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* From the Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay (Dr. G. Rodrigo); and Unidad de Cuidado Intensivo (Dr. C. Rodrigo), Asociación Española 1a de Socorros Mutuos, Montevideo, Uruguay.
Correspondence to: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Av 8 de Octubre 3020, Montevideo 11600, Uruguay; e-mail: gurodrig{at}adinet.com.uy
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Key Words: acute asthma • anticholinergics • ipratropium bromide • oxitropium bromide
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Introduction |
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Since the early 1970s, there has been a renewed interest in the use of anticholinergic medications, given the increase in prevalence, morbidity, and mortality of asthma in the past decades, and the need to develop alternatives to therapy with ß-agonist agents. The development of less toxic alternatives to atropine led to their wider use in clinical practice. The newer anticholinergic agents are water-soluble, quaternary ammonium compounds that are poorly absorbed, and when they are given by inhalation, they cause fewer systemic side effects.2 3 4 5
Two factors that have arisen in the past few years have revitalized the interest in anticholinergics bronchodilators. One was a better understanding of the cholinergic mechanisms that control airway caliber in healthy and disease states, and the second one was the development by pharmaceutical chemists of synthetic analogs of atropine that were not appreciably absorbed but retained the anticholinergic properties of the atropine. Thus, physicians worldwide regularly prescribe several anticholinergic agents, including atropine, ipratropium bromide, thiazinamium, oxitropium bromide, and glycopyrrolate. Of these, ipratropium bromide is the most widely studied.
Nevertheless, the role for anticholinergic medications is less well-defined for patients with acute asthma. The use of these drugs as the initial bronchodilator in treatment has been consistently reported6 7 8 9 to be inferior to the use of a ß-adrenergic agent on improving airflow in individuals with status asthmaticus. On the contrary, the use of both classes of bronchodilators, either simultaneously or in sequence, has produced positive10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 as well as negative trial results.32 33 34 35 36 37 38 39 40 41 42 43 44 45
Current recommendations for the use of anticholinergic agents in the emergency department (ED) and hospital management of asthma exacerbations are not precise. For example, the National Asthma Education and Prevention Program expert panel report 246 (p66) stated the following: "Anticholinergics may be considered. Adding high doses of ipratropium bromide (0.5 mg in adults, 0.25 mg in children) to an aerosolized solution of a selective ß-agonist has been shown to cause additional bronchodilation, particularly in those with severe airflow obstruction, although some studies did not demonstrate this effect." These conflicting recommendations are based on studies that offer mixed conclusions about whether anticholinergic and ß2-agonist medications lead to a better response than do ß2-agonist medications alone. Although many studies have not shown that combination therapy has a statistically significant beneficial effect, these studies have consistently shown a slightly greater improvement in lung function with combination therapy than with ß2-agonists alone.
To understand the rationale for the use of anticholinergic agents in patients with acute asthma, we must comprehend the mechanisms for bronchoconstriction and dilatation that are mediated by the autonomic nervous system. The majority of autonomic nerves in human airways are branches of the vagus nerve, the efferent preganglionic fibers of which enter the lung at the hilum and travel along the airways into the lung.47 The efferent innervation is derived from the postganglionic fibers that end in the epithelium, submucosal glands, and smooth muscle of the airways as well as in the vascular structures. Thus, the release of acetylcholine at these sites results in smooth-muscle contraction and the release of secretions from submucosal glands stimulated by their muscarinic receptors.
Cholinergic pathways may be important in regulating acute bronchomotor responses, and many stimuli can provoke bronchoconstriction via vagal pathways. Anticholinergic medications antagonize transmission at the muscarinic receptors. They will only block reflex cholinergic bronchoconstriction and will have no effect on bronchoconstriction resulting from the action of, for example, histamine on airway smooth muscle.
Cholinergic-induced bronchoconstriction appears to involve primarily the large airways, whereas ß-agonist medications relax both large and small airway constriction equally. In humans, there are at least three pharmacologically distinct subtypes of muscarinic receptor within the airways, which are known as M1, M2, and M3 receptors.48 49 The M1 receptors are present within the parasympathetic ganglion and mediate increased cholinergic transmission. They may facilitate nicotinic transmission or be responsible for maintaining cholinergic tone. Inhibition would reduce cholinergic tone and thus would reduce bronchoconstriction. M1 receptors also are found on alveolar walls, where their function is unknown. Prejunctional M2 receptors on the postganglionic nerves act as a negative feedback loop in neuronal transmission. They are activated by the release of acetylcholine and promote its reuptake, thereby limiting the degree of bronchoconstriction produced. These receptors are thought to be dysfunctional in asthma, resulting in exaggerated cholinergic reflexes. The loss of M2 receptor function has been demonstrated after viral infections. Similar changes can be seen after ozone exposure or antigen challenge.50 When the M2 receptors are dysfunctional, the resulting excessive concentrations of acetylcholine at the motor endplate can promote significant bronchoconstriction. Finally, M3 receptors are located on the airway smooth muscle. The receptor activation leads to a release of calcium ions from intracellular stores and a decrease in intracellular adenosine 3',5'-cyclic monophosphate levels, resulting in the contraction of airway smooth muscle. M3 receptors also are located on submucosal glands, where they are likely to be involved in mucus secretion.
Nonselective anticholinergic agents such as atropine, ipratropium bromide, and oxitropium bromide block both the prejunctional (M2) and postjunctional (M3) receptors. Thus, due to the blockade of the prejunctional M2 receptors, nonselective antagonists may increase the amount of acetylcholine that is released by cholinergic nerve stimulation.51 This may weaken the effect of the postjunctional M3 muscarinic receptor blockade on airway smooth muscle and submucosal glands. This suggests that antagonists that bind selectively to M3 and M1 receptors may be more effective in inhibiting cholinergic effects in the airways.
The natural anticholinergic, atropine, is rarely used at the present time, however, this drug was used extensively as a nebulized solution by intensivists and ED specialists for years.52 It is readily absorbed across the oral and respiratory mucosa and, when higher doses are used to maximize bronchodilation, the incidence of dry mouth, blurred vision, urinary retention, nausea, and tachycardia may limit the usefulness of atropine.
The principal anticholinergic agent is ipratropium bromide, a nonselective muscarinic antagonist.53 54 This drug is topically active, and the compound is poorly lipophilic and not significantly absorbed from the respiratory or GI tract. Ipratropium bromide has no or very little systemic toxicity. It does not appear to affect mucus secretion and ciliary movement. Another significant advantage to ipratropium bromide in the critically ill asthma patient is the lack of increase in heart rate, which does occur with ß2-agonist use.55 The only remarkable side effect is the inhibition of salivary secretions at high doses. It has no effect on urinary flow or intraocular tension, and possible effects on the eye (ie, glaucoma) can be prevented by using a mouthpiece during nebulization. The speed of onset of effect is 3 to 30 min with up to 50% of the response occurring in 3 min and 80% in 30 min, with a peak bronchodilator effect observed within 1 to 2 h, and a duration of action of up to approximately 6 h.56 In consequence, these properties are appropriate for acute asthma treatment.
Oxitropium bromide is a quaternary anticholinergic compound that is based on scopolamine instead of atropine. It is also a nonselective muscarinic antagonist, with a longer duration of action (up to 8 h) than ipratropium bromide, but it has a slower onset of effect.57 The peak bronchodilator effect after administration occurs within 1 to 2 h.
Finally, tiotropium bromide is a recently developed, long-acting, selective antimuscarinic medication. This agent is selective for both the M1 and M3 receptors. In human bronchi, tiotropium bromide had a similar inhibitory effect with a slow onset of action (peak bronchodilator effect observed after 1.5 to 2 h) and a very prolonged offset compared with ipratropium bromide (the effects persist for 10 to 15 h).58 Tiotropium bromide has a prolonged inhibitory effect against acetylcholine released from postganglionic nerve endings in the airways, probably via an inhibitory effect on M3 receptors.
In summary, the potential rationale for the use of a combination of ß2-agonist and anticholinergic agents in patients with acute asthma includes factors such as different sites of action (ie, proximal vs distal airways), different mechanisms of action, the onset of bronchodilator effect, and different side-effects profiles. The main purpose of this review is to evaluate the best evidence that is available to determine the role of anticholinergic agents that are added to ß2-agonist agents in the treatment of patients with acute asthma. This article answers the following question: what level of evidence is available in the literature to support the use of anticholinergic medications in combination with ß2-agonist medications in acute asthma patients? We will focus on the analysis of clinical evidence and their implications for clinical practice.
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3 was considered to be of good quality. Trials that exclusively studied patients with exacerbations of COPD were excluded. We only reviewed the literature describing the use of anticholinergic agents in children and adults with acute asthma in the ED or a similar acute-care setting. In addition, the languages of publication were restricted to those articles published in English, Spanish, French, Italian, German, or Portuguese.
The outcomes used in acute asthma studies are highly variable and include the results of pulmonary function tests (ie, peak expiratory flow [PEF] and FEV1), admissions to the hospital, return visits after ED discharge, and the administration of medications. Probably, decreasing the need for hospital admission would have the most direct effect on the patients. Outcome measures such as pulmonary function tests, and clinical and physiologic measures, although likely to be correlated with qualitative benefits, may not show us the real therapeutic value of anticholinergic therapy. Therefore, to assess the effectiveness of anticholinergic therapy we selected hospital admission as the primary outcome, and change in pulmonary function test results, clinical or physiologic measures, and adverse effects as secondary outcomes. The pulmonary function effect size (ES) was calculated from data collected as close to 90 to 120 min after the initial treatment as possible. Because the peak bronchodilator effect after the administration of ipratropium bromide and oxitropium bromide occurs within 1 to 2 h, and because approximately two thirds of patients with acute asthma require 90 min of inhaled ß-agonist treatment to have their condition improve sufficiently to be discharged from the ED,61 62 it is reasonable to expect significant improvement during this time.
The main component of an evidence-based review that distinguishes it from the traditional narrative review is an extensive, structured, and explicit search strategy that is targeted at the identification of all relevant studies.63 64 Initially, we need to develop a well-defined, clinically relevant, and concise question. In view of previous considerations, we formulated the question as follows: in children and adults, with acute asthma, does the addition of inhaled anticholinergic agents to a standard treatment of ß2-agonist agents decrease the likelihood of hospital admission or improve pulmonary function in the course of the ED visit? Additionally, we analyzed the dose of the anticholinergic treatment and the severity of exacerbation as factors that could influence the treatment response.
The search strategy included the use of MEDLINE (1966 to 2001), EMBASE (1980 to 2001), and CINAHL (1982 to 2001) databases using the following medical subject headings terms: asthma or wheeze and emergency or acute asthma or status asthmaticus and anticholinergic, or ipratropium or atropine, or oxitropium, or glycopyrrolate. Second, we searched in the Cochrane Library for the Database of Systematic Reviews and the Controlled Trials Register. Also, we performed a hand search of the 15 most popular respiratory journals. Finally, we checked the bibliographies of all trials and review articles that had been identified from the databases and medical journals.
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In the review by Osmond and Klassen,65 six randomized controlled trials (285 patients) involving pediatric and adolescent patients (age range, 1 to 17 years) with acute asthma were examined to determine the effect of treatment (ie, ipratropium bromide plus ß-agonists vs ß-agonists alone) on clinical and physiologic measures. The review was limited to a single-strategy MEDLINE search of English-language publications between 1966 and 1992, which was supplemented by Science Citation searches. Unpublished data were not considered. Six articles were included (between 1985 and 1988; ED and hospitalized patients). Three of the studies were of high methodological quality (by the scale of Osmond and Klassen65 ). These three studies assessed hospital admissions and pulmonary function. All studies used 250 µg nebulized ipratropium respiratory solution. For the purposes of combining the data, 60 min postintervention was chosen because it was the only assessment time that was common to all three studies. The pooled weighted mean difference showed a 12.5% (95% confidence interval [CI], 6.6 to 18.4%) improvement in FEV1 percent predicted in the ipratropium bromide group over the control group. The overall ES was 0.88 (95% CI, 0.42 to 1.34). There was no improvement in clinical measurements or the number of hospital admissions. The main limitation of the review was that the combined sample size derived from these three studies and having the highest validity was only 80 patients.
The meta-analysis by Plotnick and Ducharme66
is a Cochrane Library review that was updated in April 2000. It also was published in a peer-reviewed journal.67
For this analysis, we selected the Cochrane Library version. The authors assessed the effect of nebulized anticholinergic and ß-agonist drugs on hospital admissions or on pulmonary function in children and adolescents with acute asthma in the ED (age range, 18 months to 17 years). With one exception (atropine), the anticholinergic agent used was ipratropium bromide. Only randomized controlled trials were selected for analysis. The literature search included multiple databases (ie, MEDLINE, EMBASE, CINAHL, and Cochrane Database of Systematic Reviews). The 13 studies included were performed between 1985 and 1999 in ED settings (1,613 patients). Most were of high quality (ie, Jadad quality score, 5). There was no language restriction, and unpublished data were included. The review included the four ED studies identified by Osmond and Klassen.65
Trials were grouped according to the intensity of the anticholinergic agent protocol. The use of a single dose (250 µg) of a nebulized anticholinergic agent with a ß2-agonist agent did not reduce the number of hospital admissions (relative risk [RR], 0.93; 95% CI, 0.65 to 1.32). However, significant group differences in lung function (ie, FEV1) supporting the combination treatment were observed 60 min (standardized mean difference, 0.57; 95% CI, 0.21 to 0.93) and 120 min (standardized mean difference, 0.53; 95% CI, 0.17 to 0.90) after the single dose of the anticholinergic agent. In contrast, the use of multiple doses of anticholinergic agents with ß2-agonist agents, mainly in children and adolescents who experienced severe exacerbations, reduced the risk of hospital admission by 25% (RR, 0.75; 95% CI, 0.62 to 0.89). Twelve children would need to be given multiple doses of anticholinergic agents in combination with ß2-agonist agents to avoid one hospital admission compared to children given therapy with ß2-agonist agents alone (ie, the number needed to treat [NNT]; 95% CI, 8 to 32). When restricting this strategy to children with severe exacerbations, seven children (95% CI, 5 to 20) need to be treated to avoid a hospital admission. At 60 min after the last inhalation of the anticholinergic agent, a weighted mean group difference of 9.7 in the change in FEV1 percent predicted (95% CI, 5.7 to 13.7) favored the use of anticholinergic agents. There was no increase in the amount of nausea, vomiting, or tremor in patients who had been treated with anticholinergic agents. The authors concluded the following: (1) a single dose of an anticholinergic agent is not effective for the treatment of mild and moderate exacerbations and is insufficient for the treatment of severe exacerbations; (2) the use of multiple doses of anticholinergic and ß2-agonist agents improves lung function and would avoid hospital admission in 1 of 12 treated patients; although multiple doses are preferred to single doses, the available evidence only supports their use in children with severe exacerbations of asthma (ie, FEV1, 
55% of predicted); and (3) there is no conclusive evidence for using multiple doses of anticholinergic agents in children with mildto-moderate asthma exacerbations.
Two randomized, placebo-controlled trials,31 45 which were published in 2000 and were not included in previous systematic reviews, have investigated the efficacy of therapy with ipratropium bromide in children with acute asthma (Table 1 ).
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Finally, Sienra Monge et al45 conducted a randomized trial of 40 children with acute asthma to compare the effects of ß2-agonist agents (ie, salbutamol) that had been administered with ipratropium bromide (40 µg administered three times by metered-dose inhaler [MDI]) with those of ß2-agonist agents that had been administered alone. The bronchodilator effects (ie, effect on FEV1) of the administration of salbutamol alone and in combination with ipratropium bromide were considered to be similar in intensity and in action time. However, there was a favorable trend (at 1, 2, 3, and 8 h) to ipratropium bromide treatment (mean difference at 2 h, 0.28; 95% CI, -0.18 to 0.74 L).
In summary, we examined four studies (two systematic reviews and two randomized controlled trials) involving pediatric patients presenting to an ED with acute asthma who had been treated with nebulized anticholinergic agents to determine the effect of treatment on hospital admissions as the primary outcome. The studies also included pulmonary function measurements, the length of time to discharge home from the ED, the number of doses given before hospital discharge, and adverse effects as secondary end points. The addition of multiple doses of anticholinergic agents to treatment with ß2-agonist agents produced an approximately 30% reduction in the number of hospital admissions. In addition, a moderate difference was observed between groups for changes in pulmonary function. The use of multiple doses of anticholinergic medications seems to be indicated in the treatment of children and adolescents, and principally those with severe exacerbations of asthma. On the contrary, there was less benefit to adding a single dose of an anticholinergic agent to ß-agonist agents in the treatment of children with mild-to-moderate acute asthma.
Adult Studies
Our search found two systematic reviews that assessed the addition of ipratropium bromide to ß2-agonist agents in the treatment of acute adult asthmatic patients in the ED.
Stoodley et al68
conducted a systematic review to determine whether the addition of inhaled ipratropium bromide to inhaled ß-agonist therapy is effective in the treatment of adults (ie, persons 18 years of age) with acute asthma. The review included studies with ED and hospitalized patients. Only randomized controlled trials were selected for analysis. The literature search included multiple databases (ie, MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, and Current Contents). The 10 studies included in the review (1,377 patients) were performed between 1985 and 1997 (6 of these were of high quality [Jadad quality score, 4]). The main outcome measure was pulmonary function collected between 30 and 90 min after the first administered dose of ipratropium bromide. Hospital admission also was considered as an outcome measure. Compared with placebo, the use of ipratropium bromide was associated with a pooled 7.3% improvement in FEV1 (95% CI, 3.8 to 10.9%), which is equivalent to 30 L/min of PEF. Similarly, the pooled estimate of treatment effect in trials that reported data as PEF was 22.1% (95% CI, 11.0 to 33.2%). When these data were combined using ES as a common measure, the use of ipratropium bromide was associated with an ES of 0.38 (95% CI, 0.27 to 0.48). Studies enrolling patients with more severe airflow obstruction showed greater absolute benefits for combined therapy. For the three trials reporting hospital admission data (1,031 patients), therapy with ipratropium bromide reduced the risk of hospital admission by almost 30% (RR, 0.73 [95% CI, 0.53 to 0.99]; NNT, 23 [95% CI: 12 to 610]). None of the trials reported serious adverse effects that were attributable to treatment. However, a limitation of the review was that the dose-response relationship with ipratropium bromide could not be examined because all studies used 0.5 mg ipratropium bromide administered by nebulizer. Thus, the study design was not consistent with routine ED treatments, which currently include the use of high, frequent, and cumulative doses of bronchodilators.69
70
In summary, the reviewers found a modest improvement in pulmonary function when ipratropium bromide was added to ß2-agonist treatment, which is associated with a substantial reduction in the hospital admission rate of 30%.
Rodrigo and Rodrigo71
conducted a systematic review of the literature with a meta-analysis to determine whether therapy with inhaled ipratropium bromide provides additive benefits to adults with acute asthma who are being treated with ß-agonist agents in an ED. The main outcome measure was pulmonary function, and hospital admission rate also was evaluated. ES was calculated from the data collected as close as possible to 90 min after the initial dose of ipratropium bromide was administered. Only randomized controlled trials were selected for analysis. The literature search included multiple databases (ie, MEDLINE, Current Contents, Science Citation Index, and Cochrane Database of Systematic Reviews). The review included two new ED studies published after 1997. The 10 studies selected (1,483 adults) were performed between 1985 and 1999 (5 studies were of high quality [author’s own scale score, 0.7]). The overall effect was a significant but modest benefit from ipratropium bromide therapy (ES, 0.14; 95% CI, 0.04 to 0.24). This pooled ES was equivalent to a 10% increase (95% CI, 2 to 18%) in pulmonary function in the ipratropium bromide group compared with the placebo group. The analysis showed a substantial improvement with ipratropium bromide therapy in patients with extreme obstruction (ie, PEF or FEV1, < 35%; ES, 0.38; 95% CI, 0.09 to 0.67). In the five trials (1,186 patients) that studied the effect of ipratropium bromide administration on hospital admission, pooled results revealed that therapy with ipratropium bromide reduced admission rates significantly (odds ratio, 0.62 [95% CI, 0.44 to 0.88]; NNT, 18 [95% CI, 11 to 77]). Only six studies reported side effects, and none of them reported serious adverse effects that were attributable to treatment. Again, the therapeutic protocol used in almost all of the studies consisted of a single dose of nebulized ipratropium bromide mixed with ß2-agonist agents, rather than the multiple doses recommended. In summary, this systematic review revealed that the addition of single doses of ipratropium bromide to therapy with ß2-agonists offers a modest improvement in pulmonary function. In addition, the patients with more severe acute asthma benefited substantially from the addition of ipratropium bromide. The fact that the therapeutic protocol used in almost all of the studies consisted of a single dose of nebulized ipratropium bromide (500 µg) may explain why the observed benefit was modest. Despite this, the early administration of ipratropium bromide with ß2-agonist agents also leads to a 38% reduction in the admission rate.
In addition, we found six randomized controlled trials that had not been included in previous systematic reviews that concerned the effectiveness of anticholinergic agents in adults with acute asthma27 29 30 36 37 39 (Table 2 ).
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Cydulka and Emerman38 compared a single aerosolized dose of glycopyrrolate (2 mg) plus albuterol with aerosolized albuterol in 125 adult patients who had experienced acute exacerbations of asthma. Both groups received three treatments of aerosolized albuterol, 2.5 mg. Asthmatic patients receiving combination therapy experienced less of a change in FEV1 than did the control patients (52% vs 82%, respectively; p < 0.05).
Diaz et al40 studied 126 adult patients with acute asthma who had been treated in an ED. All patients received three nebulized treatments with albuterol, 2.5 mg each, over 30 min. Patients were randomized into one of the three following groups: (1) saline solution placebo administered during the three treatments; (2) 2.0 mg atropine sulfate added to the first nebulization and saline solution in the second; and (3) 2.0 mg atropine added to the first and third treatments. At 90 min, there were no significant differences among the three groups on any parameter studied, including improvement of PEF, vital signs, or number of hospital admissions. Combination therapy with atropine sulfate and albuterol offered no significant benefit over the use of albuterol alone in the treatment of patients with acute exacerbations of asthma.
Kamei et al27 designed a multicenter study to compare the inhalation of fenoterol and fenoterol plus oxitropium bromide delivered by an MDI with a holding chamber to relieve acute attacks of moderate asthma (PEF, < 70% of predicted). They randomized 69 patients to receive fenoterol (1 puff or 200 µg every 1 min for 5 min) or fenoterol plus oxitropium bromide (2 puffs or 200 µg every 1 min for 5 min). At 60 min after inhalation therapy, the pulmonary function of the oxitropium bromide group was significantly improved compared to those of the fenoterol group (mean PEF difference, 51.0 L/min; 95% CI, 1.7 to 100.6). The hospital admission rate was lower in the fenoterol group compared with that in the combination group (6.5% vs 12.1%, respectively), however, the difference was not statistically significant.
Rodrigo and Rodrigo29
designed a large, double-blind, randomized controlled trial to test the hypothesis that adult patients with acute severe asthma (ie, FEV1, < 50% of predicted) who are given combination high-dose therapy with ipratropium bromide and ß2-agonist agents will have greater improvement in pulmonary function and fewer hospital admissions than those given ß2-agonist agents alone. One hundred eighty patients who had presented to an ED were assigned in a randomized, double-blind fashion to receive albuterol and placebo or albuterol and ipratropium bromide (both drugs were administered through an MDI and spacer at 10-min intervals for 3 h, 24 puffs, or 2,880 µg albuterol and 504 µg ipratropium bromide each hour). At the end of treatment, subjects who had received ipratropium bromide had an overall 48.1% greater improvement in FEV1 (95% CI, 19.8 to 76.4%) than those in the control group. At 90 min, the response in the ipratropium bromide group was significantly higher compared to that in the control group (mean PEF difference, 52.3 L/min; 95% CI, 27.0 to 77.6). At the end of the protocol (ie, after 3 h), 39% of patients in the control group and 20% of patients in the ipratropium bromide group were admitted to the hospital. The use of high doses of ipratropium bromide reduced the risk of hospital admission by 49% (RR, 0.51 [95% CI, 0.31 to 0.83]; NNT, 5 [95% CI, 3 to 17]). Kaplan-Meier estimated curves of the proportion of patients who reached the hospital discharge threshold during the 3 h of treatment showed a significant difference in favor of the ipratropium bromide group. A subgroup analysis showed that patients who were the most likely to benefit from the addition of high doses of ipratropium bromide were those with more severe obstruction (ie, FEV1, 30% of predicted; RR, 0.61; 95% CI, 0.38 to 0.99) and longer duration of symptoms before the ED presentation (ie, 24 h; RR, 0.32; 95% CI, 0.126 to 0.64). The authors concluded that there was a significant advantage when high doses of ipratropium bromide and albuterol are combined in the ED treatment of adults with acute severe asthma.
Nakano et al30 compared the outcomes of adults with acute severe asthma (ie, PEF, < 50% of predicted) who had been treated with 4 puffs (400 µg) albuterol every 20 min for three doses plus 4 puffs of oxitropium bromide (400 µg) with each of the three salbutamol doses to the administration of salbutamol alone by means of an MDI with a spacer device. A randomized, single-blind, placebo-controlled trial was performed in 74 adult patients presenting to the ED for treatment. The increase in PEF over the course of treatment was significantly greater in the oxitropium bromide-plus-salbutamol group. The mean absolute difference in PEF at 120 min for patients receiving combination therapy compared with those receiving salbutamol alone was 37.8 L/min (95% CI, 15.9 to 59.8). They found that patients with more severe asthma (ie, baseline PEF, < 200 L/min) benefited from the addition of oxitropium bromide to salbutamol (mean difference, 44 L/min; 95% CI, 11 to 75). In addition, the proportion of need for additional treatment was less in the combination group than in the salbutamol group (odds ratio, 0.32; 95% CI, 0.11 to 0.90). Finally, there was a trend toward a reduction of hospitalization among patients receiving combination therapy compared to single-agent therapy (13.2% vs 27.8%, respectively), but this difference did not reach statistical significance.
In summary, we examined two systematic reviews and six randomized controlled trials involving adult patients with acute asthma who were treated with inhaled anticholinergic agents (ie, atropine, ipratropium, oxitropium, or glycopyrrolate). The studies included pulmonary function, hospital admission rate, and the need for additional treatment as end points (Table 2) . We concluded that there was a dose-response relationship. Thus, the use of single-dose protocols showed a modest improvement in pulmonary function with an approximately 35% decrease in hospital admissions (NNT, approximately 20) compared to patients receiving albuterol alone. On the contrary, the addition of multiple doses of anticholinergic agents (ie, ipratropium and oxitropium) to ß2-agonist treatment showed a larger difference among groups in pulmonary function, with a approximately 50% reduction in hospital admissions (NNT < 8) for the combined therapy. Patients with more severe asthma showed a substantial improvement following treatment with anticholinergic agents. On the contrary, the studies that used atropine and glycopyrrolate did not show a significant advantage for the ß-agonist treatment.
Implications for Clinical Practice
Overall, the analysis of the literature suggests that inhaled anticholinergic agents provide an additional benefit to children and adults with acute asthma who are treated with ß2-agonist medications in an ED. After an extensive review of the most relevant evidence, the following conclusions may be emphasized:
£80 per severe case that was treated (95% CI, £3 to £157). Further analysis is needed to determine whether combination therapy in adults with acute asthma reduces costs. In addition to efficacy, the methods of drug administration will influence the decision to use anticholinergic agents for acute asthma. The costs for nebulized therapy are necessarily higher than for MDI therapy because the administration of the nebulization therapy must be performed by trained health-care personnel, and the tubing and masks used for nebulization must be discarded after patient use. It has been shown that the routine substitution of an MDI with a spacer device saves hospital resources.75
There is significant evidence that anticholinergic and ß2-agonist medications can be delivered effectively to patients with acute asthma by means of an MDI with a spacer in less time, with lower costs, and with minimal toxicity.
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Received for publication February 23, 2001. Accepted for publication September 14, 2001.
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