Bronchodilator Therapy in Status Asthmaticus

Abstract

Preventing exacerbations of bronchospasm is one of the main goals of the management of chronic asthma.1National Asthma Education Program Expert panel report II: guidelines for the diagnosis and management of asthma. Department of Health and Human Services, Bethesda, MD1997Google Scholar Despite this therapeutic goal, emergency department (ED) visits for acute bronchospasm/status asthmaticus continue to be an important clinical problem. The most recent data from the Centers for Disease Control and Prevention estimate that there were more than 1.8 million ED visits for status asthmaticus in 1995.2Mannino DM Homa DM Pertowski CA et al.Surveillance for asthma—United States, 1960–1995.MMWR. 1998; 47: 1-27PubMed Google Scholar In 1994, approximately $348 million was spent providing care to acutely ill asthmatics in EDs.3Smith DH Malone DC Lawson KA et al.A national estimate of the economic costs of asthma.Am J Respir Crit Care Med. 1997; 156: 787-793Crossref PubMed Scopus (502) Google Scholar Because of this common and expensive aspect of asthma care, better treatment strategies are needed to improve outcomes and to reduce the morbidity and expense associated with status asthmaticus. The pharmacologic treatment of status asthmaticus includes high-dose inhaled bronchodilators and the early administration of oral or IV corticosteroids.1National Asthma Education Program Expert panel report II: guidelines for the diagnosis and management of asthma. Department of Health and Human Services, Bethesda, MD1997Google Scholar4British Thoracic Society Guidelines on the management of asthma.Thorax. 1993; 48: S1-S24Crossref PubMed Scopus (48) Google Scholar5Corbridge TC Hall JB State of the art: the assessment and management of adults with status asthmaticus.Am J Respir Crit Care Med. 1995; 151: 1296-1316Crossref PubMed Scopus (190) Google Scholar The selectiveβ 2-agonists are considered to be the bronchodilators of choice for patients with acute bronchospasm.1National Asthma Education Program Expert panel report II: guidelines for the diagnosis and management of asthma. Department of Health and Human Services, Bethesda, MD1997Google Scholar4British Thoracic Society Guidelines on the management of asthma.Thorax. 1993; 48: S1-S24Crossref PubMed Scopus (48) Google Scholar When inhaled in high doses, these agents are rapidly effective and well tolerated in most patients.5Corbridge TC Hall JB State of the art: the assessment and management of adults with status asthmaticus.Am J Respir Crit Care Med. 1995; 151: 1296-1316Crossref PubMed Scopus (190) Google Scholar6Lin RY Sauter D Newman T et al.Continuous versus intermittent albuterol nebulization in the treatment of acute asthma.Ann Emerg Med. 1993; 22: 1847-1853Abstract Full Text PDF PubMed Scopus (93) Google Scholar7Olshaker J Jerrard D Barrish R et al.The efficacy and safety of a continuous albuterol protocol for the treatment of acute asthma attacks.Am J Emerg Med. 1993; 11: 131-133Abstract Full Text PDF PubMed Scopus (24) Google ScholarAminophylline,8Coleridge J Cameron P Epstein J et al.Intravenous aminophylline confers no additional benefit in acute asthma treated with intravenous steroids and inhaled bronchodilators.N Z J Med. 1993; 23: 348-354Crossref Scopus (22) Google Scholar9Rodrigo C Rodrigo G 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.Chest. 1994; 106: 1071-1076Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar magnesium,10Green SM Rothcock SG Intravenous magnesium for acute asthma: failure to decrease emergency treatment duration or need for hospitalization.Ann Emerg Med. 1992; 21: 260-265Abstract Full Text PDF PubMed Scopus (118) Google Scholar11Tiffany BR Berk W Todd IK et al.Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations.Chest. 1993; 104: 831-834Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar and ipratropium bromide12Qureshi F Pestian J Davis P et al.Effect of nebulized ipratropium on the hospitalization rates of children with asthma.N Engl J Med. 1998; 339: 1030-1035Crossref PubMed Scopus (216) Google Scholar13Qureshi F Zaritsky A Lakkis H Efficacy of nebulized ipratropium in severely asthmatic children.Ann Emerg Med. 1997; 29: 205-211Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar14Garrett JE Town GI Rodwell P et al.Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma.J Allergy Clin Immunol. 1997; 100: 165-170Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar15Schuh S Johnson DW Callahan S et al.Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma.J Pediatr. 1995; 126: 639-645Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar16O'Driscoll BR Taylor RJ Horsley MG et al.Nebulized salbutamol with and without ipratropium bromide in acute airflow obstruction.Lancet. 1989; 1: 1418-1420Abstract PubMed Scopus (156) Google Scholar17Watson WTA Becker AB Simmons FE Comparison of ipratropium solution, fenoterol solution, and their combination administered by nebulizer and face mask to children with acute asthma.J Allergy Clin Immunol. 1988; 82: 1012-1018Abstract Full Text PDF PubMed Scopus (51) Google Scholar18Rebuck AS Chapman KR Abboud R et al.Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room.Am J Med. 1987; 82: 59-64Abstract Full Text PDF PubMed Scopus (222) Google Scholar19Beck R Robertson C Galdes-Sebaldt et al.Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma.J Pediatr. 1985; 107: 605-607Abstract Full Text PDF PubMed Scopus (94) Google Scholar20Lanes SF Garrett JE Wentworth CE et al.The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma: a pooled analysis of three trials.Chest. 1998; 114: 365-372Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar21McFadden ER ElSanadi N Strauss L et al.The influence of parasympatholytics on the resolution of acute attacks of asthma.Am J Med. 1997; 102: 7-13Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar22Summers QA Tarala RA Nebulized ipratropium in the treatment of acute asthma.Chest. 1990; 97: 430-434Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar have all been administered in combination with β2-agonists to treat status asthmaticus. In this issue of CHEST (see page 937), Weber and colleagues report the results of a prospective, randomized, controlled clinical trial examining the effect of combined high-dose inhaled albuterol and ipratropium bromide on the clinical outcomes of patients presenting to a municipal ED with acute bronchospasm. These authors were unable to demonstrate significant improvements in pulmonary function, ED length of stay, or the need for hospitalization in the patients who received prednisone and combined high-dose inhaled bronchodilator therapy, compared to patients who received standard therapy with high-dose albuterol and prednisone. As the authors note, there was a reduced statistical power to detect small but significant differences between the bronchodilator therapies because of the relatively small number of patients enrolled in their study. Nonsignificant trends favoring combination therapy were apparent for all three of the primary outcomes examined by Weber and colleagues. Other prospective, controlled studies examining the efficacy of high-dose combined selective β2-agonist and ipratropium bromide inhalation therapy in status asthmaticus have demonstrated mixed results. Most of these studies,12Qureshi F Pestian J Davis P et al.Effect of nebulized ipratropium on the hospitalization rates of children with asthma.N Engl J Med. 1998; 339: 1030-1035Crossref PubMed Scopus (216) Google Scholar13Qureshi F Zaritsky A Lakkis H Efficacy of nebulized ipratropium in severely asthmatic children.Ann Emerg Med. 1997; 29: 205-211Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar14Garrett JE Town GI Rodwell P et al.Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma.J Allergy Clin Immunol. 1997; 100: 165-170Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar15Schuh S Johnson DW Callahan S et al.Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma.J Pediatr. 1995; 126: 639-645Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar16O'Driscoll BR Taylor RJ Horsley MG et al.Nebulized salbutamol with and without ipratropium bromide in acute airflow obstruction.Lancet. 1989; 1: 1418-1420Abstract PubMed Scopus (156) Google Scholar17Watson WTA Becker AB Simmons FE Comparison of ipratropium solution, fenoterol solution, and their combination administered by nebulizer and face mask to children with acute asthma.J Allergy Clin Immunol. 1988; 82: 1012-1018Abstract Full Text PDF PubMed Scopus (51) Google Scholar18Rebuck AS Chapman KR Abboud R et al.Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room.Am J Med. 1987; 82: 59-64Abstract Full Text PDF PubMed Scopus (222) Google Scholar19Beck R Robertson C Galdes-Sebaldt et al.Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma.J Pediatr. 1985; 107: 605-607Abstract Full Text PDF PubMed Scopus (94) Google Scholar as well as a recent meta-analysis,20Lanes SF Garrett JE Wentworth CE et al.The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma: a pooled analysis of three trials.Chest. 1998; 114: 365-372Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar have demonstrated small but significant improvements in airway obstruction and/or clinical outcomes favoring combination therapy, while two have not.21McFadden ER ElSanadi N Strauss L et al.The influence of parasympatholytics on the resolution of acute attacks of asthma.Am J Med. 1997; 102: 7-13Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar22Summers QA Tarala RA Nebulized ipratropium in the treatment of acute asthma.Chest. 1990; 97: 430-434Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarWhen present, the improvement in airway obstruction in patients receiving combination therapy over that produced by high-doseβ 2-agonist therapy alone has been relatively small. Garrett et al14Garrett JE Town GI Rodwell P et al.Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma.J Allergy Clin Immunol. 1997; 100: 165-170Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar demonstrated a difference in FEV1 of 113 mL favoring combination therapy in acutely ill adult asthmatics 90 min after receiving treatment. A meta-analysis of the efficacy of ipratropium bromide in acute childhood asthma concluded that there was a 12.5% improvement in airway obstruction conferred by combination therapy compared to therapy with β2-agonists alone.23Osmond MH Klassen TP Efficacy of ipratropium bromide in acute childhood asthma: a meta-analysis.Acad Emerg Med. 1995; 2: 651-656Crossref PubMed Scopus (45) Google Scholar Combination therapy may be particularly beneficial in children with acute asthma, as demonstrated now in five prospective, randomized, controlled clinical trials,12Qureshi F Pestian J Davis P et al.Effect of nebulized ipratropium on the hospitalization rates of children with asthma.N Engl J Med. 1998; 339: 1030-1035Crossref PubMed Scopus (216) Google Scholar13Qureshi F Zaritsky A Lakkis H Efficacy of nebulized ipratropium in severely asthmatic children.Ann Emerg Med. 1997; 29: 205-211Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar15Schuh S Johnson DW Callahan S et al.Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma.J Pediatr. 1995; 126: 639-645Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar17Watson WTA Becker AB Simmons FE Comparison of ipratropium solution, fenoterol solution, and their combination administered by nebulizer and face mask to children with acute asthma.J Allergy Clin Immunol. 1988; 82: 1012-1018Abstract Full Text PDF PubMed Scopus (51) Google Scholar19Beck R Robertson C Galdes-Sebaldt et al.Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma.J Pediatr. 1985; 107: 605-607Abstract Full Text PDF PubMed Scopus (94) Google Scholar and in patients who present with a greater degree of airway obstruction.12Qureshi F Pestian J Davis P et al.Effect of nebulized ipratropium on the hospitalization rates of children with asthma.N Engl J Med. 1998; 339: 1030-1035Crossref PubMed Scopus (216) Google Scholar15Schuh S Johnson DW Callahan S et al.Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma.J Pediatr. 1995; 126: 639-645Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar16O'Driscoll BR Taylor RJ Horsley MG et al.Nebulized salbutamol with and without ipratropium bromide in acute airflow obstruction.Lancet. 1989; 1: 1418-1420Abstract PubMed Scopus (156) Google Scholar As in this month's report from Weber and colleagues, all of these studies have demonstrated the safety of administering selectiveβ 2-agonists and ipratropium bromide together in high doses.12Qureshi F Pestian J Davis P et al.Effect of nebulized ipratropium on the hospitalization rates of children with asthma.N Engl J Med. 1998; 339: 1030-1035Crossref PubMed Scopus (216) Google Scholar13Qureshi F Zaritsky A Lakkis H Efficacy of nebulized ipratropium in severely asthmatic children.Ann Emerg Med. 1997; 29: 205-211Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar14Garrett JE Town GI Rodwell P et al.Nebulized salbutamol with and without ipratropium bromide in the treatment of acute asthma.J Allergy Clin Immunol. 1997; 100: 165-170Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar15Schuh S Johnson DW Callahan S et al.Efficacy of frequent nebulized ipratropium bromide added to frequent high-dose albuterol therapy in severe childhood asthma.J Pediatr. 1995; 126: 639-645Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar16O'Driscoll BR Taylor RJ Horsley MG et al.Nebulized salbutamol with and without ipratropium bromide in acute airflow obstruction.Lancet. 1989; 1: 1418-1420Abstract PubMed Scopus (156) Google Scholar17Watson WTA Becker AB Simmons FE Comparison of ipratropium solution, fenoterol solution, and their combination administered by nebulizer and face mask to children with acute asthma.J Allergy Clin Immunol. 1988; 82: 1012-1018Abstract Full Text PDF PubMed Scopus (51) Google Scholar18Rebuck AS Chapman KR Abboud R et al.Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room.Am J Med. 1987; 82: 59-64Abstract Full Text PDF PubMed Scopus (222) Google Scholar19Beck R Robertson C Galdes-Sebaldt et al.Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma.J Pediatr. 1985; 107: 605-607Abstract Full Text PDF PubMed Scopus (94) Google Scholar20Lanes SF Garrett JE Wentworth CE et al.The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma: a pooled analysis of three trials.Chest. 1998; 114: 365-372Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar21McFadden ER ElSanadi N Strauss L et al.The influence of parasympatholytics on the resolution of acute attacks of asthma.Am J Med. 1997; 102: 7-13Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar22Summers QA Tarala RA Nebulized ipratropium in the treatment of acute asthma.Chest. 1990; 97: 430-434Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Thus, while neither aminophylline8Coleridge J Cameron P Epstein J et al.Intravenous aminophylline confers no additional benefit in acute asthma treated with intravenous steroids and inhaled bronchodilators.N Z J Med. 1993; 23: 348-354Crossref Scopus (22) Google Scholar9Rodrigo C Rodrigo G 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.Chest. 1994; 106: 1071-1076Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar nor magnesium10Green SM Rothcock SG Intravenous magnesium for acute asthma: failure to decrease emergency treatment duration or need for hospitalization.Ann Emerg Med. 1992; 21: 260-265Abstract Full Text PDF PubMed Scopus (118) Google Scholar11Tiffany BR Berk W Todd IK et al.Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations.Chest. 1993; 104: 831-834Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar confers additional benefit to high-doseβ 2-agonists and corticosteroids in patients with status asthmaticus, the benefit of ipratropium seems to be small but significant. As long as more than 1.8 million asthmatics with acute bronchospasm continue to present to our EDs, however, combination bronchodilator therapy with selective β2-agonists and ipratropium bromide may result in significant overall improvements in patient outcomes and cost. Maintaining proper asthma controller therapies in patients at risk for status asthmaticus should help to reduce the incidence of ED visits for asthma. It is telling that only slightly more than half of the patients enrolled in the study reported by Weber and coworkers were taking inhaled corticosteroids. Inhaled corticosteroids are the cornerstone of controller therapy for patients with persistent asthma.1National Asthma Education Program Expert panel report II: guidelines for the diagnosis and management of asthma. Department of Health and Human Services, Bethesda, MD1997Google Scholar4British Thoracic Society Guidelines on the management of asthma.Thorax. 1993; 48: S1-S24Crossref PubMed Scopus (48) Google ScholarThe regular use of these agents has been shown to reduce the need for ED therapy and hospitalization, and to reduce the cost of asthma care for these patients.24Balkrishnan R Norwood GJ Anderson A Outcomes and cost benefits associated with the introduction of inhaled corticosteroid therapy in a medicaid population of asthmatic patients.Clin Ther. 1998; 20: 567-580Abstract Full Text PDF PubMed Scopus (59) Google Scholar25Donahue JG Weiss ST Livingston JM et al.Inhaled steroids and the risk of hospitalization for asthma.JAMA. 1997; 277: 887-891Crossref PubMed Google Scholar Thus, while the treatment of status asthmaticus is being refined, ongoing efforts to identify and treat our more severely affected patients with appropriate levels of controller medications should help to reduce the overall incidence of acute exacerbations of asthma.