was recorded from three manoeuvres, additional manoeuvres to a maximum of eight were performed if a difference of greater than 5% was observed between the two highest values. All centres used the same type of spirometer, which met the American Thoracic Society standard, and which were calibrated to 3% accuracy each day. The primary efficacy variable was the relative increase from baseline in FEV1 75 min after the first dose of study drug. Secondary measures of pulmonary function included, Eaverage the mean area under the curve (AUC) FEV1 between 75 and 240 min (i.e. the area under the FEV1 time curve divided by the length of the measurement interval), Emax ; maximum FEV1 between 75 and 240 min, and FEV1 at 15 and 45 min after the first and second dose of study drug. At baseline, 75 and 240 min, patients evaluated their asthma symptoms by a visual analogue scale (VAS), (scoring on a line 10 cm long between end points scale 0–100, 0 [no symptoms] to 100 [severe symptoms] in answer to the question ‘‘How is your asthma now?’’ Study staff assessed the VAS score by measuring with a metric ruler the distance between 0 and the patient’s mark). The Acute Asthma Quality of Life Questionnaire (Acute AQLQ), was modified in collaboration with the originator of the AQLQ16 to include only 11 items in two domains (symptoms and emotional function). The Acute AQLQ, assessed health-related quality of life subjectively at baseline, 75 and 240 min. The perceived overall effect of treatment on patient wellbeing was recorded on a 15-point scale, 75 and 240 min after the first dose of study drug. Safety variables were measured at baseline, 15, 45, 75, 120, 180 and 240 min during the 4-h study. Blood pressure was monitored by a standard sphygmomanometer; blood samples were drawn for determination of serum potassium; and a 12lead electrocardiogram (ECG) was performed, recorded and assessed for heart rate, sinus rhythm and QT interval. The QT interval corrected for heart rate (QTc) was calculated using Bazett’s formula. Average, maximum and minimum effects were calculated in the same way as FEV1. Adverse events (AEs) reported or observed during the treatment period were also recorded. AEs were also collected through a question at the end of the 4-h study period ‘‘Have you had any health problems since you received the study drug?’’. For the spirometry variables, the relative increase in FEV1 from baseline to 75 min was compared between treatments using a multiplicative analysis of variance (ANOVA) model with treatment and centre as fixed factors and baseline FEV1 as a covariate. Treatment differences for spirometry variables: FEV1 at 15, 45, 75 min average FEV1 and maximum FEV1 were expressed as a ratio (in per cent). VAS, Acute AQLQ, overall treatment evaluation and safety variables were compared between treatments using an additive ANOVA with centre and treatment as fixed factors and, with the exception of the overall treatment evaluation, baseline readings as a covariate. The number of subjects with treatment failure (requiring additional medication in the 4-h period or hospitalization) was compared using the w2-test. All analyses followed the intention-to-treat approach and Pvalues less than 5% were considered statistically significant. With 40 patients per group, there was an 80% chance of detecting a true difference of 17% in FEV1, assuming a coefficient of variation of 25%. Results All 88 patients enrolled in the study were randomized to treatment, 44 were randomized to formoterol and 44 to salbutamol (Table 1). The treatment groups were well matched for level of airway obstruction at entry, FEV1 44% predicted normal in both groups and before enrolment a similar number of patients in each treatment group had taken asthma medication: 64 (73%) inhaled short-acting b2 -agonists, 31 (35%) inhaled glucocorticosteroids, 29 (33%) oral b2 -agonists, 25 (28%) xanthines, 5 (6%) systemic glucocorticosteroids, 4 (5%) long-acting b2 -agonists (alone or in combination with inhaled glucocorticosteroids) and 4 (5%) anticholinergic inhalers. During the study, two patients discontinued treatment (both in the formoterol group), one because of protocol deviation and one withdrew consent after 180 min for practical reasons, both were considered in no need of further treatment. Efficacy The mean increase in FEV1 from baseline was higher in the formoterol group than in the salbutamol group at all time points (Fig. 1a). The adjusted mean percentage increase in FEV1 from baseline at 75 min was 37% in the formoterol group compared ARTICLE IN PRESS 1070 W. Boonsawat et al. Table 1 Patient demographics at baseline (means and ranges). No. of patients Men (n) Age (years) SABA use (n) IGCS use (na) IGCS dose at entry (mg) FEV1 (l) FEV1 (% predicted normal) Pulse rate (bpm) SaO2 Formoterol Salbutamol 44 14 (32%) 45 (18–67) 34 (77%) 17 (39%) 853 (400–1600) 44 10 (23%) 43 (18–61) 30 (68%) 16 (36%) 881 (300–1200) 1.06 (0.38–1.74) 1.08 (0.47–2.00) 44 (17–60) 44 (21–59) 104 (73–137) 101 (60–129) 96 (91–100) 97 (91–100) SABA, inhaled short-acting b2 -agonist; IGCS, inhaled glucocorticosteroid; SaO2, oxygen saturation. a Total includes two patients using fluticasone/salmeterol combination inhaler. with 28% in the salbutamol group. However, the adjusted mean difference in favour of formoterol at 75 min (7.2% [95% CI: 3.2, 18.7]; P ¼ 0:18) was not statistically significant nor was the trend in favour of formoterol significant at early time points (Table 2). Emax was 51% in the formoterol group and 36% in the salbutamol group. The increase in the formoterol group was significantly higher than that after treatment with salbutamol (adjusted mean difference 11.1% [95% CI: 0.6, 22.8]; Po0:05). Similarly, Eaverage was 43% in the formoterol group and 28% in the salbutamol group and was significantly higher in formoterol-treated patients (adjusted mean difference 11.7% [95% CI: 0.9, 23.6]; Po0:05). The distribution of patients in each treatment group achieving or not achieving varying levels of increase in maximum FEV1 can be seen in Fig. 1b. No treatment failures occurred in either treatment group. Subjective symptom score assessments using the VAS (0–100 scale) decreased during the course of the study in both formoterol- and salbutamoltreated patients. Mean baseline scores were 64 in both groups and they decreased to 7.21 in the formoterol group and to 10.24 in the salbutamol group. The difference (3.04) was not statistically significant. The mean Acute AQLQ score increased during the study from 2.67–5.88 in the formoterol group and 2.49–5.69 in the salbutamol group. There were no significant differences between treatments in the mean Acute AQLQ scores for overall evaluation or for symptoms and emotion function Figure 1 Effect of formoterol and salbutamol treatment on (a) geometric mean % increase in FEV1 and (b) distribution of patients achieving various levels of % change in maximum FEV1 from baseline. domains at 75 or 240 min. Patients’ overall treatment evaluation supported these changes with comparable scores recorded for formoterol and salbutamol 75 min (4.59 and 4.25, respectively) and 240 min (5.43 and 5.50, respectively) post-dosing. Safety During the 4-h study period, the adjusted mean minimum serum potassium value was significantly lower in the formoterol group than in the salbutamol group (3.2 vs. 3.5 mmol/l, respectively; Po0:001) (Fig. 2a). The adjusted mean average serum potassium value during the study was also significantly lower in patients treated with formoterol compared with salbutamol (P ¼ 0:002; Table 3). Both systolic and diastolic blood pressure decreased after the first dose of study drug. However, there were no statistically significant differences ARTICLE IN PRESS Formoterol (OXISs) Turbuhalers as a rescue therapy Table 2 FEV1 mean change from baseline. Mean % change from baselinea (range) E15 E45 E75 Emax Eaverage 1071 Formoterol Salbutamol 19.1 (–8.5, 113.2) 31.4 (–1.4, 127.5) 37.0 (2.1, 151.6) 51.2 (1.2, 182.4) 43.2 (5.3, 176.5) 15.1 (–61.0, 81.7) 22.8 (56.6, 89.9) 27.8 (56.6, 97.4) 36.1 (48.4, 97.4) 28.2 (55.0, 83.0) Mean (%) ratio form/salba (95% conf. limits) P-value 103.5 (95.1, 112.7) 107.0 (97.2, 117.9) 107.2 (96.8, 118.7) 111.1 (100.6, 122.8) 117 (100.9, 123.6) 0.42 0.16 0.18 0.039 0.033 E15 ; effect at 15 min; E45 ; effect at 45 min; E75 ; effect at 75 min; Emax ; maximal effect between 75 and 240 min; Eaverage ; area under the curve between 75 and 240 min. a ANOVA. in blood pressure between treatment groups (Table 3). No statistically significant differences were observed between the groups in heart rate (Table 3). Similarly, there was no statistically significant difference between treatments in QTc (Fig. 2b; Table 3). Both treatments were well tolerated. Ten patients reported a total of 13 mild AEs. The most commonly reported AE was palpitation (five in the formoterol group and three in the salbutamol group). Other common AEs were dizziness, headache, fever, tremor and hypoasthaesia, each reported once with formoterol treatment. There were no serious AEs. Discussion Figure 2 Effect of formoterol and salbutamol treatment on (a) serum potassium levels, and (b) QTc over the first 4 h after initiation of treatment. An acute asthma exacerbation can be severe or even fatal and therefore immediate relief from bronchospasm is vital. Consequently, the primary treatments for acute severe asthma in hospital emergency departments are short-acting b2 -agonists, as they are effective and act rapidly. Previous studies have shown that the long-acting b2 -agonist, formoterol has a rapid onset of effect in asthma patients,4 similar to salbutamol.5,6 Furthermore, there is some evidence that formoterol Turbuhaler has a more favourable therapeutic index than salbutamol delivered via pMDI.9 In this study, cumulative doses of formoterol Turbuhaler (18, 36 and 54 mg) were at least as effective as salbutamol pMDI plus spacer (800, 1600 and 2400 mg) based on improvements in FEV1 at 15 min after each dose (15, 45 and 75 min from baseline) in patients ARTICLE IN PRESS 1072 Table 3 W. Boonsawat et al. Safety results (average values) over 4-h period following treatment. Safety variable Heart rate (bpm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) QTc interval (ms) Serum potassium (mmol/l) Difference in adjusteda means (95% CI) Mean baseline values (range) Mean treatment values (range) Formoterol Salbutamol Formoterol Salbutamol 93.6 (72–134) 90.5 (60–130) 94.7 (68–129) 90.1 (60–125) 2.0 (1.5, 5.5) 135.5 (99–203) 128.8 (100– 166) 124.8 (96–171) 120.5 (92–157) 0.8 (3.7, 5.3) 83.6 (55–126) 81.1 (59–113) 75.6 (54–108) 75.2 (54–102) 0.9 (4.3, 2.5) 421.4 (358– 527) 4.0 (2.9–5.3) 418.8 (353– 476) 3.9 (3.1–4.9) 428.5 (370– 523) 3.5 (2.8–4.3) 422.9 (342– 484) 3.7 (2.6–4.7) 3.6 (6.0, 13.1) 0.2** (0.4, 0.1) QTc ¼ QT interval corrected for heart rate.**Po0.01. Adjusted mean treatment difference from ANOVA. a presenting at the emergency department with acute severe asthma. For the emergency treatment of asthma with salbutamol at home, GINA guidelines1 suggest up to 800 mg of salbutamol to be used every 20 min, with further subsequent doses depending on the severity of asthma. For this high-dose study we chose three inhalations administered within 1 h (a cumulative dose of salbutamol 2400 mg), which should be an adequate total dose for most patients with acute severe asthma. Previous experience in patients with stable asthma and healthy volunteers suggested that a cumulative dose of formoterol 54 mg via Turbuhaler (delivered dose corresponding to 72 mg metered dose) would be the nearest equivalent dose to salbutamol 2400 mg regarding bronchodilation.4,8 As the study progressed, the difference in the FEV1 observed between formoterol- and salbutamol-treated patients widened. This increasing difference in effect was significant only after the 75 min time point. This difference probably reflected either a difference in dose/potency of the treatments or the longer duration of action observed with formoterol.4,17 No difference in onset of action has been seen between the two drugs in studies performed in stable asthma5 and following an induced bronchospasm.6 The rapid onset of bronchodilator effect of formoterol 4.5– 36 mg within 1–4 min in stable asthma and longer duration of action up to 12 h17 also has the potential to improve outcomes for patients with acute severe asthma in an emergency setting, providing it is associated with at least as good a safety profile as salbutamol. Insufficient response in FEV1 to inhaled rapid- and short-acting b2 agonists in patients with acute severe asthma may require hospitalization and the supervision of further doses of b2 -agonists to monitor for possible side effects.1 In this study, it was notable that the increase in FEV1 in response to salbutamol appeared to plateau soon after the last dose, whereas FEV1 continued to improve for the duration of the study following formoterol administration. In our study population there were no treatment failures and no patients required hospital admission after the 4-h follow-up. In addition to inducing bronchodilation, stimulation of b2 -adrenoceptors can result in extrapulmonary effects. As high doses of b2 -agonists may often be required to treat acute severe bronchoconstriction, safety may become an important consideration that dictates the dose and frequency of administration, and therefore the use of these agents.18 Therefore, blood pressure, heart rate, ECG and serum potassium were monitored during the study. There was no significant difference between the active treatments on blood pressure, ECG and heart rate. Formoterol significantly reduced average serum potassium values by more than salbutamol. However, this difference between treatments was not considered of clinical importance, with the lowest individual value on treatment observed in the salbutamol group (Table 3). Previous studies have shown that the systemic/ extrapulmonary effects of formoterol are similar or ARTICLE IN PRESS Formoterol (OXISs) Turbuhalers as a rescue therapy less pronounced than with short-acting b2 -agonists, such as terbutaline19 or salbutamol,8 especially when full dose–response curves for efficacy and safety are considered.9 The doses of formoterol and salbutamol used in this study were not equieffective. The efficacy of formoterol over 4 h was significantly better than that of salbutamol. Consequently the systemic activity measured as a decrease in serum potassium was also significantly greater after administration of formoterol, although clinically not important. Furthermore, there were no discontinuations due to AEs with either formoterol or salbutamol during the study and both treatments were equally well tolerated. The efficacy of formoterol has been demonstrated in this study based on objective lung function assessments. However, additional subjective benefits on symptoms and health-related quality of life were apparent with both formoterol and salbutamol. VAS and Acute AQLQ were both used to assess patient’s symptoms and wellbeing subjectively. Formoterol and salbutamol treatment caused equally rapid improvement in symptoms by both assessments. Both formoterol and salbutamol produced similar improvements in the symptoms and emotional function domains of the Acute AQLQ, and patients did not distinguish any difference in the overall treatment evaluation. Therefore, from a patient’s perspective, formoterol appears to be at least as good as salbutamol at improving wellbeing. These findings support those obtained in a recent placebo-controlled study in patients with methacholine-induced bronchoconstriction, where both formoterol and salbutamol provided early relief from dyspnoea (Borg scale) within the first minute after inhalation.20 While the results of this 4-h study are unlikely to warrant a revision of guidelines for treating asthma in an emergency setting,1 they offer reassurance that formoterol may be used for the safe and effective treatment of acute asthma exacerbations at home. The clinical implications of these results are important as many patients use formoterol for maintenance therapy and as an alternative asneeded therapy. This study demonstrated that patients prescribed formoterol Turbuhaler for regular or as-needed therapy can also obtain rapid and effective relief of acute severe exacerbations upon the inhalation of the maximum daily dose. Thus, the need for patients to carry and use another rapid-acting inhaled bronchodilator in the case of an emergency is not supported by these findings. To summarize, in this study formoterol 3  18 mg via Turbuhaler was well tolerated and at least as effective as salbutamol 3  800 mg via pMDI plus 1073 spacer in patients with acute severe asthma. After 75 min, formoterol demonstrated significantly better bronchodilation than salbutamol, that lasted for 4 h, which was the duration of this study. References 1. Global strategy for asthma management and prevention. WHO/NHLBI workshop report. National Institutes for Health, National Heart, Lung and Blood Institute. Publication no. 023659, 2002. 2. Weiss EB. Status asthmaticus. In: Weiss EB, Segal MS, editors. Bronchial asthma: mechanisms and therapeutics. Boston, MA: Little, Brown, 1976. p. 875–913. 3. Stanescu DC. High doses of sympathomimetic in severe bronchial asthma. Eur Respir J 1989;2:597–8. 4. Palmqvist M, Persson G, Lazer L, Rosenborg J, Larsson P, Lo. tvall J. Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 1997;10:2484–9. 5. Seberova! E, Andersson A. Oxiss (formoterol given by Turbuhalers) showed as rapid an onset of action as salbutamol given by a pMDI. Respir Med 2000;94:607–11. 6. Politiek MJ, Boorsma M, Aalbers R. Comparison of formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction. Eur Respir J 1999;13:988–92. 7. Lo. fdahl C-G, Svedmyr N. Formoterol fumarate, a new b2adrenoceptor agonist. Acute studies of selectivity and duration of effect after inhaled and oral administration. Allergy 1989;44:264–71. 8. Rosenborg J, Bengtsson T, Larsson P, Blomgren A, Persson G, Lo. tvall J. Relative systemic dose potency and tolerability of inhaled formoterol and salbutamol in healthy subjects and asthmatics. Eur J Clin Pharmacol 2000;56:363–70. 9. Rosenborg J, Larsson P, Rott Z, Bo. cskei C, Poczi M, Juha! sz G. Relative therapeutic index between inhaled formoterol and salbutamol in asthma patients. Respir Med 2002;96:412–7. ! 10. Malolepszy J, Bo. szo. rmenyi Nagy G, Selroos O, Larsson P, Brander R. Safety of formoterol turbuhaler at cumulative dose of 90 mg in patients with acute bronchial obstruction. Eur Respir J 2001;18:928–34. 11. Turner MO, Patel A, Ginsburg S, Fitzgerald J. Bronchodilator delivery in acute airflow obstruction. Arch Intern Med 1997;157:1736–44. 12. Cates CJ, Rowe BH, Bara A. Holding chambers versus nebulisers for b2-agonist treatment of acute asthma (Cochrane Review). Cochrane Database System Rev 2002:CD000052. 13. Nana A, Youngchaiyud P, Maranetra N, et al. b2-agonists administered by dry powder inhaler can be used in acute asthma. Respir Med 1998;92:167–72. 14. Tonnesen F, Laursen LC, Evald T, Sta( hl E, Ibsen TB. Bronchodilating effect of terbutaline powder in acute severe bronchial obstruction. Chest 1994;105:697–700. 15. Dejsomritrutai W, Nana A, Maranetra KN, et al. Reference spirometric values for healthy lifetime nonsmokers in Thailand. J Med Assoc Thai 2000;83:457–66. 16. Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. Am Rev Respir Dis 1993;147:832–8. 17. Ringdal N, Derom E, Wa( hlin-Boll E, Pauwels R. Onset and duration of action of single doses of formoterol inhaled via Turbuhalers. Respir Med 1998;92:1017–21. 18. Peters JI. Emergency treatment of asthma. Curr Opin Med 1995;1:65–72. ARTICLE IN PRESS 1074 19. To. tterman KJ, Huhti L, Sutinen E, et al. Tolerability to high doses of formoterol and terbutaline via Turbuhaler s for 3 days in stable asthmatic patients. Eur Respir J 1998;12:573–9. W. Boonsawat et al. 20. van der Woude HJ, Politiek M, Aalbers R. Formoterol provides rapid relief from acute dyspnoea following methacholine-induced bronchospasm. Eur Respir J 2002; 20 (Suppl. 38): 306s.