Unearthing good evidence for better care of acute asthma attacks

By Elizabeth A. Hunt, MD, and Ian Paul, MD

The World Wide Web is the place to go when you need to examine quality literature that addresses a specific clinical question. The authors illustrate how to use this tool effectively and what it reveals about novel protocols for treating acute attacks of asthma.

A debate has arisen in your pediatric practice. The pediatric emergency department (ED) where you and your partners send and see patients has put into place a new protocol. Children who are brought to the ED with an acute attack of asthma are now routinely treated with systemic corticosteroids, albuterol, and multiple-dose ipratropium bromide. Magnesium sulfate (MgSO₄) is to be added for pediatric patients whose condition is most severe. The debate centers on the addition of ipratropium bromide to the ED protocol, the change in the way albuterol is delivered—from nebulizer to metered-dose inhaler (MDI) with a spacer— and the addition of MgSO₄. It is unclear what prompted these changes, and your practice is concerned about their relative risks and benefits. Your concerns can be summarized in three questions:

• Is albuterol as effective delivered by MDI with a spacer as it is delivered by nebulizer?

• Do data support the use of ipratropium bromide?

• What is the role of MgSO₄ in an acute exacerbation?

A quick look in standard textbooks leads you to realize that getting answers is going to require more current sources. You plan a literature search but wonder how to go about it and what resources can help you assess the quality of the evidence that you find.

The practice of primary care pediatrics is difficult: You have to see a large number of patients with a wide variety of problems, yet—like the majority of your colleagues—you have little time for continuing education even though you know that learning can't stop when you leave medical school. As the scenario above shows, physicians today need access to the current literature and to be adept at determining its quality. It is also essential for you to create an efficient way to keep abreast of new clinical research findings and practice guidelines.

One way to keep up with research is to visit the Web sites of journals relevant to your practice and follow directions for having the table of contents of each issue sent to you by e-mail (Table 1). Generally, journals do not charge for this service. By scanning the table of contents, you can target articles of interest. As for current pediatric practice guidelines, they are available on the Web site of the American Academy of Pediatrics ( www.aap.org ).

TABLE 1
Selected research journals for pediatricians’ use

Of course, answering specific questions, like the three posed above, requires more than keeping up with the current literature as it comes your way. You must undertake an active search of the literature, using the World Wide Web, for relevant articles and assess their quality—all part of the process known as evidence-based medicine, or EBM. As we take you step by step through that journey in this article, we have two goals: to familiarize you with how the technique of EBM can be applied to any clinical question; and, at the same time, offer you answers to those three important, real-world questions about the treatment of acute attacks of asthma.

Search #1: What's the best way to deliver albuterol?

The first step in your investigation is to create a researchable question. One accepted strategy for formulating such a question is to focus on four basic elements, the first letters of which create the acronym "PICO":

• Patient or problem

• Intervention (cause, prognostic factor, or treatment)

• Comparison intervention

• Outcome

These four elements, applied to our question, will direct our search using PubMed, the online database and search engine of the National Library of Medicine (NLM) ( www.ncbi.nlm.nih.gov/Entrez/ ). PubMed, which includes NLM's premier bibliographic database, MEDLINE, allows you to make multiple searches of more than 11 million citations in more than 4,300 journals, using various terms relevant to the subject. During any one search session, PubMed keeps in memory all your searches, allowing you to combine and limit them in ways that are most likely to produce a useful set of citations. (Visit http://www.ncbi.nlm.nih.gov/entrez/query/static/overview.html for an introduction to PubMed and MEDLINE.)

Conducting the search. For the "P" in "PICO"—our patient population or the primary problem—we might enter "asthma" on the search line (Figure 1). Consider also conducting separate searches using the term "reactive airways disease" or other synonyms for asthma. Clicking on "History" will give you a numbered list of all your searches. By listing these numbers with the separator "OR" (which must be typed in upper case letters) between each one (for example, #1 OR #2 OR #3) you direct the search to citations that relate to at least one of the selected terms. Opting to look only in the title of articles for your search word or term? Type that word followed by "[ti]," (for "title"); the search is narrowed accordingly. Extending the search to full text of articles? Type your word followed by "[tw]" (for "text word").

A pediatrician may be tempted to make "children" a search term, but it is generally more effective to enter the clinical problem in which you are interested. Then, if your search yields an adequate number of articles, you can limit the set to the age group of interest (setting limits is discussed more fully later in this article).

"I," the intervention, is albuterol. In conducting the search for this element of the question, it may be important to consider names given to this drug in other countries (such as "salbutamol").

To identify other appropriate search terms, it is useful to determine how the NLM classifies a term. To do this, click on the heading "MeSH Browser" ("MeSH" stands for "Medical Subject Headings") to the left of the PubMed search field. This is a list of terms that the NLM uses to index articles. Entering "albuterol" produces a series of hierarchical tree structures of terms from which you can select items that match your area of interest (Figure 2). Three terms seem promising for finding more articles about albuterol: "adrenergic b-agonists," "bronchodilator agents," and "anti-asthmatic agents." Again, you can conduct an independent search of each term, gain access to the search history, and combine searches by entering "OR" between each numbered search.

"C" in this example signifies a comparison of albuterol delivered by an MDI with spacer and nebulizer-delivered albuterol. You might consider entering the term "metered-dose inhaler" within quotes, but you're aware that some authors use only the abbreviation "MDI"; by entering "MDI," you come up with 987 citations. By entering the string "meter* dose* inhaler" (the "*" is a variable that represents any letter, a function that is valuable here because the words in the term are spelled variously—"meter," "metered," "dose," "dosed"), you come up with 1,461 citations, giving you the highest yield of citations. Then, combining the two groups of citations with an "OR" yields the most inclusive set: 2,057 citations.

Another searchable term is "nebulize" followed by an asterisk ("*"), directing the search engine to include "nebulized" and "nebulizer" in the search in this example. Again, you can isolate articles that emphasize delivery system by listing on the search line the numbered searches you have performed, separated by "OR."

"O," for "outcome," might refer to hospitalization, or improvement in the 1-second forced expiratory volume (FEV₁). In this instance, however, you are interested in any difference between delivery systems and may choose not to enter a specific term.

You now have three separate categories of searches for your PICO formulation of the question: problem, intervention, and comparison. You combine the three using the "History" button again and listing the appropriate numbered searches with "AND" between them (to choose only citations that apply to all three categories) (Figure 3, line 17). At this point, you have 306 articles on line 17; to further limit articles to those most likely to be useful, click on "Limits" and use PubMed's pull-down menus to select English language, human, and children (Figure 4). Another approach is to click on the drop-down menu of the search page (next to "Sort") and choose "Pub Date" to arrange your citations in reverse chronologic order. Also, because you would like to see a study that compares the two methods of albuterol delivery, you might choose "randomized clinical trials" from the "Publication types" menu.

Another helpful technique is to scan search results for an article whose title suggests that it directly addresses your question. Once you locate the citation or abstract, you can click on "Related articles" to the right (Figure 5). This often gives you several more articles that fit your question exactly. Using the pull-down menu to the right of "Display," you can click on "Citation" to see what MeSH terms the indexers used for a particular article, which may offer terms that you had not thought to use in your own search (Figure 6).

Now that you have a list of relevant articles, you need to assess their quality. You scan the titles, use the pull-down menu next to "Display" to view some abstracts, and select several articles that appear relevant to your question. With some citations, you'll see an icon in the upper left-hand corner, above the abstract; click on this icon, and you are connected to the Web site of the publisher of the journal in which the article appeared. At a limited number of journal sites, you view the full text of articles at no charge; at the Web sites of many, however, you must use a password (yours or one belonging to your practice or the institution that employs you) to gain access to the full text of the article—a benefit that comes only with a paid subscription or purchase of one- time access to the individual article.

Assessing the quality of research. For assistance determining the quality of the articles you have selected on albuterol delivery, you turn to the series of users' guides to the medical literature that have been published in the Journal of the American Medical Association (JAMA) (Table 2). These articles will guide you in determining whether the conclusions of a particular article can be applied to your patient population. They address each major type of research question, including how to appraise articles about therapy, diagnostic tests, harm, prognosis, and etiology. An online tutorial, adapted from these users' guides and developed by Duke University Medical Center and the University of North Carolina, takes you through the critical appraisal process step by step ( www.hsl.unc.edu/lm/ebm/Evidence.htm ). Other Web sites, known as "CATbanks" ("CAT" standing for "critically appraised topic"), feature step-by-step dissection of particular articles and follow the questions posed by JAMA's users' guides to determine the quality of an article (Table 3). Not only does using these CATbanks enhance one's article-appraisal skills, but the lists are worth scanning from time to time to follow the current literature and sort out the quality of the evidence it describes.

TABLE 2
From JAMA Users’ guides to the medical literature

TABLE 3
Visiting “CATbanks”

If you are fortunate, your question may already have been addressed by the Cochrane Collaboration, a group of centers that search particular questions and perform a systematic analysis of all high-quality data available for those questions. Full-text reviews, protocols, and quarterly updates are available from Cochrane by subscription only, but it costs nothing to gain access to the Cochrane Library ( www.update-software.com ) to view a list of review topics and the summary sheet of each systematic review. Once in the database, click on "The Cochrane Library," then "Abstracts," then scroll down to the"Search" window. You enter "asthma," then scan the top 50 titles that match your term. Bingo! All three subjects that you are researching (the problem, the intervention, and the comparison) have been studied in systematic fashion.

Summarizing results. You now have several independent articles on comparative albuterol delivery systems and a systematic review that specifically addresses whether one delivery system is significantly better for exacerbations of asthma. So what is the answer to your question?

Chou and colleagues used an urban ED setting to compare albuterol delivery methods in 152 known asthmatics at least 2 years old.¹ Although this study was not blinded, it was randomized and the MDI with spacer and nebulizer groups had nearly identical baseline characteristics. Using the objective criteria of respiratory rate, inspiratory to expiratory ratio (I:E), the presence or absence of wheezing and retractions, oxygen saturation, peak expiratory flow rate, number of treatments given, percentage of patients receiving steroids, and admission rate, the investigators determined that the two groups did not differ at the end of the treatment period. Other significant differences were seen between the groups, however: Children in the nebulizer group spent a longer mean amount of time in the ED (103 vs. 66 minutes), experienced more emesis (20% vs. 9%), and had a greater mean percentage increase in heart rate (15% vs. 5%).

Another study performed in Canada yielded similar results. Also performed in an ED setting, the study compared nebulized albuterol with albuterol by MDI with spacer given for 33 mild to moderately severe flares of acute asthma in children 6 to 14 years of age.² The study was double-blinded and used placebo: Each patient used an MDI and a nebulizer without knowing which one contained albuterol. Again, baseline characteristics were similar; clinical features evaluated included heart rate, respiratory rate, pulsus paradoxus, dyspnea, use of accessory muscles, wheezing, FEV₁, and oxygen saturation. These investigators also found no difference between the groups in improvement in respiratory effort and function and the hospital admission rate. As in the Chou study, however, tachycardia was a side effect of nebulized albuterol.

The Cochrane review of the two delivery systems for treatment of acute asthma was not limited to children or albuterol, but its findings were consistent with those of the other two studies.³ Sixteen trials, constituting 686 children (2 years and older) and 375 adults, were analyzed. Taken as a whole, these trials did not show a significant difference between administration by nebulizer or by MDI with spacer in regard to change in respiratory rate, peak flow, FEV₁, development of tremor, number of patients given steroids, or admission rate. Consistent with the two trials cited above, the MDI group stayed in the ED for a significantly shorter time than the nebulizer group did and was less likely to have tachycardia.

Leversha and colleagues recently published the findings of a randomized, double-blind, placebo-controlled trial in the ED in which they demonstrated fewer hospitalizations and side effects when albuterol was delivered by an MDI and spacer than when it was delivered by nebulizer. The investigators made two other important findings⁴: Eighty-six percent of children and 85% of parents preferred the MDI with spacer over the nebulizer, and the MDI was more cost-effective. The mean cost of ED care for the MDI group was 64% of that for the nebulizer group.

Convincing data also exist for using an MDI with spacer during inpatient hospitalization. Parkin and colleagues studied 60 hospitalized children 1 to 5 years old with moderate acute asthma.⁵ Children with similar baseline characteristics were assigned to one of the two albuterol delivery systems. Outcome measures included respiratory rate, wheezing, indrawing, I:E, observed dyspnea, time to discharge, time to four-hour dosing interval, and total number of inhaled doses required. Parents were asked to report symptoms at one and two weeks after discharge. Nine patients did cross over and received nebulized albuterol, but only four met predetermined criteria for treatment failure with an MDI. At 60 hours after admission, no difference was seen between the two groups in regard to respiratory effort or the results of a physical exam. Hours to discharge, hours to four-hour dosing interval, and number of inhaled doses were similar in both groups. One and two weeks after discharge, the difference between the two groups in the percentage of symptom-free patients was insignificant.

A second, more recent study examined the clinical effectiveness and cost of both methods of albuterol delivery among the inpatient asthmatic population.⁶ Sixty-one children, 3 years and older, received albuterol through a nebulizer or an MDI and spacer. Again, the groups had comparable clinical and baseline characteristics on admission. At discharge, both had improved to a similar degree. Because this study contained a few patients whose prolonged stay skewed the mean hospital stay data, the median stay data were reported and were approximately the same for both groups.

Of great significance, the cost of using the MDI with spacer was approximately one quarter the cost of the nebulizer during the hospital stay. Investigators observed a trend toward fewer readmissions during the study period (six in the nebulizer group, two in the spacer group) and during a 12-month follow-up period (27.2% for the nebulizer group, 13.8% for the spacer group), although this difference was not statistically significant.

Taken together, these studies demonstrate that, in both ED and inpatient settings, albuterol is as effective when delivered by an MDI with spacer as it is when delivered by a nebulizer. The ED studies reported decreased time to discharge and fewer side effects in the MDI group; the inpatient studies showed similar efficacy and length of stay with decreased cost and rate of readmission. Despite these convincing data, more research is needed in this area. Because data in both the clinic setting and with severe asthmatics are limited, drawing conclusions about administering albuterol in those situations is premature.

In addition, whereas the dose of nebulizer-delivered albuterol is standardized at 0.15 mg/kg up to 5 mg, consistent guidelines are unavailable on the amount of albuterol to be delivered by MDI. Among 16 studies deemed of sufficiently high quality to be in the Cochrane review, the dosage of b-agonist delivered by an MDI with spacer varied greatly³—from two puffs per dose to a weight-based daily regimen of six puffs for children weighing <25 kg, eight puffs for 25 to 35 kg, and 10 puffs for >35 kg. The ratio of the b-agonist dosage administered by MDI with spacer and by nebulizer ranged from 1.3:1 to 1:25; in most studies, the ratio was 1:2 to 1:7. Even though the MDI dosage was generally much smaller than the nebulized dosage, patients in the MDI group did at least as well as those in the nebulizer group and experienced fewer side effects.

Last, it became clear, on reviewing many of these papers, that teaching patients about asthma and the use of an MDI with a spacer properly and thoroughly is critical to the effectiveness of the medication being delivered. A randomized, double-blind, placebo-controlled trial by Mandelberg demonstrated that, compared with a nebulized b-agonist, an MDI and spacer with a face mask attached could be used to treat infants and young children without a significant difference in response to treatment.⁷

Search #2: What's the effect of ipratropium bromide?

Earlier studies of the effectiveness of inhaled ipratropium bromide in an acute asthmatic exacerbation were inconclusive. Has a determination been made in the current literature?

Doing the search. You turn to the same technique you used to answer the first question. First, you create the clinical question in the PICO format: Of children with asthma, (Problem), does ipratropium bromide plus standard therapy (Intervention), compared with standard therapy alone (Comparison), affect Outcome (hospitalization, oxygen saturation, etc.)? Your PubMed search of the terms "asthma" and "ipratropium bromide," limited to children, English language, and randomized clinical trials, yields a reasonable number of citations to be scanned. In addition, the Cochrane database once again reveals a systematic analysis of the subject.

Summarizing results. The New England Journal of Medicine published a relevant prospective, randomized, double-blind, placebo-controlled trial by Quereshi and colleagues.⁸ All children brought to the ED with an acute exacerbation of asthma received a corticosteroid, 2 mg/kg; nebulized albuterol every 20 minutes (total, three doses); and either placebo or ipratropium bromide with the albuterol at the first and second doses. The hospitalization rate—the primary outcome measure—was reduced significantly in the treatment group overall. No significant difference in the hospitalization rate was noted between the treatment and placebo groups in children with mild or moderate disease; in those who had a severe exacerbation, however, the treatment group had significantly fewer admissions. Analysis showed that, for every seven children with a severe asthmatic exacerbation treated with ipratropium bromide in addition to steroids and albuterol, one hospitalization was prevented.

The Cochrane review included 13 trials and came to several conclusions.⁹ Addition of a single dose of an inhaled anticholinergic drug does improve lung function but does not reduce hospitalizations. Addition of multiple doses of an anticholinergic to b-agonist therapy does reduce hospitalizations by 25% in children with moderate or severe exacerbations. Measurable side effects, including nausea, vomiting, and tremor, did not increase.

Search #3: Is there a role for MgSO₄?

For your last question—the use of MgSO₄ in severe exacerbations— you turn directly to the Cochrane Library, which has a review. The authors included seven trials (five adult and two pediatric)—a total of 665 patients.¹⁰ In every study, IV MgSO₄ was compared with placebo. Overall, the peak flow rate improved only insignificantly and the admission rate did not change. In patients with severe asthma, the peak flow rate improved overall by 52.3 L/min; FEV₁ improved by 9.8% above predicted overall; and the admission rate was reduced significantly in the treatment groups. The optimal dose of MgSO₄ remains unclear but, in studies included in the Cochrane review, the dosage ranged from 25–100 mg/kg and 2 g was the predominant dosage in the adult studies.

Putting it together

Your review of the literature on pediatric asthma shows that the local hospital's decision to add multiple-dose ipratropium bromide to the ED protocol appears appropriate. Likewise, an MDI and spacer is a reasonable alternative to a nebulizer for delivering albuterol: Using an MDI and spacer results in a statistically significant decrease in heart rate and length of ED stay, and is a more cost-effective option. Also important, the use of an MDI with spacer does not require electricity, which can be an important consideration. Last, it appears that IV MgSO₄ improves lung function and reduces the hospitalization rate in asthmatic children who are clearly having a severe exacerbation on presentation or whose condition is refractory to initial therapy.

You and your partners have learned a great deal from this exercise—about current treatment of asthma and how to research a clinical question. Your patients will benefit from your dedication to continuing education.

Dr. Hunt thanks Drs. Corey, Keitz, and Greenblatt, her former colleagues and mentors at Duke University, for introducing her to evidence-based medicine and training her in its daily application as part of her residency in medicine; Drs. Kredich and Frank for offering her, while she was chief resident, a forum in which to teach EBM to pediatric residents; and medical librarians Connie Schardt and Anne Powers for making the weekly EBM journal club operational and enjoyable.

REFERENCES

1. Chou KJ, Cunningham SJ, Crain EF: Metered-dose inhalers with spacers vs nebulizers for pediatric asthma. Arch Pediatr Adolesc Med 1995;149(2):201

2. Kerem E, Levison H, Schuh S, et al: Efficacy of albuterol administered by nebulizer versus spacer device in children with acute asthma. J Pediatr 1993;123(2): 313

3. Cates CJ, Rowe BH: Holding chambers versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev 2000;2

4. Leversha AM, Campanella SG, Aickin RP, et al: Costs and effectiveness of spacer versus nebulizer in young children with moderate and severe acute asthma. J Pediatr 2000;136(4):497

5. Parkin SR, Diamond SA, Winders PM, et al: Randomised trial spacer v nebuliser for acute asthma. Arch Dis Child 1995;72:239

6. Dewar AL, Stewart A, Cogswell JJ, et al: A randomised controlled trial to assess the relative benefits of large volume spacers and nebulisers to treat acute asthma in hospital Arch Dis Child 1999;80(5):421

7. Mandelberg A, Tsehori S, Houri S, et al: Is nebulized aerosol treatment necessary in the pediatric emergency department? Chest 2000;117:1309

8. Qureshi 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

9. Plotnick LH, Ducharme FM: Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children (Cochrane Review). Cochrane Database Syst Rev 2000;4

10. Rowe BH, Bretzlaff JA, Bourdon C, et al: Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database Syst Rev 2000;2

DR. HUNT is a fellow in pediatric intensive care at the Johns Hopkins University Medical Center, Baltimore, Md., and a candidate for a master's degree in public health in epidemiology at the Johns Hopkins University School of Public Health.

DR. PAUL is assistant professor of pediatrics at Penn State College of Medicine, Hershey, Pa.

 

Elizabeth Hunt, Ian Paul. Unearthing good evidence for better care of acute asthma attacks. Contemporary Pediatrics 2002;3:99.