Comparison of intravenous salbutamol (albuterol) and aminophylline in the treatment of acute asthmatic attacks. Treatment of acute asthma. Is combination therapy with sympathomimetics and methylxanthines indicated? Gas exchange response to intravenous aminophylline in patients with a severe exacerbation of asthma. Aminophylline, salbutamol and combined intravenous infusions in acute severe asthma. Aminophylline in the treatment of acute asthma when beta 2-adrenergics and steroids are provided. Comparison of Enprofylline and Theophylline for Intravenous Treatment of Acute Asthma Comparison of intravenous aminophylline and salbutamol in severe asthma. Comparative effect of epinephrine and aminophylline in the treatment of asthma Aminophlline is effective on acute exacerbations of asthma in adults–objective improvements in peak flow, spirogram, arterial blood gas measurements and lung sounds Inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics. Does aminophylline add any benefit? Emergency therapy of asthma: comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. A controlled trial of the use of single versus combined-drug therapy in the treatment of acute episodes of asthma. Bronchodilator effect of theophylline preparations and aerosol fenoterol in stable asthma. Treatment of acute asthma. Lack of therapeutic benefit and increase of the toxicity from aminophylline given in addition to high doses of salbutamol delivered by metered-dose inhaler with a spacer. Effect of adding aminophylline infusion to nebulised salbutamol in severe acute asthma. Efficacy and safety of intravenous theophylline administration for treatment of mild acute exacerbation of bronchial asthma. Does Aminophylline Benefit Adults Admitted to the Hospital for an Acute Exacerbation of Asthma? Emergency room of treatment of asthma. Relationships among therapeutic combinations, severity of obstruction and time course of response. Which patients benefit from adding theophylline to beta 2-agonist treatment in severe acute asthma? Bronchodilator effects of terbutaline and aminophylline alone and in combination in asthmatic patients. Bronchodilator intake and plasma levels on admission for severe acute asthma. A comparison of intravenous aminophylline and salbutamol in the treatment of severe bronchospasm. Comparison of the oral and intravenous routes for treating asthma with methylprednisolone and theophylline. Emergency treatment of asthma. A comparison of two treatment regimens. Comparison of intravenous aminophylline and salbutamol in severe asthma. Aminophylline increases the toxicity but not the efficacy of an inhaled beta-adrenergic agonist in the treatment of acute exacerbations of asthma. Aminophylline therapy for acute bronchospastic disease in the emergency room. Intravenous aminophylline confers no benefit in acute asthma treated with intravenous steroids and inhaled bronchodilators. Ventricular arrhythmias during treatment for acute asthma. Comparison of intravenous and oral routes of theophylline loading in acute asthma.
Our investigation supports the use of intravenous salbutamol as an alternative to aminophylline in the early stages of acute severe asthma .  Salbutamol proved to be a marginally better bronchodilator and is likely to cause less gastrointestinal side effects than aminophylline , but tachycardia and generalized tremor are more frequent with this drug The role of bronchodilator regimens combining a sympathomimetic and a methylxanthine in the treatment of acute exacerbations of asthma remains controversial . This report describes the outcome of 157 emergency room visits for asthma in which patients were r and omly assigned to single-drug therapy with intravenous aminophylline , subcutaneous epinephrine , or inhaled isoproterenol or to one of three regimens combining a sympathomimetic and a methylxanthine . The increase in one-second forced expiratory volume after one hour of treatment with the two-drug combinations ( 0.79 + /- 0.07 liter ) was significantly greater than for epinephrine alone ( 0.57 + /- 0.08 liter ; p less than 0.05 ) but did not differ significantly from that occurring with therapy with isoproterenol alone ( 0.72 + /- 0.09 liter ; p = NS ) . This disparity reflects the greater bronchodilation effected by isoproterenol as a single agent than by epinephrine , in the dosing schedules and routes of administration chosen . Among patients presenting with severe airflow obstruction ( one-second forced expiratory volume 35 percent or less of normal ) , the bronchodilator response to isoproterenol alone was 0.88 + /- 0.14 liter versus 0.51 + /- 0.11 for epinephrine alone ( p less than 0.05 ) . It is concluded that the observed benefit derived from use of combination therapy depends on the dosage and potency of the particular sympathomimetic to which a methylxanthine is added , and on the severity of the airflow obstruction at presentation In patients with acute exacerbations of asthma , the intravenous administration of bronchodilators , such as salbutamol , entails the potential risk of worsening pulmonary gas exchange , despite an amelioration of airflow obstruction . The present study was design ed to investigate the effect of intravenous aminophylline on pulmonary gas exchange in patients hospitalized with a severe exacerbation of asthma . We studied 12 patients ( aged 41 + /- 13 yrs ) admitted to the hospital because of an exacerbation of asthma . The study was of a r and omized , double-blind , placebo-controlled design . Six patients were treated with intravenous aminophylline and six received placebo , in addition to st and ard treatment with inhaled salbutamol and intravenous corticosteroids .  Forced spirometry , respiratory gas exchange , ventilation-perfusion relationships assessed with the multiple inert gas elimination technique , and systemic haemodynamics were measured at baseline and 60 min after treatment started . In the aminophylline-treated group , mean theophylline plasma levels increased to 15.2 + /- 3.6 micrograms.ml-1 , forced expiratory volume ( FEV1 ) increased by 17 + /- 12 % , and forced vital capacity ( FVC ) by 16 + /- 10 % . The mean changes in FEV1 and FVC in the aminophylline-treated group were significantly higher than in the placebo-treated group . Likewise , minute ventilation increased by 23 + /- 14 % and arterial carbon dioxide tension ( PaCO2 ) decreased by 0.4 + /- 0.3 kPa ( 3 + /- 2 mmHg ) during aminophylline infusion . No significant changes in arterial oxygen tension ( PaO2 ) or in ventilation-perfusion distributions were shown in aminophylline-treated patients . ( ABSTRACT TRUNCATED AT 250 WORDS Twenty-one patients admitted to hospital with acute severe asthma were allocated in a r and om , single-blind manner to receive intravenous infusions for 24 hours or either aminophylline or salbutamol or a combination of the two drugs . Infusions were administered by a slow infusion pump with an initial loading dose given over 15 minutes , followed by a continuous lower dose of the drug 24 hours as follows : 1 . Aminophylline 0.285 mg/kg/min for 15 min followed by 0.014 mg/kg/min ( 20 mg/min . followed by 1 mg/min for a 70 kg subject ) . 2 . Salbutamol 0.285 microgram/kg/min for 15 min followed by 0.057 microgram/kg/min ( 20 microgram/min followed by 4 microgram/min for a 70 kg subject ) . 3 . Combined regimen of the above infusions . In addition each patient received intravenous hydrocortisone ( 4 g ) and potassium chloride ( 4 g ) in 2 litres of 5 % dextrose infused over 24 hours amd 35 % oxygen given via a Ventimask . Peak expiratory flow rates showed a significant improvement after 15 minutes treatment with aminophylline and the combined infusion , but this was not seen until 60 minutes with the salbutamol infusion . No synergistic bronchodilator effect was seen with the combined infusion . The results show that intravenous aminophylline is superior to intravenous salbutamol in the doses given in the initial treatment of acute asthma and that the combination when given intravenously is not better than aminophylline alone BACKGROUND The purpose of this study was to test the contribution of aminophylline in improving peak expiratory flow rate ( PEFR ) during emergency department treatment of acute asthma when metaproterenol sulfate and steroid therapy are also provided . METHODS In a prospect i ve , r and omized , double-blind , and placebo-controlled trial at a municipal hospital emergency department , 44 patients with acute asthma , aged 18 to 45 years , with theophylline levels below 28 mumol/L , who had failed to achieve a PEFR of 40 % predicted after one nebulized metaproterenol treatment , were recruited . An aminophylline or placebo loading dose and maintenance infusion were administered . All patients received hourly nebulized metaproterenol and initial methylprednisolone sodium succinate . The PEFR was measured hourly for 5 hours . Two-factor repeated- measures analysis of variance of improvement in PEFR ( [ final-initial PEFR]/predicted PEFR ) was assessed . RESULTS There was no difference in improvement of PEFR at any hour between the treatment and placebo groups . After 5 hours , the difference in improvement ratio was 0.40 ( aminophylline ) vs 0.36 ( placebo ) ( P = .30 ; n = 22 in each group ) . The treatment group suffered more tremor , nausea or vomiting , and palpitations ( P < .05 ) . CONCLUSION In the emergency department setting , aminophylline contributes no significant improvement in PEFR when beta 2-agonists and corticosteroids are being provided , while causing more side effects Thirty‐nine patients with asthma requiring acute treatment were included in a r and omized , double‐blind , paralle1 study which compared the effect of enprofylline ( 1.0 mg/kg ) and theophylline ( 3.0 mg/kg ) . The drugs were given intravenously over a period of 10 min . Peak flow ( PEF ) , heart rate and plasma concentrations of the drugs were determined before and after the injection . Both enprofylline and theophylline significantly increased the PEF 30 min after the injection , the mean increases over the baseline values being 21 % and 23 % , respectively . The clinical effects assessed by the patient and the physician and the significant decreases in heart rate were similar for the two drugs . Side effects were rare . Thus , 1.0 mg/kg of enprofylline was comparable to 3.0 mg/kg of theophylline in the treatment of patients with acute asthma Severe asthma is the most common respiratory emergency treated in casualty departments of most hospitals . Intravenous aminophylline has been the mainstay of bronchodilator treatment for several years , although sudden death may occur after rapid administration,1 2 and it may be cardiotoxic.3 We thought that a selective adrenoceptor agonist might therefore be worthy of trial , and we report here our results with single and double-blind comparative trials of intravenous aminophylline and salbutamol on 50 patients with severe asthma Thirty-seven patients with severe asthma were r and omized into three groups and treated double-blindly with either aminophylline , epinephrine , or a combination of these two for one hour and then with both drugs for an additional hour . All patients began with plasma theophylline levels less than 10 µg/ml and all achieved 17 µg/ml . Epinephrine produced 134 % improvement in FEV1 in one hour compared to 38 % improvement produced by aminophylline . Epinephrine and combination therapy produced the same amount of bronchodilatation in one hour . Patients whose initial PEFR was ≦100 l/min failed to improve with aminophylline alone . After two hours of treatment , there was no difference in FEV1 or PEFR among the three groups . Arrhythmias and vomiting occurred more frequently when aminophylline was used and these adverse responses did not correlate with plasma theophylline levels Second Department of Medicine , Teikyo University School of Medicine , * Clinical Research Center for Allergy and Rheumatology . National Sagamihara Ho.spital . f Section of Allergy and Respiratory Medicine . Doai Memorial Hospital IMat.sunwra Clinic and Research institute for Asthma and Imtnunological Diseases , l^Fourth Department of Medicine , Nippon Medical School , and ^International Medical Center of Japan , Tokyo , STUDY OBJECTIVE To determine the efficacy of intravenous aminophylline in the treatment of adult patients hospitalized for exacerbation of asthma . DESIGN R and omized , double-blind , placebo-controlled trial throughout the study . SETTING University Hospital Clinical Research Center . PATIENTS Forty-four patients admitted from the emergency room with a primary diagnosis asthma ; 39 patients completed the study . INTERVENTIONS Patients received either intravenous aminophylline or placebo in addition to frequent nebulized albuterol ; prednisone 0.5 mg/kg body weight every 6 h orally ; and supplemental oxygen . Aminophylline infusion rates were adjusted to achieve serum theophylline concentrations of 10 to 20 micrograms/ml . Changes were made in placebo infusion rates to maintain the double blind design . MEASUREMENTS AND RESULTS Forced expiratory volume in 1 s ( FEV1 ) and other spirometric measurements every 8 h by a blinded investigator or trained respiratory therapist . Subjective patient response and duration of hospitalization were compared . No difference in spirometric measurements was observed between the two groups at any time point . On admission to the study , FEV1 in the placebo group was 41.5 ( + /- 2.9 ) percent predicted and in the aminophylline group 34.7 ( + /- 2.3 ) percent predicted ( p = 0.08 ) . At discharge , FEV1 was 70.4 ( + /- 2.9 ) percent predicted in the placebo group and 63.7 ( + /- 2.8 ) percent predicted in the theophylline group ( p = 0.10 ) . There was no difference in subjective patient rating or duration of hospitalization between the two groups ( placebo 1.95 days and aminophylline 1.78 days , p = 0.51 ) . CONCLUSIONS Our results suggest that aminophylline therapy does not add significant benefit to other st and ard therapies in hospitalized adult asthmatic patients . Because of the risks and cost of aminophylline treatment in the hospital setting , further research is needed to determine if there are subgroups of adult asthmatics who may benefit from the addition of aminophylline to other st and ard optimal therapies Forty-eight patients who presented with acute episodes of asthma were r and omized to treatment with subcutaneously administered epinephrine , inhaled isoproterenol , or intravenously administered aminophylline . The patients ' couses were followed clinical ly and with spirometry . Although there were no significant differences between the groups before treatment for any measured variable , at the end of 1 hour , the mean improvement inforced expiratory volume in one second ( FEV1 ) was significantly greater for patients treated with epinephrine ( 0.76 L ) or nebulized isoproterenol ( 0.79 L ) than for those given aminophylline ( 0.23 L ) . Similarly , the mean duration of therapy required before discharge from the emergency room was significantly longer for patients receiving aminophylline ( 5.4 h ) than for patients treated with either epinephrine ( 3.5 h ) or isisoproeternol ( 3.0 h ) . There was no significant differences between the effects of the 2 beta agonists . These results demonstrated that short-acting sympathomimtic agents produce more rapid and potent bronchodilatation in acutely ill asthmatics than that provided by intravenously administered methylxanthines , and that there are no disadvantages to using an inhaled beta agonist rather than one administered parenterally Eighty-nine patients who presented to the hospital for treatment of acute episodes of asthma were r and omly assigned to initial therapy with subcutaneously administered epinephrine or 1 of 2 combination regimens consisting of intravenously administered aminophylline and either subcutaneously administered of epinephrine or inhaled isoproterenol . During the first hour of treatment , as a group , the patients treated with the 2-drug regimens showed greater objective improvement than did patients who received epinephrine alone . This was particularly true for patients with either severe airway obstruction or a subtherapeutic theophylline concentration at the time of presentation . There were no differences in the heart rate and blood pressure responses to the 3 regimens , and symptoms consistent with drug side effects were not reported more frequently by patients treated with 2 drugs . Thus , the combination of sympathomimetics and aminophylline appear more effective , and no more toxic , than epinephrine alone for the initial treatment of acute episodes of asthma To compare the acute bronchodilator effect of increasing doses of intravenous theophylline and inhaled beta adrenergic agonists , we administered intravenous theophylline dissolved in ethylenediamine or proxyphylline and diprophylline or placebo in a double blind fashion to nine asthmatics on three different days . At each session , 100 mg theophylline or placebo were given during each of five subsequent periods of 30 minutes ' duration and followed by inhalation of 0.4 mg fenoterol . In contrast to placebo , 500 mg theophylline in ethylenediamine or proxyphylline and diprophylline significantly decreased mean specific airway resistance ( SRaw in cmH2O.s ) from 31.2 to 23.6 or 34.2 to 23.5 at theophylline serum concentrations of 14.4 or 16.6 mg/L , respectively . Fenoterol lowered SRaw to about 40 percent of the respective baseline values independent of theophylline or placebo pretreatment . We conclude that the acute bronchodilator effect of theophylline is weak in comparison to inhaled beta agonists . Furthermore , proxyphylline and diprophylline cause a weak but not significant bronchodilation when compared to ethylenediamine We conducted a r and omized , double-blind , placebo-controlled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol in patients who presented for treatment of acute asthma . We studied 94 patients ( mean age , 35.6 + /- 11.2 years ) with moderate to severe acute asthma . All patients received therapy with salbutamol delivered with metered-dose inhaler ( MDI ) into a spacer device ( Volumatic ) in four puffs ( 400 micrograms ) at 10-min interval , and intravenous hydrocortisone ( 500 mg ) . Patients were r and omly assigned to receive either a loading dose of intravenous aminophylline followed by a routine infusion ( n = 45 ) or an equal volume of placebo as a loading dose and infusion ( n = 49 ) . The two groups showed no differences in measurements of peak expiratory flow , FEV1 , and FVC at baseline and at the end of treatment . However , the patients treated with aminophylline had significantly more adverse effects ( p < 0.05 ) . There were no differences in the final mean dose of salbutamol ( 6.3 + /- 44.5 mg for the placebo group and 5.8 + /- 4.2 mg for the aminophylline group ) , hospital admission rate ( 10.2 percent for the placebo group and 9.0 percent for the aminophylline group ) , and mean duration of Emergency Department treatment ( 2.5 + /- 1.83 h for the placebo group and 2.37 + /- 1.75 h for the aminophylline group ) . The results were similar when the patients were divided in accord with the degree of respiratory obstruction ( baseline FEV1 < 30 percent of predicted ) and theophylline level at 30 min of treatment ( placebo group patients with theophylline level < 10 mg/L vs aminophylline group patients with theophylline level > or = 10 mg/L ) . We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled salbutamol in the treatment of acute exacerbations of asthma BACKGROUND --The benefit of adding theophylline to beta 2 agonists in acute asthmatic attacks has been debated frequently . METHODS --In an open r and omised study 25 patients with severe acute asthma who presented to the emergency department were treated with either a combined nebulised salbutamol ( 5 mg/dose ) and aminophylline infusion ( 0.6 - 0.9 mg/kg/hour ) , or nebulised salbutamol alone . RESULTS --The responses to treatment as measured by peak expiratory flow ( PEF ) and the time taken to achieve maximum PEF were similar in both groups . Side effects were observed more commonly in patients receiving the combined treatment . CONCLUSIONS --Nebulised salbutamol is equally efficacious in acute asthma when given alone or in combination with aminophylline OBJECTIVE The present study was design ed to evaluate the efficacy and safety of intravenously administered theophylline ( IAT ) for the treatment of an acute exacerbation of bronchial asthma .  The theophylline was solubilized and not combined with ethylenediamine . METHODOLOGY The subjects were 22 asthmatic patients with mild acute exacerbation of bronchial asthma . All patients had been taking oral sustained-release theophylline  and their serum concentrations of  theophylline were measured . The 16 patients whose serum theophylline concentrations were < 13 microg/mL were r and omly selected and treated with IAT ( 200 mg theophylline in 200 mL saline ) for 2 h. Six patients were r and omly selected as controls and received 200 mL of saline .  Pulmonary function and asthma severity ( Borg scale ) before and after treatment were measured . RESULTS After IAT , both PEF ( before IAT , 313+/-79 L/min ; after IAT , 335+/-107 ; P<0.05 ) and FEV(1 ) ( before IAT , 1.66+/-0.47 L ; after IAT , 1.83+/-0.44 ; P<0.05 ) increased significantly . Furthermore , their severity of asthma as assessed by the Borg scale ( before IAT , 2.5+/-1.2 ; after IAT , 1.3+/-1.0 ; P<0.05 ) improved significantly . In contrast , neither FEV(1 ) , PEF , severity of asthma or Borg scale changed significantly in the group who only received saline . None of the patients treated in this study had any adverse effects . CONCLUSION These results suggest that IAT is useful for patients with mild acute exacerbation of bronchial asthma and is safe if serum theophylline concentrations are measured Intravenous theophylline ( aminophylline ) has been used for more than 50 years to treat acute exacerbations of asthma [ 1 ] . However , in the emergency department treatment of acute exacerbations of asthma , it has not been shown to be as effective as inhaled -agonists [ 2 ] and may increase minor adverse side effects when combined with -agonists [ 3 ] . Consequently , the National Heart , Lung , and Blood Institute ( NHLBI ) Expert Panel on the diagnosis and management of asthma has not recommended its routine use in the treatment of asthma in the emergency department [ 4 ] . In contrast , both the Expert Panel [ 4 ] and the British Thoracic Society [ 5 ] recommend the routine use of oral or intravenous theophylline in adults admitted to the hospital for acute exacerbation of asthma , despite the lack of controlled studies . Because theophylline has a narrow therapeutic index and its use can result in serious adverse effects when dosage is not carefully adjusted on the basis of serum concentration measurements [ 6 ] , its use can be justified only if a benefit is clear , especially since the advent of inhaled 2-selective agonists and the early use of high-dose corticosteroids [ 7 ] . Because the observation periods in two of the studies question ing aminophylline 's efficacy were 3 hours or less [ 2 , 3 ] , we postulated that the drug 's benefit may occur later in the course of therapy . Thus , the purpose of our study was to determine whether the addition of intravenous aminophylline ( during a 48-hour period ) improves pulmonary function faster than frequent nebulizations of albuterol and intravenous methylprednisolone alone . Methods Study Design and Patient Selection We did a r and omized , placebo-controlled , double-blind study in patients admitted to the medical service of a tertiary-care university teaching hospital . The study protocol was approved by the Institutional Review Board of the University of Florida , and each patient gave written informed consent . Eligible persons included adults 18 to 50 years old who were admitted to the hospital with an acute exacerbation of asthma by the emergency department physician . Each patient met the American Thoracic Society criteria for the diagnosis of asthma [ 8 ] and had failed to respond to three or more doses of inhaled albuterol ( with or without the addition of subcutaneous terbutaline ) and a loading dose of intravenous corticosteroids .  Chest radiographs , arterial blood gas values , and serum theophylline concentrations measured by fluorescence polarization immunoassay ( Abbott TDx ; Abbott Diagnostics , Irving , Texas ) [ 9 ] were obtained from each patient . Entry into the study ( design ated as time 0 ) was identified by the first spirometric measurement done by the investigators ( after treatment in the emergency department and at hospital admission ) . Patients were excluded if they were unable to perform spirometry correctly or consistently ; were intubated ; were pregnant ; had a lower respiratory tract infection ( lobar consolidation or new pulmonary infiltrate on chest radiograph ) ; had a Pco 2 greater than 50 mm Hg after three consecutive nebulized albuterol treatments ; had chronic cardiopulmonary disease , chronic bronchitis , or emphysema ; or if the patient had a forced expiratory volume in 1 second ( FEV1 ) greater than 80 % of the predicted value at time zero . Interventions All patients received routine intravenous fluids ; supplemental oxygen to keep oxygen saturation greater than 92 % by pulse oximetry ; intravenous methylprednisolone , 125 mg , in the emergency department , followed by 60 mg every 6 hours ; nebulized albuterol treatments ; and either intravenous aminophylline or placebo . The dose and frequency of administration of as-needed albuterol nebulizations were titrated to clinical response , FEV1 , and adverse effects . The dose ( 2.5 or 5.0 mg ) was selected by the internal medicine housestaff based on their judgment of the adequacy of the clinical response , the occurrence of adverse effects on heart rate or blood pressure , or if tremor or headache was intolerable . The frequency of nebulizations was based on the last measured FEV1 . The following criteria for as-needed albuterol administration were used . If the FEV1 was less than 30 % ( of the predicted value ) , albuterol treatments were given every half hour . If FEV1 was 30 % to 50 % , treatment was given every 1 to 2 hours ( the choice between 1 and 2 hours was based on the physician 's assessment of the severity of symptoms and presence of adverse effects ) . If FEV1 was more than 50 % , albuterol was given every 4 hours . This individualization of albuterol administration is consistent with recommendations in the NHLBI Expert Panel Report [ 4 ] . Albuterol ( Proventil 5 % solution ; Schering Corporation , Kenilworth , New Jersey ) was diluted to a final volume of 4 mL with normal saline and delivered by a Whisper Jet h and -held nebulizer ( Marquest , Englewood , Colorado ) driven by 100 % oxygen at a flow rate of 8 L/min . Under these conditions , 85 % of the dose of albuterol is aerosolized [ 10 ] . Patients were selected r and omly to receive an intravenous loading dose of either aminophylline or placebo , which was prepared by an unblinded clinical pharmacist . Aminophylline was added to a commercial plastic intravenous bag containing 5 % dextrose in water , whereas the intravenous solution alone was used for placebo . The intravenous bags were identical in appearance and labeling . In the patients treated with aminophylline , the loading dose was based on the serum theophylline concentration measured in the emergency department and was infused for 30 minutes . One milligram per kilogram of theophylline was administered for each 2 g/mL desired increase in serum theophylline concentration to achieve a target concentration of 15 g/mL [ 11 ] . Thereafter , a continuous infusion of aminophylline ( starting at 0.6 mg/kg hour ) or placebo was begun . The infusion rate of aminophylline was adjusted by the clinical pharmacist to maintain theophylline concentrations between 10 and 20 g/mL. To assure double-blinding , patients receiving placebo infusions had sham theophylline concentrations measured , followed by adjustment of the placebo infusion rate . The r and omization code was not revealed until the last patient completed the study . Measurements and End Points Spirometry was done using a water-sealed Collins spirometer attached to an Eagle 1 microprocessor and printer ( W.E. Collins , Braintree , Massachusetts ) . Each spirometric maneuver ( the better of two efforts ) was done approximately 1 hour after a nebulized albuterol treatment . The spirometer was calibrated each day with a 3-L syringe . Forced expiratory volume in 1 second was measured at 0 ( entry point ; baseline ) , 1 , 3 , 6 , 12 , 24 , 36 , and 48 hours . For each patient at each time point , FEV1 was converted to a percentage of the predicted value based on age , height , sex , and race [ 12 ] ( Appendix ) . Our primary outcome measure was relative improvement in FEV1 from hour 0 . The change in FEV1 from baseline to time t was st and ardized relative to the difference between the baseline value and the 100 % predicted value for that patient [ 12 ] ( Appendix ) . This measurement , when plotted against the log of time , provides a good linear fit for assessing rate of improvement in FEV ( 1 ) . It measures the improvement in FEV1 in a way that adjusts for intersubject differences in baseline severity of airway obstruction and it is also independent of body size . Some investigators have suggested that this is the best clinical method for assessing bronchodilator response [ 13 , 14 ] . Adverse effects , vital signs , and an asthma symptom score were measured at the same times as FEV1 . The symptom score was the sum of the subjective rating of the patient 's sensation of dyspnea plus the study physician 's assessment of the severity of wheezing based on auscultation . The following was the basis for the symptom score : absent = 0 , mild = 1 , moderate = 2 , and severe = 3 . The maximum possible score at each time point was 6 points . Also recorded was the number of as-needed nebulizations of albuterol  and the total dose of albuterol  given during the 48-hour study period . Whole-blood theophylline concentration was measured from a fingerstick at the bedside by an unblinded clinical pharmacist using an AccuLevel kit ( Syntex Medical Diagnostics , Palo Alto , California ) [ 15 ] at 0.5 hours and 8 hours after completion of the intravenous bolus of aminophylline or placebo and then approximately every 24 hours thereafter . The coefficient of variation for measurement of a 10-grams/mL control solution by the pharmacists participating in the study was 11 % ( n = 31 ) . This method of measuring theophylline concentration was used to avoid unblinding by the hospital laboratory computer system . The study drug infusion and intravenous methylprednisolone were discontinued at 48 hours or before if the patients became relatively asymptomatic and were ready for discharge . At that time , both  aminophylline- and placebo-treated patients were converted to oral prednisone , 40 to 60 mg daily , and to oral slow-release theophylline . Patient discharge decisions were made blinded by housestaff physicians . Because patients were charged for all hospital costs , we considered it to be unethical to keep them in the study if they became asymptomatic before 48 hours . Data Analysis Mean differences between  aminophylline- and placebo-treated patients on quantitative demographic and outcome variables were assessed by ordinary two- sample Student t-tests and Wilcoxon rank-sum tests . Because the two methods produced similar conclusions , only the results of the two- sample Student t-tests are reported , along with their associated CIs . The Fisher exact test was used to analyze categorical variables such as sex , race , smoking status , and incidence of adverse effects . For computing CIs for differences in proportions , we used the exact method of Conlon and Thomas [ 16 ] . The robust tests of O'Brien [ 17 ] and Brown and Forsythe [ 18 ] were used to compare the group 's In an effort to determine the optimal emergency therapy for acute episodes of asthma , we r and omly , assigned 102 acute ill patients to 60 minutes of treatment with inhaled isoproterenol alone , isoproterenol plus intravenous aminophylline or isoproterenol plus a single oral dose of an elixir of theophylline .  Patients requiring treatment beyond this time were given an injectable sympathomimetic agent in addition . The combination of isoproterenol and a methylxanthine was not found to be better than isoproterenol alone , and the route of administration of methylxanthine was not an important determinant of either the serum theophylline level or the therapeutic response . A major variable that influenced the duration of therapy needed to produce a remission was the severity of the obstruction at presentation . Persons whose initial 1-second forced expiratory volumes were less than 30 percent of predicted and who did not improve 35 percent or more to at least 40 percent of predicted at the end of 60 minutes of intense treatment were those who ultimately required prolonged emergency room therapy and /or hospital admission for control of their symptoms . Thus , simple objective assessment of the degree of impairment at presentation coupled with the response to initial treatment will serve to identify early a high-risk group of asthmatic patients in whom the usual emergency room therapeutic modalities will often prove ineffective The aim of this investigation was to study whether certain patients benefit from adding theophylline to the beta 2-agonist treatment of acute asthma . The study group comprised 101 patients who were taking oral theophylline .  The patients received inhaled salbutamol ( albuterol ) ( 0.15 mg/kg x 2 ) ( n = 53 ) or IV salbutamol ( 5 micrograms/kg ) ( n = 48 ) . Aminophylline ( 3 mg/kg ) was infused intravenously 60 minutes after the start of the salbutamol treatment . The mean increase in peak flow ( PEF ) after the aminophylline infusion was 22 + /- 33 L/min or 4 % + /- 6 % of the predicted value ( mean + /- SD ) . A change in PEF correlated negatively to plasma theophylline before treatment ( P less than .01 ) and positively to a change in plasma-theophylline after treatment ( P less than .05 ) . All patients with an increase in PEF of more than 10 % of the predicted value ( n = 14 ) after the theophylline infusion had plasma-theophylline levels before treatment of below 7.5 mg/L ( 41 mumol/L ) . No significant difference in the change in PEF after the theophylline infusion was found between patients who had received inhaled or intravenous salbutamol . This investigation could indicate that IV theophylline as an additive to beta 2-agonist treatment should be reserved for patients who are either not taking theophylline or who have only taken a low dose before arriving for the emergency treatment of acute asthma In 17 patients with moderate to severe asthma , we compared acute bronchodilator effects of the following drugs or drug combinations using a double-blind crossover design : terbutaline , 5 ; aminophyline 400 ; terbutaline , 5 , plus aminophyline , 400 ; terbutaline , 2.5 ; aminophylline , 200 ; terbutaline , 2.5 , plus aminophyline , 200 mg ; and placebo . The higher doses of terbutaline and aminophylline alone produced comparable bronchodilation and similarly frequent adverse side effects ; low doses of each drug also had comparable effects . The high-dose combination produced significantly ( P less than 0.05 ) greater bronchodilatation than either drug alone . The low dose combination had bronchodilator effects comparable to those produced by the higher dose of either drug alone . These findings suggest therapeutic advantages in combining high doses of theophylline and an oral beta adrenergic agonist ( terbutaline ) in asthma not well controlled on high doses of either drug alone and in combining these drugs in lower doses in patients experiencing intolerable side effects from a high dose of either drug We have measured the plasma levels of salbutamol , terbutaline and theophylline in 140 patients ( 70 men , mean age 57 yrs ) arriving for emergency treatment with severe acute asthma . The aim of the study was to investigate how the measured plasma levels correlated with the reported bronchodilator intake and whether the pretreatment beta 2-agonist levels influenced the effect of emergency salbutamol treatment . We found a highly significant correlation between the reported 24 h dose and the measured plasma concentrations for all three drugs . A plasma concentration less than 40 mumol.l-1 was found in 63 of the 107 patients who had taken theophylline , while no patient had a plasma concentration greater than 110 mumol.l-1 . A plasma concentration above the suggested therapeutic range was found in 23 of the 95 patients who had taken terbutaline ( greater than 30 nmol.l-1 ) and in 12 of the 98 patients who had taken salbutamol ( greater than 60 nmol.l-1 ) . A significant negative correlation was found between the initial plasma beta 2-agonist levels and the bronchodilation after i.v . salbutamol treatment ( 5 micrograms.kg-1 ) , while there was no clear indication that high plasma beta 2-agonist levels reduced the bronchodilator effect of a high dose of inhaled salbutamol ( 0.15 mg.kg-1 x 2 ) . We conclude that some patients arriving with acute asthma have high blood concentrations of beta 2-agonists , which possibly limit the response to i.v . beta 2-agonist treatment , while the effect of high-dose inhaled beta 2-agonists appears to be related to a lesser degree to the drug concentration on arrival . In this study overtreatment with theophylline appears to be uncommon Intravenous salbutamool or aminophylline was administered under double-blind conditions to 20 asthmatic patients presenting with severe dyspnoea and needing urgent treatment with bronchodilators . Ten patients received salbutamol and ten patients received aminophylline . Objective measurements showing improvement were recorded in nineteen patients . A greater response was produced by salbutamol although this failed to reach statistical significance . Neither drug affected pulse or blood pressure . It is suggested that intravenous salbutamol is an effective bronchodialtor in the treatment of acute exacerbation of asthma or bronchitis To compare intravenous and orally administered corticosteroids and theophylline in treating acute episodes of airways obstruction , patients with recent worsening of obstructive symptoms were r and omly divided into two groups . Group A received methylprednisolone , 80 mg/24 h , and aminophylline by continuous infusion . Group B received a comparable dose of a sustained-release theophylline and methylprednisolone , 80 mg in two equally divided doses , by mouth . Assessment of response was based on daily spirometric tests and evaluation of dyspnea and wheezing . Arterial blood gas and serum theophylline levels were also measured . The groups were comparable with respect to age , sex distribution , smoking history , and spirometric evidence of obstruction . Initial spirometric test results showed moderate obstruction , equal in the two groups . Obstruction improved markedly by both spirometric and clinical criteria in the four-day study period . The improvement in FEV1 and dyspnea index was slightly greater for group B , but the differences were not significant . We conclude that oral administration of steroids and theophylline is as effective as intravenous use in treating hospitalized patients with moderate exacerbations of airways obstruction The effectiveness of epinephrine was compared to that of a combination of epinephrine and aminophylline in the initial treatment of acute asthma . Forty-four patients with 51 episodes of acute asthma were evaluated . Peak flow spirometry served as an objective measure of airway resistance , and theophylline levels were determined at fixed intervals throughout the study . Epinephrine and aminophylline were not found to be superior to epinephrine alone . There was no correlation between mean serum theophylline levels and the magnitude of improvement . Rapidity of emergency department discharge and frequency of admission was independent of treatment method . The failure of epinephrine-aminophylline to effect more rapid or profound improvement in pulmonary function might suggest that epinephrine alone , or an equivalent sympathomimetic is a rational choice in the initial treatment of acute asthma Twenty hospital patients with severe asthma , with a pulse rate of > 120/ min , peak flow rate ( PFR ) < 25 ° ' predicted , and Pao2 < 93 kPa ( 69 - 8 mm Hg ) gave informed consent . All were given 1 g of hydrocortisone intravenously initially and oxygen by 28%h Ventimask ( except during the five minutes before each arterial puncture ) . Either aminophylline 0 - 5 g or salbutamol 500 , ig was given intravenously over one hour by constant rate infusion pump . They were dispensed in identical ampoules , labelled by number , and allocated r and omly and double blind . Response to treatment was measured by a Wright peak flow meter , the best of three readings taken 10 and 5 minutes before treatment and every 10 minutes during the infusion , and arterial gases ( Astrup micro- method ) at 0 , 15 , and 60 minutes . Pulse and blood pressure were recorded every 10 minutes and the electrocardiograph monitored continually . Patients given an intravenous bronchodilator within 3 hours before admission were excluded . Results were analysed as the mean peak increase or decrease during drug administration and also as the average increase ( or area under the curve ) , using a t test for unpaired sample s. Eleven patients received salbutamol  and 9 aminophylline . Both drugs produced a significant increase in PFR , greater after salbutamol , though the difference between the drugs was not statistically significant ( see table ) . Pulse rate fell after aminophylline but not after salbutamol , the difference between the two being significant . The diastolic blood pressure fell after salbutamol but not after aminophylline . No significant changes in blood gases occurred after either drug . Side effects occurred in 7 of the 9 patients given aminophylline and in 5 of the 11 given salbutamol . Two given aminophylline and 3 given salbutamol  experienced headache . Three of the aminophylline group and 2 of the salbutamol group experienced tremor . Nausea ( 4 patients ) , vomiting ( 1 patient ) , and ventricular extrasystoles ( 4 patients ) occurred only in those given aminophylline . In one patient , who also had mitral valve disease , the ventricular extrasystoles became fewer during the salbutamol infusion . No significant changes occurred in the serum potassium during the infusion in either group We studied 40 patients with acute exacerbations of asthma to determine the efficacy of a 3-h intravenous infusion of aminophylline in patients who were already being treated with an inhaled beta-adrenergic agonist ( metaproterenol ) .  Each patient was treated with inhaled metaproterenol at hourly intervals for 3 h. In addition , patients were r and omly assigned to therapy with either intravenous aminophylline or placebo . Neither the patient nor the house officers and nurses caring for the patient knew whether aminophylline or placebo was given . The FEV1 improved continually throughout the study to a similar extent in both treatment groups , but the patients treated with aminophylline had significantly more adverse effects ( p less than 0.025 , Mann-Whitney ) . There was no apparent benefit from aminophylline even in patients who presented to the emergency room with severe airway obstruction ( FEV1 less than 0.8L ) or with plasma theophylline levels less than 10 mg/L. We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled metaproterenol in the treatment of acute exacerbations of asthma OBJECTIVE To assess the role of aminophylline in the treatment of acute exacerbations of bronchospastic disease when used in addition to inhaled beta-agonists and intravenous corticosteroids . DESIGN R and omized , double-blind , placebo-controlled intervention study . PATIENTS One hundred thirty-three adult patients with either asthma or chronic obstructive pulmonary disease who presented to the emergency department with asthma or wheezing . INTERVENTIONS All patients received therapy with both aerosolized metaproterenol and intravenous methyl-prednisolone . Patients were r and omly assigned to receive either a loading dose of aminophylline followed by a routine infusion ( n = 65 ) or an equal volume of placebo as a loading dose and infusion ( n = 68 ) . MEASUREMENTS AND MAIN RESULTS At discharge from the emergency department , the median serum theophylline concentration for the aminophylline group was 54 mumol/L ( 9.7 mg/L ) . The two groups showed no differences ( P greater than 0.2 ) in measurements of forced expiratory volume at 1 second ( FEV1 ) , forced vital capacity ( FVC ) , or peak expiratory flow rate ( PEFR ) at baseline or at 60 or 120 minutes after aminophylline administration . Neither patient satisfaction nor physician assessment of response to therapy differed between the two groups . There was no difference ( P greater than 0.2 ) in the frequency of side effects , except for a trend toward a higher frequency of nausea ( P = 0.13 ) in the aminophylline group . There was , however , a threefold decrease in the hospital admission rate for patients treated with aminophylline ( 6 % ) compared with placebo recipients ( 21 % ) ( P = 0.016 ) . CONCLUSION Aminophylline , in doses producing levels just below the commonly accepted therapeutic range , appears to decrease hospital admissions in patients with acute exacerbation of asthma or chronic obstructive pulmonary disease . This finding , if confirmed in larger studies , may represent a substantial cost savings BACKGROUND The role of intravenous aminophylline in acute asthma is unclear despite meta- analysis of many studies comparing aminophylline with other bronchodilator therapies . AIMS The aim of this study is to determine whether continuous aminophylline infusion confers any benefit in acute severe asthmatics treated with intravenous steroids and inhaled bronchodilators . METHODS The study was r and omised , double-blind and placebo-controlled . All patients received nebulised salbutamol ( 1 mL of 0.5 % ) and ipratropium bromide ( 1 mL of 0.025 % ) with glycol diluent ( 1 mL ) at 0 , two , four , six , eight and 12 hours , and six-hourly thereafter . In addition all patients were given intravenous hydrocortisone 250 mg six-hourly and oxygen to maintain normoxia . Aminophylline infusions were adjusted to maintain therapeutic levels . Peak expiratory flow rate ( PEFR ) was measured before and after nebulised bronchodilator on a two-hourly basis in the Emergency Department ( ED ) and six-hourly on the inpatient wards . RESULTS Thirty-one patients were clinical ly sufficiently improved within 12 hours to be discharged home from the ED . The remaining 28 patients were admitted to the inpatient ward for a total trial duration of 48 hours . No significant difference was found between the placebo and treatment groups for measurements of PEFR , or for the duration of stay of the patients in hospital . The power of the study was 80 % for a 25 % to 33 % difference at a 5 % level of significance . Presentation values of PEFR and arterial blood gases did not predict which patients would require inpatient admission and which could be safely discharged home from the ED A double-blind , r and omized study was performed to determine the occurrence of ventricular arrhythmias in acute asthma patients treated with epinephrine , aminophylline , or both in combination . Sixty patients were studied with Holter monitoring during the 90-minute study period . There was no statistical difference among the study groups in frequency or grade of ventricular arrhythmia . Combination treatment of acute asthma with these drugs is as safe as treatment with either alone In a prospect i ve , r and omized clinical trial , 19 patients with an acute exacerbation of asthma were given a loading dose of aminophylline by the IV ( n = 10 ) or oral route ( n = 9 ) of administration following treatment with epinephrine .  Plasma concentrations of  theophylline were measured prior to giving the loading dose , and one , two , three , and 24 to 48 hours later . Therapeutic effectiveness was evaluated by analyzing spirometric measurements prior to giving the loading dose , and one , three , and 24 to 48 hours later . Side effects also were recorded . In the IV group , the mean peak plasma theophylline concentration was 15.1 micrograms/mL one hour after loading , and in the oral group the mean peak serum theophylline concentration was 14.2 micrograms/mL three hours after loading . There was no correlation between theophylline concentrations and normalized change in spirometric values . There was no significant difference in spirometric values between the IV and oral groups . Nausea was slightly more common in the IV group . We conclude that there is no therapeutic advantage to giving a loading dose of aminophylline by the IV route rather than orally in patients with mild-to-moderate exacerbation of asthma initially treated with epinephrine
BACKGROUND Asthma is a chronic condition in which sufferers may have occasional or frequent exacerbations result ing in visits to the emergency department ( ED ) .
Aminophylline has been used extensively to treat exacerbations in acute asthma setting s ; however , it 's role is unclear especially with respect to any additional benefit when added to inhaled beta(2)-agonists .
OBJECTIVES To determine the magnitude of effect of the addition of intravenous aminophylline to inhaled beta(2)-agonists in adult patients with acute asthma treated in the ED setting .